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Albumin is a major protein of human or animal blood plasma. Clinical use of albumin, as an active ingredient, requires its extraction and purification, which is traditionally carried out by known methods, such as those of Cohn et al. (J. Am. Chem. Soc., 68, 459, 1946) and Kistler et al. (Vox Sang., 7, 1962, 414-424) which are additionally applicable to an industrial scale.
Albumin requirements amount to about 100-300 kg per million inhabitants according to country; for that reason, it is necessary, for clinical purposes, to provide an albumin free from pathogenic viruses and contaminants, which are sources of diseases. Thus, as regards transfusion-transmissible viruses, safety is ensured by viral inactivation methods such as liquid-state pasteurisation of an albumin composition at 60° C. for 10 hours in the presence of a biologically compatible stabiliser (sodium caprylate and/or tryptophanate). This viral safety has been established for more than 60 years and the literature does not report any proven case of virus transmission, e.g. hepatitis B, A or C, or HIV. However, some authors mentioned some cases correlated with the presence, after transfusions, of parvoviruses B 19 in albumin compositions or albumin derivate products. Furthermore, a case has also been reported of an albumin composition that would have led to Creutzfeldt-Jakob disease in a patient having undergone liver transplantation (Créange A., 1995).
Some studies revealed a series of adverse effects occurring after an albumin transfusion due to the presence of lipopolysaccharide substances (pyrogens) in amounts lower than the detection threshold of authorised methods, but capable of occurring during perfusions with large volumes of albumin (e.g. plasma exchanges).
Other side effects are related to the presence of albumin polymers occurring during albumin purification and especially during the above-mentioned pasteurisation step. Others are related to the presence of added stabilisers to prevent the thermal denaturation linked to pasteurisation, especially in patients with allergic backgrounds.
In order to avoid the risk of transmissible infectious agents being present, it has been suggested to produce a so-called “recombinant” albumin, according to U.S. Pat. No. 6,210,683: the gene of albumin is introduced into a host cell, yeast or bacterium, having a high proliferation potential. In turn, this host cell produces albumin in the culture medium or its cytoplasm. This albumin is then separated from the cells by extraction and purified. However, the presence of host cell proteins is often detected and the purification methods must therefore have a very high resolution, which is generally detrimental to the yield. The production cost of a recombinant albumin may then prove to be too high in comparison to that of an albumin generated from plasma.
Another possibility to get round the above-mentioned drawbacks is to implement filtration methods extensively used for the retention of viruses, and chemical or bacteriological contaminants, etc., using qualified filters with variable porosities. One can mention for instance ultrafiltration that has been used from time to time in the absence of other means of virus elimination to ensure the biological safety of an extraction protein such as growth hormone (hGH). The method requires a tangential flow and is only intended for protein solutions or polypeptides having molecular weights equal to or lower than 65 kDa and low concentrations. This leaves chance for viruses to pass through due to the manufacturing imprecision of filtration membranes. Moreover, filter clogging occurs in front operation, resulting in a blockage of the filtrate flow. Filter clogging is all the faster as protein or polypeptide concentration increases.
To increase the viral safety of biological solutions further, it is contemplated to implement nanofiltration, the preferred method for the retention of particles with sizes equal to or greater than about 15-20 nm. This particle retention on qualified filters is easily achieved on a large scale with aqueous solutions or solutions containing small-sized solutes, peptides, amino-acids, mineral ions or organic compounds smaller than about 5 kDa.
The nanofiltration of large-sized solutes has been achieved, fox example, with blood coagulation factors, factor IX and factor XI. The article by Burnouf-Radosevich et al. (Vox Sang., 67, p. 132-138, 1994 in reference with Burnouf et al., Vox Sang., 57, p. 225-232, 1989 and Burnouf-Radosevich et al., Transfusion, 22, p. 861-867, 1992) shows that the working conditions of the nanofiltration method imply small volumes of factor IX and factor XI concentrates (3-4 litres), with protein concentrations not exceeding 1 g/L (0.21 g/L and 0.75 g/L, respectively).
Actually, during the nanofiltration process, the large-sized solutes accumulate on the filter, which slows down the filtrate flow until the filter is completely clogged.
The technical solutions to this clogging which consist of implementing a tangential flow nanofiltration, increasing the pressure and changing the directions of the flows do not prove to be efficient because the clogging is progressive and irreversible. An industrial development is therefore greatly compromised because it requires the use of very numerous filters and very large volumes of solutions to be filtered, which generates a prohibitive cost and abnormally increased manufacturing times.
To avoid the clogging phenomenon, a solution consists of adjusting the physicochemical parameters influencing the recovery yield of solutes, while avoiding the passage of contaminants through the filter. Varying these parameters—such as ionic strength, the nature of the solute to be filtered and the pH of the solution to be filtered—as well as the working conditions of the filtration—such as flow rate and pressure—has been the subject of many studies. For instance, the scientific publications by C. Wallis et al., Ann. Rev. Microbiol., 33, p. 413-437, 1979 and S. Jacob, Methods of Biochemical Analysis, 22, p. 307-350, 1974, show that the effect of each parameter can individually result in increased or decreased efficiency of virus retention and recovery yield of solutes, and that combining several parameters does not systematically favour a synergy of the effects of improvement of the filtration conditions.
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The following prior art publications are considered as being relevant for an understanding of the invention.
[1.] N. P. Lovrich, M. J. Gaffney, T. C. Pratt, C. L. Johnson, C. H. Asplen, L. H. Hurst and T. M. Schellberg, National forensic DNA study report, National Institute of Justice (2003) http://www.ncjrs.gov/pdffiles1/nij/grants/203970.pdf.
[2.] J. M. Butler, Short tandem repeat typing technologies used in human identity testing. Biotechniques 43 (2007) ii-v.
[3.] C. Ladd, H. C. Lee, N. Yang and F. R. Bieber, Interpretation of complex forensic DNA mixtures. Croat. Med. J 42 (2001) 244-246.
[4.] G. Peter, C. Neumann, A. Kirkham, T. Clayton, J. Whitaker and J. Lambert, Interpretation of complex DNA profiles using empirical models and a method to measure their robustness. Forensic Sci. Int.: Genetics 2 (2008) 91-103.
[5.] A. J. Pakstis, W. C. Speed, J. R. Kidd and K. K. Kidd, Candidate SNPs for a universal individual identification panel. Hum. Genet. 121 (2007) 305-317.
[6.] K. K. Kidd, A. J. Pakstis, W. C. Speed, E. L. Grigorenko, S. L. Kajuna, N. J. Karoma, S. Kungulilo, J. J. Kim, R. B. Lu, A. Odunsi, F. Okonofua, J. Parnas, L. O. Schulz, O. V. Zhukova and J. R. Kidd, Developing a SNP panel for forensic identification of individuals. Forensic Sci. Int.: 164 (2006) 20-32.
[7.] B. Budowle and A. van Daal, Forensically relevant SNP classes. Biotechniques 44 (2008) 603-608, 610.
[8.] N. Horner, S. Szelinger, M. Redman, D. Duggan, W. Tembe, J. Muehling, J. V. Pearson, D. A. Stephan, S. F. Nelson and D. W. Craig, Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays. PLoS Genet. 4 (2008) e1000167.
[9.] J. S. Buckleton, C. M. Triggs and S. J. Walsh, Forensic DNA evidence interpretation, CRC Press, Boca Raton, 2005.
[10.] L. A. Foreman and I. W. Evett, Statistical analyses to support forensic interpretation for a new ten-locus str profiling system. Int. J. Legal Med. 114 (2001) 147-155.
[11.] The International HapMap Consortium, The international HapMap project. Nature 426 (2003) 789-796.
[12.] J. B. Fan, A. Oliphant, R. Shen, B. G. Kermani, F. Garcia, K. L. Gunderson, M. Hansen, F. Steemers, S. L. Butler, P. Deloukas, L. Galver, S. Hunt, C. McBride, M. Bibikova, T. Rubano, J. Chen, E. Wickham, D. Doucet, W. Chang, D. Campbell, B. Zhang, S. Kruglyak, D. Bentley, J. Haas, P. Rigault, L. Zhou, J. Stuelpnagel and M. S. Chee, Highly parallel SNP genotyping. Cold Spring Harb. Symp. Quant. Biol. 68 (2003) 69-78.
[13.] Y. Q. Hu and W. K. Fung, Evaluation of DNA mixtures involving two pairs of relatives. Int. J. Legal Med. 119 (2005) 251-259.
[14] J. Ragoussis. Genotyping technologies for genetic research. Annu Rev Genomics Hum Genet. 2009; 10:117-33.
DNA profiling has become a major tool in the forensic world [1]. The current gold standard for forensic DNA profiling is the sizing of 9-15 short tandem repeat (STR) markers [2]. This method has been found to be very efficient for analyzing DNA profiles from specimens containing DNA from a single individual or a simple mixture of two individuals. However, the identification of an individual in complex mixtures (usually more than two individuals), has proven to be difficult [3, 4].
A number of studies have proposed to use bi-allelic single nucleotide polymorphisms (SNPs) for forensic identification [5-7]. These studies propose using SNPs with allele frequencies close to 0.5 in order to increase statistical power. For a given individual, and it is determined to what extent the individual's DNA, if present in the mixture can account for any difference in allelic frequencies in the mixture and the population at large. In a recent study, the use of high density SNP microarrays (including 500,000 SNPs or more) was shown to enable the identification of an individual in complex mixtures [8]. That study noted that with the large amount of information on allele frequencies of hundreds of thousands of SNPs, one can identify the presence of a single individual when the genotype of the individual is known for the same hundreds of thousands of SNPs, even if the DNA mixture contains DNA from thousands of individuals. The study was mainly presented in the context of the anonymity of individuals participating in large genome-wide association studies (GWAS). The use of their method for forensic purposes is suboptimal for various reasons. First, the method does not efficiently allow the exclusion of relatives, giving the defense an opportunity to claim that the suspect's relative rather than the suspect himself is represented in the mixture. Second, the method requires accurate allele frequency data for an appropriate reference population, which in many instances might not be available. Third, genotyping hundreds of thousands of SNPs provides genetic information which might be sensitive with regards to protecting individuals' privacy. Lastly, genotyping hundreds of thousands of SNPs is costly for the routine use in forensic laboratories.
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The field of this invention pertains to portable building structures and, in particular, to collapsible shelters for use as changing rooms and toilet enclosures of the type commonly seen at beaches, special events, parks, construction sites, and also those of modular or foldable design as cited below.
A collapsible portable shelter can be used for privacy aboard small watercraft, at campsites and other public places where conventional portable toilet shelters are impractical due to their large size, weight, or hardware components necessary to assemble into a self supporting structure, making them inconveniently, unsuitable and impractical aboard small boats, campers and similar recreational vehicles and vessels due to a lack of space.
Examples of present portable toilet and changing structures are disclosed in U.S. Pat. Nos: 4,493,118 Braxton, 4,305,164 Sargent, 4,726,155 Nahamias, 4,640,061 Trumley, 4,539,721 Moore, 4,163,294 Patterson, 4,065,885 Blick, 4,035,964 Robinson, 3,526,066 Hagar, 3,940,806 Mustee, 1,917,629 Anderson, however, none of the above citations disclose a collapsible or hand carried feature as described in the present invention.
Other examples of portable shelters fall into the classification of hunting blinds, including U.S. Pat. Nos. 3,513,605 Smith, 4,123,869 Witt, 4,224,754 Derryberry, 4,682,436 Ritson, 4,825,578 Robinson, 4,761,908 Hayes, 4,833,813 McLemore.
Articles of bellows like side wall configurations are described in U.S. Pat. Nos: 4,492,313 Touzani, 2,780,378 Romano, 3,474,844 Lindstrom, 4,044,836 Martin, 3,956,778 Tanaka, 4,773,458 Touzani, 4,775,564 Shriver, 992,009 Miller and Switzerlnd Pat. No. 264,553 Schaufelberger.
No previous privacy shelter is as portable, versatile and convenient in use, particularly on watercraft, land vehicles or at public places as is the new invention described herein.
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1. Field of the Invention
The present invention relates to building panels formed of thin-walled, molded hardboard and adapted to be used for interior and exterior roof and wall surfaces on a wide variety of building structures.
In accordance with the present invention it has been found that hardboard formed of composite wood fibrous material can be molded in both wet and dry processes into relatively intricate shapes and profiles to provide roofing and siding products that closely resemble real wood and lumber yet requiring much lower quantities of wood materials for manufacture and consequently having a lower weight per foot of surface area coverage than real wood counterparts.
Moreover, in accordance with the present invention it has been found that relatively intricate and complex shapes and profiles can be molded in thin walled hardboard material to provide increased strength and resistance to wind uplift forces, drying out and curl up at corners of the panels, even though the panels weigh substantially less than real wood components and considerably less than substantially thicker, pressed fiber panels heretofore used, which panels often required much greater thicknesses in order to provide suitable stiffness and structural characteristics.
2. Description of the Prior Art
Various hardboard panels, panel siding and lap siding products of hardboard have been utilized for surfacing the exterior walls and roofs of buildings. In addition, lap siding and roofing products formed of aluminum and vinyl have been utilized and many of these products have attempted to replicate or simulate the appearance of historical or traditional siding and roofing materials made of wood.
A number of U.S. patents have been issued on roofing, panel siding, panels and lap siding products and are listed below as follows:
______________________________________ Fink et al RE. 24,246 Turek 3,897,667 Montross 373,373 Gadsby 3,899,855 Ochs 2,264,546 Carothers 3,943,677 Brady 3,333,384 Allen et al 4,366,197 Kneisel 3,326,493 Eaton 4,015,392 Johnson 3,643,394 Geimer et al 4,061,813 Mattes 3,703,795 Kirkhuff 4,065,899 Wilson et al 3,720,031 Golder et al 4,102,106 Hanlon et al 3,796,586 Tellman 4,188,762 Wilson et al 3,848,383 Tellman 4,261,152 Eaton et al 3,848,384 Tellman 4,266,382 Kirkhuff 3,852,934 Gleason et al 4,279,106 Wheeler 3,868,300 Hanlon et al 4,366,197 ______________________________________
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Attenuation, or insertion loss in decibels, is the metric by which all hearing protection is judged by consumers and labeled as required by United States Environmental Protection Agency law. The standard solution to provide such protection has been physically occluding the ear canal with either a compressible, oversized earplug, typically constructed of expandable foam, silicone, putty/resins, or fibers. Thus a bias in the metrics of hearing protection performance to date has always been attenuation; however, this is a very narrow viewpoint which completely ignores often-important interface issues for the users. For example, a user's situation awareness and ability to localize sound stimuli is compromised. Comfort is often gained at the expense of attenuation. The occlusion effect causes unnatural sounding feedback of the user's own voice, making it difficult to modulate the voice output resulting in objections to using the protector and increasing the difficulty of achieving effective in-canal voice pickup for radio communications.
To further elaborate, current technology designed to provide both hearing protection and communications is based on the principle of occluding the outer ear in order to shelter it from the ambient environment. Most common is an earplug of some type which is inserted in the open ear canal, expanding along the radial surfaces of the canal as necessary until a physical seal is established. Furthermore, hearing protection devices, also known as HPDs, are only valuable when properly selected and fit to the user, and worn properly, to counteract imminent acoustical hazards, which unfortunately is often too late. Earplugs, by their very nature, introduce their own set of problems. They are frequently uncomfortable to wear, with the user being very aware of their presence. Additionally, due to significant differences between individuals with respect to the size and shape of their ear canals, it is difficult to provide a single earplug device that fits all users comfortably and effectively. As a result, many currently available earplugs suffer from the following problems, among others: Production of the occlusion effect Impaired localization Compromised speech understanding Severely degrades the user's situation awareness Often ineffective protection due to improper sizing and insertion Uncomfortable and unnatural feeling Harbor and introduce bacteria and promote fungal infection Challenges in compliance, that is, convincing the user to wear a HPD they “might” need User's speech is too loud or too low User's lack of confidence in actual protection provided and impaired situation awareness Occlusion effect provides its own unnatural 15 dB of amplification of the user's voice in the ear canal Impaction of cerumen, that is, earwax Not compatible and interoperable with a user's (e.g., a soldier's) current ensemble and communications equipment.
Thus, there remains a need to develop improved earplug devices which avoid or minimize the above-mentioned issues. In particular, it would be highly desirable to provide automatic attenuation for the preservation of a user's hearing functionality during and after noise hazards, while simultaneously providing for external signal detection and localization, as well as radio-connected and selectively attenuated ambient pass-through speech communications.
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1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are useful as antibiotics, and to pharmaceutical compositions comprising such compounds. The compounds are useful medications for the prophylaxis and treatment of various bacterial infections.
The following publications are cited in this application:
Storm et al., xe2x80x9cPolymyxin and related peptide antibiotics,xe2x80x9d Ann. Rev. Biochem., 46: 723-763 (1977).
Weinstein et al., xe2x80x9cSelective chemical modifications of Polymyxin B,xe2x80x9d Bioorganic and Medicinal Chemistry Letters, 8: 3391-3396 (1998).
Kimura and Matsunaga, xe2x80x9cPolymyxin B octapeptin and polymyxin B heptapeptide are potent outer membrane permeability-increasing agents,xe2x80x9d Journal of Antibiotics, 45(5): 742-749 (1992).
Srinivasa and Ramachandran, xe2x80x9cChemical modification of peptide antibiotics: Part VI-Biological activity of derivatives of polymyxin B,xe2x80x9d Indian J. Biochemistry and Biophysics, 14: 54-58 (1978).
PCT WO 88/00950 to Fauchere et al.
DE Patent No. 1,906,699 to Pfizer.
DE Patent No. 2,204,887 to Rhone-Poulenc.
J. E. Kapusnik-Uner, M. A. Sande, H. F. Chambers in Goodman and Gilman""s xe2x80x9cThe Pharmacological Basis of Therapeutics,xe2x80x9d 9h Ed. (J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, A. G. Gilman, Eds.); McGraw-1-Ell, New York: p 1123-1153 (1996).
M. R. W. Brown, S. M Wood, J. Pharm. Pharmacol. 24: 215-218 (1972).
S. Srimal, N. Surolia, S. Balasubramanian, A. Surolia, Biochem. J., 315: 679-686 (1996).
J. L. Shenep, R. P. Barton, et al., J. Infect. Dis. 151: 1012-1018 (1984).
M. G. Tauber, A. M. Shibl, C. J. Hackbarth, J. W. Larrick, M. A. Sande, Antimicrob. Agents Chemother. 156: 456-462 (1987).
G. S. Doig, C. M. Martin, et al., Crit. Care Med. 25:1956-1961 (1997).
C. Verwaest, J. Verhaegen, P. Ferdinande, M. Schetz, G. Van Den Berghe, L. Verbist, P. Lauwers, Crit. Care Med. 25: 63-71 (1997).
G. S. Bauldoff, D. R. Nunley, J. D. Manzetti, J. H. Dauber, R. J. Keenan, Transplantation 64: 748-752 (1997).
P. Diot, F. Gangadoux, C. Martin, H. Ellataoui, Y. Furet, M. Breteau, E. Boissinot, E. Lemarie, Eur. Resp. J. 10: 1995-1998 (1997).
S. E. Bucklin, P. Lake, L. Logdberg, D. C. Morrison, Antimicrobial Agents Chemother. 39: 1462-1466 (1995).
B. L. Jaber, B. J. Pereira, Am. J. Kidney Dis. 30(Suppl. 4): S44-56 (1997).
J. R. Berg, C. M. Spilker, S. A. Lewis, J. Membrane Biol. 154: 119-130 (1996).
L. Weinstein in xe2x80x9cThe Pharmacological Basis of Therapeutics,xe2x80x9d 5 1h Ed. (L. S. Goodman, A. Gilman, Eds.); MacMillan, N.Y.:, p1230-1233 (1975).
Physician""s Desk Reference, Medical Economics Co., Oradell, N.J.: (1993).
M. Helander, Y. Kato, I. Kilpelainen, R. Kostiainen, B. Lindner, K. Nummila, T. Sugiyama, T. Yokochi, Eur. J. Biochem. 237: 272-278 (1996).
Entries 2542 and 7734, The Merck Index, 12 th Edition, Merck and Co., Whitehouse Station, N.J.: (1996).
K. Vogler, R. O. Studer, W. Lergier, P. Lanz, Helv. Chim. Acta 43: 1751-1760 (1960).
K. Vogler, R. O. Studer, P. Lanz, W. Lergier, E. Boehni, Experientia 20: 365-366 (1964).
T. Kurihara, H. Takeda, H. Ito, Yakugaku Zasshi 92: 129-134 (1972).
K. Nakajima, Chem. Pharm. Bull. 15: 1219-1224 (1967).
M. Teuber, Z. Naturforsch. Teil B 25: 117 (1970).
Y. Kimura, H. Matsunaga, M. Vaara, J. Antibiot. 45: 742-749 (1992).
S. Chihara, A. Ito, M Yahata, T. Tobita, Y. Koyama, Agric. Biol. Chem. 38: 521-529 (1974).
S. Chihara, A. Ito, M Yahata, T. Tobita, Y. Koyama, Agric. Biol. Chem. 38: 1767-1777 (1974).
S. Chihara, T. Tobita, et al., Agric. Biol. Chem. 37: 2455-2462 (1973).
D. A. Stoma, K. S. Rosenthal, P. E. Swanson, Ann. Rev. Biochem. 46: 723-763 (1977).
M. Vaara, Drugs Exp. Clin. Res. 17: 437-444 (1991).
PCT WO 90/15628.
G. Radhakrishna, L. K. Ramachandran, Indian J. Biochem. Biophys. 20: 213-217 (1983).
C. P. Coyne, J. T. Moritz, J. Endotoxin Res. 1: 207-215 (1994).
J. L. Fauchere, K. Mosbach CH Appl. 86/315106 August 1986.
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
2. State of the Art
Bacteria are ubiquitous microbes capable of causing significant morbidity and mortality in infected individuals. Healthy individuals, having intact immune systems, rapidly eliminate pathogenic bacteria. However, many conditions render patients vulnerable to bacterial infection. Thus, individuals suffering from primary immunodeficiency disorders, such as AIDS, commonly develop infections. Alternatively, individuals may become susceptible to bacterial infection as the result of secondary immunodeficiencies due to other underlying disorders. For example, patients with diseases such as diabetes, connective tissue disorders, or trauma frequently develop complications due to severe bacterial infections. In such patients, overwhelming bacterial infections may result in a cascade of physiological changes leading to septic (or endotoxic) shock, which often culminates in the patient mortality.
Although most bacteria are capable of producing sepsis, a sub-class of bacteria, known as Gram-negative bacteria, which includes Eschericia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are the usual etiologic agents. The profound pathogenic effects of these microbes are due to a structural component, unique to Gram-negative bacteria, known as an outer membrane.
The outer membrane, which surrounds the bacterial cell, and protects it from environmental assaults, includes a molecule known as lipopolysaccharide (LPS). LPS is a complex structure with three components: 1) an outer region consisting of polymerized di- to penta-saccharide repeating units whose composition varies with bacterial species; 2) an inner region including of oligosaccharides linked by a sugar 2-keto-3-deoxy-C-mannose-octonate to a disaccharide backbone; and lipid A. This latter molecule, a glucosamine disaccharide with attached phosphate and acyl (fatty acid) groups, is responsible for most of the biological activity of the molecule.
The pathological effects of LPS are due to both intact LPS present in the outer membrane of the cell (bound LPS) and LPS that is released from the membrane and shed into blood (soluble LPS). Regardless of form, LPS elicits its biological effects by binding to a receptor found on a mononuclear phagocyte known as a monocyte. The interaction stimulates cellular processes resulting in the release of pro-inflammatory mediators such as TNF-xcex1, IL-1xcex2, IL-6 and PGE2, which, then leads to arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea and organ dysfunction that characterize septic shock.
Bacterial infections are usually treated with a molecularly diverse group of agents known as antibiotics, which act by a wide variety of mechanisms well known to those skilled in the art. While these drugs are sometimes capable of resolving the effects of bacteremia, infections with Gram-negative bacteremia presents special challenges. For example, treatment with conventional antibiotics while leading to the death of the pathogen, results in the release of toxic bacterial components, such as LPS. Thus, treatment with antibiotics may increase the amount of LPS or products of LPS such as endotoxin into the circulation.
Certain antibiotics, however, are able to neutralize the action of LPS, and mitigate its effects by binding to the molecule. Examples of such antibiotics include the polymyxin, circulin and octapeptin antibiotics, most notably polymyxin B and polymyxin E (also known as colistin), which are cyclic polypeptide compounds produced by strains of Bacillus polymyxa.
The lipid-bearing, polycationic polymyxin forms a complex with anionic phospholipids of the LPS and inserts into the membrane. This event disrupts the LPS, leading to loss of essential intracellular components and rapid bacterial cell death. In addition to its killing effects on intact bacteria, polymyxin also has high affinity for xe2x80x9cfreexe2x80x9d LPS components, most importantly, the lipid A portion of the lipopolysaccharide of the LPS (endotoxin). Complexation of lipid A by polymyxin prevents most of the pathophysiologic consequences of endotoxin in experimental systems.
Combinations of polymyxin B sulfate and/or colistin sulfate with various other compounds are widely used in opthalmic, otic, and topical applications against Gram-negative organisms. Strains of Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, and Shigella are typically sensitive to polymyxins at concentrations of 0.05-2.0 micrograms/mL in vitro, while most strains of Pseudomonas aeruginosa are inhibited by less than 8 micrograms/mL. Intrinsically resistant strains include Proteus mirabilis, Serratia marcesens, Providencia, and Edwardsiella tarda. More recently introduced uses of the polymyxins include the use of oral colistin for prophylactic gut clearance and of nebulized colistin for treatment of Pseudomonas infections in cystic fibrosis patients. In current development are the systemic use of macromolecular polymyxin-dextran conjugates and the extracorporeal use of polymyxin adsorbents for intervention in Gram-negative sepsis.
Polymyxin was at an earlier time administered parenterally and colistin sulfate is formulated for parenteral use; however, parenteral use of polymyxins is rare due to their nephrotoxicity and neurotoxicity. These effects are believed to have as their source the interaction of the polymyxins with phospholipids of mammalian cells. Neurological side effects of colistin administration include circumoral parasthesia pain at the site of intramuscular injection, numbness, tingling, or formication in the extremities, generalized pruritis, vertigo, dizziness, slurring of speech, and respiratory paralysis via neuromuscular blockade. Nephrological side effects include acute tubular necrosis, interstitial nephritis, proteinuria, hematuria, cylindruria, azotemia, and reduced glomerular filtration rate. The magnitude of these effects increases with continued therapy; however, the effects are generally reversible upon cessation of treatment.
For these reasons, polymyxin B, in intravenous form, is only given to hospitalized patients under constant supervision. Polymyxins and related antibiotics are not used routinely for systemic infections. Application of polymyxins to intact skin, denuded skin, or mucous membranes results in no systemic reactions because the drugs are poorly absorbed. Side effects following large (600 mg) oral doses of the antibiotic include nausea, vomiting, and diarrhea. Neurotoxic reactions have additionally been observed, the most severe being respiratory paralysis when given soon after anesthesia and/or muscle relaxants.
Given polymyxin""s significant systemic toxicities, the advent of anti-pseudomonal xcex2-lactams, the fluoroquinolone family of antibacterial agents, and aminoglycosides effective against Gram-negative organisms superseded parenteral use of polymyxin.
Antibacterial agents are important weapons in the fight against pathogenic bacteria. However, an increasing problem with respect to the effectiveness of antibacterial agents relates to the emergence of strains of bacteria that are highly resistant to such agents. Microbial resistance to the polymyxins is slow to develop and typically involves alterations in the composition of LPS components.
It would therefore be desirable to find antibacterial agents that are active against Gram-negative bacteria, in particular, drug resistant strains. It would also be advantageous to have antibacterial agents that demonstrate high activity and selectivity toward their targets and have high bioavailability, low toxicity, for example, nephrotoxicity, and other side effects. The present invention provides such agents.
This invention is directed to novel multibinding polymyxin, circulin and octapeptin antibiotics. The multibinding compounds of this invention are useful in the treatment and prevention of bacterial infections.
In particular, the compounds can be used to treat bacterial infections caused by Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, Enterobacter sp., Salmonella sp., Pasteurella sp., Bordetella sp., Shigella sp., Proteus mirabilis, and Serratia marcesens.
In one of its composition aspects, this invention provides a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a polymyxin, circulin or octapeptin antibiotic or other suitable compound which binds to the LPS present in bacteria, in particular, Gram-negative bacteria.
In another of its composition aspects, this invention provides a multibinding compound of formula I:
(L)p(X)qxe2x80x83xe2x80x83I
wherein each L is independently a ligand comprising a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS and/or which demonstrates antibacterial properties; each X is independently a linker; p is an integer of from 2 to 10; and q is an integer of from 1 to 20; and pharmaceutically-acceptable salts thereof.
Preferably, q is less than p in the multibinding compounds of this invention.
Examples of suitable ligands include polymyxin A, polymyxin B1, polymyxin B2, polymyxin D1, polymyxin E1, polymyxin E2, circulin A, octapeptin A1, octapeptin A2, octapeptin A3, octapeptin B1, octapeptin B2, octapeptin B3, octapeptin C1. The xcex3-amino group on the DAB subunits on the ligands is a preferred site for attachment to the linker(s).
In still another of its composition aspects, this invention provides a multibinding compound of formula II:
Lxe2x80x2xe2x80x94Xxe2x80x2xe2x80x94Lxe2x80x2xe2x80x83xe2x80x83II
wherein each Lxe2x80x2 is independently a ligand comprising a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS and/or which demonstrates antibacterial properties; and Xxe2x80x2 is a linker; and pharmaceutically-acceptable salts thereof.
Preferably, in the above embodiments, each linker (i.e., X, Xxe2x80x2 or Xxe2x80x3) independently has the formula:
xe2x80x94Xaxe2x80x94Zxe2x80x94(Yaxe2x80x94Z)mxe2x80x94Ybxe2x80x94Zxe2x80x94Xaxe2x80x94
wherein
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S), xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94 or a covalent bond where R is as defined below;
Z is at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Ya and Yb at each separate occurrence are selected from the group consisting of xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2C(O)xe2x80x94, xe2x80x94NRxe2x80x2C(O)NRxe2x80x2xe2x80x94, xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90C(Xa)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94 and a covalent bond; where n is 0, 1 or 2; and R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic.
In yet another of its composition aspects, this invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrates antibacterial properties; and pharmaceutically-acceptable salts thereof.
This invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a multibinding compound of formula I or II.
The multibinding compounds of this invention are effective antibiotics, which are useful for treating a variety of bacterial infections. Accordingly, in one of its method aspects, this invention provides a method for treating various bacterial infections. Examples of such infections include infections caused by Enterobacter sp., E. coli, Klebsiella sp., Salmonella sp., Pasteurella sp., Bordetella sp., Shigella sp., Pseudomonas aeruginosa, Proteus mirabilis, and Serratia marcesens.
When used to treat bacterial infections, for example, the method involves administering to a patient having a bacterial infection a pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically-effective amount of a multibinding compound comprising from 2 to 10 ligands covalently attached to one or more linkers wherein each of said ligands independently comprises a polymyxin, circulin or octapeptin antibiotic or other suitable compound which exhibits multibinding properties toward LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrates antibacterial properties; and pharmaceutically-acceptable salts thereof.
This invention is also directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to various sites on bacteria. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarizability and/or polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like.
This invention is also directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to sites on various bacteria. The diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage. The library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarizability and/or polarization. The library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like.
This invention is also directed to libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties with respect to various sites on bacteria. These libraries are prepared via the methods described above and permit the rapid and efficient evaluation of what molecular constraints impart multibinding properties to a ligand or a class of ligands which bind to the LPS present in bacteria, especially gram negative bacteria, and/or which demonstrate antibacterial properties.
Accordingly, in one of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties, which method comprises:
(a) identifying a ligand or a mixture of ligands which includes a polymyxin, circulin or octapeptin compound or other suitable compound which binds to the LPS present in bacteria and/or which demonstrates antibacterial properties, wherein each ligand contains at least one reactive functionality;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and
(d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties.
In another of its method aspects, this invention is directed to a method for identifying multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties, which method comprises:
(a) identifying a library of ligands which includes polymyxin, circulin or octapeptin and other suitable compounds which bind to the LPS present in bacteria and/or which demonstrate antibacterial properties wherein each ligand contains at least one reactive functionality;
(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand;
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands; and
(d) assaying the multimeric ligand compounds produced in (c) above to identify multimeric ligand compounds possessing multibinding properties.
The preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b). Sequential addition is preferred when a mixture of different ligands is employed to ensure heteromeric or multimeric compounds are prepared. Concurrent addition of the ligands occurs when at least a portion of the multimer compounds prepared are homomultimeric compounds.
The assay protocols recited in (d) can be conducted on the multimeric ligand compound library produced in (c) above, or preferably, each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).
In one of its composition aspects, this invention is directed to a library of multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties which library is prepared by the method comprising:
(a) identifying a ligand or a mixture of ligands which include polymyxin, circulin or octapeptin compounds or other suitable compounds which bind to the LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrate antibacterial properties; wherein each ligand contains at least one reactive functionality;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the ligand or mixture of ligands identified in (a) with the library of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
In another of its composition aspects, this invention is directed to a library of multimeric ligand compounds which exhibit multibinding properties toward LPS and/or which demonstrate antibacterial properties and which may possess multivalent properties which library is prepared by the method comprising:
(a) identifying a library of ligands which includes a polymyxin, circulin or octapeptin compound or other suitable compounds which bind to the LPS present in bacteria and/or which demonstrate antibacterial properties wherein each ligand contains at least one reactive functionality;
(b) identifying a linker or mixture of linkers wherein each linker comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and
(c) preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of the library of ligands identified in (a) with the linker or mixture of linkers identified in (b) under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands.
In a preferred embodiment, the library of linkers employed in either the methods or the library aspects of this invention is selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, linkers of different polarizability and/or polarization and amphiphilic linkers. For example, in one embodiment, each of the linkers in the linker library may comprise linkers of different chain length and/or having different complementary reactive groups. Such linker lengths can preferably range from about 2 to 100 xc3x85.
In another preferred embodiment, the ligand or mixture of ligands is selected to have reactive functionality at different sites on the ligands in order to provide for a range of orientations of said ligand on said multimeric ligand compounds. Such reactive functionality includes, by way of example, carboxylic acids, carboxylic acid halides, carboxyl esters, amines, halides, pseudohalides, isocyanates, vinyl unsaturation, ketones, aldehydes, thiols, alcohols, anhydrides, boronates and precursors thereof. It is understood, of course, that the reactive functionality on the ligand is selected to be complementary to at least one of the reactive groups on the linker so that a covalent linkage can be formed between the linker and the ligand.
In other embodiments, the multimeric ligand compound is homomeric (i.e., each of the ligands is the same, although it may be attached at different points) or heteromeric (i.e., at least one of the ligands is different from the other ligands).
In addition to the combinatorial methods described herein, this invention provides for an iterative process for rationally evaluating what molecular constraints impart multibinding properties to a class of antibacterial multimeric compounds or ligands. Specifically, this method aspect is directed to a method for identifying multimeric ligand compounds possessing multibinding properties with respect to the LPS present in certain bacteria, especially Gram-negative bacteria, or which possess antibacterial properties, which method comprises:
(a) preparing a first collection or iteration of multimeric compounds which is prepared by contacting at least two stoichiometric equivalents of the ligand or mixture of ligands which bind to the LPS present in certain bacteria, especially Gram-negative bacteria; and/or which demonstrate antibacterial properties; with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands;
(b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties;
(c) repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties;
(d) evaluating what molecular constraints imparted multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)-(c) above;
(e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration;
(f) evaluating what molecular constraints imparted enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above;
(g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.
Preferably, steps (e) and (f) are repeated at least two times, more preferably at from 2-50 times, even more preferably from 3 to 50 times, and still more preferably at least 5-50 times.
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1. Technical Field
This patent application relates to detection of objects such as a buried explosive device while operating from a moving platform.
2. Background Information
An electromagnetic device known as a super lens is capable of manipulating the near field of an antenna and focusing electromagnetic waves to resolutions beyond the diffraction limit. Numerous super lenses have been fabricated to operating from radio frequency (RF) wavelengths up to optical wavelengths. One approach described by Merlin, R., in “Radiationless Electromagnetic Interference: Evanescent-Field Lenses and Perfect Focusing”, Science, Volume 317, Issue 5840, pp. 927-(2007) uses grating like surfaces and arrays rather than volumetric structures. Subwavelength structures can control the near field, and are capable of focusing well beyond the diffraction limit, operating at arbitrary frequencies, forcing convergence to a spot on the focal plane.
It is also known that a synthetic aperture radar (SAR) is a form of radar system that uses relative motion between an antenna and its target region to provide distinctive long-term coherent-signal variations that are exploited to obtain finer spatial resolution than is possible with conventional beam-scanning means. See for example, the book by Fawwaz. T. Ulaby, Microwave Remote Sensing: Active and Passive, Volume II (Norwood, Mass.: Artech House, Inc., 1986). It is also known that the spatial resolution of a densely packed antenna array can be much smaller than the diffraction limit. Such “super gain” antennas are described in C. A. Balanis, Antenna Theory (3rd Edition) (Hoboken, N.J.: John Wiley & Sons, 2005) and/or R. E. Collin and F. J. Zucker (eds.), Antenna Theory, Part I (New York: McGraw-Hill, 1969). The entire teachings of these publications are hereby incorporated by reference.
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Applications of advancing medical technology, such as cardiopulmonary bypass, are associated with a variety of complications. Even in short term use, blood oxygenators produce sufficient activation of clotting pathways to require the use of heparin to inhibit blood coagulation.
An invariable complication of such surgical procedures is a hemorrhagic state manifested by a prolonged bleeding time, causes of which include failure to adequately neutralize heparin and the continuous stimulation of platelets, as manifested by a fall in platelet count, stimulation of thromboxane synthesis and release of platelet granule constituents. (See Colman, J. Anesthesiology, vol. 66 (5), May, 1987, p. 595). Reversal of heparin is required to restore normal coagulation status and reduce post-operative blood loss.
Protamine is an arginine-rich polypeptide (32 amino acids from salmon) commonly used at the conclusion of cardiovascular surgical procedures to neutralize the anticlotting effects of heparin. The use of protamine, however, has been linked to several post-surgical complications, some of which are postoperative systemic hypotension, allergic reactions, catastrophic pulmonary vasoconstriction, acute pulmonary hypertension, complement activation, noncardiogenic pulmonary edema, decreased cardiac output (later event), and thrombocytopenia/leukopenia.
The underlying biochemical basis for these physical complications is poorly understood, but allergic reactions to protamine, have been well documented. Since protamine, usually isolated from fish, can be recognized as a foreign protein by the human immune system, patients with prior protamine exposure are at particular risk during subsequent exposures (Just Viera, J. O., Amer. Surgeon 50, (1984), 151-163). Additionally, studies suggest that a non-immunological pathway via complement activation may be responsible for many of the acute reactions observed during protamine reversal of heparin anticoagulation.
To avoid the use of protamine, a number of approaches have been proposed. Construction of bypass circuits with materials that do not activate the coagulation cascade have been suggested, as well as the use of non-heparin anticoagulate preparations. Neutralizing agents for heparin other than protamine are also currently being sought. Horrow, "Effective Hemostasis in Cardiac Surgery", chap. 2, Ellison and Jobes, Eds, in press, 1988. All of these alternatives, presently in various stages of research, have yet to reveal a suitable substitute for protamine that has gained widespread acceptance.
PF4 is a well characterized heparin-binding protein found in human plasma at concentrations of 5-20ng/ml. In plasma, in in vitro studies, PF4 has been demonstrated to reverse the effect of heparin on clot formation. Michalski, Brit. J. Haematol, 38, 561-571 (1978).
In vivo experiments demonstrate that PF4 is cleared rapidly from circulation in both rats and rabbits. This rapid clearance is due to PF4 binding to endothelial cells. PF4 bound by endothelial cell surfaces can be released into the bloodstream by subsequent administration of heparin. In humans, a similar rise in circulating PF4 concentration is observed following heparin administration.
Platelet concentrate has been shown to have heparin neutralizing activity when administered to humans after bypass surgery, and the effect was attributed to PF4. Walker, Br. Heart J. 52:12-14 (1984).
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1. Field of the Invention
The instant invention relates to that class of devices that serve to test conductivity of wiring in vehicles where such wiring via a harness unit, so-called ultimately connects a power source within such vehicles to the rear lights on trailer vehicles amenable to being towed by such vehicles.
2. Prior Art
The following references are to be found within the particular field of the instant invention, but he claims and specifications set forth therein do not anticipate those that are endemic to the instant invention:
______________________________________ Inventor Invention Pat. No. Date ______________________________________ Whisenand Electrical Tester with 5,367,250 1/22/94 Electrical Energizable Test Probe Jeter Trailer Light Converter 4,781,393 11/1/88 Schneider, III Compact Lamp and Circuit 5,278,511 1/11/94 Tester for Vehicles, Particularly Automobiles Lieu et al. Portable Apparatus for 5,250,908 10/5/93 Testing Multi-Harness and Electrical Assemblies to Identify Wiring Errors Lemon Apparatus for Determining 5,192,912 3/9/93 Wiring Orientation at Electrical Connectors Including Plural Light Indicators and Rotary Switch McConchie Sr. Diagnostic Test Apparatus for 4,884,033 11/28/89 Electrical System of Automotive Vehicle Butchko Vehicle Light Testing System 4,866,390 9/12/89 for Testing a Plurality of Lights Using a Scanning Sequence Borland Auto Harness Integrity Tester 5,635,843 6/3/97 ______________________________________
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The present invention relates to a novel apparatus for reducing levels of organic pollutants present in groundwater or other fluid.
Attention is called to U.S. Pat. Nos. 2,203,690; 3,520,806; 3,686,827; 3,750,688; 3,869,382; 3,881,295; 3,958,590; 3,999,653; 4,024,882; 4,155,849; 4,168,228; 4,172,031; 4,182,677; 4,302,337; and 4,248,705.
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Many medical deficiencies and diseases result from the inability of cells to produce normal biologically active compounds. Many of these deficiencies can be remedied by implanting a source of the needed biologically active compounds and/or pharmaceutical agents into the individual having the deficiency. A well known disease that can be remedied by implanting biological material and/or a pharmacological agent is Type I diabetes mellitus, wherein the production of insulin by pancreatic Langerhans islet cells is substantially deficient, impaired, or nonexistent.
Type I or insulin dependent diabetes mellitus (IDDM) is a major, expensive public health problem causing renal and vascular disease, heart disease, blindness, nerve damage, major disability, and premature death. One treatment approach is the transplantation of insulin producing pancreatic islet cells (9,000 to 12,000 islets/kg), which can return blood sugar levels to normal and free patients from the need to take exogenous insulin. If blood sugars, insulin, and C-peptide levels can be normalized at an early stage of the disease, the complications of diabetes can be avoided. Major barriers to the clinical application of islet cell transplantation have been the problems of graft rejection, the scarcity of human organs, and the expense of their procurement. The medications used to prevent rejection are costly, increase the risk of infection, and can, themselves, induce hyperglycemia, hyperlipidemia, hypertension, and renal dysfunction, although progress is being made towards less toxic drug regimens.
Injection of islet cells is appealing because it is less invasive than whole organ pancreatic grafts and entails a lower morbidity rate. Transplanted human islets (allografts) have been shown to survive in the liver after administration of immunosuppressive drugs, but reliable long term function has been difficult to achieve. Injection into the liver is usually accompanied by heparinization to avoid thrombosis, which can increase the risk of ocular complications. Furthermore, human islets are a scarce and expensive cell type. Therefore, many researchers have suggested using animal cells (xenografts), particularly porcine islets. Pigs are plentiful, although porcine islets are relatively difficult to isolate and are fragile.
Unfortunately, the immunologic barriers to the successful transplantation of xenografts are even more difficult to surmount than those for the transplantation of allografts. Humans have natural pre-formed antibodies that can react with a saccharide, Gal alpha 1,3Gal(Gal), expressed on the cells of lower mammals to trigger hyperacute rejection. In addition, the complement regulatory proteins (decay accelerating factor, membrane cofactor protein, CD59) that normally help to control damage induced by complement activation cannot function because they are species specific.
In light of the above hypothesis the immunoisolation of living allogeneic or xenogeneic insulin-producing islet cells by semi-permeable membranes may provide a means for correcting diabetes mellitus. In order to avoid hyperacute rejection, the recipient's antibodies should be prevented from “seeing” the foreign proteins and activating complement. The encapsulating material should also reliably safeguard the patient from infectious processes (e.g., bacteria) unwittingly transferred with the animal cells. Materials used for immunoisolation should allow insulin, glucose, oxygen, and carbon dioxide to pass freely. These molecules have diameters less than 35 Angstroms (3.5 nm). Studies suggest that pore diameters of 30 nm can exclude the immigration of immunoglobulins, complement, and cytokines (e.g., tumor necrosis factor) providing immunoisolation. Unless immune tolerance can be established, such membranes should also prevent the out-migration of xeno-antigens into the host where they can activate the indirect pathway resulting in T helper cell activation. Immune graft rejection by direct cytotoxicity appears to be a major cause for loss of transplanted cells since donor cell viability is better in immune-compromised (CD4+ T cell depleted) mice. In addition, CD4+ cells secrete interferon-[gamma] that attracts and activates macrophages and NK cells. Macrophages, in turn, recruit T-cell help and initiate rejection. B-cell humeral mediated immunity also plays a role in xenograft rejection. There is, however, ample evidence that the immune response is not the sole source of xenograft failure.
Researchers, working with ovarian cell xenografts microencapsulated in HEMA (hydroxyethyl methacrylate-methyl methacrylate), found that cells began to lose function before the antibody response occurred. Other causes of graft failure include an inflammatory response to the chemistry of the encapsulating material, nutrient deficiency, accumulation of waste products and free radicals within the encapsulating material, and inadequate oxygen delivery.
In view of the foregoing, there is a need in the art for improved methods and/or implantable devices for providing insulin to treat and/or cure diabetes.
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Unlike other renewable energy sources, biomass can be converted directly into liquid fuels. The two most common types of biofuels are ethanol (ethyl alcohol) and biodiesel. Ethanol is an alcohol, which can be produced by fermenting any biomass high in carbohydrates (starches, sugars, or celluloses) through a process similar to brewing beer, once fermentable sugars have been obtained from the biomass material. The breakdown of the biomass into monomers (monosaccharides) requires the material to be softened through pretreatment, enzymes be added that hydrolyze the polymeric forms of sugars contained in the biomass into monosaccharides, and fermentation of both the 6-carbon and 5-carbon sugars to ethanol or to other desired bio-products.
Ethanol production in the United States grew from just a few million gallons in the mid-1970s to over 3.9 billion gallons in 2005. National energy security concerns, new Federal gasoline standards, and Government incentives have been the primary stimuli for this growth. Ethanol is mostly used as a fuel additive to cut down a vehicle's carbon monoxide and other smog-causing emissions. Flexible-fuel vehicles, which run on mixtures of gasoline and up to 85% ethanol, are now available.
Ethanol production received a major boost with the passage of the Clean Air Act (CAA) Amendments of 1990. Provisions of the CAA established the Oxygenated Fuels Program and the Reformulated Gasoline Program in an attempt to control carbon monoxide and ground-level ozone problems. The desires to improve air quality and enhance energy security have encouraged an increased demand for ethanol.
The majority of ethanol produced in the U.S. is produced from starch obtained from maize (maize) grain. It is anticipated that current starch supplies will be insufficient to meet future demands for fermentable sugars. Ligno-cellulosic biomass, such as stover, can be used as an alternative source of fermentable sugars for the production of ethanol.
Stover consists of all parts (leaves, stalks; with the exception of kernels) of plants such as maize, sorghum, soybean, sugarcane, or other plants that are left in the field after the harvest. This stover biomass is rich in cellulose and hemicellulose, which are cell-wall polysaccharides that can release fermentable sugars upon treatment with enzymes (such as cellulases). The biomass conversion of maize stover is currently not very cost-effective.
One strategy to improve the overall efficiency of converting stover biomass to ethanol is to modify the chemical composition of maize stover, specifically the plant cell wall polymer lignin. Lignin has been shown to shield the cellulose, resulting in reduced access by cellulases. In addition, lignin has been shown to be an inhibitor of cellulases.
Brown midrib (bm) mutants of maize, easily identified by the reddish-brown color of their central leaf vein, have been known for more than 75 years. Similar mutants have been found in sorghum, sudangrass, and pearl millet (Barriere and Argillier, 1993, Agronomie 13: 865-876). These mutants have generated significant agronomic interest because their tissues are more easily digested by ruminants, providing better nutrition for livestock (Cherney et al., 1991, Adv. Agron. 46: 157-198). However, the known varieties of these plants are not widely grown as they often suffer from slow growth, increased susceptibility to pests, and an increased tendency to lodge, all of which lead to decreased yields.
The maize brown midrib mutations, specifically the bm1 mutation, result in the production of abnormal lignin (Kuc and Nelson, 1964, Arch. Biochem. Biophys. 105: 103-113). Four independent maize bm mutants are known, each affecting the lignin biosynthetic pathway. Bm1 mutants have reduced expression of cinnamyl alcohol dehydrogenase (CAD) activity (Halpin et al., 1998, Plant J. 14: 545-553). The CAD enzyme converts cinnamyl aldehydes to their alcohol derivatives in the last step of monolignol synthesis. The reduction of CAD activity in maize bm1 mutants leads to large increases in the hydroxycinnamylaldehyde content of the lignin (Provan et al., 1997, J. Sci. Food Agric. 73: 133-142), and such aldehydes have been implicated in formation of the red chromophore responsible, in part, for the defining coloration of the mutants (Higuchi et al., 1994, J. Biotechnol. 37: 151-158).
Two independent mutations have been identified in the O-methyltransferase (OMT) gene of bm3 maize (Vignols et al., 1995, Plant Cell 7: 407-416). The bm3 gene encodes caffeic acid O-methyltransferase, or more accurately named, a 5-hydroxyconiferaldehyde/5-hydroxyconiferyl alcohol O-methyltransferase (Humphreys et al., 1999, Proc Natl Acad Sci USA 96: 10045-10050). This enzyme catalyzes the methylation of the 5-position hydroxyl group of 5-hydroxyconiferyl aldehyde and 5-hydroxyconiferyl alcohol in monolignol synthesis. The net result of the bm3 mutation is a reduction in both the total amount of lignin deposited in the cell wall and a shift in lignin composition away from syringyl-type lignin because conversion of 5-hydroxyconiferyl aldehyde and 5-hydroxyconiferyl alcohol to sinapyl aldehyde and sinapyl alcohol, respectively is required for syringyl lignin synthesis. In bm3 mutants, the lignin also contains increased amounts of 5-hydroxyguaiacyl units, but in addition has a greatly reduced ratio of syringyl to guaiacyl units, as well as decreases in p-coumaric acid esters and overall lignin content (Chabbert et al., 1994, J. Sci. Food. Agric. 64: 349-355).
To improve the efficiency of converting biomass to ethanol, it would be advantageous to increase the amount of fermentable sugars in a plant stover. This invention provides that and related needs.
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The present invention is directed to low calorie fat substitutes. More specifically, it is directed to an emulsion containing protein, fat and carbohydrate which is useful as a low calorie fat substitute.
In today's health conscious society, there is a growing demand for low calorie foods. Excess body weight not only creates a feeling of low self-confidence in social situations but also has been shown to contribute to the impairment of the cardiovascular function of the individual. Moreover, the reduction of the physical performance capacity of the individual is another consequence of excess body weight.
Many approaches have been suggested to control excess body weight. The use of chemical appetite suppressors and appetite inhibitors is a well known approach but these chemical agents are often unsafe for long term use and/or have undesirable side effects. Moreover, they are usually available only through a physician's prescription.
Low-calorie foods have also been widely advocated as a diet regimen to control excess body weight. Such low-calorie foods include low-calorie spreads, which are typically water-in-oil (w/o) emulsions; and low calorie sauces, such as salad dressings and mayonnaise, which are typically oil-in-water emulsions.
One other approach generally undertaken in the production of low-calorie foods is to increase the protein content, thereby decreasing the fat content. This approach is referred to in a number of United States Patents.
U.S. Pat. Nos. 3,642,492, 3,644,326, 3,689,288, 3,708,307, 4,057,655, 3,723,407, 4,058,510, 4,079,154, 4,089,987, 4,091,116, 4,104,413, 4,113,716, 4,125,630, 4,140,808, 3,892,873, 3,899,605, 3,800,052, 3,798,339, 3,852,503, 3,853,839, 3,843,828, 3,842,062, 3,829,592, 3,865,956, 3,870,811, 3,873,751, 3,922,375, 3,930,039, 3,935,323, 3,969,534, 4,147,810, 4,307,118, 3,793,464, 3,642,490, 3,642,493, 3,914,435, 3,930,056, 4,072,610, 4,031,261, 3,757,005, 3,978,243, 3,982,039, 4,007,283, 4,018,752, 4,029,825, 4,137,329, 4,186,218, 4,194,018, 4,103,038, 4,031,267, 4,275,084, 4,271,201, 4,169,160, 4,183,970, 4,188,141, 4,194,019, 4,205,904, 4,325,977, 4,333,958, 4,143,174, 4,376,133, 4,486,345, 4,497,836, 4,560,454, 4,279,939, 4,340,612, 4,293,571, 4,362,761, 4,267,100, 4,265,924, 4,260,636, 4,259,361, 4,251,562, 4,248,895, 4,247,566, 4,218,940, and 4,230,738 all refer to the use of vegetable, animal, egg, and/or milk proteins in various compositions as well as referring to various processes for the formation of these compositions and/or improved processes for extraction and treatment of vegetable, egg, animal and/or milk proteins.
U.S. Pat. No. 3,726,690 refers to acidified imitation dairy foods comprising a fat, milk solids, or an edible protein, water or milk, an edible emulsifier, and a mixture of a Xanthomonas colloid and locust bean gum.
U.S. Pat. No. 3,891,778 refers to a low calorie spreadable food product containing the additive formed by extracting soybean protein, acidifying and then precipitating the extracted protein.
U.S. Pat. No. 3,929,892 refers to a method for making a low calorie cream cheese product comprising providing a mixture of water and cottage cheese curd, adding a fat source to the mixture to provide a substrate and adding non-fat milk solids to the substrate.
U.S. Pat. No. 4,305,964 refers to an artificial cream-type food product having a continuous liquid aqueous phase comprising a dispersed oil phase and gelled water beads.
U.S. Pat. No. 4,209,503 refers to a food containing a whey colloidal precipitate.
U.S. Pat. No. 4,212,893 refers to a acidified whole milk beverage containing locust bean gum as a stabilizer.
U.S. Pat. No. 4,305,970 refers to a water in oil emulsion (w/o) comprising a continuous fatty phase, a dispersed liquid aqueous phase and dispersed, gelled, aqueous spherical ingredients.
U.S. Pat. No. 4,379,175 refers to an imitation cream cheese product containing milk, milk-fats and dry cottage cheese curd.
U.S. Pat. No. 4,515,825 refers to a low fat spread containing a dispersed phase consisting of a cream comprising water and oil, a thickening agent and heat denatured whey protein as an emulsion stabilizer and a continuous fat phase.
U.S. Pat. No. 4,352,832 refers to a stabilized dressing containing acetic acid in combination with a buffering salt.
U.S. Pat. No. 4,252,835 refers to a base thickener comprising a mixture of glutamic acid and acetic or citric acid.
U.S. Pat. No. 4,244,983 refers to a process for making a low fat imitation cream cheese by adding dry cottage cheese curd.
U.S. Pat. No. 4,217,370 refers to a process for the production of microencapsulated lipids in proteinaceous matter.
Existing fat substitute technologies focus on the mouthfeel of foods, substituting viscosifying agents to mimic the rheology of foods rich in oils and fats. The quality of low fat foods is generally poor, being easily distinguishable from that of full fat foods. For example, in taste panel comparison of full-fat with low fat mayonnaise, the initial flavor of both is pleasant but the rich texture and mouthfeel is virtually absent from the low-fat mayonnaise. The lack of a rich mouthfeel is viewed quite negatively in taste panel testing. The most frequent comments describing this effect are "watery, weak or flat". As a result, the low-fat mayonnaise is considered to be distinctly inferior to the full-fat mayonnaise. To reduce the fat content of their diets, consumers appear to be willing to sacrifice the richness of full fat foods for the health benefits of texturally inferior low-fat products. Development of a fat substitute that possesses a rich aftertaste is perceived as a major need in the improvement of low-fat foods.
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Chairs often include backrests, or a chair back. A backrest may be stationary or may be reclinable. Some office chairs or other chairs may also include a seat that is rotatable. When the chair seat rotates, the back may also rotate with the seat due to the back's connection to the seat. Examples of chairs that include chair backs can be appreciated from U.S. Pat. Nos. 8,480,171, 8,469,454, 8,419,133, 8,348,342, 8,282,172, 8,002,351, 7,547,067, 6,932,430, 6,869,142, 6,817,667, 6,733,080, 6,598,937, 6,367,876, 6,086,153, 6,048,029, 5,755,490, 5,725,277, 4,380,352, 4,235,408, 4,219,233, 3,910,633, 3,863,982, 3,055,628, 3,042,448, and 2,650,648.
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(1) Field of the Invention
The present invention relates to an aluminum-beryllium-silicon based alloy to be favorably used for producing automobile engine parts, etc.
(2) Related Art Statement
Automobile engines, particularly high-performance engines, are required to operate at high rpms to generate high outputs, and therefore lighter high-strength materials, that is, materials having higher specific strengths, are demanded for this requirement.
Further, weight reduction is also important for enhancing drivability. In order to prevent drop in rigidity even if thinned or lighter materials are used, lighter materials having higher Young""s modulus, that is, materials having higher specific moduli of rigidity are required.
Furthermore, from the standpoint that outputs are ensured by keeping a clearance constant against changes in temperature, materials having smaller coefficients of thermal expansion and excellent wear resistance and heat resistance are demanded.
In addition, as viewed from the manufacturing methods, moving parts of the high-performance engines are made mainly of forged products which can fully exhibit the potentials of the alloys thereof, so that materials having excellent plastic workability are desired. Casings and the like having thin and complicated shapes can be produced by casting only. Therefore, castable alloys are naturally desired.
Under the above circumstances, Alxe2x80x94Si based aluminum alloys have been generally used for engine parts. In order to increase the specific strength of such alloys, primary Si crystals are made finer by quenching or a highly heat-resistive hard ingredient is incorporated.
For example, materials having strength and toughness enhanced by quenching in powder metallurgy are reported in xe2x80x9cLight metals, Vol. 49, No. 4, 1999, pp 178-182, and composite materials (MMC) in which ceramic particles or intermetallic compound particles are dispersed in an Al matrix are reported in xe2x80x9cLight metals, Vol. 49, No. 9, 1999, pp 438-442.
However, since these materials have low ductility, it is difficult to shape them by conventional forging methods, and it is also difficult to use them for producing cast products.
Further, since their specific gravities are equivalent to or greater than that of Al, their specific strength does not rise, so that there remains a problem that it is difficult to realize high rpms to generate high outputs.
On the other hand, Al alloys in which an appropriate amount of Be is incorporated into Al have been known as materials having high specific moduli of rigidity for a long time. As examples of such alloys, Al alloys are proposed in U.S. Pat. Nos. 2,399,104, 5,578,146, etc.
However, since all of such alloys are produced by using the powdery metallurgy as a producing method, it is extremely difficult to plastically work the alloys into complicated shapes by forging.
On the other hand, for example, U.S. Pat. Nos. 5,417,778, 5,667,600, etc. disclose Al alloys which employ the casting method.
However, the Al alloys obtained by this method have tensile strengths of about 170 to about 320 MPa and low elongations of around 2%. However, if the alloy is extruded to cover these defects, primary crystals of Be are elongated to unfavorably increase anisotropy.
Al alloys into which Be is incorporated at high concentrations are likely to be expensive, so that such alloys can be used for limited purposes only.
The present invention has been developed in view of the above-mentioned circumstances, and is aimed at providing aluminum-beryllium-silicon based alloys which are not only light, of high specific modulus of rigidity and of high specific strength, but also have small coefficients of thermal expansion and excellent wear resistance and heat resistance with castability and plastic workability comparable to those of the conventional Al alloys.
The breakthrough history of the present invention will be explained below.
In order to realize the above objects, the present invention made investigations on elements effective to enhance wear resistance and reduce the coefficient of thermal expansion with respect to Al as a base material. As a result, they discovered that Si is useful as such elements, and discovered that if Si is incorporated in an amount of not less than 0.1 mass % (preferably and less than 5 mass %), excellent wear resistance and advantageously reduced coefficient of thermal expansion can be attained.
Next, the present invention made investigations upon elements to reduce the specific gravity and increase the specific modulus of rigidity with respect to the above Alxe2x80x94Si alloys, and came to know that Be is effective.
However, it was also discovered that the addition of Be increases the specific modulus of rigidity but unfavorably decrease strength at high temperatures.
In view of this, the inventors then repeatedly made strenuous investigations to prevent reduction in the strength of high temperatures due to the decreased specific gravity. As a result, the present inventors came to know that the addition of Mg is extremely effective for realizing this purpose.
It was also discovered that Cu, Ni, Co, Fe and a very small amount of Y or Ti are effective as ingredients for enhancing strength at high temperatures.
Particularly, it was further discovered that the addition of Fe makes crystals of Be granular, which facilitates working such as extrusion.
The present invention was accomplished based on the above knowledge.
(1) The present invention relates to an aluminum-beryllium-silicon based alloy comprising 5.0 to 30.0 mass % of Be, 0.1 to 15.0 mass % of Si and 0.1 to 3.0 mass % of Mg, the balance being Al and inevitable impurities.
As the aluminum-beryllium-silicon alloy (1), the following are preferable.
(2) The aluminum-beryllium-silicon based alloy further comprises at least one of 0.1 to 3.0 mass % of Cu, 0.05 to 1.5 mass % of Ni, 0.05 to 1.5 mass % of Co and 0.05 to 1.5 mass % of Fe.
The aluminum-beryllium-silicon based alloy (1) or (2) further comprises 0.01 to 0.8 mass % of Y and 0.01 to 0.1 mass % of Ti.
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1. Field of the Invention
The present invention relates generally to expandable medical implants for supporting a body lumen and, more particularly, to expandable, intraluminal devices, generally referred to as stents.
2. Description of the Related Art
Stents are implanted into body lumens, such as blood vessels, to maintain the patency of the lumens. These devices are frequently used in the treatment of atherosclerotic stenoses in blood vessels, especially in conjunction with percutaneous transluminal coronary angioplasty (PTCA) procedures. After treating a blood vessel, a stent is implanted to support the vessel wall and thereby reduce the likelihood of restenosis. Stents are most commonly implanted in coronary arteries; however, stents may also be used in a wide variety of other body lumens. For example, stents may be deployed in the biliary, carotid, superficial femoral and popliteal arteries or even veins
Over the years, a wide variety of stent types have been proposed. Although the structures of stents may vary substantially, virtually all stents are configured to be expandable from a collapsed condition having a small diameter to an expanded condition having a larger diameter. While in the collapsed condition, the stent is delivered through the blood vessel, or other body lumen, to the treatment site. After the treatment site is reached, the stent is radially expanded to an implantable size for supporting the vessel wall. Expansion of the stent from the collapsed condition to the expanded condition can be achieved in a variety of different ways. Various types of stents are described below based on their means for expansion. For additional information, a variety of stents types are described by Balcon et al., “Recommendations on Stent Manufacture, Implantation and Utilization,” European Heart Journal (1997), vol. 18, pages 1536-1547, and Phillips, et al., “The Stenter's Notebook,” Physician's Press (1998), Birmingham, Mich.
Balloon expandable stents are manufactured in the collapsed condition and are expanded to a desired diameter with a balloon. During delivery, a balloon expandable stent is typically mounted on the exterior of an inflatable balloon located along the distal end portion of a catheter. After reaching the treatment site, the stent is expanded from the collapsed condition to the expanded condition by inflating the balloon. The stent is typically expanded to a diameter that is greater than or equal to the inner diameter of the body lumen. The expandable stent structure may be held in the expanded condition by mechanical deformation of the stent as taught in, for example, U.S. Pat. No. 4,733,665 to Palmaz. Alternatively, balloon expandable stents may be held in the expanded condition by engagement of the stent walls with respect to one another as disclosed in, for example, U.S. Pat. Nos. 4,740,207 to Kreamer, 4,877,030 to Beck et al., and 5,007,926 to Derbyshire. Further still, the stent may be held in the expanded condition by one-way engagement of the stent walls together with endothelial growth into the stent, as disclosed in U.S. Pat. No. 5,059,211 to Stack et al.
Balloon expandable stents are typically manufactured from stainless steel and generally have a high radial strength. The term “radial strength,” as used herein, describes the external pressure that a stent is able to withstand without incurring clinically significant damage. Due to their high radial strength, balloon expandable stents are commonly used in the coronary arteries to ensure patency of the vessel. During deployment in a body lumen, the inflation of the balloon can be regulated for expanding the stent to a particular desired diameter. Accordingly, balloon expandable stents are often preferred in applications wherein precise placement and sizing are important. Balloon expandable stents are also commonly used for direct stenting, wherein there is no pre-dilation of the vessel before stent deployment. Rather, during direct stenting, the expansion of the inflatable balloon dilates the vessel while also expanding the stent.
Although balloon expandable stents are the first stent type to be widely used in clinical applications, it is well recognized that balloon expandable stents suffer from a variety of shortcomings which may limit their effectiveness in many important applications. For example, in one significant shortcoming, existing balloon expandable stents are not biased toward the expanded condition and therefore do not return to the expanded condition after being deformed, bent, or pinched. Accordingly, when a high external pressure overcomes the radial strength of a balloon expandable stent, the stent may be caused to permanently deform inward (i.e. collapse) such that the lumen is substantially reduced in size. Worse yet, external pressures may cause the stent to completely collapse, with potentially fatal clinical implications. Therefore, balloon expandable stents are not well-adapted for use in blood vessels which are subjected to large torsional or flexion/extension stresses (e.g., the superficial femoral artery and popliteal artery) and/or wherein the stent is vulnerable to large external pressures (e.g., the superficial femoral artery and carotid artery).
In another shortcoming, balloon expandable stents often exhibit substantial recoil (i.e., a reduction in diameter) immediately following deflation of the inflatable balloon. Accordingly, it may be necessary to over-inflate the balloon during deployment of the stent to compensate for the subsequent recoil. This is disadvantageous because it has been found that over-inflation may damage the blood vessel. Furthermore, a deployed balloon expandable stent may exhibit chronic recoil over time, thereby reducing the patency of the lumen. Still further, balloon expandable stents often exhibit foreshortening (i.e., a reduction in length) during expansion, thereby creating undesirable stresses along the vessel wall and making stent placement less precise. Still further, many balloon expandable stents, such as the original Palmaz-Schatz stent and later variations, are configured with an expandable mesh having relatively jagged terminal prongs, which increases the risk of injury to the vessel, thrombosis and/or restenosis.
Self-expanding stents are manufactured with a diameter approximately equal to, or larger than, the vessel diameter and are collapsed and constrained at a smaller diameter for delivery to the treatment site. Self-expanding stents may be placed within a sheath or sleeve to constrain the stent in the collapsed condition during delivery. Alternatively, detachable tabs or pins may be used for locking the stent in the collapsed condition. After the treatment site is reached, the constraint mechanism is removed and the stent self-expands to the expanded condition. Typically, self-expansion of the stent results from the inherent properties of the material constituting the stent. Most commonly, self-expanding stents are made of Nitinol or other shape memory alloy.
Because self-expanding stents are biased towards the preset expanded condition, if the self-expanding stent is caused to deform under pressure, the stent will return to its expanded condition when the pressure is removed. Accordingly, self-expanding stents overcome many of the shortcomings, such as the risk of permanent collapse, associated with balloon expandable stents. Therefore, self-expanding stents are often deployed in areas of the body where large external forces may cause the vessel, and therefore the stent, to temporarily deform radially inward. After the external force is reduced or removed, the self-expanding stent returns to its fully expanded condition, thereby eliminating the danger of permanent stent deformation and obstruction of the lumen.
One of the first self-expanding stents used clinically is the braided “WallStent,” as described in U.S. Pat. No. 4,954,126 to Wallsten. The WallStent generally comprises a metallic mesh in the form of a Chinese finger cuff. The cuff provides a braided stent that is not superelastic, but technically still falls in the self-expanding stent family. Although the WallStent provided a significant improvement in stent technology for certain applications, such as the treatment of long lesions, the WallStent and other stents of this type often exhibit undesirable metal prongs that remain along the longitudinal ends thereof as a result of the manufacturing process. Another disadvantage of the WallStent is the inherent rigidity of the material (e.g., a cobalt-based alloy having a platinum core) used to form the stent. The combination of the rigidity and the terminal prongs has been found to produce substantial difficulties during navigation through the patient's vasculature. Accordingly, the procedure produces undesirable risks from the standpoint of injury to healthy tissue along the passage to the target vessel.
Another example of a self-expanding stent is disclosed in U.S. Pat. No. 5,192,307 to Wall wherein a stent-like prosthesis is formed of plastic or sheet metal that is expandable or contractible for placement. The stent may be biased in an open position and lockable in a closed position or, alternatively, may be biased towards a closed position and lockable in an open position. In the former case, a pin may be used to hold the stent in the collapsed condition. The pin is removed to allow the stent to assume the expanded condition. One or more hooks may be formed into the wall for locking the stent. The hooks engage complementary recesses formed in an opposing wall to mechanically interlock the rolled up sheet forming the stent.
Although self-expanding stents provide a number of advantages over balloon expandable stents, self-expanding stents also suffer from a wide variety of shortcomings. In one well-recognized shortcoming, self-expanding stents lack the high radial strength of balloon expandable stents and therefore self-expanding stents may deform under relatively low external pressures. In another shortcoming, self-expandable stents often exhibit significant foreshortening during radial expansion. As a result, stents of this type may not provide predictable longitudinal coverage when fully deployed. Furthermore, self-expanding stents necessarily require a constraining mechanism for holding the stent in the collapsed condition during delivery. For example, as described above, a self-expanding stent may be placed in a separate deployment sheath for constraining the stent during delivery. During deployment of a self-expanding stent, the sheath is retracted to uncover the stent incrementally from the distal end to the proximal end, thereby allowing the stent to expand from one end to the other. However, this often results in the stent jumping or springing forward from the delivery system in an undesirable manner, sometimes causing the stent to buckle or bunch up during delivery. Still further, it has been found that self-expanding stents do not re-dilate well in cases of re-treatment and are not well suited for direct stenting.
In yet another shortcoming, self-expanding stents typically impose a continuous chronic outward stress on the vessel wall that may create significant risks of damage to the vessel wall and may lead to restenosis. It is common to find that, after two to four weeks, a self-expanding stent has expanded well into the wall of the artery, thereby supporting the vessel from within the smooth muscle layer, rather than from within the lumen. This is not a desirable result since most physicians intuitively feel it is advantageous to preserve the native, physiologically correct vessel properties as far as possible.
In addition, self-expanding stents are currently available only in 0.5 mm increments. This is a problem because exact sizing, within 0.1 to 0.2 mm expanded diameter, may be necessary to adequately reduce the effects of restenosis. Furthermore, these devices are often oversized by up to 30-50% to ensure location retention and vessel patency, thereby producing a chronic outward stress, as described above. Thus, greater selection and adaptability in expanded size is needed. As a result of these and other shortcomings, self-expanding stents have limited effectiveness in many important applications.
Heat expandable stents are similar in nature to self-expanding stents. However, this type of stent utilizes the application of heat to produce expansion of the stent structure. Stents of this type may be formed of a shape memory alloy, such as Nitinol. Still other types of heat expandable stents may be formed with a tin-coated, heat expandable coil. Heat expandable stents are often delivered to the affected area on a catheter capable of receiving a heated fluid. Heated saline or other fluid may be passed through the portion of the catheter on which the stent is located, thereby transferring heat to the stent and causing the stent to expand. However, heat expandable stents have not gained widespread popularity due to the complexity of the devices, unreliable expansion properties and difficulties in maintaining the stent in its expanded state. Still further, it has been found that the application of heat during stent deployment may damage the blood vessel.
In summary, although a wide variety of stents have been proposed over the years for maintaining the patency of a body lumen, none of the existing schemes has been capable of overcoming most or all of the above described shortcomings. As a result, clinicians are forced to weigh advantages against shortcomings when selecting a stent type to use in a particular application. Accordingly, an urgent need exists for a new and improved stent structure that successfully combines the desirable qualities of a balloon expandable stent and a self-expanding stent. It is desirable that such a stent be balloon expandable for providing accurate placement and sizing at a treatment site. It is also desirable that such a stent has sufficient radial strength to maintain patency of the lumen while subjected to substantial external forces. It is also desirable that such a stent be crush-recoverable, such that the stent returns to its deployed state in the event that the stent becomes crushed or pinched. It is also desirable that such a stent be provided with an effective constraining mechanism for holding the stent in the collapsed condition during delivery. It is also desirable that such a stent be configured to exhibit little or no longitudinal foreshortening during radial expansion. It is also desirable that such a stent be sufficiently flexible along the longitudinal axis to conform to the curved shape of a body lumen. It is also desirable that such a stent has the capability to conform to the interior of the body lumen. The present invention addresses these needs.
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1. Field of the Invention
The present invention relates to a method and apparatus for fixation, stabilization and fusion of the human occipitocervical junction.
2. Description of the Related Technology
The normal range of motion of the craniospinal junction includes 27° of flexion and extension, and 90° of lateral rotation; the craniospinal junction is thus the most mobile and articulatable part of the human body. It is also the most active part of the human body in movement throughout the day, typically performing greater than 3 million motions a year. The craniospinal junction transmits the entire nervous structure to the body (with the exception of the vagus nerve), and is thus unfortunately susceptible to a host of degenerative disorders. Emblematic of these is rheumatoid arthritis, a chronic degenerative condition that arises in 2% of the population, causing predictable changes in the joints and bone structure of the cervical spine, often including vertical migration of the odontoid and trauma to the ligamentous structures of the craniocervical junction.
25% of rheumatoid arthritis sufferers develop atlantoaxial subluxation and 9% develop basilar invagination. Clinically these patients invariably experience severe neck pain and neurological deficits, including weakness and sensory loss. Untreated, patients suffer progressive decline, losing the ability to walk. The untreated patient with myelopathy due to compression of the spinal cord has a 50% likelihood of dying within 1 year. Surgical intervention is therefore necessary to stabilize the craniocervical junction, restore neurologic function and prevent further neurologic deterioration. However, occipitocervical stabilization in rheumatoid arthritis can be especially challenging because of such factors as poor bone quality, poor nutritional status and long term steroid use.
There are also other common causes of cranio-cervical instability, including traumatic fractures, which can include approximately 3,000 fractures of the upper spine related to head trauma each year; congenital diseases, including Down's, Morquio's and spondyloepiphyseal dysplasia syndromes, with a prevalence of at least 50,000; osteogenesis imperfecta, with a prevalence of 7,000 patients; cancer, with about 1000 cases per year; and numerous causes of bone softening. Tumors and infections may also cause destruction of the stabilizing elements.
However, the largest group of patients suffering from poor craniocervical stabilization lies in the pediatric group amongst a large group of children who have been misdiagnosed with neuropsychiatric disorders, such as Asperger's Syndrome, autism, Attention Deficit Hyperactivity Disorder and forms of dyslexia who harbor underlying disorders of the brainstem and spinal cord which result from subtle and sometimes gross anomalies which result in mechanical deformation and abnormal stresses of the neuraxis at the craniocervical junction. Various disorders have been found to frequently result in chronic and subtle neurological changes: retroflexion of the odontoid, platybasia, non-traditional forms of basilar invagination and an abnormal clivo-axial angle, which can result in deformity of the brainstem and upper spinal cord.
The clivioaxial angle is depicted in FIG. 1, while an example of basilar invagination is depicted in the image that is shown in FIG. 2, with compression to the brainstem being clearly visible. These conditions have been reported to cause such symptoms as sleep apnea, delayed speech, gastroesophageal reflux, and altered behavior such as attention deficit disorder, headaches, and a myriad of other sensori-motor syndromes. The ubiquity of craniospinal junction pathology has only recently been appreciated.
Hitherto, patients undergoing craniospinal stabilization have required an arduous surgery and recovery. Some patients undergo a decompressive surgery from the front of the neck (transoral resection of the uppermost part of the spine), followed by fusion in the back of the neck, and followed by 3 months of stabilization in a halo brace, which encompasses the head (held by 4 screws in the skull) and the upper body.
Numerous fixation devices have been described such as those that are disclosed in U.S. Pat. Nos. 5,030,220; 5,034,011; 5,545,164; 5,507,745; 6,547,790; 6,524,315; 6,902,565 B2 and U.S. Published Patent Applications US2005/0288669 A1; US2005/0283153 A1 and US2005/0080417 A1, all of which are hereby incorporated by reference as if set forth fully herein.
A need exists for a system and methodology that accomplishes the goals of reduction of deformity, successful immobilization and fusion of the craniospinal junction, in a shortened surgery, thereby allowing the patient to return to a normal quality of life within a short period of time.
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Platelet Activating Factor (PAF), 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, is an ether lipid produced by a variety of different cell types. Recent studies [Snyder, F., Ann. Rep. Med. Chem., 17,243 (1982); Pinckard, R. N., et. al., J. Adv. Inflammation Res., A, 147 (1982); O'Flaherty, J. T., et. al., Clin. Rev. Allergy, 1, 353 (1983); Vargaftig, B. B., et. al., J. Trends. Pharmacol. Sci., A, 341 (1983)] have shown PAF to be an important mediator of allergic disease. When injected into mammals, PAF induces hemodynamic and hematological changes including hypotension, platelet aggregation, neutropenia, disseminated intravascular coagulation, increases in vascular permeability, bronchoconstriction, tissue injury (hypoxia and necrosis) and eventually death (reviewed by Cammussi, G. Kidney Int. 29, 469, (1986). In recent years, it has been postulated that PAF is the mediator of tissue injury in mammals undergoing endotoxic shock due to bacterial sepsis (Terashita, Z., Y. Imura, K. Nishikawa and S. Sumida 1985, Eur. J. Pharmacol. 109:257-261; Doebber, T. W., M. S. Wu, J. C. Robbins, B. M. Choy, M. N. Chang and T. Y. Shen 1985, Biochem. Biophys. Res. Comm. 127:799-808; Inarrea, P., Gomez-Cambronero, J. Pascual, M. del Carmen Ponte, L. Hernando and M. Sanchez-Crespo. 1985, Immunopharmacology, 9:45-52). These studies, in mammals, have shown that PAF is produced in large amounts when the said mammal has been treated with endotoxin. In addition, mammals undergoing endotoxic shock exhibit all of the clinical symptoms associated with the administration of PAF. In addition, PAF is implicated in asthma, respiratory distress syndrome, lung edema and other inflammatory and cardiovascular diseases.
The compounds of the present invention have proven to be specific inhibitors of the biological fects of PAF and are consequently useful for the treatment of asthma, anaphylactic and septic (endotoxic) shock, psoriasis, bowel necrosis, adult respiratory distress syndrome, transplant rejection, thrombosis, stroke, cardiac anaphylaxis and cancer.
Concurrently, with the realization that PAF is an important mediator of inflammatory diseases in mammals, a number of structurally different antagonists of PAF have been developed. References to some of these antagonists are listed hereinbelow.
Terashita, Z.; Imura, Y. Takatani, M. Tsushima, S.; Nishikawa, K., J. Pharmacol. Exp. Ther., 1987, 242, 263-268. PA0 Takatani, M.; Yoshioka, Y.; Tasaka, A.; Terashita, Z.-I.; J. Med. Chem., 1989, 32, 56-64. PA0 Tsushima, S.; Takatani, M.; Kohei, N. Eur. Patent Appln. EP 301751 (Feb. 1, 1989). PA0 Tomesch, J. C. U.S. Pat. No. 4,820,718 (Apr. 11, 1989). PA0 Gustafson, A.; Handley, D. A.; Tomesch, J. C.; Prashad, M. FASEB J, 1989, 3, A1224. PA0 Page, C.; Abbott, A. TIPS, July 1989, 10, 1. PA0 U.S. Pat. No. 4,916,145 (Oct. 4, 1990). PA0 European Patent Appln. EP 327,962 (Aug. 16, 1989). PA0 European Patent Appln. EP 301,751 (Feb. 1, 1989). PA0 European Patent Appln. EP 353,474 (Feb. 7, 1990). PA0 Spanish Patent Appln. ES 2,010,937 (Dec. 1, 1989). PA0 Spanish Patent Appln. ES 2,010,932 (Dec. 1, 1989). PA0 European Patent Appln. EP 353,777 (Feb. 7, 1990). PA0 U.S. Pat. No. 4,820,718 (Nov. 4, 1989).
BRIEF SUMMARY OF THE INVENTION
The compounds of the present invention are represented by the formula: ##STR1## wherein:
(A) X is a divalent radical selected from the group consisting of: ##STR2## wherein Y is a divalent radical selected from the group represented by OCH.sub.2, (CH.sub.2).sub.n, (CH.sub.2).sub.n+1 O; p is the integer 0, 1, 2, or 3; n is the integer 0, 1, or 2; R.sub.4 is selected from the group consisting of hydrogen, phenyl, --COR.sub.6 or --SO.sub.2 R.sub.7 ; wherein R.sub.6 is selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkoxy, phenyl, aminophenyl, substituted phenyl and substituted aminophenyl and the substituents are selected from the group consisting of one or more of the following C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen and trifluoromethyl; R.sub.7 is selected from the group of C.sub.1 -C.sub.25 alkyl, C.sub.1 -C25 alkenyl, phenyl and substituted phenol and the substituents are selected from the group consisting of C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkoxy, halogen and trifluoromethyl; R.sub.5 is selected from the group consisting of --COR.sub.6 and --SO.sub.2 R.sub.7 wherein R.sub.6 and R.sub.7 are as previously described above with the proviso that when ##STR3## and Y is (CH.sub.2).sub.n with n=0, R.sub.4 cannot be hydrogen or phenyl;
(B) R.sub.1 represents one or more substituents of the aromatic ring which may be the same or different and is selected from the group consisting of:
(i) C.sub.1 -C.sub.25 alkyl, C.sub.1 -C.sub.25 alkenyl, C.sub.1 -C.sub.25 alkoxy, C.sub.1 -C.sub.25 alkenyloxy, C.sub.1 -C.sub.25 thioalkyl, phenyl, phenoxy, substituted phenyl, and substituted phenoxy wherein the substituents are selected from the group consisting of C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkoxy, halogen, and trifluoromethyl; PA1 (ii) halogen, trifluoromethyl, cyano, and nitro; PA1 (iii) --CO.sub.2 R.sub.7, --CONHR.sub.7, --OCONHR.sub.7, and --NHCOR.sub.7 wherein R.sub.7 is as previously described above;
(C) the moiety R.sub.2 represents one or more substituents of the pyridine ring which may be in any position and are selected from the group consisting of hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy, and halogen;
(D) the heterocycle is bonded to the X-group at optionally the 2, 3, or 4 position;
(E) the group R.sub.3 is selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 halogen (bromine, chlorine or fluorine) substituted alkyl, benzyl, hydrogen or N-oxide; Z.sup..crclbar. represents a pharmacologically acceptable anion.
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The male sexual response includes the filling of vascular channels that are empty in the flaccid penis, with blood at pressures approaching systemic levels. Erection occurs when the arteriolar and sinusoidal smooth muscles of the vessels within the corpora relax, thus lowering resistance in these channels and allowing arterial blood to surge into the penis. Exit of the arterial blood is simultaneously impeded by an increase in venous resistance. Further distention of the sinusoids is restrained by the minimally distensible tunica albuginea that raises the pressure further and also restricts venous outflow. Thus, the corpora cavernosa and corpus spongiosum can be filled with blood and the penis can be erect with little demand on cardiac output. These vascular changes that occur during erection are thought to be controlled by vasoactive intestinal polypeptide, perhaps aided by alpha-adrenergic blockade, acetylcholine and nitric oxide.
The female sexual response cycle is typically divided into four phases including desire, excitement, which includes physiological changes such as vasocongestion in the pelvis, vaginal lubrication, and expansion and swelling of the external genitalia, orgasm, and resolution. Disorders of female sexual desire or response are estimated to affect from 30 to 50 percent of the adult female population. These disorders may have a variety of causes including psychogenic etiologies, anatomical disorders, drug-induced disorders, diabetes mellitus, post-surgical disorders, atherosclerosis, post-traumatic disorders, as well as endocrine etiologies. Depending upon the etiology of the disorder, effective treatment may be had by overcoming any boundaries to the physiological changes that take place during excitement including vasocongestion. Thus, in certain cases, it may be possible to enhance the female sexual response by stimulating vasocongestion.
There are a wide variety of pharmacological agents used for the enhancement of erection and treatment of sexual dysfunction and as pro-libido agents. Some examples include: serotonin receptor agonists and antagonists (see, e.g., EP 385,658; WO 94/15,920; GB 2,248,449; and GB 2,276,165), dopamine receptor agonists (see, e.g., WO 93/23,035; WO 94/21,608; Pomerantz S. M., Pharmacol. Biochem. Behav. 39:123–128, 1991; and Ferrari F. et al. Psychopharmacology 113:172–176, 1993); adrenergic receptor agonists (see, e.g., WO 95/13,072; EP 611,248; U.S. Pat. No. 5,229,387; and WO 92/11,851); inhibitors of phoshodiesterase (see, e.g., DE 4,338,948; and WO 94/28,902); histamine receptor agonists (see, e.g., U.S. Pat. Nos. 4,013,659; 4,126,670; 4,767,778; WO 91/17,146; U.S. Pat. No. 5,047,418; and EP 0,458,661); neuropeptide Y antagonists (see, e.g., WO 95/00,161); angiotensin II receptor antagonists (see, e.g., EP 577,025); cholinesterase inhibitors (see, e.g., U.S. Pat. Nos. 5,177,070; and 4,633,318); combinations of agents with the different types of biological activity (see, e.g., U.S. Pat. No. 5,145,852; and WO 95/05,188); derivatives of vasoactive intestinal peptide (see, e.g., U.S. Pat. No. 5,147,855; EP 540,969; and EP 463,450); prostaglandins (see, e.g., WO 93/00,894; and EP 459,3770); antidepressants and antipsychotics (see, e.g., U.S. Pat. No. 4,931,445; GB 2,448,449; and Naganuma et al. Clin. Exp. Pharm. Physiol. 20:177–183, 1993); nitric oxide donors (see, e.g., WO 92/21,346; DE 4,305,881; DE 4,212,582; and WO 94/16,729); calcitonin gene related peptide (see, e.g., Steif, C.G. et al., Urology, 41:397–400, 1993); and androgens (see, e.g., JP 06,211,675; HU 62,473; and WO 94/16,709). Unfortunately, many or all of these pharmacological agents are associated with adverse effects including aggravation or induction of schizophrenia, serotonin syndrome, central nervous system and endocrine system dysfunction, pain, echytomosis and priapism.
Accordingly there is a need in the art to identify new pharmacological agents or compositions which are useful for enhancement of the sexual response in mammals.
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The present invention is in the field of intraocular lens devices for correction of aphakia by implantation in the posterior chamber of the human eye. With respect to prior art problems and proposed solutions thereto, reference is made to the description of the development of prior art intraocular lens and various prior patents and publications as discussed and cited in my earlier U.S. Pat. No. 4,328,595.
Notwithstanding the advances in the art represented by the above-noted and other prior art, problems of maintaining flexibility and stability of an intraocular lens in the eye have continued to occur. One particular problem resides in the fact that many of the prior known lenses that curve back upon themselves frequently malfunction as a consequence of the haptic moving out of position whenever the eye is compressed. Another problem resides in the fact that the implantation of an intraocular lens necessarily takes place in a restricted area to which access is difficult. Implantation has been effected by the use of conventional prior known surgical implements and by the use of newly developed special implements designed for implanting a particular type of lens. Unfortunately, many of the tools employed in lens implantation surgery are large in comparison to the size of the lens and are consequently cumbersome and difficult to use. Attempts to solve one or more of the aforementioned problems are demonstrated in U.S. Pat. Nos. 3,436,763; 3,673,616; 3,975,779; 4,080,709; 4,087,866; 4,092,743; 4,104,339; 4,122,556; 4;.136,406; 4,198,714; 4,285,072; 4,370,760; 4,377,873; 4,412,359; 4,451,938; 4,463,457; 4,463,458; 4,490,860; 4,476,591; 4,485,499; 4,490,860; 4,502,162; 4,502,163; 4,503,570; 4,504,981; 4,512,039; 4,512,040 and 4,513,546. Additionally, British Patent No. 2,053,689 also illustrates an attempt to solve one or more of the aforementioned problems.
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The following references disclose various aspects related to, inter alia, optical frequency combs, tunable laser sources, high-Q optical resonators, and second harmonic generation. Some of those disclosed aspects may be employed in examples of inventive apparatus or methods disclosed or claimed herein. Each of the following references is incorporated by reference as if fully set forth herein: [1] P. Del Haye, A. Schliesser, O. Arcizet, T. Wilken, R. Holzwarth and T. J. Kippenberg, “Optical frequency comb generation from a monolithic microresonator”, Nature 450, 1214 (2007); [2] M. J. R. Heck, J. F. Bauters, M. L. Davenport, J. K. Doylend, S. Jain, G. Kurczveil, S. Srinivasan, Y. Tang and J. E. Bowers. “Hybrid Silicon Photonic Integrated Circuit Technology”, IEEE J. Sel. Topics Quant. Electron. 19, 6100117 (2013); [3] J. C. Hulme, J. K. Doylend, and J. E. Bowers, “Widely tunable Vernier ring laser on hybrid silicon”, Opt. Express 21, 19718-19722 (2013); [4] T. Komljenovic, et al., “Heterogeneous Silicon Photonic Integrated Circuits”, J. Lightwave Technol. 34, 20-35 (2016); [5] S. Srinivasan, M. Davenport, T. Komljenovic, J. Hulme, D. T. Spencer, and J. E. Bowers, “Coupled-Ring-Resonator-Mirror-Based Heterogeneous III-V Silicon Tunable Laser”, IEEE Photon. J. 7, 2700908 (2015); [6] T. Komljenovic, S. Srinivasan, E. Norberg, M. Davenport, G. Fish, and J. E. Bowers, “Widely Tunable Narrow-Linewidth Monolithically Integrated External-Cavity Semiconductor Lasers”, IEEE J. Sel. Topics Quantum Electron. 21, 1501909 (2015); [7] J. Li, H. Lee, T. Chen, and K. J. Vahala, “Low-Pump-Power, Low-Phase-Noise, and Microwave to Millimeter-Wave Repetition Rate Operation in Microcombs”, Phys. Rev. Lett. 109, 233901 (2012); [8] H. Lee, T. Chen, J. Li, K. Y. Yang, S. Jeon, O. Painter and K. J. Vahala, “Chemically etched ultrahigh-Q wedge-resonator on a silicon chip,” Nature Photon. 6, 369-373 (2012); [9] Th. Udem, J. Reichert, R. Holzwarth, and T. W. Hänsch, “Absolute Optical Frequency Measurement of the Cesium D1 Line with a Mode-Locked Laser”, Phys. Rev. Lett. 82, 3568 (1999); [10] M. H. P. Pfeiffer, A. Kordts, V. Brasch, M. Zervas, M. Geiselmann, J. D. Jost, and Tobias J. Kippenberg, “Photonic Damascene process for integrated high-Q microresonator based nonlinear photonics”, Optica 3, 20 (2016); [11] Q. Li, T. C. Briles, D. A. Westly, J. R. Stone, B. R. Ilic, S. A. Diddams, S. B. Papp, and K. Srinivasan, “Octave-spanning microcavity Kerr frequency combs with harmonic dispersive-wave emission on a silicon chip”, Frontiers in Optics/Laser Science, Paper FW6C.5 (2015); [12] N. Volet, A. Spott, E. J. Stanton, M. L. Davenport, J. Peters, J. Meyer, and J. E. Bowers, “Semiconductor optical amplifiers at 2.0-μm wavelength heterogeneously integrated on silicon”, in Conference on Lasers and Electro-Optics SM4G.4 (2016); [13] L. Chang, Y. Li, N. Volet, L. Wang, J. Peters, and J. E. Bowers, “Thin film wavelength converters for photonic integrated circuits”; Optica 3, 531 (2016); [14] Z. Li, Y. Fu, M. Piels, H. Pan, A. Beling, J. E. Bowers, and J. C. Campbell, “High-power high-linearity flip-chip bonded modified unitraveling carrier photodiode”, Opt. Express 19, B385-6390 (2011); [15] M. L. Davenport, S. Skendžić, N. Volet, J. C. Hulme, M. J. R. Heck, and J. E. Bowers, “Heterogeneous Silicon/III-V Semiconductor Optical Amplifiers”, IEEE J. Sel. Topics Quantum Electron., 22, 3100111 (2016); [16] A. Spott, M. Davenport, J. Peters, J. Bovington, M. J. R. Heck, E. J. Stanton, I. Vurgaftman, J. Meyer, and J. Bowers, “Heterogeneously integrated 2.0 μm CW hybrid silicon lasers at room temperature”, Opt. Lett. 40, 1480-1483 (2015); [17] M. Piels, J. F. Bauters, M. L. Davenport, M. J. R. Heck, and J. E. Bowers, “Low-Loss Silicon Nitride AWG Demultiplexer Heterogeneously Integrated With Hybrid III-V/Silicon Photodetectors”, J. Lightwave Technol. 32, 817-823 (2014); [18] Yang, K. Y., Oh, D. Y., Lee, S. H., Yang, Q.-F., Yi, X. & Vahala, K. Integrated Ultra-High-Q Optical Resonator. arXiv preprint arXiv:1702.05076 (2017); [19] U.S. Pat. No. 8,818,146 entitled “Silica-on-silicon waveguides and related fabrication methods” issued Aug. 26, 2014 to Vahala et al; [20] U.S. Pat. No. 9,293,887 entitled “Chip-based laser resonator device for highly coherent laser generation” issued Mar. 22, 2016 to Li et al; and [21] U.S. non-provisional application Ser. No. 15/587,897 entitled “High-Q optical resonator with monolithically integrated waveguide” filed May 5, 2017 in the names of Vahala et al.
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1. Field of the Invention
The present invention relates to a liquid biocidal composition containing (a) formaldehyde adduct compounds and (b) an isothiazolone, which is intended to provide synergistic biocidal. activity against bacteria and fungi. More particularly, the present invention relates to the use of a biocide composition which includes formaldehyde adduct compounds and 1,2- benzisothiazolin-3-one.
2. Description of the Prior Art
Synergistic biological activity exists when the combination of lesser quantities of two biocidal agents results in an equal or greater inhibitory effect than is achieved by the use of either agent acting alone. The synergistic interaction of two or more antimicrobial agents produces an effect that is more than additive in its resultant biological activity.
Formaldehyde adduct compounds are known biocides; their proposed biological target is the cell wall of susceptible microorganisms (S. P. Denyer, 1990. Mechanisms of action of biocides. International Biodeterioration, 26:89). Examples of such adduct compounds includeN-methyl-2-hydroxymethyleneoxypropyl-2xe2x80x2-hydroxypropylamineanditsformaldehyde oligomers (manufactured by Creanova Inc., Somerset, N. J. under the trademark NUOSEPT(copyright) 145, hereinafter xe2x80x9cNMPFAxe2x80x9d); oxazolidines such as (4,4-dimethyloxazolidine, manufactured by Creanova Inc. under the trademark NUOSEPT(copyright) 101, hereinafter xe2x80x9cDMOxe2x80x9d), mixtures of bicyclic oxazolidines (such as (5-hydroxymethoxymethyl-1-aza-3,7-dioxabicyclo(3.3.0) octane,5-hydroxymethyl-1-aza-3,7-dioxabicyclo(3.3.0)octane,5-hydroxypoly[methyleneoxy-methyl-1-aza-3,7-dioxabicyclo (3.3.0) octane; manufactured by Creanova Inc. under the trademark NUOSEPT(copyright) 95, hereinafter xe2x80x9cMBOxe2x80x9d; and 2-[(hydroxymethyl) amino]ethanol, (manufactured by Creanova Inc. under the trade mark NUOSEPT(copyright) 91, hereinafter xe2x80x9cHMAExe2x80x9d).
The compound 1,2-benzisothiazolin-3-one (hereinafter xe2x80x9cBITxe2x80x9d), an isothiazolone, is an antimicrobial agent. Isothiazolones are disclosed in U.S. Pat. Nos. 3,761,488; 4,105,431; 4,252,694; 4,265,899; 4,279,762; 4,871,754, and 5,620,997. Studies on the microbiological target of BIT suggest that the compound acts on the cytoplasmic membrane thiol-enzymes. (See, e.g., Fuller, S. J., Denyer, S. P., Hugo, W. B., Pemberton, D., Woodcock, P. M. and Buckley, A. J., (1985). The mode of action of 1,2-benzisothiazolin-3-one on Staphylococcus aureus, Letters in Applied Microbiology, 1, 13-15.)
Biocidal combinations with synergistic activities for various microorganisms are known. Different formaldehyde donor compounds have been combined with 3-iodo-2-propynyl butyl carbamate (IPBC), a well known fungicide, to broaden the antimicrobial spectrum of activity. (U.S. Pat. No. 5,428,050; U.S. Pat. No. 4,844,891; D. Pendelton et al. (1987), Modern Paint and Coatings August p:30; September, p:148.) Also, biocidal combinations containing an isothiazolone and other compounds have been disclosed. Some synergistic combinations include isothiazolones and metal complex with functional ligands (U.S. Pat. No. 4,608,183); isothiazolones and hydroxymethylamino acetic acids (U.S. Pat. No. 4,980,176); isothiazolones and substituted anilides (U.S. Pat. No. 5,212,193); and, isothiazolones and triazines (U.S. Pat. No. 5,294,614).
It is an object of the present invention to provide a synergistic biocidal combination, which is more efficacious than known microbicidal compositions.
Another object of the present invention is the provision of a synergistic combination of biocides which is water-soluble and can be uniformly distributed.
Still another object of this invention is the provision of a water-soluble preservative mixture for use in architectural coating applications (i.e. paints, stains) and other coating related materials (adhesives, sealants, joint compounds, latex emulsions, etc), which is effective against a wide range of fungi and bacteria.
It has been found that the composition of the present invention comprising a mixture of a formaldehyde adduct compound and an isothiazolone exhibits synergistic antimicrobial activity against a wide range of microorganisms; the biological activity of the two compounds acting together being greater than the sum of both compounds acting separately. Synergistic antimicrobial activity may be the result of each biocide having a different mechanism of action on the target microorganisms. The advantages of using a synergistic combination include:
a.) a broadened antimicrobial spectrum of activity;
b.) an increase in effectiveness;
c.) a reduction of the use levels; and
d.) a decrease in the toxicity of a given agent to the host and the environment.
The present invention, which combines formaldehyde adduct compounds and 1,2-benziosthiazolin-3-one (BIT), provides a composition having synergistic activity against a wide range of bacteria and fungi.
The present invention is directed to a mixture of two biocides designed to control unwanted bacterial and fungal growth in water-based applications, including but not limited to, paints, e.g., acrylics, polyvinyl acetates, styrene-butadienes, etc., coatings, adhesives, sealants, latex emulsions and joint compounds. The liquid biocidal composition of the present invention comprise a mixture of formaldehyde adducts, including NMPFA, DMO, MBO or HMAE, and BIT. The weight ratio of the formaldehyde adduct compound to BIT in the composition of the present invention ranges from about 100:1 to 1:100, more preferably from about 30:1 to 1:30, and most preferably from about 6:1 to 1:6. The BIT can be in the form of an acid or base.
The synergistic antimicrobial activity of the present invention is demonstrated by testing over a range of concentrations and ratios of NMPFA and BIT. The synergistic antimicrobial activity of the present invention is also demonstrated by testing the formaldehyde adduct compounds DMO, MBO or HMAE, and BIT. The examples presented below serve to illustrate the invention and to demonstrate the synergistic results obtained when the two compounds are used in combination, as compared with their effectiveness when used individually.
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Conventional electronic devices have largely been developed to satisfy a particular need. This is no more apparent than with a traditional telephone. A user would use the telephone specifically to vocally communicate with a person at a remote location. Other devices developed for specific purposes included traditional radios with FM and/or AM tuners, televisions for receiving and displaying broadcast audio-visual programs, and early computers were developed to process and analyze large quantities of data.
Despite intensive preventive efforts over the past several years in hospital and other healthcare facilities, the incidence of life threatening infections caused by a growing array of antibiotic resistant bacteria (sometimes referred to as “superbugs”) has grown significantly and is now posing a serious problem for medical staff worldwide. According to an editorial in the journal “Science” (July 2008), the number of deaths in 2006 attributable to bacterial infections in healthcare facilities in the United States exceeded the U.S. death toll attributed to HIV/AIDS in the same year, and probably result in as many as 70,000 deaths per year in the United States. This is despite the best efforts of healthcare personnel properly to clean their facilities and the equipment contained therein.
The major causative agents (bacteria) for hospital-based infections (nosocomial infections) are Clostridium difficile (C. difficile); E. coli; Pseudomonas aeruginosa; methicillin-resistant Staphylococcus aureus (MRSA); and vancomycin-resistant Enterococcus (VRE).
Approximately 5% of all acute care hospitalizations in the U.S. develop a nosocomial infection with an incidence rate of five infections per thousand patient days, and an added expenditure in excess of $4.5 billion (Wentzel R, Edmond M D, “The Impact of Hospital Acquired Blood Stream Infections,” Emerg. Inf. Dis., March-April 2001:7(174)). When this rate is applied to the 35 million patients admitted to 7,000 acute-care institutions in the U.S., it is estimated that there are more than 2 million cases per year. Nosocomial infections are estimated to double, at least, the mortality and morbidity risks of any admitted patient.
The significant, and growing, incidence of antibiotic resistant bacteria in healthcare facilities has been termed by some as a “Silent Epidemic”. On the international scene, a World Health Organization survey of 55 hospitals in 14 countries representing four WHO regions (Europe, Eastern Mediterranean, South-East Asia and Western Pacific) reported that an average of 8.7% of hospital patients had nosocomial infections. The WHO estimates that, at any time, over 1.4 million people worldwide suffer from infection acquired in hospital.
Of particular concern in this context are the bacteria C. difficile and MRSA. Until recently, C. difficile was relatively uncommon, but has now become epidemic in many regions of the world. Indeed, it is now recognized by a growing number of public health officials as a worldwide epidemic (pandemic) with incalculable financial and health implications. MRSA has been identified by the American Academy of Orthopaedic Surgeons as the single biggest concern for surgical procedures, and concurs with recent journal articles that it constitutes a “silent epidemic.” Under current healthcare facility cleaning and sterilizing procedures, both C. difficile and MRSA, as well as the aforementioned E. coli; Pseudomonas aeruginosa; and vancomycin-resistant Enterococcus (VRE), are ineffectively treated and subsequently removed, so that colonies of these pathogens accumulate in healthcare facilities, especially on porous surfaces such as carpets and drapes.
Attempts to combat and kill nosocomial infections caused by bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus are hampered by the fact that the bacteria grow within biofilms that protect them from adverse environmental factors. A biofilm is an aggregate of microorganisms in which cells adhere to each other and/or to a surface. They are frequently embedded in a self produced matrix of extracellular polymeric substance (EPS), a polymeric conglomeration generally composed of extracellular DNA, proteins and polysaccharides. Biofilms form on surfaces, e.g. in hospital settings, in the presence of water vapor.
Free floating microorganisms in planktonic (single cell) mode attach to a surface, and if not immediately removed, will anchor themselves more permanently to the surface. These first colonists provide more diverse adhesion sites for the arrival of other cells, thus beginning to build a matrix that holds the biofilm together and provides additional anchoring sites for arriving cells. The biofilm grows through a combination of cell division and recruitment. When the biofilm is established, the aggregate cell colonies are apparently increasingly antibiotic resistant. It has also been reported that biofilm bacteria apply chemical weapons to defend themselves against disinfectants and antibiotics (see “Biofilm Bacteria Protect Themselves With Chemical Weapons”, Dr. Carsten Matz et. al., Helmholtz Centre for Infection Research, Brauschweig, reported on Inforniac.com, Jul. 23, 2008).
Bacteria living in a biofilm have significantly differently properties from the planktonic form of the same species, as the dense and protected environment of the film allows them to co-operate and interact in various ways. Traditional antibiotic therapy is usually not sufficient to eradicate chronic infections, and one major reason for their persistence seems to be the capability of the bacteria to grow within biofilms that protect them from adverse environmental factors.
Also of growing concern are threatened bioterrorist and warfare attacks using potentially lethal bacteria. Some of the deadliest bacteria, for example anthrax, are highly resistant to conventional sterilization agents and treatments. Contamination of public facilities with such bacteria constitutes a significant threat to human life with residual amounts of such bacteria being almost impossible to remove using current methods.
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1. Technical Field
The present invention relates to a light receiving device, a light receiving device manufacturing method, and a light receiving method.
2. Related Art
Conventionally known light-harvesting-antenna-type light receiving elements make use of surface plasmons propagating along the surface of electrically conductive materials such as metal as disclosed in, for example, Japanese Patent Application Publication No. 2007-248141 and Tsutomu Ishi, et al., “Si Nano-Photodiode with a Surface Plasmon Antenna”, Japanese Journal of Applied Physics, Japan, March 2005, Vol. 44, No. 12, pp.L364-L366. Furthermore, known polarization dispersing elements convert linearly polarized incoming light into radially or concentrically polarized light as disclosed in, for example, Rumiko Yamaguchi, et al., “Liquid Crystal Polarizers with Axially Symmetrical Properties”, Japanese Journal of Applied Physics, Japan, July 1989, Vol. 28, No. 9, pp. 1730-1731 and Shin Masuda, et al., “Optical Properties of a Polarization Converting Device Using a Nematic Liquid Crystal Cell”, OPTICAL REVIEW, Japan, 1995, Vol. 2, No. 3, pp. 211-216.
Here, the light-harvesting-antenna-type light receiving elements exhibit largely varying light collection efficiency depending on the polarization direction of the incoming light. Therefore, such light receiving elements may suffer from poor light collection efficiency when irradiated with light polarized in a single direction.
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1. Technical Field
Fuel cells have been championed as viable alternatives over existing battery technology for portable electronic devices; however, a key issue for widespread adoption and success of fuel cell technology involves addressing the meager performance of these devices due to poor efficiency and durability of the catalysts. The present disclosure is generally directed to bulk metallic glass materials for energy conversion and storage applications. More particularly, the present disclosure is directed to a new class of materials that can circumvent Pt-based anode poisoning and the agglomeration/dissolution of supported catalysts during long-term fuel cell operation. An exemplary implementation of the present disclosure involves use of Pt58Cu15Ni5P22 bulk metallic glass to create a new class of high performance nanowire catalysts for use in fuel cell applications.
2. Background Art
Amorphous alloys were developed approximately fifty years ago following reports concerning the formation of Au-Si metallic glass [1]. Researchers developed rapid quenching techniques for chilling metallic liquids at cooling rates of 105-106° K/s. However, these high cooling rates limited the potential geometries of these alloys to thin sheets/lines and stymied the range of potential applications [2]. Recently, the development of several multi-component alloys capable of solidifying into glass at relatively low cooling rates (1˜102° K/s)—materials that vitrify without crystallization—has permitted the production of large-scale bulk metallic glass (BMG) samples on the order of 30 mm [3]. These BMGs represent a new class of engineering materials with an unusual combination of strength, elasticity, hardness, corrosion resistance and processability [4-8]. The random atomic structure in BMGs is devoid of dislocations and associated slip planes. These systems can result in elasticities of 2% (Zr-based BMG formers [6]) and yield strengths of up to 5 GPa (Co-based BMG formers [9]). During yielding, however, BMGs can suffer from macroscopically brittle failure at ambient temperatures [10]; however, when samples with small dimensions are characterized, significant global plasticity is observed [11-13].
A wide range of BMG-forming alloys have been developed, including Zr-[14-16], Fe-[17, 18], Cu-[19], Ni-[20], Ti-[21], Mg-[22], Pd-[23], Au-[24] and Pt-based compositions [25]. As discussed by Wang et al. [2] and Schroers [26], applications for these materials can range from thermoelectric devices to biocompatible implants and have already impacted fields ranging from sports (i.e., tennis rackets, golf clubs etc.) to Micro/Nano Electromechanical systems (MEMs/NEMs) devices.
One of the challenges with BMGs is that the current approach towards developing these materials to exhibit specific properties is carried out by synthesizing and characterizing each alloy composition individually. The common strategy is a trial and error approach that can result in hundreds of time-consuming experiments [24, 25]. Such an approach is highly inefficient towards rapid identification of bulk metallic glass forming compositions, limiting advancements in this field. A combinatorial approach could provide an elegant solution to the task of mapping systems that could form new bulk metallic glass alloys with desirable properties. Successful combinatorial techniques have previously been developed in the pharmaceutical industry [27] and are now being considered as a viable approach for mapping alloys across compositional phase diagrams [28, 29]. For example, Sakurai et al. used a combinatorial arc plasma deposition (CAPD) to search for Ru-based thin film metallic glass by making libraries. Each library consisted of 1089 CAPD samples deposited on a substrate [30].
With specific reference to fuel cell technology, a fuel cell electrode has three primary functions: (i) allowing access to reacting gases, (ii) providing active electrocatalytic sites, and (iii) allowing transport of electrons as well as ions. Electrical power is generated by oxidizing the fuel electrochemically, e.g., by digesting carbon-based fuels with the help of an internal catalyst. However, poisoning and/or deposition on the anode can significantly interfere with the operation/efficiency of fuel cell systems. For example, sulfur is a potent poison for nickel electrocatalysts present in many current anodes. Similarly, conventional anode technology—which generally involves anodes fabricated from porous carbon coated with platinum—is highly susceptible to impurities in the hydrogen fuel which, if present, easily bind with the platinum, “poisoning” the electrode and decreasing fuel cell performance Carbon deposition, which reduces the activity of the anode, can occur if the steam-to-carbon ratio of the fuel gas is too low. Nickel effectively functions as a catalyst for carbon deposition (coking), thereby blocking the active sites of the anode and, in the worst case, destroying its structure. Technologies/techniques are needed that ensure durability and efficiency of fuel cell operation, despite the potential for poisoning and/or deposition phenomena interfering with anode functionality.
The role of surface chemistry in catalytic development is significant. The surface chemistry of a material in the praxis of a metal/electrolyte interface can be described by either heterogeneous or electrochemical reactions where one can term the activation surface a catalyst. The activity of the catalyst can be due to structural or chemical modifications of the electrode surface and additions to the electrolyte. Structural effects can be caused by variations in the electronic state and by variation in the geometric nature (i.e. crystal planes, clusters, alloys, surface defects) [46]. To correlate the electrocatalytic ability with a physiochemical property of a material, plots can be made of electrochemical activity (either current density at constant potential, or potential at constant current density) versus the physiochemical property. Balandin first proposed these as volcano plots [47], if the resulting plot is a bell curve (see FIG. 4—adapted from [48]).
Heterogeneous catalysis is relevant to the design and operation of direct alcohol fuel cells. The optimum heterogeneous catalyst will provide the correct reaction site geometry, along with the proper electronic environment, to facilitate the reaction of interest. An example of this can be found from catalyst development in direct alcohol fuel cells where a major challenge is the search for efficient electrocatalysts that would remedy the Pt-based anode poisoning by a carbonaceous intermediate (most likely CO) during alcohol oxidation. Direct alcohol fuel cells are of particular interest because of the high power density of liquid fuels (e.g. methanol, ethanol). The best catalysts for methanol oxidation are based on Pt—Ru systems. However, the high cost of Ru has led to research aiming to identify other less expensive metals, M, that exhibit enhancement of Pt or Pt—Ru catalytic activity. A guide to the design of efficient Pt-M methanol oxidation binary systems is provided in a review by Ishikawa et al., where the theoretical predictions for the effect of the second metal is provided by three key reaction steps (methanol dissociative chemisorption, CO poison adsorption, and CO removal via its oxidation by adsorbed OH) [49]. The effects of these Pt-M systems can be grouped into two main categories: 1. Ligand effect—modification of the Pt electronic properties by the second metal [50]. 2. Synergistic effect—bi-functional mechanism whereby the second metal disrupts the continuity of the Pt lattice and provides sites for OH adsorption [51-53].
More recently, the electronic effect has been studied using the density functional theory to estimate the direction and extent of the d-band energy center, ed, shifts when metals of different Wigner-Seitz radii and electronegativity are found together [54-56]. Of note, the addition of Cu, Fe, Co, and Ni to Pt results in a Pt ed down-shift, which in turn is both theoretically predicted and experimentally found to lead to decreased CO adsorption [57-61].
Corrosion challenges are substantial with conventional fuel cell catalysts. The surface chemistry activity is also related to the structural stability and corrosion of the surface. For instance, in direct alcohol fuel cells, electrocatalyst durability has been recently recognized as one of the most important issues that must be addressed prior to direct alcohol fuel cell commercialization [62, 63]. Presently, the most widely used catalyst system is platinum in the form of small nanoparticles (2-5 nm) supported on amorphous carbon-particle aggregates (Pt/C). The poor durability of the Pt/C catalyst is evident by a fast and significant loss of platinum electrochemical surface area (ECSA) during the time of fuel cell operation [62-64]. The mechanisms for the loss of platinum ECSA can be summarized as follows[62, 63]: 1. Loss of Pt nanoparticles from the electrical contact due to corrosion of the carbon support. 2. Pt dissolution and redeposition (migration of the soluble Pt+ species within the polymer electrolyte and the eventual chemical reduction by hydrogen crossover from the anode through the proton exchange membrane. 3. Ostwald ripening (Pt nanoparticle aggregation driven by surface energy minimization.)
For these reasons, there has been considerable recent interest in the development of nanowire fuel cell catalysts [65-67]. Previous nanometallic synthesis efforts have focused on bottom up assembly through the reduction of salt precursors or electrochemical deposition processes to create the following: Pt and Pd nanotubes [68], Au-Ag nanoporous nanotubes [69], NiCu [70], PtCo nanowires [71], Pt3Ni(111) single crystals [72], and Pd-Pt bimetallic nanodendrites [73]. Many of these strategies involve complex synthesis methods due to the difficulty in forming metallic alloys into the nanometer-length scales necessary for maintaining a high dispersion (noble metal utilization). Of further note, Chen et al. reported an enhanced durability for pure platinum nanotubes (PtNTs) and suggested that the activity of the PtNTs could be further improved by employing platinum alloy nanotubes [68].
Based upon these initial challenges, there is a clear need for a new type of catalyst material that does not suffer from durability issues and that displays the high electrochemical activity consistent with a multi-component catalyst system. Bulk metallic glasses (BMGs) are of particular interest for these kinds of surface chemistry studies because the surface and structure of these alloys can be patterned down to the same scale as conventional supported catalysts [26]. The absence of crystallites, grain boundaries, and dislocations in the amorphous structure of bulk metallic glass results in a homogeneous and isotropic material down to the atomic scale, which displays very high strength, hardness, elastic strain limit and corrosion resistance. BMGs represent a positive step in this direction as these amorphous metals can be formed into nanowires (FIG. 3d) that circumvent the very complex synthesis, low throughput, low reproducibility, and high cost typically associated with nanowire fabrication [74-77].
These and other objectives are satisfied according to the systems and methods of the present disclosure.
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Otitis media (OM) is a highly prevalent pediatric disease worldwide and is the primary cause for emergency room visits by children (Infante-Rivand and Fernandez, Epidemiol. Rev., 15: 444-465, 1993). Recent statistic indicate that 24.5 million physician office visits were made for OM in 1990, representing a greater than 200% increase over those reported in the 1980's. While rarely associated with mortality any longer, the morbidity associated with OM is significant. Hearing loss is a common problem associated with this disease, often times affecting a child's behavior, education and development of language skills (Baldwin, Am. J. Otol., 14: 601-604, 1993;Hunter et al., Ann. Otol. Rhinol. Laryngol. Suppl., 163: 59-61, 1994; Teele et al., J. Infect. Dis., 162: 685-694, 1990). The socioeconomic impact of OM is also great, with direct and indirect costs of diagnosing and managing OM exceeding $5 billion annually in the U.S. alone (Kaplan et al., Pediatr. Infect. Dis. J., 16: S9-11, 1997).
Whereas antibiotic therapy is common and the surgical placement of tympanostomy tubes has been successful in terms of draining effusions, clearing infection and relieving pain associated with the accumulation of fluids in the middle ear. the emergence of multiple antibiotic-resistant bacteria and the invasive nature associated with tube placement, has illuminated the need for more effective and accepted approaches to the management and preferably, the prevention of OM. Surgical management of chronic OM involves the insertion of tympanostomy tubes through the tympanic membrane while a child is under general anesthesia. While this procedure is commonplace (prevalence rates are ˜13%; Bright et al., Am. J. Public Health, 83(7): 1026-8, 1993) and is highly effective in terms of relieving painful symptoms by draining the middle ear of accumulated fluids, it too has met with criticism due to the invasive nature of the procedure and its incumbent risks (Berman et al., Pediatrics, 93(3):353-63, 1994;Bright et al., supra.; Cimons ASM News, 60: 527-528;Paap, Ann. Pharmacother., 30(11): 1291-7, 1996).
Progress in vaccine development is most advanced for Streptococcus pneumoniae, the primary causative agent of acute OM (AOM), as evidenced by the recent approval and release of a seven-valent capsular-conjugate vaccine, PREVNAR® (Eskola and Kilpi, Pedriatr. Infect. Dis. J. 16: S72-78, 2000). While PREVNAR® has been highly efficacious for invasive pneumococcal disease, coverage for OM has been disappointing (6-8%) with reports of an increased number of OM cases due to serotypes not included in the vaccine (Black et al., Pedriatr. Infect. Dis J. 19: 187-195; Eskola et al., Pedriatr. Infect. Dis J., 19: S72-78, 2000; Eskola et al., N. Engl. J. Med. 344: 403-409, 2001; Snow et al., Otol. Neurotol., 23: 1-2, 2002). Less progress has been made for non-typeable Haemophilus influenzae (NTHi), the gram-negative pathogen that predominates in chronic OM with effusion (Klein, Pedriatr. Infect. Dis J., 16: S5-8, 1997;Spinola et al., J. Infect. Dis., 154: 100-109, 1986). Hampering development of effective vaccines against NTHi, is the currently incomplete understanding of the pathogenesis of NTHi-induced middle ear disease. Contributing to this delay is a lack of understanding of the dynamic interplay between microbe-expressed virulence factors and the host's immune response as the disease progresses from one of host immunological tolerance of a benign nasopharyngeal commensal, to that of an active defensive reaction to an opportunistic invader of the normally sterile middle ear space.
Currently there is a poor understanding of how NTHi causes OM in children. The identification of putative virulence factors necessary for induction of OM will contribute significantly to the understanding of the host-pathogen interaction and ultimately, the identification of potential vaccine candidates and targets of chemotherapy. There is a tremendous need to develop more effective and accepted approaches to the management and preferably, the prevention of otitis media. Vaccine development is a very promising and cost effective method to accomplish this goal (Giebank, Pedriatr. Inject. Dis J., 13(11): 1064-8, 1994: Karma et al., Int. J. Pedritr. Otorhinolaryngol., 32(Suppl.): S127-34, 1995).
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1. Field
The present invention relates to methods and apparatus for monitoring and controlling the properties of fluids, and more particularly to a method and apparatus for quality control of fluids during manufacturing processes.
2. Description of Related Art
When manufacturing lubricating fluids blended with additives, analytical testing is required to verify that the properties of the blended lubricant are within defined specifications. The blending operation, in some exemplary approaches, may be performed in a tank or by in-line blending processes. Typical analytical tests, such as Fourier Transform Infrared (FT-IR) spectroscopy, kinematic viscosity as per ASTM D-445 or metal analyses—inductively coupled plasma spectrometry (ICP) as per ASTM D-5185, are performed on samples in a laboratory. Depending on laboratory operations and conditions, tests may require more than an hour for completion, and the blending process is typically suspended until satisfactory results are obtained. The delays may be extended if the results are unsatisfactory.
Systems for in-situ (e.g., performed in an operating system, such as an engine or transmission) monitoring of lubricating fluids are known. One such system is disclosed in U.S. Pat. No. 6,278,281 entitled “Fluid Control Monitor” issued to Bauer, et al. This patent describes a technique employing AC electro-impedance spectroscopy (referred to hereinafter as impedance spectroscopy or “IS”), and is implemented by means of probe electrodes placed in contact with the fluid to be tested. The method of operation includes making IS measurements at a first frequency that is less than 1 Hz and a second frequency that is greater than 1 Hz, comparing the two IS measurements, and declaring a “pass” or “fail” condition based on a previously determined empirical relationship.
However, this prior art lubricating fluid monitoring system effectively analyzes only a single characteristic of the IS spectra based on the difference of two IS measurements. Consequently, it is not capable of determining the complex properties of compound fluids, as is required when performing quality control measurements of fluids having a plurality of additives. Thus, a need exists for a real-time, in situ monitoring system for quality control of fluids during manufacturing operations.
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Structures and techniques have been proposed to enhance the performance of semiconductor devices, such as by enhancing the mobility of the charge carriers. For example, U.S. Patent Application No. 2003/0057416 to Currie et al discloses strained material layers of silicon, silicon-germanium, and relaxed silicon and also including impurity-free zones that would otherwise cause performance degradation The resulting biaxial strain in the upper silicon layer alters the carrier mobilities enabling higher speed and/or lower power devices. Published U.S. Patent Application No. 2003/0034529 to Fitzgerald et al. discloses a CMOS inverter also based upon similar strained silicon technology.
U.S. Pat. No. 6,472,685 B2 to Takagi discloses a semiconductor device including a silicon and carbon layer sandwiched between silicon layers so that the conduction band and valence band of the second silicon layer receive a tensile strain. Electrons having a smaller effective mass, and which have been induced by an electric field applied to the gate electrode, are confined in the second silicon layer, thus, an n-channel MOSFET is asserted to have a higher mobility.
U.S. Pat. No. 4,937,204 to Ishibashi et al. discloses a superlattice in which a plurality of layers, less than eight monolayers, and containing a fractional or binary or a binary compound semiconductor layer, are alternately and epitaxially grown. The direction of main current flow is perpendicular to the layers of the superlattice.
U.S. Pat. No. 5,357,119 to Wang et al. discloses a Si—Ge short period superlattice with higher mobility achieved by reducing alloy scattering in the superlattice. Along these lines, U.S. Pat. No. 5,683,934 to Candelaria discloses an enhanced mobility MOSFET including a channel layer comprising an alloy of silicon and a second material substitutionally present in the silicon lattice at a percentage that places the channel layer under tensile stress
U.S. Pat. No. 5,216,262 to Tsu discloses a quantum well structure comprising two barrier regions and a thin epitaxially grown semiconductor layer sandwiched between the barriers. Each barrier region consists of alternate layers of SiO2/Si with a thickness generally in a range of two to six monolayers. A much thicker section of silicon is sandwiched between the barriers.
An article entitled “Phenomena in silicon nanostructure devices” also to Tsu and published online Sep. 6, 2000 by Applied Physics and Materials Science & Processing, pp. 391-402 discloses a semiconductor-atomic superlattice (SAS) of silicon and oxygen. The Si/O superlattice is disclosed as useful in a silicon quantum and light-emitting devices In particular, a green electromuminescence diode structure was constructed and tested. Current flow in the diode structure is vertical, that is, perpendicular to the layers of the SAS. The disclosed SAS may include semiconductor layers separated by adsorbed species such as oxygen atoms, and CO molecules. The silicon growth beyond the adsorbed monolayer of oxygen is described as epitaxial with a fairly low defect density. One SAS structure included a 1.1 nm thick silicon portion that is about eight atomic layers of silicon, and another structure had twice this thickness of silicon. An article to Luo et al. entitled “Chemical Design of Direct-Gap Light-Emitting Silicon” published in Physical Review Letters, Vol 89, No. 7 (Aug. 12, 2002) further discusses the light emitting SAS structures of Tsu.
Published International Application WO 02/103,767 A1 to Wang, Tsu and Lofgren, discloses a barrier building block of thin silicon and oxygen, carbon, nitrogen, phosphorous, antimony, arsenic or hydrogen to thereby reduce current flowing vertically through the lattice more than four orders of magnitude The insulating layer/barrier layer allows for low defect epitaxial silicon to be deposited next to the insulating layer
Published Great Britain Patent Application 2,347,520 to Mears et al. discloses that principles of Aperiodic Photonic Band-Gap (APBG) structures may be adapted for electronic bandgap engineering In particular, the application discloses that material parameters, for example, the location of band minima, effective mass, etc, can be tailored to yield new aperiodic materials with desirable band-structure characteristics. Other parameters, such as electrical conductivity, thermal conductivity and dielectric permittivity or magnetic permeability are disclosed as also possible to be designed into the material
The resistance to carrier flow in semiconductor devices is a significant source of inefficiency, particularly in majority carrier devices such as metal-oxide semiconductor field-effect transistors (MOSFETs). Accordingly, it would be desirable to provide enhanced semiconductor materials that could reduce carrier flow on-resistance in such devices.
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Dementia is characterized as the loss of cognitive function having a severity so as to interfere with a person's daily activities. Cognitive function includes activities such as knowing, thinking, learning, memory, perception, and judging. Symptoms of dementia can also include changes in personality, mood, and behavior of the subject.
Dementia is a collection of symptoms that can be caused by any of a variety of diseases or conditions; it is not itself a disease. Although, in some cases, dementia can be cured by curing the underlying disease (e.g. infection, nutritional deficiency, tumor), in most cases dementia is considered incurable.
Dementia is considered a late-life disease because it tends to develop mostly in elderly people. About 5-8% of all people over the age of 65 have some form of dementia, and this number doubles every five years above that age. It is estimated that as many as half of people in their 80s suffer from some form of dementia. The most common cause of dementia is Alzheimer's disease, which affects about 4 million Americans and appears to be increasing in frequency more than most other types of dementia. Other causes of dementia include AIDS or HIV infection, Creutzfeldt-Jakob disease, head trauma (including single-event trauma and long term trauma such as multiple concussions or other traumas which may result from athletic injury), Lewy body disease, Pick's disease, Parkinson's disease, Huntington's disease, drug or alcohol abuse, brain tumors, hydrocephalus, and kidney or liver disease.
Furthermore, people suffering from mental diseases or disorders can suffer from varying levels of diminishment of cognitive function that do not rise to the level of dementia. Additionally, generally healthy individuals may also perceive some loss of cognitive function, most commonly a reduction in the function of memory. Loss or diminishment of memory may occur in any of the four commonly designated phases of memory, namely learning, retention, recall and recognition, and may be related to immediate memory, recent memory or remote memory. Loss of motor function may occur as a result of any of a number of causes, including many of those discussed above for which there is also a loss of cognitive function.
High energy laser radiation is now well accepted as a surgical tool for cutting, cauterizing, and ablating biological tissue. High energy lasers are now routinely used for vaporizing superficial skin lesions and, to make deep cuts. For a laser to be suitable for use as a surgical laser, it must provide laser energy at a power sufficient to heart tissue to temperatures over 50° C. Power outputs for surgical lasers vary from 1-5 W for vaporizing superficial tissue, to about 100 W for deep cutting.
In contrast, low level laser therapy involves therapeutic administration of laser energy to a patient at vastly lower power outputs than those used in high energy laser applications, resulting in desirable biostimulatory effects while leaving tissue undamaged. For example, in rat models of myocardial infarction and ischemia-reperfusion injury, low energy laser irradiation reduces infarct size and left ventricular dilation, and enhances angiogenesis in the myocardium. (Yaakobi et al., J. Appl. Physiol. 90, 2411-19 (2001)). Low level laser therapy has been described for treating pain, including headache and muscle pain, and inflammation.
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Existing methods of x-ray generation include (1) bremsstrahlung x-rays from a tube, (2) inverse Compton scattering in either a small linear accelerator (LINAC) [W. S. Graves, J. Bessuille, P. Brown, S. Carbajo, V. Dolgashev, K.-H. Hong, E. Ihloff, B. Khaykovich, H. Lin, K. Murari, E. A. Nanni, G. Resta, S. Tantawi, L. E. Zapata, F. X. Kärtner, and D. E. Moncton, “Compact x-ray source based on burst-mode inverse Compton scattering at 100 kHz,” 17 Phys. Rev. ST Accel. Beams 120701 (2014)] or a small storage ring [M. Bech, O. Bunk, C. David, R. Ruth, J. Rifkin, R. Loewen, R. Feidenhans'l and F. Pfeiffer, “Hard X-ray phase-contrast imaging with the Compact Light Source based on inverse Compton X-rays,” 16 J. Synchrotron Rad. 43-47 (2009)], and (3) large scientific facilities such as synchrotrons and x-ray free electron lasers.
Bremsstrahlung x-rays from a tube have low brightness, are not monochromatic except at fixed wavelengths, and are not coherent. While bremsstrahlung is the source of medical x-rays and is widely used for scientific work, it is many orders of magnitude less intense than the other sources. Inverse Compton scattering has demonstrated good performance but does not rely on coherent x-ray generation via a modulated beam and so it is orders of magnitude less efficient than the proposed method. Synchrotron and x-ray free electron laser facilities have the highest demonstrated x-ray performance but may cost in the range of $100 million to $1 billion and may have a size on the order of kilometers.
Some of the present inventors previously conceived of apparatus and methods for generating coherent radiation using an array of discrete electron beamlets from a nanocathode array, as described in U.S. Pat. No. 8,787,529 B2 (W. Graves, F. Kaertner and D. Moncton, “Compact Coherent Current and Radiation Source,” issued 22 Jul. 2014), which is herein incorporated by reference in its entirety.
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Hypertension is a serious condition that can damage vital organs, such as the heart and kidneys, and other parts of the body, such as the central nervous system. Individuals who have hypertension may have, or be at risk of developing, dangerous diseases such as coronary heart disease and kidney failure. Hypertension, which is the leading modifiable risk factor for cardiovascular disease mortality, causes more than 7 million deaths every year worldwide.
Hypertension is the most common chronic medical condition in developed countries as well as the most common indication for physician visits and prescription medication use. Hypertension affects more than 50 million individuals in the United States and over one billion individuals worldwide, and overall prevalence may continue to increase with the advancing age of the population.
Unfortunately, despite the importance of blood pressure control and the availability of multiple classes of antihypertensive agents, the treatment of hypertension remains suboptimal. Data from the most recent National Health and Nutrition Examination Survey demonstrate that only 34% of patients with hypertension have blood pressures at their therapeutic goal. Additionally, it was shown that the majority of patients with hypertension will require two or more antihypertensive agents to achieve their goal blood pressure. Even with optimal compliance with multiple antihypertensive agents of different classes, a significant fraction of patients will not be able to achieve their goal blood pressure. The overall prevalence of resistant hypertension, defined as elevated blood pressure in spite of the use of three or more antihypertensive agents, is unknown, but small studies suggest that it ranges from 5%-16% in primary care settings to greater than 50% in nephrology clinics. Given data suggesting that increasing age and obesity are important risk factors for the development of resistant hypertension, it is expected that the overall prevalence of this condition is likely to increase due to demographic changes in the population.
Systolic blood pressure tends to increase with age and systolic hypertension is an important health issue, prominent in the elderly (Duprez, Am. J. Med. 121:179-184 (2008)). It has been suggested that this occurs as large vessels such as the aorta lose their elasticity with age and is less able to buffer the pulsative nature of cardiac output. There exists a need for a treatment for patients in such clinical setting, for example, patients with systolic hypertension accompanied with low diastolic pressure (Franklin et al. J. Hypertension 29:1101-1108 (2011).
Metabolic syndrome is a cluster of disorders including obesity, hypertension, hypertrigleridemia, hypercholesterolemia and elevated blood sugar. Individuals with this spectrum of disorders are at increased risk of diabetes, heart disease and stroke. Agents capable of treating more than one of these disorders are desirable.
Hypertensive emergencies are defined as severe elevations in blood pressure associated with resultant organ damage (i.e. pulmonary edema, renal impairment, visual impairment, intracranial hemorrhage, or encephalopathy). The treatment of hypertensive emergencies involves aggressive and controlled blood pressure lowering in a highly monitored intensive care setting using intravenous blood pressure lowering agents. Therapeutic agents and method of treatment is needed to gradually lower blood pressure and minimize damage of end organs such as the brain, kidney, heart, and eye.
The frequency of chronic kidney disease also continues to increase worldwide as does the prevalence of end-stage renal disease. Although chronic kidney disease is often caused by hypertension, other factors such as a decrease in renal blood flow and increase in sodium retention or reabsorption can lead to renal diseases. Increased age and diabetes can also contribute to renal disease. Especially the elderly, which are a growing segment of the world population, are at increased risk for renal disease. The presence of chronic kidney disease is also associated with a large increase in cardiovascular morbidity and mortality. Consequently, the identification and reduction of chronic kidney disease has become a vital public health priority.
Thus, there remains a need for new and useful agents that are capable of (i) reducing an individual's blood pressure and/or (ii) promoting renal blood flow and/or (iii) inhibiting or decreasing sodium reabsorption.
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Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of 36 amino acids, was first isolated from porcine brain by Tatemoto et al in 1982 (NATURE, vol. 296, p. 659(1982)). NPY is widely distributed in central nervous system and peripheral nervous system, and plays various roles as one of the most abundant peptides in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system and markedly promotes fat accumulation via the mediation of secretion of various hormones or the action of the nervous system. It is known that continuous intracerebroventricular administration of NPY induces obesity and insulin resistance due to these actions (INTERNATIONAL JOURNAL OF OBESITY, vol. 19, p. 517(1995); Endocrinology, vol. 133, p. 1753(1993)). It is also known that NPY has central actions such as depression, anxiety, schizophrenia, pain, dementia, circadian rhythm control and the like (DRUGS, vol. 52, p. 371(1996); THE JOURNAL OF NEUROSCIENCE, vol. 18, p. 3014(1998)). Furthermore, in the periphery, NPY coexists with norepinephrine in sympathetic-nerve terminals and is related to the tonicity of the sympathetic nervous system. It is known that peripheral administration of NPY causes vasoconstriction and enhances the activities of other vasoconstrictive substances such as norepinephrine (BRITISH JOURNAL OF PHARMACOLOGY, vol. 95, p. 419(1988)). It is also reported that NPY could participate in the development of cardiac hypertrophy as a result of the sympathetic stimulation (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 97, p. 1595(2000)).
On the other hand, it is reported that NPY is also involved in the secretory function of sexual hormones and growth hormone, sexual behavior and reproductive function, gastro-intestinal motility, bronchoconstriction, inflammation and alcohol preference (LIFE SCIENCE, vol. 55, p. 551(1994); THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 101, p. S345(1998); NATURE, vol. 396, p. 366(1998)).
NPY has a variety of pharmacological effects resulting from NPY binding to some NPY receptors to which peptide YY and pancreatic polypeptide, which are the analogs of NPY, also bind. It is known that these pharmacological effects of NPY are mediated by the action of at least five receptors with or without synergistic interactions (TRENDS IN NEUROSCIENCES, vol. 20, p. 294(1997)).
It is reported that the central effects mediated by NPY Y1 receptor include remarkable orexigenic effect (ENDOCRINOLOGY, vol. 137, p. 3177(1996); ENDOCRINOLOGY, vol. 141, p. 1011(2000)). Further, NPY Y1 receptor is reported to be involved in anxiety and pain (NATURE, vol. 259, p. 528(1993); BRAIN RESEARCH, vol. 859, p. 361(2000). In addition, the pressor effect mediated by the strong vasoconstrictor action in the periphery is also reported (FEBS LETTERS, vol. 362, p. 192(1995); NATURE MEDICINE, vol. 4, p. 722(1998)).
It is known that the effects mediated by NPY Y2 receptor include an inhibitory effect on the release of various neurotransmitters in the sympathetic nerve endings (BRITISH JOURNAL OF PHARMACOLOGY, vol. 102, p. 41(1991); SYNAPSE, vol. 2, p. 299(1988)). In periphery, NPY Y2causes constriction of blood vessel or vas deferens directly or via the control of release of various neurotransmitters (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 261, p. 863(1992); BRITISH JOURNAL OF PHARMACOLOGY, vol. 100, p. 190(1990)). Inhibition of lipolysis in adipose tissues is also known (ENDOCRINOLOGY, vol. 131, p. 1970(1992)). Further, inhibition of ion secretion in the gastro-intestinal tract is reported (BRITISH JOURNAL OF PHARMACOLOGY, vol. 101, p. 247(1990)). On the other hand, the effects on the central nervous system functions such as memory, anxiety and the like are also known (BRAIN RESEARCH, vol. 503, p. 73(1989); PEPTIDES, vol. 19, p. 359(1998)).
It is reported that NPY Y3 receptor exists mainly in brainstem and heart, and is related to the regulation of blood pressure and heart rate (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 258, p. 633(1991); PEPTIDES, vol. 11, p. 545(1990)). It is also known that NPY Y3 is involved in the control of catecholamine secretion in adrenal gland (THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 244, p. 468(1988); LIFE SCIENCE, vol. 50, p. PL7(1992)).
NPY Y4 receptor has high affinity for pancreatic polypeptide in particular. As for the pharmacological effects of NPY Y4, inhibition of pancreatic exocrine secretion and gastro-intestinal motility is reported (GASTROENTEROLOGY, vol. 85, p. 1411(1983)). Further, it is reported that NPY enhances the secretion of sexual hormones in the central nervous system (ENDOCRINOLOGY, vol. 140, p. 5171(1999)).
As for the effects mediated by NPY Y5 receptor, fat accumulation effects including orexigenic effect are prominent (NATURE, vol. 382, p. 168(1996); AMERICAN JOURNAL OF PHYSIOLOGY, vol. 277, p. R1428(1999)). It is also reported that the NPY Y5 receptor mediates some CNS effects, such as seizure and epilepsy, or pain and morphine withdrawal symptoms, and the control of circadian rhythm (NATURE MEDICINE, vol. 3, p. 761(1997); PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 96, p. 13518(1999); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 284, p. 633(1998); THE JOURNAL OF NEUROSCIENCE, vol. 21, p. 5367(2001). In addition, diuretic effect and hypoglicemic effect in the periphery are reported (BRITISH JOURNAL OF PHARMACOLOGY, vol. 120, p. 1335(1998); ENDOCRINOLOGY, vol. 139, p. 3018(1998)). NPY is also reported to enhance cardiac hypertrophy as a result of the sympathetic accentuation (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 97, p. 1595 (2000)).
The effects of NPY are expressed when NPY binds to the NPY receptors in the central or peripheral nervous system. Therefore, the action of NPY can be prevented by blocking its binding to NPY receptors. For this reason, it is expected that substances antagonize NPY binding to NPY receptors may be useful for the prophylaxis or treatment of various diseases related to NPY, for example cardiovascular disorders such as angina, acute or congestive heart failure, myocardial infarction, hypertension, nephropathy, electrolyte abnormality, vasospasm, etc., central nervous system disorders such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal, circadian rhythm disorders, schizophrenia, memory impairment, sleep disorders, cognitive impairment, etc., metabolic diseases such as obesity, diabetes, hormone abnormality, gout, fatty liver, etc., genital or reproductive disorders such as infertility, preterm labor, sexual dysfunction, etc., gastro-intestinal disorders, respiratory disorders, inflammatory diseases or glaucoma, and the like. (TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 15, p. 153(1994); LIFE SCIENCE, vol. 55, p. 551(1994); DRUGS, vol. 52, p. 371(1996); THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 101, p. S345(1998); NATURE, vol. 396, p. 366(1998); THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 284, p. 633(1998); TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 20, p. 104(1999); PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 97, p. 1595(2000); THE JOURNAL OF NEUROSCIENCE, vol. 21, p. 5367(2001); PHARMACOLOGY & THERAPEUTICS, vol. 65, p 397(1995); ENDOCRINOLOGY, vol. 140, p. 4046(1999); AMERICAN JOURNAL OF PHYSIOLOGY, vol. 280, p. R1061(2001); AMERICAN JOURNAL OF PHYSIOLOGY, vol. 278, p. R1627(2000); CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE, vol. 2, p. 425(1999); CURRENT RHEUMATOLOGY REPORTS, vol. 3, p. 101(2001), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 165, p. 1217(2002).
It was recently found that, as a result of the study by the present inventors, certain NPY receptor antagonists are useful for the prophylaxis or treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis (International application publication WO99/27965).
International application publication WO01/62738 discloses a variety of imidazoline derivatives, and mentions that the derivatives have excellent NPY receptor antagonistic actions and also show excellent pharmacokinetics such as transport into brain or transport to cerebrospinal fluid, etc. However, the said literature does not describe the compounds of the present invention.
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The invention relates to novel compositions and methods for enhancing permeation of topically administered drugs by incorporating therein pyroglutamic acid esters as dermal penetration enhancing agents.
Transdermal drug delivery to achieve systemic effect is an area of much current interest and activity. While the cutaneous route of input is advantageous in many respects such as ease of use, better patient compliance, decreased first pass metabolism etc. the excellent barrier nature of the skin has so ar limited the drugs considered suitable for transdermal delivery to very few. The use of adjunctive chemicals known as skin penetration enhancers widens the scope of transdermal drug delivery. Such use involves controlled impairment of the skin's protective layer, the stratum corneum. Ideally, no elements of the skin other than this horny layer should be involved in such a drug delivery approach, because participation of any living tissue could result in cellular insult and lead to an irritant or allergic response. So an ideal penetration enhancer is one which speeds the permeation of the drug through the stratum corneum, without itself crossing this barrier, or if it crosses, undergoes fast metabolic destruction and/or detoxification in the viable area of the skin. This invention deals with an analagous series of penetration enhancers of the latter type.
It is well known that a number of therapeutically active agents, such as .beta.-blockers, antihypertensives, antiarrhythmics, antianginal agents, vasodilators, antiemetics, antibacterials, antifungals, corticosteroids, antiinflammatories and the like when administered to warm-blooded animals by a number of various routes such as by intravenous infusion, intramuscular injection, oral, rectal or buccal routes, enter the general circulation and produce the appropriate systemic therapeutic effect. It is also known that the aforementioned methods of administration have certain disadvantages. For example, the intravenous and intramuscular routes are not only painful for the patient, but also must be performed by a trained individual. Buccal and rectal administration often produce discomfort and annoyances for the patient. Oral administration, although generally acceptable for the patient, often does not deliver much of the therapeutic agent to systemic circulation. This diminished drug delivery is usually attributed to poor absorption from the gastrointestinal tract and/or to degradation of the agent by the acidic medium of the stomach, by the enzymes in the gastrointestinal tract and surrounding tissue, or by the rapid metabolism by enzymes of the liver through which the drug must pass before it enters the systemic circulation. For example, drugs such as anti-bacterials, narcotic analgesics, .beta.-blockers and others require relatively high doses when given orally due to the remarkable liver metabolism encountered. Effective delivery of such drugs through the skin would require much lower doses because the so-called "first pass" metabolism would be avoided. Additionally, the topical application of the drug has the advantage that their pharmacological action is exhibited gradually over an extended period of time avoiding the possibility of inducing undesirable physiological action by abrupt increase in concentration in vivo.
But most drugs are not absorbed in sufficient concentration through the skin to exhibit pharmacological effect. This is because skin is an effective barrier to penetration. The outer layer of the epidermis, called the stratum corneum, offers the maximum resistance to penetration, whereas the lower-layers are relatively permeable. For proper treatment of dermal conditions, it is important that the active agent penetrate the stratum corneum where it is retained. From this reservoir in the outer layer, the therapeutic agent could be slowly released and penetrates the underlying areas where it could exhibit its therapeutic or cosmetic effect. When dermatological agents such as sunscreens, which protect the underlying tissue from external factors (ultraviolet rays) are used, maximum retention in the stratum corneum is essential. On the other hand, the relative permeability of the layers of the epidermis below the stratum corneum can also allow access to the systemic circulation; indeed, it is necessary for the therapeutic agent to penetrate the stratum corneum in order to provide systemic therapeutic effect from the transdermal route.
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1 Field of the Invention
This invention relates to DNA repair enzymes and, in particular, to 1) methods for purifying DNA repair enzymes, and 2) methods and means for administering DNA repair enzymes to living cells in situ, e.g. human skin cells, so that the enzymes can enter the cells and enhance the repair of damaged DNA in the cells.
2. Description of the Prior Art
Skin cancer is a serious human health problem. The incidence of non-melanoma skin cancer in the United States is 500,000 per year, and 23,000 per year for melanoma. Annual deaths are 2,000 and 6,000 respectively, and 800,000 deaths from skin cancer are predicted in the next 88 years if current trends continue.
The causal link between non-melanoma skin cancer and ultraviolet light exposure from the sun has been clearly established, and sun exposure is an important causative factor in melanoma. The target for ultraviolet light damage leading to cancer is widely accepted as DNA.
Xeroderma pigmentosum is a human genetic disease in which patients develop solar damage, pigmentation abnormalities and malignancies in sun-exposed skin. A review of the disease was authored by J. H. Robbins, K. H. Kraemer, M. A. Lutzner, B. W. Festoff and H. G. Coon, entitled "Xeroderma Pigmentosum: An Inherited Disease with Sun Sensitivity, Multiple Cutaneous Neoplasms, and Abnormal DNA Repair", and published in the ANNALS OF INTERNAL MEDICINE, volume 80, number 2, pages 221-248, February, 1974. The disease occurs in 1 of 250,000 worldwide. Cells from xeroderma pigmentosum patients are deficient in repair of ultraviolet damage to DNA, which results in a cancer incidence 4,800 times the frequency of the general U.S. population. There is no cure, and treatment consists of avoiding sun exposure and excising skin lesions. Death occurs 30 years earlier in these patients than among the general U.S. population.
Research into the basic mechanisms of DNA repair has established outlines of biochemical pathways which remove ultraviolet damage in DNA. Bacterial repair systems have been demonstrated to differ significantly from repair in human cells. However, the enzyme endonuclease V (also referred to herein as T4 endonuclease V and denV endonuclease V) has the ability to enhance DNA repair in human cells as evidenced by increased UV-specific incision of cellular DNA, increased DNA repair replication, and increased UV survival after treatment with the enzyme.
The endonuclease V enzyme is produced by the denV gene of the bacteriophage T4. It has been established that this enzyme catalyzes the rate limiting, first step in the removal of UV-induced DNA damage, namely, single strand incision of DNA at the site of damage. In particular, the enzyme exhibits glycosylase and apurinic/apyrimidinic endonuclease activities and acts at the site of ultraviolet induced pyrimidine dimers. See "Evidence that the UV Endonuclease Activity Induced by Bacteriophage T4 Contains Both Pyrimidine Dimer-DNA Glycosylase and Apyrimidinic/Apurinic Endonuclease Activities in the Enzyme Molecule" by H. R. Warner, L. M. Christensen and M. L. Persson, in JOURNAL OF VIROLOGY, 1981, Vol. 40, pages 204-210: "denV Gene of Bacteriophage T4 Codes for Both Pyrimidine Dimer DNA Glycosylase and Apyrimidinic Endonuclease Activities" by S. McMillan, H. J. Edenberg, E. H. Radany, R. C. Friedberg and E. C. Friedberg, in JOURNAL OF VIROLOGY, 1981, Vol. 40, pages 211-223, and "Physical Association of Pyrimidine Dimer DNA Glycosylase and Apurinic/Apyrimidinic DNA Endonuclease Essential for Repair of Ultraviolet-damaged DNA" by Y. Nakabeppu and M. Sekiguchi, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, 1981, Vol. 78, pages 2742-2746.
Other enzyme having the ability to repair DNA damage have also been identified. These enzymes include O.sup.6 -methylguanine-DNA methyltransferases, photolyases, uracil- and hypoxanthine-DNA glycosylases, apyrimidinic/apurinic endonucleases, DNA exonucleases, damaged-bases glycosylases (e.g., 3-methyladenine-DNA glycosylase), correndonucleases alone or in complexes (e.g., E. coli uvrA/uvrB/uvrC endonuclease complex), and other enzymes and enzyme complexes whose activities at present are only partially understood, such as, the products of the ERCC genes of humans and the RAD genes of yeast. Various of these enzymes have been purified to homogeneity from microorganisms, and the genes for some of the enzymes have been cloned. As used herein, the term "DNA repair enzymes is intended to include the foregoing enzymes, the T4 endonuclease V enzyme, and other enzymes now known or subsequently discovered or developed which have the ability to participate in repair of damaged nucleic acids and, in particular, damaged DNA.
To date, the use of exogenous enzymes in DNA repair systems has been limited to laboratory experiments designed to study the biochemical and evolutionary relationships among DNA repair pathways. Clinical application of these laboratory results has not been undertaken because, inter alia, there has been no effective way of purifying commercial quantities of DNA repair enzymes, and there has been no effective, non-toxic way of administering DNA repair enzymes to living cells. The present invention addresses both of these long-standing problems in the art.
Purification of DNA enzymes for commercial use requires a homogenous final product, high yield, speed, simplicity and low cost. The existing methods of the art have been unable to meet these goals, as follows:
(1) P. Seawell, E. C. Friedberg, A. K. Ganesan and P. C. Hanawalt, "Purification of Endonuclease V of Bacteriophage T4" in DNA REPAIR: A LABORATORY MANUAL OF RESEARCH PROCEDURES, edited by E. C. Friedberg and P. C. Hanawalt, Marcel Dekker, Inc., N.Y., 1981, Volume 1, Part A, pages 229-236.
This method uses phage T4 infected E. coli, and purification relies on phase-separation and two ion-exchange chromatography steps (DEAE- and phospho-cellulose). The DEAE chromatography step limits the yield of the method because all proteins must bind in order to elute the enzyme of interest. The method is not rapid: each chromatography step is preceded by dialysis, each elution requires at least 20 hours, and each fraction is assayed for activity. The process is neither simple nor inexpensive: tedious phase separation and repetitive assays are performed, and all spent dialysate and separated phases are discarded. Significantly, the authors of this method describe their final product as being only partially purified.
The basic steps of the Seawell et al. method were first described by E. C. Friedberg and J. J. King in "Dark Repair of Ultraviolet-irradiated Deoxyribonucleic acid by Bacteriophage T4: Purification and Characterization of a Dimer-Specific Phage-Induced Endonuclease", JOURNAL OF BACTERIOLOGY, 1971, Vol. 106, pages 500-507. This earlier version of the method included an additional DNA-cellulose step, which was omitted in the later version. A method similar to the Friedberg and King method was described by S. Yasuda and M. Sekiguchi, "T4 Endonuclease Involved in Repair of DNA" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, Dec., 1970, Vol. 67, pages 1839-1845. Instead of using a DNA-cellulose step as in the Friedberg and King method, the Yasuda and Sekiguchi method included an optional gel filtration step.
(2) Y. Nakabeppu, K. Yamashita and M. Sekiguchi, "Purification and Characterization of Normal and Mutant Forms of T4 Endonuclease V" JOURNAL OF BIOLOGICAL CHEMISTRY, 1982, Vol. 257, pages 2556-2562.
The basic steps of this method were first described by S. Yasuda and M. Sekiguchi, "Further Purification and Characterization of T4 Endonuclease V", BIOCHIMICIA ET BIOPHYSICA ACTA, 1976, Vol. 442, pages 197-207. These methods are similar to the Seawell et al. method, except that they substitute cation exchange (carboxymethyl Sephadex) chromatography for anion exchange (DEAE) chromatography, and add additional chromatography steps including either hydroxylapatite or gel filtration and UV DNA cellulose (the Yasuda and Sekiguchi method also differs from the Seawell et al. method in that it does not include a phosphocellulose step). These methods have the same difficulties as the Seawell et al. method with the additional problems of lower yield, less speed and simplicity, and greater cost.
(3) K. M. Higgins and R. S. Lloyd, "Purification of the T4 Endonuclease V", MUTATION RESEARCH, 1987, Vol. 183, pages 117-121.
This method uses an E. coli strain which harbors a plasmid containing the phage T4 denV structural gene under the control of the phage lambda rightward promoter. The chromatography steps are single-stranded DNA agarose, chromatofocusing and cation exchange (carboxymethyl-Sephadex). The yield is low compared to the present invention, in that 12 liters of bacteria are required for 15 mg pure enzyme. The yield is also limited by the requirement that all proteins bind to the chromatofocusing column in order to elute the desired enzyme. The method is not rapid: each chromatography step is preceded by dialysis and concentration by ultrafiltration; at least two of the steps require on the order of 17.5 hours for elution; and each step is followed both by enzyme activity assays and polyacrylamide gel analysis of each fraction. The method is not simple: the single-stranded DNA agarose chromatography requires pooling of 84% of the collected fraction (520 ml of 700 ml eluent), extensively diluting the loaded protein; experiments in connection with the present invention showed that the chromatofocusing step was not reproducible using DEAE agarose and Servalyte ampholines; ultrafiltration is required in addition to dialysis; and tedious, repetitive activity assays and gel analysis are performed after each step. The method is expensive: large ultrafiltration devices are used and discarded at every step; the single-stranded DNA agarose is exposed to crude bacterial lysates with active nucleases which drastically reduce the useful life of the column; and costly chromatofocusing reagents including Pharmacia PBE 94 gel and polybuffer ampholines must be used.
In addition to the foregoing, two methods have been published for the purification of O.sup.6 -methylguanine-DNA methyltransferase. See B. Demple, A. Jacobsson, M. Olsson, P. Robbins and T. Lindahl, "Repair of Alkylated DNA in Escherichia coli: Physical properties of O.sup.6 -methylguanine-DNA methyltransferase" in THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 257, pages 13776-13780, 1982, and Y. Nakabeppu, H. Kondo, S. Kawabata, S. Iwanaga and M. Sekiguchi, "Purification and Structure of the Intact Ada Regulatory Protein of Escherichia coli K12 O.sup.6 -Methylguanine-DNA Methyltransferase" in THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 260, pages 7281-7288, 1986. The Demple method uses phosphocellulose chromatography before DNA-cellulose and gel filtration, and includes a final phenylagarose chromatography step. The Nakabeppu method uses two rounds of ion-exchange (DEAE-) chromatography followed by phosphocellulose and gel filtration chromatography.
A general review of purification methods for DNA repair enzymes can be found in DNA REPAIR: A LABORATORY MANUAL OF RESEARCH PROCEDURES, edited by E. Friedberg and P. C. Hanawalt, published by Marcel Dekker, N.Y. Volume I, part A, of this text contains methods for purifying five enzymes: photolyase, endonuclease V (discussed above), AP endonuclease, uracil-DNA glycosylase and hypoxanthine-DNA glycosylase, in chapters 18-22, respectively. Volume II, chapters 3-5, discuss the Demple method referred to above and methods for purifying 3-methyladenine-DNA glycosylases. Volume III, Section IV, contains methods for purification of photolyase, the uvrABC excision nuclease and the uvrD helicase in chapters 23-25. None of these methods, nor the two methods discussed above for purifying O.sup.6 -methylguanine-DNA methyltransferase, use the purification procedures of the present invention.
Various approaches have been considered in the field of DNA repair for delivering DNA repair enzymes to mammalian cells. The goal of these efforts has been to discover and characterize the pathways of DNA repair in mammalian cells and their evolution, not to develop commercial methods for augmenting DNA repair. Thus, researchers have not used normal cells, such as skin epidermal keratinocyte cells, as target cells, but rather have concentrated on fibroblasts from patients with xeroderma pigmentosum. Similarly, prior research has focused on non-physiological techniques for introducing DNA repair enzymes into cells which are useful only in the laboratory and which compromise the physiology of the target cells. The published reports regarding this work include:
(1) K. Tanaka, M. Sekiguchi and Y. Okada, "Restoration of ultraviolet-induced unscheduled DNA synthesis of xeroderma pigmentosum cells by the concomitant treatment with bacteriophage T4 endonuclease V and HVJ (Sendai virus)", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., 1975, Vol. 72, pages 4071-4075; and K. Tanaka, H. Hayakawa, M. Sekiguchi and Y. Okada, "Specific action of T4 endonuclease V on damaged DNA in xeroderma pigmentosum cells in vivo", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., 1977, Vol. 74, pages 2958-2962.
In these two reports, fibroblasts derived from patients with xeroderma pigmentosum were treated with inactivated Sendai virus and endonuclease V after UV irradiation. Proteins on the coat of the Sendai virus rendered the cells permeable to endonuclease V. This treatment enhanced DNA repair replication and increased survival of the treated cells. This method of introducing the enzyme is not practical for commercial application because of the pathogenicity of the Sendai virus. Large external enzyme concentrations are also required. In its discussion section, the Tanaka et al. reference discusses approaches to the study of the evolution of macromolecular (i.e. DNA repair) systems in organisms and mentions liposome methods and erythrocyte ghost/HVJ methods as other methods for introducing macromolecules into cells. Significantly, Tanaka et al. ultimately conclude that the Sendai virus method is the most simple and applicable method in basic research for the introduction of rather small macromolecules of about 20,000 daltons, i.e., the T4 endonuclease V molecule.
(2) G. Ciarrocchi and S. Linn, "A cell-free assay measuring repair DNA synthesis in human fibroblasts", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., 1978, Vol. 75, pages 1887-1891.
In this report, human normal and xeroderma pigmentosum fibroblasts were disrupted by osmotic shock after UV irradiation, and incubated with endonuclease V. DNA repair synthesis was increased in both types of cells, and repair in xeroderma pigmentosum cells increased to the level of normal cells. This method for introducing enzyme into cells was only employed for in vitro research, as it destroys the integrity of the cell membrane and viability is drastically affected. Large external enzyme concentrations are also required.
(3) D. Yarosh and R. Setlow, "Permeabilization of Ultraviolet-irradiated Chinese hamster cells with polyethylene glycol and introduction of ultraviolet endonuclease from Micrococcus luteus", MOLECULAR AND CELLULAR BIOLOGY, 1981, Volume 1, pages 237-244.
In this method, hamster cells were treated with polyethylene glycol after UV irradiation and then incubated with a DNA repair enzyme which acts similarly to endonuclease V. The enzyme entered the cells and acted on resident DNA. The method was toxic to target cells, probably because it relied on permeabilization, and vital molecules exited as the enzyme entered. This method also requires large external enzyme concentrations for efficacy.
(4) J. H. J. Hoeijmakers, "Characterization of genes and proteins involved in excision repair of human cells", JOURNAL OF CELL SCIENCE SUPPL., 1987, Vol. 6, pages 111-125.
This reference summarizes a body of research in which proteins were introduced into the nuclei of cells by microinjection. When endonuclease V was injected into the nuclei of xeroderma pigmentosum cells, DNA repair synthesis was increased. This method is applicable only for laboratory research.
(5) K. Valerie, A. P. Green, J. K. de Riel and E. E. Henderson, "Transient and stable complementation of ultraviolet repair in xeroderma pigmentosum cells by the denV gene of bacteriophage T4", CANCER RESEARCH, 1987, Vol. 47, pages 2967-2971.
In this method, the denV gene under the control of a mammalian promoter was transfected into xeroderma pigmentosum cells. Clones selected for uptake of the denV gene showed increased incision of UV-DNA, enhanced DNA repair synthesis and increased resistance to ultraviolet irradiation. The transfection process is very inefficient (less than one success per million cells) for normal human cells. These methods fall into the category of gene therapy, and are beyond the scope of the current art for commercial use.
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