text:
|Publication number
|Publication type
|Application number
|Publication date
|Nov 2, 2004
|Filing date
|Dec 4, 2000
|Priority date
|Dec 4, 2000
|Fee status
|Also published as
|Publication number
|Marc Hendriks
|Original Assignee
|Medtronic, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (19), Non-Patent Citations (20), Referenced by (14), Classifications (34), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention relates to medical devices (e.g., implantable pulse generators) that include a polymer and a polynucleotide. Preferably, the medical device can be used to prevent or treat medical device-associated infections. In some aspects of the present invention, the medical devices carry a polynucleotide that encodes an antimicrobial peptide and inhibits the growth of pathogens. In other aspects of the present invention, the medical devices carry eukaryotic cells (e.g., endothelial cells) that express an antimicrobial peptide and inhibit the growth of pathogens.
The insertion of implants has become a widely accepted and often life-saving procedure. The past few years have seen a dramatic increase in the variety and numbers of medical devices. It is estimated that currently world-wide there are some 6,000 distinct types or generic groups of medical devices, and some 750,000 or more brands and models, ranging from very simple devices to very complex systems. A study in 1989 estimated that world-wide approximately 1,000,000 implants are performed annually; the number of additionally used catheters for diagnostic and therapeutic means exceeds this number considerably.
Infection is the most feared, if not the most serious complication of the numerous devices and materials inserted. Treatment of such infections is difficult and most often infection is irreversible, requiring in many cases complete removal of the catheter or implant. Technological refinements in materials and design and increasing surgical experience generally lowers the incidence of infectious complications; however, infection remains a constant cause of morbidity and mortality.
The impact and clinical importance of implant-related infections may be more appreciated considering several factors. One important factor is the millions of patients in whom prostheses of one sort or another are present. Another important factor is the severity of illness that results from device-related infections. In most instances, infection involving a totally implanted device results in function-loss and the need for surgical removal in order to achieve a cure. Depending on the device type, e.g., with prosthetic heart valves or vascular grafts, mortality is high following infection. A third factor is the economic consequences that are measured in the costs of making the diagnosis and in treating a device-related infection. It is estimated that the costs of treating an infected joint prosthesis exceed four- to sixfold the costs of the original prosthetic joint replacement.
Approaches to reduce device-related infections initially were focused on improvements of the surgical technique, including modification of the operating room area and the use of prophylactic antibiotics at the time of surgery. Despite the introduction of these meticulous aseptic measures the occurrence of device-related infections could not be completely eliminated.
An alternative approach is to focus on the implant itself, and consequently on modification of the device to enhance infection-resistance by providing surfaces on the device that promote appropriate integration of the surrounding tissue(s) with the device surface. The underlying concept is that encouraging rapid colonization and integration of the device surface with tissue cells protects the implant surface from bacterial colonization.
A considerable amount of attention and study has been directed toward preventing colonization of bacterial and fungal organisms on the surfaces of orthopedic implants by the use of antimicrobial agents, such as antibiotics, bound to the surface of the materials employed in such devices. The objective of such attempts has been to produce a sufficient bacteriostatic or bactericidal action to prevent colonization. Practice of the prior art coating methods results in an orthopedic implant or medical device wherein the effectiveness of the coating can diminish over time. After insertion of the medical device or orthopedic implant, the antibiotics can leach from the surface of the device into the surrounding environment. Moreover, bacterial pathogens have become increasingly resistant to commonly used antibiotics. In some cases, there are no remaining first-line options for therapy. A recently published trend analysis on bacterial pathogens isolated from blood in England and Wales from 1990 to 1998 showed an upward trend in total numbers of reports of bacteraemia. The five most cited organisms accounted for over 60% of reports each year. There was a substantial increase in the proportion of reports of Staphylococcus aureus resistant to methicillin, Streptococcus pneumoniae resistance to penicillin and erythromycin, and Enterococcus faecalis and Enterococcus faecium resistance to vancomycin.
Antimicrobial peptides are a type of antibiotic. The first antimicrobial peptides were identified in 1939 by Dubos who demonstrated that 'an unidentified soil bacillus' produced antibacterial compounds that could prevent pneumococcal infections in mice (Boman et al., "Antimicrobial Peptides," Ciba Foundation Symposium, John Wiley and Sons, Chicester (1994)). In the 1960s, a bee venom toxin and a peptide in frog skin were claimed to be antibacterial. Since then, antimicrobial peptides have been isolated from insects (cecropins from the moth Hyalophora cecropia and Drosophila melanogaster, insect defensins from the fleshflies Phormia terranovae and Sacrophaga peregrina), from the skin of the African clawed frog Xenopus laevis (magainins), from the horse shoe crab (tachyplesins), and mammalian granulocytes (defensins), macrophages (murine microbicidal proteins), and platelets (thrombocidins). Their widespread distribution is remarkable and makes it highly likely that these components play an important protective role as a first line of defense against infections. Although antimicrobial peptides vary considerably in length, almost all of them are of cationic nature.
In humans, numerous antimicrobial peptides have been isolated and characterized from multiple sources, including neutrophils (also referred to in the art as polymorphonuclear leukocytes), T cells, bronchoalveolar lavage, platelets, plasma, wound fluid, and various organs. Furthermore, over the past few years a range of antimicrobial peptides have been found in epithelial tissue of airways, urogenital tissue, skin, and intestine. These findings suggest that host defense by means of antimicrobial peptides might be more general than ever was assumed initially.
Antimicrobial peptides are able to kill a wide variety of gram-positive and gram-negative bacteria. At least three sequential events are required for target cell lysis: membrane binding; permeabilization; and finally damaging of DNA. It is believed that after binding to the cell membrane, the antimicrobial peptides form voltage-dependent channels in the lipid bilayers of the cell membrane. The amphiphatic nature of antimicrobial peptides makes them soluble in aqueous media and promotes their ability to insert in membranes. The net positive charge on antimicrobial peptides favors interactions with negatively charged lipid head groups, and provides an initial driving force for insertion of an antimicrobial peptide into a membrane. Moreover, this mechanism of action is one which bacteria have difficulty evading by developing resistance.
Documents cited herein.
U.S. Patents:
U.S. Pat. No.
Issue Date
Labbe et al.
Jul. 31, 1990
Bally et al.
Dec. 31, 1991
Mulligan et al.
Oct. 7, 1997
Mar. 2, 1999
Sankaram et al.
Nov. 30, 1999
International Patent Applications:
Application No.
Smela et al.
Smela et al.
Other documents:
Ausubel, R.M., ed. Current Protocols in Molecular Biology (1994)
Boman et al., "Antimicrobial Peptides," Ciba Foundation Symposium,
John Wiley and Sons, Chicester (1994)
Dichek et al., Mol. Biol. Med., 8 257-266 (1991)
Genbank Accession Nos:
Krijgsveld et al., J. Biol. Chem., 275, 20374-20381 (2000)
Sambrook et al, Molecular Cloning: A Laboratory Manual., Cold Spring Harbor Laboratory Press (1989)
Smela et al. Science, 268, 1735-1738 (1995)
Turner et al., Antimicrob. Agents Chemother., 42, 2206-2214 (1998)
All documents listed in Table 1 hereinabove are hereby incorporated by reference herein in their respective entireties. As those of ordinary skill in the art will appreciate readily upon reading the Summary of the Invention, Detailed Description of the Preferred Embodiments, and claims set forth below, many of the devices and methods disclosed in the documents of Table 1 may be modified advantageously by using the teachings of the present invention.
The present invention has certain objects. That is, various embodiments of the present invention provide solutions to one or more problems existing in the prior art with respect to preventing infections associated with implantable medical devices. Those problems include the continued prevalence of infections associated with medical devices, and the ineffectiveness of traditional antibiotics to prevent infection by resistant strains of microorganisms. Various embodiments of the present invention have the object of solving at least one of the foregoing problems.
In comparison with known medical devices, various embodiments of the present invention provide one or more of the following advantages: (a) inhibiting the growth of pathogenic microorganisms by exposure of the microorganisms to antimicrobial peptides; (b) providing a polynucleotide encoding an antimicrobial peptide to a cell present in a patient such that the cell expresses the antimicrobial peptide; (c) providing a cell that expresses an antimicrobial peptide; and (d) making an antimicrobial peptide available at the site of implantation of a medical device and thereby decreasing the likelihood of a medical device associated infection.
Some embodiments of the invention include one or more of the following features: (a) a carrier having a surface that includes a polymer and a polynucleotide associated with at least a portion of the polymer, where the polynucleotide is not present in a cell; and (b) a carrier having a surface that includes a polymer and a cell associated with at least a portion of the polymer, where the cell expresses an antimicrobial peptide.
The terms "medical device," "carrier," and "implantable pulse generator" are described in greater detail herein.
As used herein, the term "porous polymer" refers to a polymer that has pores distributed throughout, and is capable of absorbing liquids.
As used herein, the term "polynucleotide" refers to a polymeric form of nucleotides of any length, either ribonucleotides or deoxynucleotides, and includes both double- and single-stranded DNA and RNA. A polynucleotide may include nucleotide sequences having different functions, including for instance coding sequences, and non-coding sequences such as regulatory sequences. A polynucleotide can be obtained directly from a natural source, or can be prepared with the aid of recombinant, enzymatic, or chemical techniques. A polynucleotide can be linear or circular in topology. An "introduced polynucleotide" is a polynucleotide that has been introduced to a cell, for instance by ex vivo gene transfer. A polynucleotide can be, for example, a portion of a vector, such as an expression vector, or a fragment.
The phrase "not present in a cell" means the polynucleotide is not present in a eukaryotic or a prokaryotic cell, and is not present in a viral particle.
As used herein, the phrase "associated with" in the context of polynucleotides or cells refers to how they are combined with a carrier polymer. The polynucleotides or cells can be, for instance, incorporated into a polymeric coating or film on the carrier, coated on top of a polymeric coating or film on the carrier, or present under a polymeric coating or film on the carrier. The polynucleotides or cells can also be incorporated into microscopic containment vehicles which are incorporated into a polymeric coating or film on the carrier, coated on top of a polymeric coating or film on the carrier, or present under a polymeric coating or film on the carrier.
As used herein, the term "film" refers to a sheet material.
As used herein, the phrase "natural porous polymer" refers to a polymer that is present in or produced by nature, i.e., it is not artificial or man-made.
As used herein, the phrase "synthetic porous polymer" refers to a polymer that is artificial or man-made, i.e., it is not present in or produced by nature.
"Coding region" and "coding sequence" are used interchangeably and refer to a nucleotide region that encodes a polypeptide and, when placed under the control of appropriate regulatory sequences expresses the encoded polypeptide. The boundaries of a coding region are generally determined by a translation start codon at its 5′ end and a translation stop codon at its 3′ end. A regulatory sequence is a nucleotide sequence that regulates expression of a coding region to which it is operably linked. Nonlimiting examples of regulatory sequences include promoters, transcription initiation sites, translation start sites, translation stop sites, and terminators. "Operably linked" refers to a juxtaposition wherein the components so described are in a relationship permitting them to function in their intended manner. A regulatory sequence is "operably linked" to a coding region when it is joined in such a way that expression of the coding region is achieved under conditions compatible with the regulatory sequence.
"Peptide" and "polypeptide" are used interchangeably herein to refer to a polymer of amino acids and does not refer to a specific length of a polymer of amino acids. Thus, for example, the terms oligopeptide, protein, and enzyme are included within the definition of peptide. This term also includes post-expression modifications of the peptide, for example, glycosylations, acetylations, phosphorylations, and the like. The term "antimicrobial peptide" is described in detail herein.
The term "condensed" as used herein describes a polynucleotide that has been compacted to isolated spheres or toroids so that the interaction of the DNA with the solvent is minimal.
As used herein, the phrase "linked to a receptor ligand" refers to attachment of a receptor ligand to the surface of an encapsulated or condensed polynucleotide. The attachment can be by a covalent bond, hydrogen bonding, or Van der Waals forces.
Unless otherwise specified, "a," "an," "the," and "at least one" are used interchangeably throughout the specification and mean one or more than one.
FIG. 1 shows an implantable pulse generator (IPG) 12 implanted in a patient 10.
Medical Devices
The present invention provides medical devices that include a polymer and a polynucleotide associated with the polymer. The polynucleotide is not present in a cell. Preferably, the medical devices are useful for the prevention or treatment of medical device-associated infections. In some aspects of the invention, the medical devices include a carrier and a polynucleotide. Preferably, the polynucleotide includes a coding region that encodes an antimicrobial peptide. In other aspects, the medical devices include a carrier and a cell that expresses an antimicrobial peptide.
A variety of carriers can be used in the medical devices of the present invention, including, for example, stents, vascular grafts, stent grafts, synthetic patches, infusion sleeves, medical electrical leads and electrodes, indwelling catheters, heart valves, annuloplasty rings, ear tubes, cerebrospinal fluid shunts, implantable drug pumps, and implantable pulse generators (IPGs) and the electrical leads associated with IPGs. Examples of IPGs include pacemakers, implantable cardioverter defibrillators, implantable defibrillators, and neurostimulators. Any of these devices can be used as carriers for the polynucleotides or cells of the invention. The following description focuses on IPGs, although it applies equally to other medical devices.
FIG. 1 shows a preferred aspect of the invention where the IPG 12 is inserted into a pocket that is formed in the patient 10, for instance in the left pectoralis major area, a traditional pacemaker implant site. The IPG has a surface that contacts the tissue that makes up the wall of the pocket into which the IPG has been implanted. The IPG can be coated with a natural or synthetic polymeric coating or film for holding the polynucleotides or cells in place. Polymeric coatings and films are described in greater detail herein.
Whether the carrier is an IPG or other medical device, the polynucleotides or cells are associated with the carrier polymer. The medical devices of this invention preferably include a first polymer composition in which the polynucleotides or cells are present. The first polymer composition of this invention can be prepared from a homopolymer, a copolymer (i.e., a polymer of two or more different monomers), or a composition (e.g., a blend) with one or more polymers or copolymers, for example. The composition preferably forms a viscoelastic, tear-resistant, biocompatible polymer. The term "viscoelastic" refers to the prescribed "memory" characteristics of a molecule that allow the molecule to respond to stress as if the molecule was a combination of elastic solids and viscous fluids. The term "tear resistent" indicates that when the polymer is exposed to expansion stress, the material does not substantially tear. Tearing refers to the propagation of a nick or cut in the material while under stress. The term "biocompatible" is used herein to refer to a material that does not have toxic or injurious effects on biological systems.
Preferably, the first polymer composition decreases or does not exacerbate irritation to the tissue surrounding the pocket into which the IPG is inserted. The first polymer composition is preferably non-inflammatory and nonthrombogenic when applied alone or alternatively when used with anti-thrombogenic agents such as heparin, and the like, or with anti-inflammatory agents such as cyclosporins, and the like. The first polymer composition is also preferably a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability.
The first polymer compositions of this invention can include one or more synthetic or natural polymers. Suitable polymers include those that are compatible with the polynucleotides or the cells. Preferably, the first polymer is a porous polymer. In one aspect of the invention, the porous polymer is a film on at least a portion of the structure. In another aspect, the porous polymer is an integral portion of the structure. Preferably, the porous polymer is biocompatible, and sufficiently tear-resistant, non-inflammatory, and nonthrombogenic. Preferably, the porous polymer is biodegradable.
Preferably, the porous polymer is a natural porous polymer or a synthetic porous polymer. Examples of natural porous polymers include gelatin, fibrin, collagen, elastin, hyaluronic acid, chondroitin sulfate, dermatan sulfate, heparin sulfate, heparin, cellulose, chitin, chitosan, mixtures or copolymers thereof, or a wide variety of others typically disclosed as being useful in implantable medical devices. Examples of synthetic porous polymers include silicone, polyurethane, polysulfone, polyethylene, polypropylene, polyamide, polyester, polycarboxylic acids, polyvinylpyrrolidone (PVP), maleic anhydride polymers, polyamides, polyvinyl alcohols (PVA), polyethylene oxides, polyacrylic acid polymers, polytetrafluoroethylene, polyhydroxyethylmethacrylic acid (pHEMA), polyaminopropylmethacrylamide (pAPMA), polyacrylamido-2-methylpropanesulfonic acid (pAMPS), polyacrylamide, polyacrylic acid, mixtures or copolymers thereof, or a wide variety of others typically disclosed as being useful in implantable medical devices. Additional examples of synthetic porous polymers include biodegradable synthetic porous polymers, such as polyglycolic acid, polylactic acid, polydiaxonone, poly(,-caprolactone), polyanhydrides, poly(∃-hydroxybutyrate), poly(ortho esters), poly(amino acids), polyiminocarbonates, and mixtures or copolymers thereof. In materials which do not include pores in their usual structural configurations, pores between one micrometer in diameter or as large as 1000 micrometers in diameter can be introduced by conventional means such as by introducing a solvent soluble particulate material into the desired structure and dissolving the particulate material with a solvent. However, no particular pore size is critical to this invention. Those skilled in the art will recognize that the methods for forming the first polymer composition can be modified to include other polymers, as contemplated in this invention, without undue experimentation.
In one aspect of the present invention, the porous polymer is made of a polymer other than fibrin and has fibrin incorporated within the pores. Typically, and preferably, such a porous polymer is in the form of a sheet material of a synthetic polymer that is biostable. Such synthetic biostable polymers include silicone, polyurethane, polysulfone, cellulose, polyethylene, polypropylene, polyamide, polyester, polytetrafluoroethylene, and combinations thereof.
If the porous polymer is in the form of a porous sheet or film, it can be made by a variety of methods. These methods can include, for example, forming the films using a solid particulate material that can be substantially removed after the film is formed, thereby forming pores. By using a solid particulate material during film formation, the size of the pores can, to some extent, be controlled by the size of the solid particulate material being used. The particulate material can range from less than about 1 micrometer in diameter to about 1000 micrometers, preferably about 1 micrometer to about 100 micrometers, more preferably about 25 micrometers to about 60 micrometers. For uniformity of pores, the particulate material can be screened through successively finer mesh sieves, e.g., through 100, 170, 270, 325, 400, and 500 mesh analytical grade stainless steel mesh sieves, to produce a desired range of particle sizes.
In one method according to the present invention, a porous polyurethane sheet material can be made by dissolving a polyether urethane in an organic solvent such as N-methyl-2-pyrrolidone; mixing into the resulting polyurethane solution a crystalline, particulate material like a salt or sugar that is not soluble in the solvent; casting the solution with particulate material into a thin film; and then applying a second solvent, such as water, to dissolve and remove the particulate material, thereby leaving a porous sheet. A portion of the particulate material may remain within the film. As a result, it is preferred that the solid particulate material be biocompatible.
Drugs, for instance, but not limited to anticoagulants, such as heparin, warfarin, aspirin, hirudin, and tissue plasminogen activator, or anti-inflammatory agents, such as dexamethasone, beclamethasone, cyclosporin, and superoxide dismutase, can be incorporated into the IPG prior to implantation in an amount effective to prevent or limit thrombosis or inflammation. A drug immersion procedure can be used to incorporate the drug. A solution of the drug can alternatively be added at the time that polynucleotides or the cells are added to the IPG. The drug can also be incorporated into the polymer matrix before it has completely polymerized. For example, powdered drug can be dusted onto the IPG during the polymerization process.
The shape of the polymer film or coating can be modified based on the methods used to cover the IPG. It can be spray coated onto the IPG or a film can be molded over the IPG. The first polymer composition of this invention can cover at least a portion of the IPG.
The IPG can also be positioned within a mold and the compounds forming the first polymer composition incorporated into the mold. The first polymer composition forming a sheet or sleeve can be prepared in an extended shape and then compressed or dehydrated into a final shape to fit over the IPG.
Polynucleotides or cells can be added to the IPG by mixing the monomer solution of the first polymer composition with polynucleotides or cells or by directly applying the polynucleotides or cells to the polymerized composition. In one aspect, polynucleotides or cells are added to the IPG at the time of formation of the first polymer composition.
Alternatively, the polynucleotides or cells can be added to the polymer coated IPG either at the time of device manufacture, or by the physician prior to device implantation. Where the first polymer composition is capable of dehydration and rehydration, the IPG can be supplied in a sterile, dehydrated form and polynucleotides or cells can be added to the IPG by rehydration of the first polymer composition positioned on the IPG by immersing, wicking, or spraying a liquid containing the polynucleotides or cells onto the IPG prior to IPG implantation. An example of such a liquid for addition of polynucleotides is, for instance, 10 mM Tris-HCl and 1 mM EDTA, about pH 7.4 to about pH 8.0 (TE buffer), and the like. An example of such a liquid for addition of cells is, for instance, a balanced salt solution, including HBSS or a tissue culture media, and the like. The liquid used to deliver polynucleotides or cells to the first polymer coating should support the stability of the polynucleotides or cells and should include pH buffered solutions, in a form that is biocompatible and preferably nonimmunogenic. Optionally, the liquid can include stabilizers such as albumin, glycerol, or the like. Optionally, the polynucleotides can be present in association with compounds that aid delivery of the polynucleotide to a cell. Such compounds include liposomes and condensing agents, and are described in detail herein. Where the polynucleotides or cells are incorporated into a polymer solution for spray application or air pump applications, the polymer should be of sufficiently low viscosity to facilitate the application of the solution to the IPG.
In another aspect of the IPGs of this invention, a second polymer composition can be added over the first polymer composition following, or at the time of, adding the polynucleotides or cells. Preferably, the second polymer composition is biodegradable and the second polymer composition coats at least a portion of the first polymer composition and polynucleotides. For example, after the polynucleotides or cells are added to an IPG having a first polymer composition coated thereon, the IPG can be sprayed with or immersed in a solution to form a coating of a biodegradable polymer such as collagen, gelatin, polylactic acid, or methylcellulose, with or without a coagulation inhibitory or anti-inflammatory compound. Advantageously, the second covering of polymer provides even greater sustained release capabilities. Suitable polymers for use in the second polymer composition include, but are not limited to, those listed above for the first polymer composition, and combinations thereof, or a wide variety of others typically disclosed as being useful in IPGs.
The polynucleotides or cells can also be included within a microscopic containment vehicle that can be stimulated to release the polynucleotides or the antimicrobial peptides expressed by the cells. This microscopic containment vehicle can be coated onto the delivery device directly or into or onto a polymer coating or film. The polynucleotides or cells are enclosed within such a vehicle. Upon stimulation of the containment vehicle, the polynucleotides or the antimicrobial peptides expressed by the cells are released from the containment vehicle. Stimulation of the containment vehicles can be accomplished using a variety of techniques known to the art.
Examples of microscopic containment vehicles include, but are not limited to, those described in International Patent Application Nos. WO 96/28841 (Ohman) and WO 96/34417 (Smela et al.) and Smela et al., Science, 268, 1735-1738 (1995), which disclose micromachined structures and microactuators. In one example, such micromachined structures include conducting bilayers made of a layer of polymer and a layer of gold that are used as hinges to connect rigid plates to each other and to a silicon substrate. The bending of the hinges is electrically controlled and reversible, allowing precise three-dimensional positioning of the plates. The use of differential adhesion allows the structures to be released from the silicon substrate. Thus, complex shapes can be formed, such as cubes, of micrometer size that could be used to contain polynucleotides or cells in association with a medical device such as an IPG, until they are needed for therapeutic or preventative treatment.
Microscopic containment vehicles can also include micropumps, reservoirs, with piezoelectric valves. The body of the pump and reservoir can be made of a polymeric material while the valves contain a piezoelectric material, which allows opening and closing of the valves and pumping movement by electrical stimulation. The reservoirs contain the polynucleotides or cells. Upon stimulation of the piezoelectric material, the valve is opened to release the polynucleotides or the antimicrobial peptides expressed by the cells. Implantable piezoelectric pumps are known (see, for example, U.S. Pat. No. 4,944,659 (Labbe et al.)) and can be modified by one of skill in the art to form containment vehicles for the present invention.
In another aspect, the present invention also provides methods for local delivery to a patient of a polynucleotide or local delivery to a patient of a cell encoding an antimicrobial peptide. The methods include providing a medical device that includes a carrier that has a polymer associated with it, and a polynucleotide associated with at least a portion of the polymer. Alternatively, the methods include providing a medical device that includes a carrier and a polymer, and a cell associated with at least a portion of the polymer. The cell expresses an antimicrobial peptide.
The present invention further provides methods for making a medical device for local delivery of a polynucleotide or local delivery of a cell encoding an antimicrobial peptide. The IPGs of this invention can be provided in a sterile, dehydrated form, in a hydrated form with polynucleotides or cells or as a first polymer covered IPG supplied with the necessary materials to facilitate adding the polynucleotides or cells and further coating or covering of the IPG as needed. Therefore, this invention also relates to a kit that includes an IPG with a first polymer composition, buffers suitable for rehydrating the IPG and adding the polynucleotides or cells and a container to facilitate sterile addition of the polynucleotide to the IPG. Optionally, the kit can include further coatings or coverings to be applied over the first polymer composition. In a preferred aspect, the kit includes: an IPG that includes a surface that contacts the tissue of a patient, and a first polymer composition covering at least a portion of the surface of the IPG; a polynucleotide-adding or cell-adding composition to be applied to the IPG; and a container to house the IPG and the composition during application of the polynucleotide-adding or cell-adding composition.
The polynucleotides of the present invention can be associated with the medical devices of the present invention, or can be introduced to a cell that is associated with the medical devices of the present invention. Such cells are described herein in the section entitled "Cells expressing an antimicrobial peptide." The polynucleotides include a coding region that encodes a peptide, preferably an antimicrobial peptide. Antimicrobial peptides are also referred to in the art as peptide antibiotics. An antimicrobial peptide is a peptide that will inhibit the growth of, or kill, pathogens, i.e., microorganisms that cause disease. Typically an antimicrobial peptide is between about 5 amino acids to about 150 amino acids in length.
The antimicrobial peptides encoded by the polynucleotides that are associated with the medical devices of the present invention aid in the prevention or treatment of medical device-associated infections. The polynucleotides are released from the carrier and are taken up by cells adjacent to the carrier in the patient, for instance, cells present in the tissue that makes up the wall of the pocket into which the carrier has been implanted. Preferably, the polynucleotides are released from the carrier over a period of time (i.e., there is a sustained release of the polynucleotides), preferably during the first 14 days after implantation, more preferably during the first 7 days after implantation.
The infections can be caused by pathogens including viruses, fungi, or bacteria. The types of bacteria that can cause medical device-associated infections include gram-positive and gram-negative bacteria, including, for example, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus spp., and Enterococcus spp.
A polynucleotide encoding an antimicrobial peptide can be obtained from, for instance, insect, bacterial, amphibian, marine, mammal, and plant sources. Preferably, the polynucleotide is from a human. Whether the peptide encoded by a polynucleotide is an antimicrobial peptide can be tested using methods known to the art. For instance, Turner et al. (Antimicrob. Agents Chemother., 42, 2206-2214 (1998)) disclose radial diffusion assays, broth microdilution assays, and colony counting assays to measure the antimicrobial properties of a peptide. The antimicrobial properties of a peptide can also be measured by evaluating membrane permeabilization, for instance, the membrane permeabilization of the inner and outer membranes of, for instance, E. coli (Turner et al., Antimicrob. Agents Chemother., 42, 2206-2214 (1998)). Other methods for testing the antimicrobial properties of a peptide are available at, for instance, Steinberg et al. (In: Methods in Molecular Biology, Vol. 78: Antibacterial peptide protocols, Shafer (ed.), Humana Press, Totowa, New Jersey, pp. 169-186 (1997)). Without intending to be limiting, examples of polynucleotides encoding antimicrobial peptides include thrombocidins (see Krijgsveld et al., J. Biol. Chem., 275, 20374-20381 (2000), and the coding sequences disclosed at the following GenBank Accession numbers; NM—021010, AJ277280, AF295370, AJ237673, AF217245, NM—004345, AF071216, U50931, AF040153, Z71389, U73945, M97925, Z38026. Optionally, a polynucleotide encoding an antimicrobial peptide can further include a coding region that encodes a signal peptide. Nucleotide sequences encoding many signal peptides are well known to the art and can be linked to a coding region so that the nucleotides encoding a signal peptide and the nucleotides that include a coding region are contiguous and in the same reading frame.
The coding region encoding the antimicrobial peptide is typically inserted in a vector. A vector is a replicating polynucleotide, such as a plasmid vector, viral vector, cosmid vector, or artificial chromosome vector, to which another polynucleotide may be attached so as to bring about the replication of the attached polynucleotide. A vector can be linear or circular. Preferably, the vector is a plasmid. A vector provides for the expression of the antimicrobial peptide encoded by the coding region. Construction of vectors containing a polynucleotide of the invention employs standard ligation techniques known in the art. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual., Cold Spring Harbor Laboratory Press (1989) or Ausubel, R. M., ed. Current Protocols in Molecular Biology (1994). Typically, a vector is capable of replication in a bacterial host, for instance E. coli. Optionally, a vector is capable of replication in a eukaryotic cell. Preferably, a vector does not integrate into the genomic DNA present in a eukaryotic cell.
A vector optionally includes regulatory sequences operably linked to the coding region. The invention is not limited by the use of any particular promoter, and a wide variety are known. Promoters act as regulatory signals that bind RNA polymerase in a cell to initiate transcription of a downstream (3′ direction) coding region. The promoter used in the invention can be a constitutive or an inducible promoter. It can be, but need not be, heterologous with respect to the patient receiving the medical device.
Promoter sequences are known for eukaryotes. Operably linked to 25 to 30 bases upstream from the site where transcription is initiated. Often, another sequence found 70 to 80 bases upstream from the start of transcription is the CXCAAT region where X may be any nucleotide. Operably linked to the 3′ end of most eukaryotic coding regions is an AATAAA sequence that may be a signal for addition of the poly A tail to the 3′ end of mRNA that results from transcription of the coding sequence. These sequences can be suitably inserted into a vector. The promoter that is normally operably linked to a coding region encoding an antimicrobial peptide can also be used.
Transcription of a coding region encoding an antimicrobial peptide from vectors in the cell of a patient receiving a medical device of the present invention can be controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, and Hepatitis-B virus.
Transcription in a patient's cell of a coding region encoding an antimicrobial peptide can be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually having about 10 to 300 nucleotides, that act on a promoter to increase its transcription. Enhancers are relatively orientation- and position-independent, having been found 5′ and 3′ to coding regions, within an intron as well as within the coding sequence itself. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, alpha-fetoprotein, and insulin). Enhancers from eukaryotic cell viruses are also known and include the SV40 enhancer on the late side of the replication origin, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position 5′ or 3′ to the coding region encoding an antimicrobial peptide, but is preferably located at a site 5′ of the promoter.
A vector can optionally include a ribosome binding site (e.g., a Kozak site) and a start site (e.g., the codon ATG) to initiate translation of the transcribed message to produce the antimicrobial peptide. It can also include a termination sequence to end translation. A termination sequence is typically a codon for which there exists no corresponding aminoacetyl-tRNA, thus ending peptide synthesis. The vector can optionally further include a transcription termination sequence. Transcription termination sequences in vectors for eukaryotic cells typically include a polyadenylation signal 3′ of the coding region.
The polynucleotides that are included as a part of the medical device can be present as naked DNA. For instance, the polynucleotides can be dissolved in solution, or precipitated by, for example, calcium phosphate. Alternatively, the polynucleotides can be enclosed. For example, the polynucleotides can be enclosed in a synthetic lipid bilayer vesicle, including, for instance, a liposome. Examples of liposomes include multivesicular liposomes, unilamelar liposomes multilamellar liposomes and plurilamellar liposomes. Liposome encapsulation can provide for the controlled release of polynucleotides present in the liposomes. Methods of producing liposomes that control the rate of release of an encapsulated material into an aqueous environment are known to the art (see, for instance, U.S. Pat. No. 5,993,850 (Sankaram et al.); and U.S. Pat. No. 5,077,056 (Bally et al.)).
The polynucleotides can be condensed. Condensed DNA is DNA that has been compacted to isolated spheres or toroids so that the interaction of the DNA with the solvent is minimal. DNA can be compacted to a condensed state by neutralizing its charge, e.g., by addition of a polycation, or otherwise reducing its interactions with solvent. However, the polycation can cause aggregation or precipitation of the DNA if a chaotropic agent is not employed to prevent it. Compaction therefore can be accomplished by judicious use of both the polycation (to condense the DNA) and (as needed) of a chaotropic agent (to prevent aggregation or precipitation). Methods for condensing DNA are known to the art, see, for instance, U.S. Pat. No. 5,877,302 (Hanson). Examples of polycations include, for instance, polylysine, Arg-Lys mixed polymers, polyarginine, polyornithine, histones, avidin, protamines, and polyethyleneimine.
Optionally, a polynucleotide that is encapsulated or condensed can be actively directed to selected cell types, preferably granulocytes, monocytes, macrophages, neutrophils, platelets, T-cells, B-cells, or fibroblasts. One method used to direct liposomes actively to selected target cells involves attachment of antibodies which bind specifically to an epitope on the surface of the target cell. Methods for raising antibodies against cells, cell membranes, or isolated cell surface antigens are known in the art. Another method used to direct liposomes actively to selected target cells involves attachment of receptor ligands to the surface of the encapsulated or condensed polynucleotides. Preferably, the receptor ligand is covalenty attached, for instance, by cross-linking the ligand to the surface of the encapsulated or condensed polynucleotide. Preferably, a receptor ligand is specifically bound by a receptor carried by the target cells. One class of receptor ligands of interest is carbohydrates, especially mono- and oligosaccharides. Suitable ligands include galactose, lactose, and mannose. For example, mannose can be used as a receptor ligand to target the polynucleotide to macrophages and monocytes, and mannose-6-phosphate can be used as a receptor ligand to target the polynucleotide to fibroblasts.
Cells Expressing an Antimicrobial Peptide
Cells suitable for use in the present invention include a wide variety of eukaryotic cells that express antimicrobial peptides. The cells (for example, a macrophage) can naturally express an antimicrobial peptide. Alternatively, the cells can be modified to include a polynucleotide described herein (see the section entitled "Polynucleotides") such that the cell expresses an antimicrobial peptide. A cell that naturally expresses an antimicrobial peptide (for example, a macrophage) can be modified to include a polynucleotide encoding an antimicrobial peptide. Preferably, the cells that are associated with a medical device are also able to secrete the antimicrobial peptides. Suitable cells for use in the present invention typically include inflammatory cells, including, for instance, macrophages. Other suitable cells are mesenchymal or mesodermal cells, including, but not limited to endothelial cells and fibroblasts, whether they are autologous or allogeneic, genetically engineered or not modified to include a polynucleotide encoding an antimicrobial peptide. Mixtures of such cells can also be used. Inflammatory cells are particularly suitable for use in the present invention because they naturally express antimicrobial peptides.
Preferably, the cells used are suitable to be modified to include a polynucleotide encoding an antimicrobial peptide, for instance by ex vivo gene transfer. Ex vivo gene transfer is a process by which cells are removed from a body, preferably the body of the patient that is to receive the IPG, and using well known techniques are genetically manipulated, usually through the introduction, e.g., by transfection, of polynucleotides into the cells in vitro. The modified cells are then returned to the body for therapeutic purposes. A polynucleotide that has been introduced to a cell, for instance by ex vivo gene transfer, is referred to as an introduced polynucleotide. Ex vivo gene transfer is an effective approach because the target cells to be used in the procedure can be manipulated as needed to optimize gene transfer efficiency and thus the effectiveness of the overall procedure. Typically, the ex vivo gene transfer uses cell types that can be readily retrieved from the body, cultured ex vivo, and then returned to the body. Such cells include blood and marrow cells, liver hepatocytes, skin fibroblasts, muscle myoblasts, vascular endothelial cells, and inflammatory cells.
There are a wide variety of methods that can be used to deliver polynucleotides to the eukaryotic cells if they are to be modified to express, preferably secrete, an antimicrobial peptide. These are well known to one of skill in the art. The desired polynucleotide can be inserted into an appropriate vector. There are a number of viruses, live or inactive, including recombinant viruses, that can also be used. A retrovirus can be genetically modified to deliver any of a variety of coding regions. Adenovirus has been used in a variety of experiments to deliver polynucleotides capable of directing and expressing a polypeptide in a cell.
Depending on the maximum genome size that a particular viral genome can accommodate or that can be associated with a virus particle, the virus delivering polynucleotide to the cell can include a polynucleotide encoding one or more polypeptides.
In one embodiment of the present invention, endothelial cells are obtained from a patient and grown in cell culture. During proliferation in cell culture, they are infected with a genetically engineered retrovirus which integrates the coding region encoding the antimicrobial peptide into the chromosomes of the infected cells. This can be accomplished, for example, according to the teachings of U.S. Pat. No. 5,674,722 (Mulligan et al.) and Dichek et al., Mol. Biol. Med., 8, 257-266 (1991).
The cells can be coated directly on the carrier and covered by a polymer, incorporated into the polymer, or coated on top of a polymeric coating or film on the carrier. They can also be included within a microscopic containment vehicle that can be stimulated to release the antimicrobial peptide expressed by the cells. The microscopic containment vehicle can be coated on the carrier and covered by a polymer, incorporated into the polymer, or coated on top of a polymeric coating or film on the carrier. Preferably, the cells express the antimicrobial peptide over a period of time, preferably during the first 14 days after implantation, more preferably during the first 7 days after implantation.
The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, therefore, that other expedients known to those skilled in the art of disclosed herein, may be employed without departing from the invention or the scope of the appended claims. The present invention further includes within its scope methods of making and using the medical devices described hereinabove.
The complete disclosure of all patents, patent applications, and publications, and electronically available material (e.g., GenBank amino acid and nucleotide sequence submissions) cited herein are incorporated by reference. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention defined by the claims.
All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.
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|U.S. Classification
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|Dec 11, 2000
Owner name: MEDTRONIC, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HENDRIKS, MARC;REEL/FRAME:011647/0634
Effective date: 20001201
|May 24, 2005
|Certificate of correction
|Apr 17, 2008
|Fee payment
Year of fee payment: 4
|May 2, 2012
|Fee payment
Year of fee payment: 8
|May 2, 2016
|Fee payment
Year of fee payment: 12


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Sneeze births please, and we'll BROOK NO ARGUMENT(1000 Posts)
Over here Brookers. I'll stick a cake in the oven
No symptoms or baby yet. Had an awful night sleep with aching hips and back. Was also far too hot. Slept without covers even though room was only 12 degrees, and still felt sweaty and yuk.
Grumpy now today. Cat is on my lap dough punching me, he's trying to show his love but I'm getting annoyed at the nagging and claws going into my leg. It's silly to say I just want a decent night of sleep, because that's not going to happen with a baby either.
Plan was to walk to swimming pool this morning, go swimming, then walk home. Long walk including a hill and swim to bring on labour. It feels a bit pointless though, as there really is nothing to indicate this baby will be here soon. I've had like 10 BH this whole pregnancy, and that's it.
Still, I'm a Brooker, and you're all Brookers. Being grumpy and disillusioned is not brooking! I will have this baby
eventually when the MW forces him out today!
Oh stacks, I feel for you, it's rubbish when you're overdue. Especially when you're tired and uncomfortable. Remember though, lots of people don't get Pre-labour symptoms, so there is no reason why today won't be the day you meet your boy xx
Still brooking for you, Stacks, walking is a good way of getting things started, so it's worth a try!
Whim that woman sounds a bit loopy. I always wonder why people say those sorts of things (presumably for 'something to say') but don't they know you have no choice what gender baby you are going to have, you just want a baby. Drives me mad. Especially with what we all know about prolonged TTC/mcs etc. Grr. I am slightly worried about cord prolapse too since I stupidly googled about transverse babies and it is one of the risks. Think MiniGen is still transverse and brooking like mad it will move soon. Still, I scrubbed the kitchen floor this morning, which may have helped (early nesting?)
Smegs you are tough. I would have been terrified with that man sitting by me! And thank goodness for your nips of steel to have thrush to contend with. Hope you are both better soon.
Hi to everyone else. Ooh and happy scan day, Sparks!
Happy scanning and happy sneezing... but only one of each activity for Sparks/*Stacks*.
Not quite a parallel to TTC I hope Stacks - 18mths overdue would be v tough! However, from personal experience, DS was 15 days beyond scan due date, so you may have to be a little patient yet (though brooking that's not necessary and tiniStack hurries up). Hope you get some sleep and peace of mind.
Whims - she's clearly a twat.
Just been to dentist - everyone v lovely about babybump but did feel quite weird as tiny hands blatantly danced out from my side in response to the treatment. Felt v exposed on the dentist's chair with a 37wk bump. I last saw hygienist in Jan and we'd discussed infertility - her sister has had 3 attempts at IVF and they're young and healthy etc. She seems to know so many women who are struggling in early 30s. Feel so sad for folk going through this. Meanwhile my 2 cousins are in a stand-off because the sister who has experienced 3 MCs is devastated that her younger sister didn't tell her at wk5 that she was pregnant (but guessed because of her not drinking). V sad for all family that it seems impossible to celebrate the first of the next generation as Christmas approaches. Cruel world innit.
But it's ok because Pope Benedict has just made his first 'tweet'. I'm sure you're all overjoyed.
Oh and Smegs - go girl. He sounds unbalanced, a tad. Hope thrush clears up quickly - not fun for you, but everything else sounds v positive. It's lovely you have 2DDs and anyone who thinks otherwise doesn't know what they're on about. xxx
Sorry I've not been around much. Yesterday was a bit traumatic! Sounds like smegs had a bad experience as well. Did you tell the receptionist or GP about what happened? They might be able to take things further?
So bad news first: a cyclist and I had a collision yesterday. He came through a red light just as I was turning right and went into the front of my car. He then refused to give me his details although I eventually got his mobile number off of him. I reported it to the police and had to go down with my documents and have given him the incident number and insurance details. We both thought he'd only damaged one of his fingers but he's broken his wrist again.
I am so very, very cross. I am a cyclist too. I am obsessive about checking for them but he must have been obscured by the waiting traffic at the lights and just zipped past and into me. Thankfully I wasn't going very fast (5-10mph max?) but I hope this gives him a jolly good scare and he doesn't through red lights again! I'm just worried he decides to try to claim on my insurance (he, of course, is not insured) whereas my DH is all up for making him pay for the damage done to our car (not that much, but this will, of course, put our insurance premiums up for the next few years!). I just want it all to go away.
But then good news - I answered a MN survey about ironing. I don't do any ironing and answered to that effect - but have won £100!
Gosh bartlet what a funny day! Hope you're not shaken still. You remind me tock I must find a dentist. Not high on list of priorities. The list is long, and includes, for example, 'find out where the hosp I'm meant to give birth in is'.
Try and get some rest today stacks
while you still can
Bloody phone app keeps gobbling my posts!!
So super quick one to say all is very well twinks!! Official NHS due date is 21st June so few days earlier than private scan!!!
Yay for twinkle, and Sparks of course
whims, smegs sorry to hear you've both encountered idiots with too much to say. Sounds like you both handled it well
Hope that thrush clears up soon too smegs.
bartlet I'd have been really shaken by that accident, hope you're ok. Treat yourself with your £100 bonus for not ironing. I don't iron either, but no ones ever paid me for it ;)
sparks great scan news, hope you enjoy going public
I'm 30 weeks tomorrow, which is exciting. It feels like a big milestone, not that it means much in terms of the pregnancy. It's flying by though, can't believe the baby will be here within 12 weeks
What lovely news for Little (30wks) and Sparks (official NHS due date). That's made my day. Plus Gen was very nice about my bump on FB. Thanks lovely!
Bartlett - sounds v upsetting/unsettling. Cycling scares me a little, esp' inner city cycling. I always give cyclists a big berth whenever possible, just in case. Impressed at your win and pleased to be among fellow refusalists when it comes to the hot iron. I v occasionally iron something if I'm going to an occasion and am completely cack-handed.
Anyone getting those weird crippling cramps in top of inner thighs? TiniTock must be digging right down into pelvic area, I guess, but it's enough to make you gasp with discomfort. Didn't have this (or quite full-on BHix) with DS so a bit surprised...
Btw Bartlett - my first thought on reading about the cyclist running into you was that you were a pedestrian - extremely pleased in a way that you were in the car, ifykwim. The former would have been absolutely awful... xxx
Bartlet, that sounds awful re the cyclist. Sounds like you were very sensible in getting his details etc. But hurrah re the win! Hope you enjoy spending it.
Sparks, great re scan and due date. Enjoy teling everyone! Have you decided when to tell work yet?
Tock you do have a beautiful bump! I'm feeling a bit whale-like at the moment and quite looking forward to (hopefully) losing some weight in the New Year. But it really is a small price to pay to get a baby and I am so excited about it all now. And only 7 days of work left for me - whoop!
Little, that is brilliant re 30 weeks. I do think it's a milestone - means you are three-quarters of the way there.
Gen - I think I felt a lot more whale-like a couple of weeks ago. Baby has engaged so perhaps that's why? Also looking forward to slimming down myself come January - but like you say it's the least of our priorities and a bonny bump is just what we all wanted and brooked for. I'm sure you look lovely btw - it's hard to be objective when you're diffed and looking in the mirror. So great about your Mat leave; I hope you have a lovely few weeks before babyGen makes an appearance. I'm starting mine officially on 2 Jan but having said that I've had a v poor year work-wise so won't make much difference to me and we will be living on a v tight budget on basic SMP for most of next year; I'm hoping to rise to the challenge. Thank goodness for KIT days - I can do 10 days of a big project and get some dosh in my biz a/c. When do you plan to return to work or are you leaving your options open?
Waves and stollen to all. Brooking for Stacks.
Just a quick update from me. No baby still, but I did get a good nights sleep last night! Feel so much better today for it.
Today is DH's first day of his Christmas holidays, so we're going to get some more tidying and things done, and just spend some time together. So a quiet day for me on the MN front I think.
Great scan news Sparks did you get any good pictures? I really enjoyed all my scans, though its such a long wait from the 20w scan to meeting your baby.
Little grata on 30w, it is a nice marker for 3/4 of your pregnancy. Not too long now till you meet baby. Are you all ready? I left buying things really late, but I think it's a bit more normal to have things done just a little sooner than me
Forgotten what else I read. Sorry. Hope everyone else is well. Will try and post again later.
Glad you're feeling better stacks. Hello tock you do indeed have a lovely neat bump. I feel more compact than on previous occasions, but I've still put on loads of weight.
Today is going to be a long day as I have supemarket, obstetrician and a toddler who hates me for not being his daddy.
Tock, I officially start mat leave on 2 Jan too, but start holiday from next Friday - whoop! I would love to have 9 months off, but that all depends on money and DH works for himself. Well actually, he's a SAHD at the moment, so we're swapping roles and he has to go out and bring home the bacon! We'll see. I shall be doing KIT days too! Thanks for your kind words re bump. Yes, I think I will feel more compact when baby decides to engage as my bump is very high up. Will try to use fancy phone to do a pic this weekend.
Stacks, glad you had a good night's sleep and you and DH are now off together. You do know this will bring on the baby, don't you?
Whim, enjoy your busy day.
Any news of Nutella?
DH is off out to meet up with work for lunch. I've got MW appointment at 2:30 when I think she'll offer a sweep. Fingers crossed. Though I'm really nervous that its going to be horrible and painful. However, I'm not nervous of labour being painful .
Going to walk to appointment today. It's about a mile or so each way, and hopefully combined with a sweep should get something moving?
Nutella has been posting a little on the Dec thread and seems well.
I should go nosey at people's bump pictures. I've got a pic taken of bump in nursery on due date... Was meant to be last pic, but seems ages ago now. I'll put it on fb later, as DH took it on a real camera, rather than phone.
Yay on the excellent scan news sparks! Are you going to tell people now? I was looking forward to telling people the whole first tri then got all weird about it when i was finally able to! Hope you have recovered from your hives
bartlett that sounds v scary about the cyclist glad you are OK. Was there much damage to your car? Sounds like he was very silly indeed and there was nothing you could have done.
stacks glad you got a good sleep in and brooking ministacks decides to make his grand entrance!!
Cant remember who asked abiut my 20 week scan but it was amazing thank you and i loved it the sonographer was also a really really lovely woman who chatted through everything she was doing so there were no nervous silences. We didnt find out the sex so its an UBB (although DH and I call it 'he' and I definitely reckon boy). 24 weeks tomorrow its really flying by!
MiniStacks is head down, but back to back and even less engaged than he was two weeks ago. MW decided not to do sweep, as he's so high it's unlikely to work, and she probably couldn't reach anyway. Another appointment booked for Monday to do one then.
So, anyone got any fool proof methods of turning baby and making him engage - and stay there!?
Ooh Stacks - that's a bit nerve-wracking for you though I think it's good that MW didn't do sweep. You could walk up and down stairs but sideways - it rocks the pelvis and might give him room to move down a bit. Downward dog also good for creating room and squatting afterwards if you think he has moved round a bit. Also - if you have a yoga ball/birthing ball try doing rapid clockwise circles (make sure knees are below hips) or figures of 8... Did the MW suggest anything?
Will write to all of you properly soon... <wonders where Nuts is now she's 38wks...>
Midwife doesn't seem at all concerned tock. Gave no advice at all. I'm a bit worried because he was in a stable lie for months (back to left, head down) but the last couple of weeks has been really unstable, I've felt him left, right, back and front... Always head down luckily, but on Sunday he was really low down, such that it was uncomfortable to lean forwards at all. Next morning though he was high and turned.
Still measuring to dates, but there's a lady in dec thread who's got extra fluid making baby unstable. They've got her monitored in hospital and will be doing a CS. Too many risks to mum and baby with an unstable lie...
Hmm, sounds like you'll have to crawl around on your hands and knees for the next few days stacks, to get him in the right position. And no reclining on the sofa, it'll only encourage him to stay back to back!
I saw the Mw today, all fine, but he is breech atm. I could tell before i saw her as I can feel his head at the top of my bump! Still loads of time for him to get in position, but i might be doing those moves myself soon!
Actually, that's several of the third tri bumps that need shifting. stacks, gen, and olives too I think?
X- post stacks, hope you're not overly concerned?
I'm not that concerned, I trust that if there was something to be worried about, the midwife would be worried. Though then I wonder if I put too much trust in these things. She was one MW covering for the 5 that should have been there today, and as such running really late again.
Monday isn't too far away, and I'll just keep an eye on his position till then. I've been very aware of positioning for weeks though, as DH was an emergency CS for MIL as he turned back to back late in pg. As such he nags if I slouch on sofa etc. I thought my swimming yesterday would have been good for positioning, he just seems to spin round at night - though I don't think I lay on my back (it makes me feel really sick if I do it during the day).
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Blondes, Brunettes & Redheads.
Feature Gallery - International Blondes edition 1.
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By entering, you state you are not living in a country or jurisdiction that prohibits sexually explicit material. This site contains sexually explicit materials. Do not enter this site if you are under the age of 18. All models are18 years of age or older.
ENTER Galleries - - or - - EXIT.
Penthouse Pet Galleries.
|© 2002 - 2006 SexyRhonda.com & C(n)BC affiliate sites.


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Detailed reproductions of English, French and American SHORT SABERS, HUNTING SWORDS, CUTLASSES, and HANGERS. Hilts are of Iron or Brass, handles of various Woods, Horn, Antler, or Bone. Below are some swords I have in stock, or have built in the past
SOLD - Antler Handle Hunting Sword This sword features brass hardware copied directly from originals in my collection. Mid-18th century style with a polished antler grip. The slightly upswept 22 inch blade has a single back fuller and false edge with a dark finish. SALE PENDING
SOLD - Iron Mounted Hunting Sword Short hunting sword with stag grip. The forged iron guard features a shell and accents in sterling silver. Slightly upswept blade has a single back fuller and false edge.
SOLD - American Officer's Short Saber A very special reproduction of an American made sword of the Rev War period. Mounted in Sterling Silver, all aspects of this sword were copied closely from originals. The guard is a variation of the common "4 slot" pattern with flamboyant edge and piercings. The grip is carved from stag, closely resembling the look of bone or ivory. The 27 inch hand forged blade is a close copy of one in my collection; identical in dimension, thickness, and balance; having both wide and narrow fullers so common on swords of the period. Complimenting the sword is a fine silver mounted scabbard by Wick Ellerbe. Highly detailed, the scabbard features tooled designs and hardware copied from an original. Simply, one of the finest reproductions of an American saber. $3000
SOLD - American Saber This Rev War period sword has features typical of the light sabers being made in the colonies. The straight, carved bone grip, oversized ball pommel, and guard with outward branches were all popular on American made sabers. The 27 inch, hand forged and lightly curved blade would have served well with mounted militia and other light troops.
SOLD - Early Hanger/Cutlass by Kyle Willyard & Jared Secrest. This was built to be a sword with a history. The guard is copied from a 17th century English Mortuary sword with the thought that it had been paired with a newer blade, early in the 18th century. A joint project between myself and my apprentice, this sword has been aged to reflect a long period of use. The 25 inch, hand forged blade with single back fuller and slight upsweep has been carefully copied from an original blade in both dimension and weight. Often the grips of these swords were octagon in shape and wire wrapped, but this one features a grip of smooth ebony. A sturdy, well-made sword, equally at home on land or sea. $1200
For Antique Arms See our New webpage
Original Saber c. 1780-1810. Featuring an impressive 30 inch blade with both wide and narrow fullers and nice patina. Brass stirrup guard and pommel in the style common to the period. The wood grip was once covered in a leather wrap bound by wire but has since been removed. This is a well-made, well-balanced quality saber that would look good for carry or display. $800
SOLD - Original Saber c. 1790 This saber dating from just after the American Revolution features the classic stirrup guard with reeded bone grip and pillow shape pommel. This type was often carried by noncommissioned officers, see Paterson's book, The American Sword, pages 8-10 for a similar example. The 30 inch blade has a single wide fuller and interesting patina. This sword has great balance; is tight, solid and would be an excellent choice for carry or display. $850
Original Double Edged Sword. Possibly Spanish in origin, the sword has a hand-made 25 inch blade that still shows traces of file marks from the manufacture. An iron crossguard with hand filed designs along with a carved horn grip finish off this sword. Guard is slightly loose and the grip appears to have been fitted for a pommel cap that is now missing. A unique, hand crafted sword that may well be one of a kind. $350
Original German Hunting Sword The 20 inch blade is identical to those produced during the second half of the 18th c. with the typical engraving and hunt scenes. The brass guard is engraved with "F. R. 1847" and I am fairly certain that is when this sword was put together, perhaps using an older blade. The stag grip is in excellent condition. The leather scabbard is original to the sword though the drag is an obvious later replacement. $390
Antique American Officer's Saber c. 1790-1805 This saber is an early and more rare variation of the popular Eagle Pommel. The 4-slot guard is a hold-over from the Rev War period. Patterson shows a similar sword on page 104 of his book "The American Sword". Sword is solid and in good condition. The guard retains much of the original gilding and the blade features typical military engravings of the period including a stand of arms and liberty cap. Much of the gold fill in the engraving is still present and the blade shows some of its original bluing. Blade measures 30 inches, 35 1/4 inches overall. This is a great piece of American history. $1150
Original European Hunting Sword Mid-Late 18th century. The 20 1/2" blade is most likely German made with the usual hunting scene and knot-work engravings. Shagreen covered wood grip shows signs of once having straps on the top and bottom. Broken guard has been remounted. This piece has seen a hard life, but is still attractive and would make a nice example for study or display. $425
SOLD - Original Dutch Hanger 1770-1785 Nearly identical to 48.S in Neumann's Swords and Blades of the American Revolution. Undoubtedly some of these made their way to America during the Revolution. Sword features a slightly curved blade with single back fuller, brass guard. The blade measures 26 1/4 inches, 31 1/2 inches overall. The blade does have some deep pitting and appears to have been "cleaned" at some period. All hardware appears to be original, including the leather grip wrap and wire. Overall, the sword is in very solid condition with no play in the grip, however, the larger outward branch on the guard is broke at the connection to the cross guard (though still solid and hardly noticeable). $410
Previously Sold Swords
SOLD - American NCO Hanger. Recently finished for a customer, this sword and scabbard was a collective work, with the hanger being made by Kyle Willyard and apprentice Jared Secrest. The finely balanced weapon is paired with a custom made scabbard by Wick Ellerbe. The hanger features a 24 inch, hand-forged and fullered blade with correct period shape, weight, and ballance. The guard is forged iron with a reeded wood grip. Scabbard features iron hardware with designs adapted from existing original examples.
SOLD - George Washington's Battle Sword Detailed reproduction of the famous sword features heavy silver-plated hardware, carved grip of polished and dyed moose antler, and sterling silver band. Scabbard is a work of art by Glen and Cami McClain with tooled leather and sterling silver hardware. This is an exceptional reproduction and a combined effort that will probably not be offered again.
Copy of George Washington Sword Recently made for a customer.
SOLD - Iron Mounted Hunting Sword featuring a hand forged blade, iron shell guard, ferrule, and pommel cap with capstand. stag grip, and chain guard. This was a joint project with my apprentice, Jared Secrest and carries both our touchmarks. The graceful, hand-forged blade measures 18 inches long and the sword is 23 inches overall. Aged finish.
SOLD - American Hanger This complete set represents a rare offering of one of my swords, paired with an exceptional scabbard by Glenn McClain. All work was custom made for this set. The hanger features a 25 3/4 inch, hand forged blade, forged iron guard and pommel, all with aged finish. The grip is of ebony. The custom scabbard has detailed, iron mounts and embossed design work on the leather. Also included is a custom shoulder carriage with buckle made by Ed Wilde.
Horn Grip Cuttoe Recently made for a customer.
SOLD - Brass Hilted Short Saber recently made for a customer. Features brass mounts, ebony grip and sterling silver ribbon. Gadrooning on pommel and guard.
American Cuttoe with brass guard, lion-head pommel and chain. Carved ebony grip with sterling silver ribbon. Hand forged blade.
SOLD-American Hanger with Shell Guard Features a hand forged, 25 inch blade. Forged, iron shell guard and pommel. The grip is red elk, left in the rough. This is the type of hanger or hunting sword that would have been made here in the colonies during war-time, when imported blades would have been scarce.
SOLD-Iron mounted American hanger. Features a hand-forged blade and guard, made in my shop, draw-filed and polished by hand. Polished antler handle. Lightly aged finish.
Early Double Shell Cutlass recently made for a customer. Features a custom falchion blade by Del Tin. Pierced iron guard and antler grip. Aged finish.
American Hanger with Iron with forged iron guard and hardware, polished antler grip. Hand forged blade. One of a pair of hangers made for Martin's Station, Wilderness Road State Part, Virginia.
SOLD-American Hunting Sword with Iron Shell Guard. During the war years, American officer's, militia, and those on the frontier often resorted to the local blacksmith for their sidearms. While these pieces may not have been executed as neatly as their European counterparts, they have a style all their own. This one features a 17 1/2 inch, hand-forge blade, forged guard and shell, iron cap, all with a fully aged finish. Antler handle with carving. Comes with a custom iron mounted, hand-tooled leather scabbard made by Glen McClain.
American Iron-Mounted Hanger recently made for a customer. Features hand forged iron guard and ebony grip. Lightly aged finish.
Early European Double Shell Cutlass recently made for a customer. Aged iron hardware and polished antler grip.
SOLD-Iron mounted American hanger. Features 24 3/4 inch hand-forged blade and guard, made in my shop, draw-filed and polished by hand. Polished antler handle. Lightly aged finish. Blade is light-weight and well balanced. 29 1/4 inches overall.
SOLD-Iron mounted American hanger. Features 24 1/2 inch hand-forged blade and guard, made in my shop, draw-filed and polished by hand. Polished antler handle. Lightly aged finish. Blade is light-weight and well balanced. 29 1/4 inches overall.
SOLD - SWORD-Small sword with original blade This small sword features a beautiful, original blade mounted on the guard of my own manufacture. All furniture has been aged to match the patina of the blade. The blade has some light nicks and minor pitting that are consistent with it's age. This sword would display well, or carry into the field. 27 inch blade, 33 3/4 inches overall.
SOLD Early European Hanger or Cutlass with double Iron Shell Guards, and polished Antler Handle. 27 inch blade. All lightly aged. This is one sturdy sword that would be equally at home on land or sea.
SOLD American Hunting Sword with Iron Shell Guard. During the war years, American officer's, militia, and those on the frontier often resorted to the local blacksmith for their sidearms. While these pieces may not have been executed as neatly as their European counterparts, they have a style all their own. Fully aged finish with a 17 inch blade. The blade is hand-forged, the first made in my shop in the last several years.
SOLD Iron mounted Hunting Sword with shell guard.
SOLD Officer's saber with Dog-Head Pommel, and brass guard, ebony grip with brass ribbon.
SOLD English Hunting Sword of mid-18th century style. Features brass mounts and shell guard, and an ebony grip with spiraling flutes. 27 inch curved blade with single fuller. Comes with scabbard.
A cutlass that I recently finished for a customer. Aged iron blade and hardware and polished antler handle.
Hanger/Cutlass recently made for a customer. Hand iron guard, ebony handle and iron pommel. Aged finish.
American NCO Hanger, Revolutionary War period, that I recently made for a customer. Forged iron guard, lightly aged. Polished antler grip.
Early Hanger I made some time back with double shell guards and branches.
Send email to Old Dominion Forge
Or, write to:
Old Dominion Forge, Kyle Willyard, Prop.
4186 N State Road 15720
Bloomfield, IN 47424


text:
How to Peddle the Zeitgeist #8
This was posted by Tom Sutpen
|your thoughts:
The series is: How to Peddle the Zeitgeist
3 comments:
- Scott said...
Jerry Seinfeld was a 60's icon?
- July 11, 2013 1:20 PM
- -K- said...
Michael J. Pollard is a common sight here in the Hollywood/West Hollywood area. Keeps to himself, always walking alone, rather strangley dressed as a sort of high end club kid.
- July 11, 2013 6:43 PM
- nanoalchemist said...
Tiny Tim?
Also, I really think Michael Pollard is underrated. I found this a while ago.
- July 15, 2013 1:39 PM
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CHICAGO – One of the great new premium channel TV series, which piggybacked on the "Twin Peaks" return on the Showtime Network, is "I'm Dying Up Here." Set in the 1970s, it tells the stories of fictional stand up comedians in Los Angeles, and one of the Consulting Producers and series writers is Cindy Caponera.
Gary Oldman
Film Review: 'The Space Between Us' Falls Into a Black Hole & DiesSubmitted by PatrickMcD on February 2, 2017 - 10:21pm
CHICAGO – You know you're in trouble when the opening scene of a film inspires forehead slapping levels of incredulity. And that's just the beginning of what I felt while watching "The Space Between Us," another entry in the long line of would-be weepies about young lovers torn apart, usually by class or disease.
HollywoodChicago.com Hookup: 35 Pairs of Passes to 'Criminal' With Kevin Costner, Ryan ReynoldsSubmitted by HollywoodChicago.com on April 11, 2016 - 9:40am
CHICAGO – In the latest HollywoodChicago.com Hookup: Film, we have 35 pairs of advance-screening movie passes up for grabs to the new crime drama "Criminal" starring Kevin Costner and Ryan Reynolds!
Film Review: Dull Soap Opera in 'Dawn of the Planet of the Apes'Submitted by PatrickMcD on July 10, 2014 - 11:55pm
CHICAGO – "Dawn Of The Planet Of The Apes" just goes to show you can have the most expensive and best looking visual effects money can buy, but it doesn't mean a damn thing if you haven't got a good tale to tell.
HollywoodChicago.com Hookup: 30 Pairs of Passes to 'Dawn of the Planet of the Apes' With Gary OldmanSubmitted by HollywoodChicago.com on July 6, 2014 - 2:35pm
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Blu-ray Review: 'RoboCop' Remake Struggles with IdentitySubmitted by NickHC on July 5, 2014 - 9:33am
CHICAGO – After years of being envisioned with numerous directors ("Noah's" Darren Aronofsky was once attached), a new version of "RoboCop" has arrived. While the original 80s classic stood out for its foresight into current cultural turmoil, this remake is more a product of movies of the past, and to be more specific, our recent beloved superhero movies.
Film Review: 'RoboCop' Reboot Lacks Fun Factor, Fearful VillainSubmitted by HollywoodChicago.com on February 14, 2014 - 1:15am
CHICAGO – You get the sense that a writer for the new "RoboCop" felt very proud of himself when he coined the cheeky word "robophobic" as a play on a current cultural hot button. The Samuel L. Jackson moment of self-fulfilled glory reminded me of the rest of the plot that was missing.
Blu-ray Review: Glorious 'JFK 50th Commemorative Ultimate Collector's Edition'Submitted by BrianTT on November 16, 2013 - 4:27pm
CHICAGO – Oliver Stone reached the peak of his fascination with controversy, history, and epic productions when he made 1991's "JFK," arguably the masterpiece of the director of "Platoon," "Natural Born Killers," "Nixon," and many more beloved films. "JFK" is a remarkable cinematic achievement, a movie that has lost none of its power 22 years after its release, looking like something that could come out today, especially now that we're in the peak of Kennedy mania as we approach the 50th anniversary of his assassination, one of the most important events in American history.
Film Review: Lazy, Horrendous 'Paranoia' Wastes Talented CastSubmitted by BrianTT on August 15, 2013 - 3:33pm
CHICAGO – Much like 2011's silly "Abduction" with Taylor Lautner, the title of "Paranoia" isn't exactly accurate. Just as that previous film wasn't really about an abduction, paranoia is only a minor aspect of Robert Luketic's new thriller.
HollywoodChicago.com Hookup: 25 Pairs of Passes to 'Paranoia' with Liam Hemsworth, Harrison FordSubmitted by HollywoodChicago.com on August 12, 2013 - 10:47pm
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CHICAGO – In the latest HollywoodChicago.com Hookup: Film with our unique social giveaway technology, we have 25 pairs of advance-screening movie passes up for grabs to the new thriller "Paranoia" starring Liam Hemsworth and Harrison Ford!
Interview: Novelist Matt Bondurant on 'Lawless' Book-to-Film AdaptationSubmitted by PatrickMcD on August 27, 2012 - 3:22pm
CHICAGO – Ernest Hemingway said the best way to handle Hollywood film adaptations is to meet at the border, throw your book in, have Hollywood throw the money back, and then run from each other in opposite directions. How does that astute observation apply today? Matt Bondurant had his novel adapted into the new film "Lawless."


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snappyHexMesh problems 1.5->1.6
Hi. I have a snappyHexMesh case which worked fine with 1.5 but upgrading to 1.6, I get the following error message:
Shell refinement iteration 0
Marked for refinement due to refinement shells : 0 cells.
Determined cells to refine in = 1.52 s
Selected for internal refinement : 13280 cells (out of 138087)
hexRef8 : Dumping cell as obj to "/home/gavin/OpenFOAM/gavin-1.6/run/shuttleSnappy/cell_106631.obj"
cell 106631 of level 3 uses more than 8 points of equal or lower level
Points so far:8(21039 32067 37690 37691 49159 152912 154100 155267)#0 Foam::error::printStack(Foam::Ostream&) in "/opt/foam/OpenFOAM/OpenFOAM-1.6/lib/linuxGccDPOpt/libOpenFOAM.so"
... it then gives me a long stack trace which I won't reproduce unless someone thinks its important. Can anyone suggest what might be causing this problem or what it means?
Hi Gavin,
did you remove any left-over files (foamClearPolyMesh)? If the problem persists in 1.6.x feel free to report a bug.
Hi Mattijs,
I didn't try that - but just have and it made no difference.
By 1.6.x - is there a bug-fixed version of 1.6 now? (I've been away on holiday for a few weeks). If so I will try with that before posting a bug report; if you think its likely to be a bug.
Same problem here!
Same problem here! And absolutely no idea how to get or even search for a solution. Any help is very appreciated.
problem solved for hexRef8 problem:
> foamCleanTutorials
as the snappyHexMesh has create several time folders for saving the iteration data of HexMeshes
not just
> foamCleanPolyMesh
Good luck!
I had the same problem and it was caused by locationInMesh that was close to the surface of the object. In my case, it was not caused by the upgrade though, but same error message none the less.
Here is the original thread: http://www.cfd-online.com/Forums/ope...rnal-flow.html
If any of you still have this problem, you might want to try to move the point further away from the surface.
|All times are GMT -4. The time now is 15:05.


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Today, some people get attracted to swinging lifestyle. These swingers learn to live with the various aspects of life and love to swinger clubs and parties. Some couples also plan swinger parties at their homes. However, there is a perception that large parties satisfaction over small parties. Actually, the adventure quotient of the party depends on the people at the party and not the location of the occasion.
So, if you are planning a party for your swinger friends, follow the given below tips and put a mediocre surroundings in a richly entertaining bout.
1 The success of the swinger party depends on the guests in the hall. Remember not to invite a crowd; invite friends who are open to swinging activities. People with a shy personality can spoil the evening. Each swinger must participate in the activities. Motivate newbie to open their belts and to take full advantage of the opportunity.
2 If you are a restricted meeting, select a location that limited space. This initiates a better interaction between the guests. Swingers talk to each other and a level of comfort that enhances the development of the party environment.
3 Invite people with similar interests. Each has a swinger swinger personal choice as far as activities. Some people like bi-sexual activities, while some believe in exhibitionism. Therefore, invite people you can swing without fear.
4 Your guest list should people in the same age group. Not to invite young or old couples. A balance;
5 You have to keep a good balance between male and female swingers at the party. The number of females must have a minimum number of males; otherwise, several men will leave the party without swinging.
The basic things cause an environment where everyone enjoys the evening at the handle and interact with other swingers.


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Rabbits, groundhogs, and feral dogs (Oh My!)
I usually only blog about woodworking, mostly because I personally find that far more interesting than the daily monotony that is homesteading (weeding, collecting eggs, trimming hooves, etc…). This has been an interesting couple of weeks though.
I don't consider myself a violent person, I'm very slow to anger, and make it a point not to pick fights. And I dont like to kill anything, and try very hard not to do it unless it's for food. Now thats not to say I can't apply violence when it is absolutely necessary.
I grew up hunting a bit with a trusty BB gun, like many boys, and am actually a pretty consistently good shot with a rifle or shotgun. During college I did start training as a martial artist and kept it up for about 5-6 years and earned a black belt (I recently started training again, mostly for fitness). Those skills served me well on the farm this week…. Read more…


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COLTON, Calif. — Stater Bros. Markets here is experiencing slight sales gains — estimated at 2% or less — as a result of perceived consumer anxiety over a possible work stoppage at other companies by the retail clerks, Jack Brown, chairman and chief executive officer, said here yesterday. Referring to the 141-day strike-lockout that occurred in late 2003 and early 2004, Brown said, "Last time, people weren't prepared, but even our own people have been filling their pantries a bit over the
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Wednesday, February 10, 2010
Girish Puthenchery: Malayalam lyricist Gireesh Puthenchery passed away!
First of all, the reason why I have used different spellings for the same name in the heading of this article is because surfers are searching the internet about the late Malayalam lyricist and Screen play writer with both the spellings. His actual name is Gireesh but we did not want surfers who are searching with the other name to miss out on the sad news.
The noted Malayalam lyricist and Screen play writer is no more. Gireesh, who served as a governing council member of the Indian Performance Rights Society (IPRS), died at a private hospital on Wednesday Feb 10, 2010 at the age of 48.
Kamal who is a famous Malayalam film director who has used many of Girirsh's lyrics in his movies said "I am at a loss to say anything. He used to say that he kept a separate pen to write for my films."
Well known singer M.G. Sreekumar, who has sung innumerous songs which had Gireesh's lyrics in them had no words to describe the tragic loss. Before his untimely death, Gireesh had written more than 1,700 songs in over 300 Malayalam films.
Posted by Admin at Wednesday, February 10, 2010
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Apricot Fruit Jelly for Cheese
A deeply fruity flavoured apricot jelly with an almost caramel colour.
The idea is taken from the tradition of serving dried apricots with cheese. Best enjoyed with goats' and ewes' cheeses
A must for preparing a truly great cheeseboard experience.
Available as a bundle of three jars where if you would like, you can switch jars 2 and 3 for any other of Hillside Foods' delicious fruits for cheese flavours.
Flavours available:
- Apricot
- Bramley Apple
- Pear
- Plum & Port
Shelf life: 18 months
apricot (65%), sugar, fruit pectin, lime juice, may contain apricot stones. Once opened keep refrigerated and consume within 4 weeks.
Nutrition Typical values per 100g energy 421kcal/1783kj fat 0.7g of which saturates 0.0g carbohydrate 94.1g of which sugars: 93.0g fibre 10.1g protein 4.4g salt 0.1g
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|3 to 5 working days
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|2 to 3 working days
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