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The present invention provides novel broad spectrum antiseptic compounds that further have properties that allow them to be coated/impregnated into polymer surfaces. Methods for coating these antiseptic compounds onto medical devices especially indwelling medical devices to prevent the growth of pathogens in such devices and hence, to prevent infection to patients via such devices are provided. The invention also provides antiseptics that are useful as general surface disinfectants and sterilizers, fluid disinfectants and biocide preservatives.
1. A medical device coated or impregnated with a composition comprising chlorhexidine and a dye selected from the group consisting of gentian violet and brilliant green, wherein the medical device is selected from the group consisting of an endotracheal tube, a vascular catheter, a nephrostomy tube, a stent, an orthopedic device, a prosthetic valve, a urinary catheter, a peritoneal catheter, an epidural catheter, a central nervous system catheter, a blood exchanging device, a vascular access port, an extracorporeal circuit, a vascular graft, a pump, a glove, a table, and a medical implant.
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28. A method for preventing nosocomial infections in a subject comprising coating or impregnating a medical device that the subject is required to use with a composition comprising chlorhexidine and a dye selected from the group consisting of gentian violet and brilliant green, wherein the medical device is selected from the group consisting of an endotracheal tube, a vascular catheter, a nephrostomy tube, a stent, an orthopedic device, a prosthetic valve, a urinary catheter, a peritoneal catheter, an epidural catheter, a central nervous system catheter, a blood exchanging device, a vascular access port, an extracorporeal circuit, a vascular graft, a pump, a glove, a table, and a medical implant.
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38. An article comprising a glove coated or impregnated with a composition comprising brilliant green and chlorhexidine.
The present invention is a divisional of application Ser. No. 10/044,842, filed on Jan. 11, 2002, which claims priority to U.S. Provisional Application Ser. No. 60/261,447 filed on Jan. 12, 2001 and U.S. Provisional Application Ser. No. 60/316,165 filed on Aug. 30, 2001, the entire contents of each of which are incorporated herein by reference in their entirety.
1. Field of the Invention
The present invention relates generally to the fields of preventing infections. More particularly it provides novel broad spectrum antiseptic compositions that further have properties that allow them to be coated/impregnated into polymer surfaces or used as antiseptics in different applications. The invention provides methods for coating these antiseptic compositions onto medical devices such as catheters, tubes, stents and sutures, to prevent the growth of pathogens in such devices and hence, to prevent infection to patients via such devices. In addition, the invention provides novel antiseptics that could be used in disinfecting and sterilizing organic and inorganic surfaces, water and other fluids.
2. Description of Related Art
Most nosocomial infections are caused by the contamination of medical devices resulting in serious hospital-acquired infections. Nosocomial pneumonias are the second most common nosocomial infections, and are associated with the highest attributable mortality and morbidity. Recent data have shown that at least 300,000 episodes of nosocomial pneumonia occur annually in the United States (Official Statement, American Thoracic Society). The attributable mortality of this infection is 33%-50%, hence, around 100,000 patients die annually because of nosocomial pneumonia (CDC, 1993; Leu et al., 1989). The risk of nosocomial pneumonia increases 6- to 20-fold from the use of mechanical ventilation (Official Statement, American Thoracic Society).
The endotracheal tube is considered a common vehicle for colonization/contamination leading to nosocomial pneumonia. The endotracheal tube connects the oropharyngeal environment with the sterile bronchoalveolar space, significantly increasing the risk of nosocomial pneumonia. Endotracheal tubes are typically constructed of polyvinylchloride, which is known to be very difficult to impregnate with antiseptic or antimicrobial agents. Thus, there are no endotracheal tubes that are impregnated with antibiotics or antiseptics currently in use.
Another leading cause of serious nosocomial infections is bloodstream infections. The primary contributors to nosocomial bloodstream infections are vascular catheters. It is estimated that around 400,000 vascular catheter-related bloodstream infections (CRBSI) occur annually in the United States (Raad, 1998). The attributable mortality of these infections in the intensive care unit (ICU) was estimated in JAMA in 1994 to be 25% (Reiselman et al., 1994). Hence, these infections are a major cause of morbidity and mortality in hospitalized patients. These catheters are mostly polyurethane short-term catheters used in the ICU and long-term silicone catheters used in cancer/AIDS patients.
The most frequent causes of nosocomial infections are urinary tract infections (UTI), contributing to 34% of all nosocomial infections (Klempner et al., 1998). Nosocomial UTI are usually associated with contamination of urinary catheters. In addition, nosocomial surgical wound infections are common complications of surgical procedures, particularly in cancer and immunocompromised patients with devitalized tissue and decreased immunity. Surgical wound infections contribute to 17% of all nosocomial infections (Platt and Bucknall, 1988). Many surgical wound infections are associated with the contamination of sutures.
Antibiotics are strictly antibacterial agents that are usually used in treatment of systemic or bloodstream infections and are given through oral, intravenous, subcutaneous, or intramuscular routes to achieve systemic bloodstream levels. Examples include penicillin, cephalosporins, vancomycin, minocycline, and rifampin.
Antiseptics on the other hand, are antimicrobial agents often with broad spectrum antimicrobial activity against bacteria, fungi or viruses. These agents are used on the skin and external mucosal surfaces usually because of limitations related to absorption, penetration or systemic toxicity. These agents are not used in the treatment of bloodstream infections. Examples include chlorhexidine and povidone iodine.
Antibiotics and antiseptics have been used to impregnate vascular catheters. The concern with the use of antibiotics has been that resistance might develop to antibiotics, preventing their use therapeutically and systemically in hospitalized patients. Furthermore, the durability of the existing antiseptics has been limited. For example, the use of chlorhexidine/silver sulfadiazine on polyurethane surfaces has had limited effectiveness. Moreover, chlorhexidine/silver sulfadiazine impregnating the surface of vascular catheters resulted in limited activity against gram-negative bacilli, such as Pseudomonas.
What is needed is an effective antiseptic having broad spectrum activity against resistant staphylococci, vancomycin-resistant enterococci, resistant Pseudomonas aeruginosa and Candida species, to be used in conjunction with indwelling devices that will inhibit or prevent the nosocomial infections typically associated with the use of these indwelling devices. It would be further desirable to develop devices impregnated with the antiseptic to enhance the resistance to infection. For example, the creation of antiseptic-impregnated catheters would prevent organisms from adhering or migrating on catheter surfaces.
The present invention overcomes these and other drawbacks inherent in the art by providing novel antiseptic derivatives with broad-spectrum activity against various microbes including resistant bacteria and fungi. Methods of preparing these antiseptic compounds and methods for utilizing them are provided.
Therefore, the invention provides an antiseptic composition comprising a basic reagent and a dye. The basic reagent may be bonded to the dye. In one aspect, the basic reagent and the dye are bonded ionically to form the antiseptic compound. In another aspect, the basic reagent and the dye are bonded covalently to form the antiseptic compound. The basic reagent and the dye can be combined in any amount to obtain the antiseptic composition of the invention, however, in a particular embodiment, an equimolar amount of the basic reagent is added to the dye solution. The inventors also contemplate that the antiseptic composition of the invention can be made by combining other amounts of the dye and basic reagent for example, one may combine, in molar ratios, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1.85, 1:90, 1:95, to 1:99 of either dye:basic reagent or basic reagent:dye. This includes all the intermediate ranges as well, for example it includes molar ratios such as, 1.1:1, 1.2:1, 1.3:1, 1-4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 and the like for other values listed. It also includes the ranges in between these values such as 1.11: 1, 1.12:1 and so on. The skilled artisan will therefore recognize that the dye and basic reagent can be combined in different molar ratio amounts to obtain the antiseptic composition disclosed and that the invention is therefore not limited to any particular molar ratio of dye:basic reagent or basic reagent:dye.
In certain embodiments, the dye can be a triarylmethane dye, a monoazo dye, a diazo dye, an indigoid dye, a xanthene or a fluorescein dye, an anthraquinone dye, or a quinoline dye. In other specific embodiments, the dye is gentian violet, or crystal violet, ethyl violet, brilliant green, an FD&C dye, or a D&C dye. In one example, the FD&C dye is Blue No. 1 or Green No. 3. In another example, the triarylmethane dye is gentian violet. In yet another example, the monoazo dye is FD&C Yellow No. 5 or FD&C Yellow No. 6. In still another example, the diazo dye is D&C Red No 17. The indigoid dye, may preferably be FD&C Blue No. 2. An example of a xanthene dye is FD&C Red No. 3, of an anthraquinone dye is D&C Green No. 6 and an example of a quinoline dye is D&C Yellow No. 1. In addition, Table 1 provides a list of different dyes that may be used in this invention. One of skill in the art will recognize that these examples are non-limiting and that the antiseptic compounds and compositions of the present invention can be made using almost any dye.
A wide variety of basic reagents can be used to form the antiseptic composition. The basic reagents include any nucleophilic species which includes all electron donor species. Some of the basic reagents that can be used include a guanidium compound, a biguanide, a bipyridine, a phenoxide antiseptic, an alkyl oxide, an aryl oxide, a thiol, an aliphatic amine, or an aromatic amine and halides such as F, Br and r. Some examples of guanidium compounds that may be used include chlorhexidine, alexidine, and hexamidine. One example of a bipyridine compound that can be used to synthesize the antiseptics of the invention is octenidine. Examples of phenoxide antiseptics used include colofoctol, chloroxylenol, and triclosan.
The invention also provides an antiseptic compound comprising a basic reagent bound to a dye. In some particular embodiments, the basic reagent and the dye are bound ionically. In other particular embodiments, the basic reagent and the dye are bound covalently. Some examples of the invention, the antiseptic compound comprises compositions such as gendine, genlenol, genlosan, or genfoctol.
In some embodiments, the antiseptic compound provided herein is further capable of impregnating and/or coating a surface.
In some aspects, the surface is composed of a polymer. Examples of such polymeric surfaces include polyvinyl chloride, polyurethane, polyethylene, silastic elastomers, polytetrafluoroethylene, dacron, collodion, carboethane or nylon. Alternatively, the surface may be composed of silicone or may be a silk suture. For example, these novel antiseptic derivatives have the potential for serving as impregnators of medical device surfaces, such as endotracheal tubes made of polyvinyl chloride, vascular catheters made of either polyurethane or silicone, and silk sutures used for suturing surgical wounds.
In other embodiments, the antiseptic compound can coat and/or impregnate an organic surface. Examples of organic surfaces include the skin, a mucosal surface, a wound. Examples of wounds are surgical wounds, trauma wounds, burn wounds and the like.
In yet other embodiments, the antiseptic compound can coat and/or impregnate an inorganic surface. Examples of such inorganic surfaces include floors, table-tops, counter-tops, surfaces of a hospital equipment, wheelchair surfaces, etc. Virtually any surface comprising a material that is capable of being coated by, impregnated with, absorbing or otherwise retaining the antiseptic compounds of the invention may be disinfected and/or sterilized using the present antiseptic compounds and their compositions. Thus, the antiseptic compound of the invention can be used to disinfect, sanitize and sterilize a wide variety of surfaces.
The invention also provides medical devices coated with a basic reagent and a dye. In one aspect the medical devices are coated with a basic reagent and a dye that are ionically bound. In another aspect the medical devices are coated with a basic reagent and a dye that are covalently bound. Examples of medical devices include endotracheal tubes, a vascular catheter, an urinary catheter, a nephrostomy tube, a biliary stent, a peritoneal catheter, an epidural catheter, a central nervous system catheter, an orthopedic device, a prosthetic valve, and a medical implant. The vascular catheter may be a central venous catheter, an arterial line, an pulmonary artery catheter, and a peripheral venous catheter. The central nervous system catheter may be an intraventricular shunt. Other medical devices that can benefit from the present invention include blood exchanging devices, vascular access ports, cardiovascular catheters, extracorpeal circuits, stents, implantable prostheses, vascular grafts, pumps, heart valves, and cardiovascular sutures, to name a few. Regardless of detailed embodiments, applicability of the invention should not be considered limited with respect to the type of medical device, implant location or materials of construction of the device.
The invention also provides methods for coating a medical device with an antiseptic compositions comprising: a) immersing a medical device in a solvent comprising a basic reagent and a dye; b) drying the device; and c) washing off excessive composition. In some embodiments, the solvent used to immerse the device can be methylene chloride, methanol, or a combination thereof.
The invention also provides methods for preventing nosocomial infections in a subject comprising coating a medical device that the subject is required to use with a composition comprising an antiseptic compound comprising a basic reagent bound to a dye. The subject can be human or an animal model.
The type of nosocomial infection that can be prevented by the methods of this invention include, but are not limited to, pneumonia, bacteremia, fungimia, candidemia, a urinary tract infection, a catheter-exit site infection, and a surgical wound infection.
The nosocomial infections that can be prevented may be caused by bacteria. In some embodiments the bacteria are drug resistant bacteria. Some non-limiting example of drug resistant bacteria include methicillin-resistant staphylococci, vancomycin-resistant enterococci, and resistant Pseudomonas aeruginosa.
The nosocomial infection may be caused by a fungus. In some cases the fungal agent is a drug resistant fungi. Examples of a drug resistant fungi include members of the Candida species. Other pathogenic organisms that can cause the nosocomial infections are cited elsewhere in this specification and coating devices and surfaces with the antiseptics of the present invention can prevent infections by these organisms as well.
The invention also provides methods for disinfecting and/or sterilizing a surface comprising applying the antiseptic composition of the invention to the surface. Examples of surfaces that may be disinfected and/or sterilized include organic surfaces such as skin, mucosal surfaces, wound surfaces and the like. Other examples include inorganic surfaces such as floors, table-tops, counter-tops, hospital equipment, wheel chairs, gauze, cotton. The skilled artisan will realize that most any surfaces can be disinfected or sterilized by the antiseptic compositions provided herein.
The invention also provides methods for disinfecting and/or sterilizing a fluid comprising adding a composition comprising a basic reagent and a dye into the fluid. The inventors contemplate that different types of fluids may be disinfected and some non-limiting examples include water, such as water in coolers and swimming pools, metal working fluids, and petroleum.
The invention also provides several novel biocide preservative compounds comprising the antiseptic compositions described above. Also provided are methods for preserving substances by applying the compositions of the invention on the substance. A variety of substances may be preserved by the biocide preservatives of the invention and they include wood, paint, plastic and paper.
Thus, the antiseptic compositions of the present invention have broad uses including use in healthcare by providing sterile medical devices and surface sterilization and decontamination, as environmental decontaminents, fluid decontaminents and in the industrial world as biocide preservatives.
As used herein the specification and claim(s), the words "a" or "an" when used in conjunction with the word "comprising" may mean one or more.
As used herein the specification and claim(s), the words "ionic bonding" or "ionically bound" refers to the electrostatic interactions among ions which can be formed by the transfer of one or more electrons from one atom or group of atoms to another, to create an ionic bond between the basic reagent and the dye comprising an antiseptic compound.
As used herein the specification and claim(s), the words "covalent bonding" or "covalently bound" refers to the chemical bond formed by the sharing of one or more pairs of electrons between the basic reagent and the dye comprising an antiseptic compound.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
Indwelling catheters and other similar implanted medical devices are used routinely in hospitals on a diverse group of patients. A common cause of failure of these medical devices is infection. Pathogens often attach to and proliferate in such devices and eventually invade the patient leading to nosocomial infections. Microorganisms usually migrate along the surfaces of devices to invade sterile environments, such as the bronchoalveolar space leading to pneumonia, the bloodstream leading to bacteremia, or the urinary bladder leading to urinary tract infections.
The present invention provides a series of novel antiseptic compositions with broad-spectrum activity against various nosocomial microorganisms, including resistant bacteria and fungi. For example, the antiseptic compositions are effective against resistant staphylococci, vancomycin-resistant enterococci, resistant Pseudomonas aeruginosa and Candida species. These novel antiseptics also have unique properties that enable penetration/impregnation of various polymers, such as polyvinyl chloride, polyethylene, silastic elastomers, polytetrafluoroethylene, dacron, collodion, carboethane, nylon, polymers used in the formation of endotracheal tubes, silicone and polyurethane polymers used in the formation of vascular catheters and surgical silk sutures. Thus, they are suitable for coating a wide range of device surfaces.
The inventors demonstrate herein that these novel antiseptics maintain prolonged antimicrobial activity on device surfaces, and thus may be used for the entire lifespan of these indwelling devices. This is an improvement over existing coated or impregnated devices where the antimicrobial activity of the device diminishes over time and eventually disappears altogether. For example, several prior art patents and publications describe methods of coating which generated medical devices wherein the effectiveness of the coating diminishes over time. After insertion of the medical device, the antibiotics and/or antiseptics quickly leach from the surface of the device into the surrounding environment. Over a relatively short period of time, the amount of antibiotics and/or antiseptics present on the surface decreases to a point where the protection against bacterial and fungal organisms is no longer effective. Thus, the present invention provides safe antiseptic treated devices wherein the antiseptic coating has a durability that may last through the life-span of the device. This significantly decreases patient mortality and morbidity associated with the various nosocomial infections such as nosocomial pneumonias, nosocomial bacteremias, nosocomial urinary tract infections and nosocomial surgical wound infections. For example, creation of antiseptic-impregnated/coated catheters prevents organisms from adhering to or migrating on catheter surfaces. Thus, when a pathogenic organism approaches the catheter surface, it is killed by the antiseptics.
The invention also provides methods for the synthesis of novel broad-spectrum antiseptic derivatives. The general method for synthesis of the novel antiseptic derivatives involves the binding of a dye with one or more basic reagents. Different types of dyes and basic reagents can be used to prepare the antiseptic compounds of this invention.
The dyes that may be used to synthesize the antiseptic compounds of the invention include but are not limited to, gentian, or crystal violet, ethyl violet, brilliant green, etc., and the FD&C dyes such as Blue No. 1 and Green No. 3. In addition, other dyes include the following FD&C and D&C colors: (1) Monoazo dyes such as, but not limited to, FD&C Yellow No. 5, FD&C Yellow No. 6, (2) Diazo dyes such as, but not limited to, D&C Red No. 17, (3) Indigoid dyes such as, but not limited to, FD&C Blue No. 2, (4) Xanthene (Fluorescein) dyes such as, but not limited to, FD&C Red No. 3, (5) Anthraquinone dyes such as, but not limited to, D&C Green No. 6, (6) Quinoline dyes such as, but not limited to, D&C Yellow No. 1. An extensive list of dyes and stains that may be employed is also provided in Table 1.
The basic reagents can be alkyl and aryl oxides, thiols, sulfides, phosphorous, aliphatic and aromatic amines, guanidines and halides such as F−, Bf− and I−. Some examples of the basic reagents that can be used include phenoxide antiseptics (such as clofoctol, chloroxylenol, triclosan) or guanidium compounds (such as chlorhexidine, alexidine, hexamidine) or bipyridines (such as octenidines).
One unique feature of these novel antiseptics is that they do not require another vehicle to attach to a surface. The adhesive potential of the dye makes them self-adhesive to surfaces of devices.
The antiseptic compound is therefore applied on the surface of a device by simply immersing the device in the antiseptic solution, air drying and washing out excessive antiseptic. The self-impregnating property of the dyes such as for example, the triarylmethane dyes, removes the need for another binding agent. This is another feature of the composition provided by this invention which is a considerable improvement over other known compositions. Previously known compositions require other impregnating/coating agents and/or must typically be extruded into the device as it is made. Both these methods are time consuming and involve additional steps and techniques. For example, one method of coating devices first requires application or absorbtion of a layer of surfactant, such as tridodecylmethyl ammonium chloride (TDMAC) followed by the antibiotic coating layer, to the surface of the medical device. Another method used to coat surfaces of medical devices with antibiotics involves first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antibiotic composition (Solomon and Sherertz, 1987; U.S. Pat. No. 4,442,133). Other methods of coating surfaces of medical devices with antibiotics are taught in U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pH of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917,686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ionically bind antibiotics); U.S. Pat. No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); and U.S. Pat. No. 4,952,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders). Furthermore, most of the methods previously employed to coat the surfaces of medical devices use antibiotics such as tetracyclines, penicillins, cephalosporins and the beta-lactam antibiotics. The main drawback with antibiotics is the emergence of resistant strains.
Thus, the invention provides novel antiseptic derivative compounds with broad-spectrum antiseptic activity against bacteria and fungi including nosocomial and multidrug-resistant varieties with the additional ability to impregnate, bind, coat, adhere and/or attach to various device surfaces without the assistance of impregnating vehicles such as tridodecylmethylammonium chloride (TDMAC). Furthermore, the novel antiseptic compounds of the invention also have an extended antimicrobial efficacy that can cover the life of the device.
One example of the novel broad-spectrum antiseptic derivatives of this invention is gendine, which consists of the combination of gentian violet and chlorhexidine. Gentian violet, on its own, is a good impregnating triarylmethane dye. Bhatnager et al., 1993 have shown in an in vitro study that gentian violet alone can be used to impregnate the surface of CSF silicone shunts and prevent the colonization of S. epidermis on these surfaces. However, after impregnating the surfaces of various polymers, including polyvinylchloride, gentian violet on its own has no activity against Pseudomonas aeruginosa, which is the second most common cause of nosocomial pneumonia and the third most common cause of nosocomial urinary tract infections. Antiseptics such as chlorhexidine cannot attach on their own onto the surfaces of polyvinylchloride tubes or silicone catheters and silk sutures. They require an impregnating vehicle. Furthermore, on their own they are not highly active against Pseudomonas aeruginosa. On the other hand, upon the binding of gentian violet with chlorhexidine, the new antiseptic agent synthesized, is a potent and effective broad-spectrum antiseptic and has the additional ability to coat/impregnate various device surfaces. Gendine is unique in its ability to impregnate various device polymers, such as polyvinylchloride used in the formation of endotracheal tubes, silicone and polyurethane polymers used in the formation of vascular, as well as peritoneal, epidural, urinary and intraventricular catheters. In addition, gendine is able to impregnate the silk sutures used in surgical wounds.
In addition to Gendine, other antiseptics encompassed by this invention are Genlenol and Genfoctol.
The invention also provides methods to generate a wide variety of antiseptic medical devices. Some examples include antiseptic endotracheal tubes, antiseptic vascular catheters, including central venous catheters, arterial lines, pulmonary artery catheters, and peripheral venous catheters, antiseptic urinary catheters, antiseptic nephrostomy tubes, antiseptic biliary stents, antiseptic peritoneal catheters, antiseptic epidural catheters, antiseptic central nervous system catheters, including intraventricular shuts and devices, antiseptic prosthetic valves, orthopedic implants and antiseptic sutures.
The nosocomial bacterial infections result in diseases such as bacteremia, pneumonia, meningitis, osteomyelitis, endocarditis, sinusitis, arthritis, urinary tract infections, tetanus, gangrene, colitis, acute gastroenteritis, bronchitis, and a variety of abscesses, and opportunistic infections. Bacterial pathogens include Gram-positive cocci such as Staphylococcus aureus, coagulase negative staphylocci such as Staphylococcus epidermis, Streptococcus pyogenes (group A), Streptococcus spp. (viridans group), Streptococcus agalactiae (group B), S. bovis, Streptococcus (anaerobic species), Streptococcus pneumoniae, and Enterococcus spp.; Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, and Branhamella catarrhalis; Gram-positive bacilli such as Bacillus anthracis, Corynebacterium diphtheriae and Corynebacterium species which are diptheroids (aerobic and anerobic), Listeria monocytogenes, Clostridiuni tetani, Clostridium difficile, Escherichia coli, Enterobacter species, Proteus mirablis and other spp., Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella, Shigella, Serratia, and Campylobacterjejuni. The antibiotic resistant bacteria that can be killed by the antiseptic coated devices of the present invention include Staphylococci (methicillin-resistant strains), vancomycin-resistant enterococci (Enterococcus faecium), and resistant Pseudomonas aeruginosa.
Fungal infections that may be prevented include fungal infections (mycoses), which may be cutaneous, subcutaneous, or systemic. Superficial mycoses include tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, and other candidoses such as vaginal, respiratory tract, biliary, eosophageal, and urinary tract candidoses. Systemic mycoses include systemic and mucocutaneous candidosis, cryptococcosis, aspergillosis, mucormycosis (phycomycosis), paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, and sporotrichosis. Fungal infections include opportunistic fungal infections, particularly in immunocompromised patients such as those with AIDS. Fungal infections contribute to meningitis and pulmonary or respiratory tract diseases.
Other pathogenic organisms that may be prevented from causing the infections include dermatophytes (Microsporum canis and other M spp.; and Trichophyton spp. such as T. rubrum, and T mentagrophytes), yeasts (e.g., Candida albicans, C. Parapsilosis, C. glabrata, C Tropicalis, or other Candida species including drug resistant Candida species), Torulopsis glabrata, Epidermophytonfloccosum, Malassezia fuurfur (Pityropsporon orbiculare, or P. ovale), Cryptococcus neoformans, Aspergillus fumigatus, and other Aspergillus spp., Zygomycetes (Rhizopus, Mucor), hyalohyphomycosis (Fusarium Spp.), Paracoccidioides brasiliensis, Blastomyces dermatitides, Histoplasma capsulatum, Coccidioides immitis, and Sporothrix schenckii. Fungal infections include Cladosporium cucumerinum, Epidennophyton floccosum, and Microspermum ypseum.
The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
Impregnation Procedure
The general procedure involves, and when applicable, prior preparation of the basic reagent (such as chlorhexidine) in anhydrous solvent, addition of the basic reagent to a solution of a dye (such as Gentian violet) in anhydrous solvent (or addition of the dye to the basic solution), stirring the resulting mixture for 30-90 minutes at ambient conditions, evaporating the solvent also under ambient conditions, and finally dissolution of the residue prior to impregnation. The following procedure illustrates impregnation with Gendine, an example for employing a basic guanidium derivative (e.g., chlorhexidine) and triarylmethane dye (e.g., Gentian violet).
Potassium tert-butoxide in THF, 7.35 ml of 1M solution, was added to a solution of CHX diacetate, 1.533 g; 2.45 mmol in 35 ml THF. The resulting heterogeneous solution was stirred for 20 minutes, then added to a solution GV, 1.0 g; 2.45 mmol, in 30 ml THF (GV used as an example of Triarylmethane Dye). The mixture was stirred at ambient conditions for 1 hour, then placed under the hood overnight to evaporate the solvent. The resulting residue was dissolved in 30 ml DCM (or MeOH). When applicable, the base (such as neutral form of chlorhexidine) is added to a stirring solution of dye (such as GV) in DCM and the resulting mixture is stirred for at least 1 h. With anionic dyes, dissolution is achieved with the addition of at least one equivalent of a quaternary amine (such as tetraethylammonium) prior to addition of the base. One-centimeter device segments were immersed in the DCM solution for the appropriate period, generally PVC and PU for 10 minutes; Silicone (Si) and Silk Suture for 2 hours. The devices were removed from the solution, and traces of solution were removed from the lumen when applicable. The impregnated devices were placed under the hood to dry for at least 4 hours, preferably over night, then washed with distilled water until the washings were colorless or very faint, and finally placed under an aseptic hood to dry under ambient conditions for at least 4 hours, preferably overnight.
In Vitro Antimicrobial Activity
The antimicrobial activity of impregnated catheters was evaluated in duplicate by a modified Kirby-Bauer technique. BBL Mueller Hinton II agar plates (obtained from Fisher Scientific) were inoculated with 0.5 McFarland of the appropriate microorganism (hospital isolates from the MD Anderson Cancer Center). Then 10 mm segments of impregnated devices were embedded in the inoculated plates and placed in an incubator at about 37� C. for at least 18 hours. Zones of inhibition were measured perpendicular to the long axis of the device. Bioactivity against yeast constituted of two zones; a large outer zone of partial growth inhibition, and an inner smaller zone of complete inhibition. This later zone is reported herein.
Results and Discussion
Tables 2 and 3 illustrate zones of inhibition obtained for Gendine-impregnated devices:
Again data in Table 4 shows how silicone catheters impregnated with GN are more effective in inhibiting MRSA, PS and C. parapsilosis than catheters impregnated with either GV or CHX.
Similarly, Table 5 indicates that PU catheters impregnated with GN are more effective than PU catheter impregnated with GV in inhibiting Pseudomonas aeruginosa, and more effective than PU catheters impregnated with CHX against all three organisms, MRSA, PS and C. parapsilosis.
Table 6 as well shows that silk sutures coated or impregnated with GN are significantly more effective in inhibiting MRSA, PS and C. parapsilosis than sutures coated with either GV or CHX.
In addition to the simplicity of the impregnation procedure, and the availability of the requisite reagents, one unique feature of gendine-impregnated devices is its broad spectrum activity, not only against the worldwide problematic gram-positive MRSA, which has increased in frequency at an alarming rate as a cause of device-related infections, but also against Pseudomonas aeruginosa, an increasingly prevalent opportunistic human pathogen, and the most common gram-negative bacterium found in nosocomial infections. They are intrinsically more resistant than gram-positive bacteria to many antiseptics, particularly when present in a biofilm or when associated with a device infection (Platt et al., 1988).
For PVC and silicone (Si) devices, this invention shows no activity against Pseudomonas aeruginosa, when impregnated with either the immobilizing dye (gentian violet) or CHX alone. All devices impregnated with GN exhibit fair to good activity against Pseudomonas aeruginosa. This is important especially since Pseudomonas aeruginosa is responsible for 16% of nosocomial pneumonia cases (and is considered by the Centers for Disease Control as the second most common cause of nosocomial ventilator associated pneumonia), 12% of nosocomial urinary tract infections, 8% of surgical wound infections, and 10% of nosocomial bloodstream infections (Van Delden and Iglewski, 1998).
Staphylococcal resistance to antiseptics are known worldwide (Russel A. D., 1997). In addition to CHX, low-level resistance to three antiseptics (acriflavin, benzalkonium chloride, and hexamidine diisethionate is documented (Reverdy et al., 1992; Townsend et al., 1985; Heir et al., 1995). The present study reveals that all GN-impregnated devices, including sutures, exhibit significant biocidal activity against methicillin-resistant staphylococci. This finding is extremely important in light of the fact that methicillin-resistant staphylococci (MRSA and MRSE) are the leading causes of device-related infections, including vascular catheter-related bacteremia and surgical wound infections. In addition S. aureus is one of the leading causes of nosocomial pneumonia (Klempner et al., 1998).
The effectiveness of gendine-impregnated devices against Candida is no less noteworthy. As revealed from this study, silicone catheter and suture impregnated with GN exhibit fair to good activity against C. Parapsilosis, which is not the case for either GV or CHX-impregnated devices. Catheter-related candidemia is now the third leading cause of vascular catheter-related bloodstream infections (Raad et al., 1992). In addition, candidemia in severely immunocompromised patients (i.e., HIV, bone-marrow recipients and leukemia patients) is an important cause for morbidity and mortality and catheters are a major source for this infection (Tumbarello et al., 1998; Gonzalez et al., 1996; Lecciones et al., 1992; Wey et al., 1989). The known chlorhexidine-sulfadiazine impregnated catheters and the minocycline-rifampin impregnated catheters do not have significant prophylactic effect against fungi (Tacconelli et al., 1997; Raad et al., 1997).
Other GV Preparations
Antiseptics chloroxylenol [p-chloro-m-xylenol; 4-chloro-3,5-dimethylxylenol (PCMX)], Clofoctol [α-2,4-dichlorophenly)-4-(1,1,3,3-tetramethylbutyl)-o-cresol (CFTL), and Triclosan [2,4,4′-trichloro-2′hydroxydiphenyl ether] (TLS) are three of the phenolic antiseptic reagents included in this study. The first disinfectant is the first halophenol employed in many antiseptic and disinfectant formulations. Neither the neutral form of PCMX nor its sodium salt could produce in vitro zones of inhibition on their own through coating or impregnating the catheter devices and sutures. However, when the salt is reacted with GV (as an example of a triarylmethane dye), the resulting products (new products such as Genlenol, Genlosan and Genfoctol) are immobilized on the devices producing large in vitro zones of inhibition against various nosocomial pathogens. Meanwhile, Genlenol (GV+.PCMX−) not only increased the zone against MRSA considerably for the silicone catheter, but also produced a large zone against C. parapsilosis. Similar results were observed for silk sutures. Improvements in the zones of inhibition against C. parapsilosis are also observed for PVC tubes and PVC catheters, and to a large extent against Alcaligenes faecalis (a gram negative bacillary organism) for the PVC tubes. These results are summarized in Tables 7-10. Similar trends were observed for Genfoctol (GV+.CFTL−), but with much larger zones for sutures against MRSA and C. parapsilosis.
In general, many other gentian violet basic preparations significantly affect the efficacy and biocidal activity of coated sutures and silicone-impregnated catheters against MRSA and C. Parapsilosis. Some examples are shown below in Table 11.
The above data clearly demonstrate significant improvement in the biocidal activity of impregnated or coated silicone catheters and silk sutures by the antiseptic derivatives of the invention.
The antiseptic devices of the invention pose no significant risk. Hence, preclinical studies (animal studies) may not be required. This section is concerned with the development of human treatment protocols using the antiseptic medical devices of the present invention.
The various elements of conducting a clinical trial, including patient treatment and monitoring, will be known to those of skill in the art in light of the present disclosure.
The following information is being presented as a general guideline for use in establishing the use of the antiseptic medical devices.
Candidates will be patients who are seriously ill and are required to use a medical device such as those described in the sections above. The medical devices in these cases will be treated with Gendine, Genelol, Genfoctol, Genlosan or other antiseptic derivatives that can be synthesized by the methods provided herein, and the patients will be monitored for the occurrence of nosocomial infections.
To monitor the development of infections and to evaluate the efficacy of the antiseptic coated/impregnated medical devices in preventing the spread of infectious agents through the devices it is contemplated that the patients will be examined for appropriate tests every month. Tests that will be used to monitor the effectiveness of the treated medical device include: physical exam, X-ray, blood work and other clinical laboratory methodologies used to detect pathogens in the patients and also methods to detect presence of pathogens in the medical device. Described below is a study guideline for patients using central venous catheters.
Patient Eligibility. Patients will be recruited from intensive care units, bone marrow transplant and melanoma services and other hospital divisions where catheters are used routinely on inpatients. Patients who require a new insertion of a central venous catheter (CVC) and have none of the exclusion criteria will be approached to obtain informed consent. The exclusion criteria are the following:
The eligible consenting patient will be informed that the catheter to be inserted has either been coated with an antiseptic compound (for example Gendine) or has not been coated, but the subject will not be informed as to whether the specific catheter to be inserted contains the compound.
Each female with child bearing potential will have a urine sample prior to catheter placement to test for pregnancy (if appropriate).
Catheter insertion. Catheters will be inserted into a subclavian vein or internal jugular vein using gown, mask, sterile gloves and full sterile drapes. Skin will be prepped using povidone iodine allowing 1 minute of exposure time. After insertion, the catheter will be secured to the skin using tape and the skin puncture site will be covered with povidone-Iodine ointment. Then, the insertion site and the surrounding area will be covered with sterile gauze and taped securely.
Catheter maintenance. Catheters will be inspected every 72 hrs for evidence of site infection (erythema around catheter, purulent drainage, swelling tenderness over catheter). Every 72 hrs (or sooner if necessary) the dressing will be removed and the exit site will be re-prepped with povidone-iodine. All fluids, medications, etc. administered through each lumen will be documented.
Catheter types. The inventors contemplate using different types of catheters. For example, control catheters consist of triple lumen polyurethane catheters and single lumen polyurethane catheters will be tested among several others. The test catheters will be identical to the control catheters in appearance, but they will be coated with the antiseptics of the invention, for example, Gendine.
Trial design. The trial is a prospective randomized design. The patient, the health care worker inserting the catheter, the microbiologist culturing the catheter, and the evaluator will be blinded as to whether the catheter is coated or not coated with the antiseptics of the invention. They will, however, be identifiable by an assigned code number. After informed consent has been obtained a catheter will be pulled out of a box containing 6 test and control catheter placement trays. The boxes will consist of either triple or single lumen catheters and will be labeled as such. The trays will be placed in the boxes such that test and control catheters will alternate from top to bottom. Each box will contain 3 test and 3 control catheters. The unique identification number of the catheter will be recorded and will be included with the data analysis. Both the investigators and the patients will be blinded to the catheter identity throughout the study.
Statistical Considerations. Assuming a conservative baseline colonization and/or infection rate of at least 20% for central venous catheters, randomizing 75 patients to each arm would allow one to detect a change in catheter-related infection rates from 20% to 5% one sided significance and 80% power. If, after entering 150 patients, the infection rate in the test arm has dropped by 50% (that is from 20% to 10%) then the study will be expanded to include 400 patients (200 in each arm). Using the selection criteria described above, the inventors estimate that they will test about 40 patients each month. Aiming for a total of 150 evaluable patients the study will be completed in approximately 6 months.
Termination of Study. Patients will be kept on study until the catheter is removed. The indication for catheter removal will be documented for each catheter. These include but are not limited to:
When the patient becomes febrile, blood will be withdrawn simultaneously through the lumen of the catheter and peripheral vein for quantitative blood culture. At the time of catheter removal, the catheter will be removed under aseptic conditions and the tip and intracutaneous segments saved for culturing using the roll plate and sonication quantitative catheter culture technique. At the time of removal each lumen will be marked as to its prior use (hyperalimentation).
Patient Evaluation
1. Pre-insertion evaluation. Pertinent history will be taken and physical examination will be done regarding inclusion and exclusion criteria. Demographic data as well as details pertaining to underlying malignancy, treatment and antimicrobial treatment (including antimicrobial prophylaxis for infections in general in patients with hematologic malignancies) will be recorded. Investigational nature of study will be explained and informed consent will be obtained from patient. Pregnancy tests (serum or urine) will be obtained on all female patients with child bearing potential. If the test is positive, the patient will be excluded.
Initial catheterization procedure details will be recorded including catheter type, site and date of placement; difficulty of insertion, and complications if any. The difficulty of insertion will be determined by noting the following (a) number of attempts, to insert the catheter (b) time spent during insertion (c) malpositioning and repositioning of a catheter.
2. Post-insertion evaluation. All patients will be monitored until the catheter is removed. Catheter site evaluation will be undertaken every 72 hrs with the change of dressing. Special attention will be given to erythema, infiltration, pain, tenderness, swelling, suppuration, palpable cord in vessel, tissue warmth, lymphangitis or phlebitis. Details pertaining to chemotherapy, antineoplastic and antimicrobials, will be recorded. Catheter usage as for agents that might cause sclerosis of the vessel involved, hyperalimentation, blood and blood products administration, and drawing of blood will be noted. The catheter insertion site will be recorded on every patient. In addition, events of repositioning the catheter after displacement will be recorded. Microbiologic evaluation of insertion site will be undertaken in the form of site cultures if suppuration is present. If catheter related septicemia is suspected, blood cultures will be drawn simultaneously through catheter and by peripheral venipuncture. Another set of cultures will be drawn 24 hours later. If thrombophlebitis is suspected venous flow study of involved vessel will be done. If line related infection is suspected (including in patients with fever of unknown origin) or septicemia is documented, catheter will be changed over guide wire and distal as well as the proximal 5-7 cm of the catheter will be evaluated for semiquantitative cultures by the inventors. The purpose of this procedure is diagnostic and not therapeutic. It will attempt to make a definitive diagnosis of catheter related infection by isolating the organism from the catheter using quantitative techniques.
3. End of evaluation. When it is decided to withdraw the line, the catheter will be evaluated by the inventors for quantitative cultures. In addition, a quantitative blood culture will be drawn through the CVC lumen if the lumen is patent and peripherally if the patient is febrile.
Catheter Assessment
Success will be measured if there is no catheter related infection and failure will be indicated by the presence of a catheter related infection.
Adverse Reactions. All patients will be monitored for an unexpected adverse reaction (e.g. increased inflammation, phlebitis) associated with the coated catheter, using a statistical sequential test method. The study will be stopped if major adverse reaction is identified. Otherwise, the study will continue until 75 patients in each group have been enrolled.
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.
Tacconelli, Tumbarello, Pittiruti, Central venous catheter-related sepsis in a cohort of 366 hospitalized patients, Eur. J. Clin. Microbiol. Infect. Dis., 16:203-209, 1997.
Patent Citations
Non-Patent Citations
Referenced by
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This fast-cooking flatbread traditionally accompanies dal or curry dishes, but it's versatile enough to pair well with almost any soup or even to dip in hummus.
YIELD: Makes 12 rounds
ACTIVE TIME: 1 hr
TOTAL TIME: 2 hr (includes standing)
Stir together flour and salt in a large bowl, then make a well in center and add water to well. Using a fork, stir until a dough forms. Turn dough out onto a lightly floured surface and knead, adding more flour as needed, until smooth and elastic (dough will be slightly sticky), about 8 minutes.
Transfer to a clean bowl and cover bowl with plastic wrap. Let dough stand at room temperature at least 1 hour.
Divide dough into 12 equal pieces and roll each piece into a ball, then cover with a kitchen towel (not terry cloth). Dip 1 ball of dough into additional flour, shaking off excess, then flatten ball with your hands on lightly floured surface.
Roll dough into a 5- to 6-inch round with a lightly floured rolling pin, lifting and rotating as necessary. Shake off excess flour, then transfer round to a sheet of wax paper and cover with another kitchen towel (not terry cloth). Repeat with remaining balls, arranging rounds in 1 layer (do not stack).
Heat a dry 10-inch cast-iron or heavy skillet over medium heat until hot. Lightly grease skillet with a paper towel dipped in oil, then cook one round of dough until underside is golden brown in spots, about 30 seconds. Gently turn over and cook until deep golden brown in spots, 30 seconds to 1 minute. Turn over again and cook, gently pressing with tongs, until chapati is cooked through, 30 seconds to 1 minute more. (Chapatis may puff up.)
Keep warm, wrapped in another kitchen towel, and cook remaining rounds. Serve immediately.
Cooks' Note: Dough can be made 12 hours ahead and chilled (after standing at room temperature 1 hour), covered with plastic wrap.

subset: commoncrawl


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BLISS Blood Orange + White Pepper Sugar Scrub
£31.00 Product Code 1725021
- Overview
Bliss' blood orange and white pepper sugar scrub is a vibrantly scented body scrub that lathers for gentle and supremely sudsy, skin cleansing and exfoliating action.
- Details
- Blood orange and white pepper body scrub
- Sucrose granules to gently exfoliate
- Vitamins A, C and E
- Sunflower oil for soft and supple skin
- Warm, invigorating scent
- 340g
- Regrettably, this product is non-returnable
- Delivery & Returns
Delivery Option Duration Price Standard Delivery 3-5 working days, M-F only. £5.95 Next Day Delivery Next working day on all orders placed before 1pm, M-F only. £12 Saturday Delivery Saturday only on orders placed before Friday 1pm £15.95 Delivery to Europe £20 Outside of Europe Click here for International Delivery Terms for overseas shipping. £25


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Dragon Ball vs One Piece vs Toriko "Project Versus J" Teaser Site Opens
833d ago - Project Versus J are still sketchy, beyond the general premise that the Namco Bandai crossover fi... | Gaming
Project Versus J Countdown Site Launched
834d ago - Sal Romano: ''It's been a while since we heard from Project Versus J, Namco Bandai's PlayStation... | Gaming
Follow AnimeShinbun on Twitter
Now - You can now follow AnimeShinbun on twitter and get the hottest news of the day as well as early contest announcements. | Promoted post
Project Versus J - Scan 4
920d ago - From V-Jump magazine comes another scan for the anime crossover game for PS3/PSVita, Project Vers... | Gaming
Project Versus J Art, Screenshots
930d ago - Namco Bandai Games has released art and screenshots for the anime crossover game, Project Versus J. | Gaming
Saiyan Island: 60 Character Wishlist for Project Versus J
930d ago - In order to celebrate 45 years of Shonen Jump, Namco Bandai is working a brand new anime crossove... | Gaming
Naruto Confirmed Playable in Project Versus J?
932d ago - Naruto will be joining DBZ, OP, and Toriko. | Gaming
Project Versus J (Dragon Ball x One Piece) Confirmed for PS3, Vita (3rd Scan)
934d ago - A new scan shows off screenshots and confirms the game for PS3/Vita | Gaming
Project Versus J Scan 2 (DBZ, One Piece Game)
940d ago - A new scan for the crossover game has been released. | Gaming
Project Versus J (DBZ x One Piece x Toriko)
941d ago - A new Dragon Ball Z, One Piece, and Toriko Game cross over game has been announced. | Gaming
9 stories found


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GenreRomance, Comedy, Drama
Release DateApril 13, 2012 (Limited)
Duration88 min.
StudioOlive Films
Official Siteclick here
REVIEWS RATE: Critics Readers [Rate It]
Cast and Crew
DirectorJulie Gavras
ProducerBertrand Faivre, Sylvie Pialat
ScreenwriterJulie Gavras, Olivier Dazat
- William Hurt as Adam
- Isabella Rossellini as Mary
- Joanna Lumley
- Kate Ashfield
- Simon Callow
- Luke Treadaway
"Late Bloomers" begins when Mary (Isabella Rossellini) and Adam (William Hurt), a high-functioning couple, realize that they have entered the senior category. Adam's reaction to this "discovery" is as frantic as his denial, and he desperately looks for a fountain of youth. Mary, on the other hand, decides to deal with the situation by doing what she does best: taking care of everyone. With humor and a great eye for complex emotions, writer/director Julie Gavras shows that while the experience of aging is real, the pressure to act any "certain age" is one of the biggest obstacles to a good life after 60.


text:
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Comments Thread For: BoxingScene.com's Television Picks of The Week
Is there a big event going on in boxing this week?
Just kidding.
Its here. The most anticipated date on the boxing calendar this year arrives and fever pitch is setting in. Two phenomenal fights lead the way on a single card and its not the only quality action of the week.
Boxing is at its best when it has a Superfight on tap and a degree of history doesnt hurt either.
Both are at hand in Las Vegas.
These are the picks of the week. [Click Here To Read More]
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Canelo Cunningham era? What is that about? Anyway speaking of Cunningham, He had way more speed and skill than Tyson Fury, but he still got knocked out. It was the weight that broke the camels back, not a straw. Floyd might be getting into the ring with a light heavy come fight night
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Mississippi State head coach John Cohen continues to feel freshman arms are what get you beat in Southeastern Conference.
Against Sacred Heart however, they get you a 6-5 victory on Saturday night.
The town of Maben honored DONALD LEE Former member of the Superbowl Champion Green Bay Packers Football team with a variety of special community-wide activities Saturday.
For the Daily News
The Cotton District Arts Festival is on Saturday, April 23, and this year's festival is not to be missed!
By SHELIA BYRD
Associated Press
Republican Lt. Gov. Phil Bryant's hands-on approach to redistricting may have shown he can be vulnerable in the 2011 governor's race.
By HOLBROOK MOHR
Associated Press
Distinguished Young Women of Starkville formerly Starkville's Junior Miss Scholarship Program, awarded scholarships to high school girls throughout the area on February 26. Â
By Ruth Morgan
For the Oktibbeha County Heritage Museum
By Dottie Dewberry
Maben News
The Trace Way Restaurant hosted the self-defense class sponsored by the National Crime Prevention Task Force on Monday, March 7, at 6:30 p.m.
"The future belongs to those who believe in the beauty of their dreams."
— Eleanor Roosevelt


text:
Dr. Debra Eisner specializes in general podiatry in Haverhill, Massachusetts.
Primary Location for Dr. Eisner
Board Certification, Specialty and Expertise
Dr. Debra Eisner has been identified as specializing in General Podiatry.
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text:
Tylan LPCVD Furnace Operation (short)
Clean substrates
Diffusion clean with HF last
Enable the furnace
Verify Pump program running
Go to the furnace and use the STATUS button to verify that the system is in 'RUN' mode and running the "PUMP program".
End Pump program
ALARM ACK twice
Verify the Tube is vented
Ten minutes after the pump program has ended you must manually test that the tube is vented. Push MANUAL on the boat puller, push FAST, then LOOK AT THE TUBE while you hold down OUT. You should immediately see the boat start to come out. If it does not, stop and wait 10 more minutes and test it again.
Load your program (only after verifying manually that tube is vented)
From TYCOM type "LO <program name> <furnace#>" <RET>. You will be asked to enter the deposit time.
Run program
Load your wafers
Send in tube
ALARM ACK once
Monitor furnace
Take pressure readings during the gross leak check, leak check and the deposition steps of the program and write the values in the logbook.
Unload wafers
End program
ALARM ACK twice
Load pump program
Run Pump program
Measure wafers and log results
Disable the furnace.
Process Monitoring and Machine Qualification
To provide a standard procedure to monitor Poly thickness and uniformity both wafer-to-wafer and within-a-wafer.
To be completed after major maintenance such as a tube change or on a set schedule to be determined or as needed based on user feedback.
Test results are recorded on Coral.
- Use four wafers with 1000A of SiO2.
- Clean at wbdiff in the following sequence; 5:1:1 H2O:H2O2:NH4OH ten minutes, rinse, 5:1:1 DI;HCl:H2O2 ten minutes, rinse, spin dry.
- Load program POLYEMIT into Tylanpoly furnace. Time variable is 00:15:00.
- Load wafers into boats using very clean tweezers or vacuum wand. Load wafers with the major flat up into the boats in the following positions:
1st boat: (Front), 20 empty slots,
1st two dummies,
1st boat: two test wafers(slot 23 & 24),
1st boat: one dummy.
2nd boat: one dummy,
2nd boat: two test wafers (slot 2 &3),
2nd boat one dummy, 21 empty slots.
Test wafer location
Use Nanospec to measure poly thickness at the flat, center, bottom, left and right on each wafer. Test sites should be no more than about 15mm from the edge of the wafer.
Record results on the on coral. If test's values aren't not within 10% of plotted test average, contact the Diffusion Process/Maintenance team.
Save wafers in a box with the date, furnace number, program name and growth time. They may be re-tested sometime in the future.
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Around the Nation
5:38 am
Wed November 7, 2012
New Mother Votes Before Delivering Baby Girl
By editor
Originally published on Wed November 7, 2012 8:31 am
Good morning. I'm Renée Montagne. First-time mother and first-time voter Galicia Malone of Chicago didn't expect to become both on the same day. After going into labor a 3:00 AM, the 21 year old stopped by New Life Celebration Church to vote before driving to the hospital where she delivered a baby girl.
In order to get through her contractions as she marked her ballot, Malone said she told herself to read and breathe, read and breathe, read and breathe, and vote. It's MORNING EDITION. Transcript provided by NPR, Copyright National Public Radio.


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July 5, 2015
- Heading north on S. Kansas Ave. when driver crossed center lane
- Hit two parked vehicles
- Driver taken to hospital with non-life threatening injuries
- Unknown why the driver was driving on the sidewalk
- Two other vehicles were unoccupied
Stay Connected Anywhere
TOPEKA, Kan. (WIBW) - A man ended up in the hospital this afternoon, after driving down a sidewalk.
Police say the driver was northbound on S. Kansas Avenue when he drifted across the center line.
He then drove up onto the sidewalk, hitting a parked van and pushing the van into another vehicle.
Police are not sure why he was driving on the side walk. The driver was taken to Stormont Vail with minor injuries.
The two other vehicles were unoccupied at the time.
Police ask anyone with information on the crash to call Crime Stoppers at 234-0007.
Click Here to access the online Public Inspection File
Viewers with disabilities can get assistance accessing this station's FCC Public Inspection File by contacting the station with the information listed below. Questions or concerns relating to the accessibility of the FCC's online public file system should be directed to the FCC at 888-225-5322, 888-835-5322 (TTY), or firstname.lastname@example.com.


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The UNEP Environmental Assessment of Ogoniland
The Shell Petroleum Development Company of Nigeria Ltd (SPDC) welcomes the United Nations Environment Programme (UNEP) report 'Environmental Assessment of Ogoniland'.
Summary of the key recommendations of the UNEP report
The UNEP Environmental Assessment of Ogoniland
The United Nations Environment Programme (UNEP) released its Environmental Assessment of Ogoniland in August 2011. The report was commissioned by and delivered to the Federal Government of Nigeria. It makes recommendations to the government, the oil and gas industry and communities to begin a comprehensive cleanup of Ogoniland, restore polluted environments and put an end to all forms of ongoing oil contamination in the region.
Restoring Ogoniland
UNEP assessed that the environmental restoration of Ogoniland could take many years to achieve even with coordinated efforts on the part of government agencies at all levels, industry operators and communities. UNEP also presented its recommendations as a major opportunity to bring new investment, employment opportunities and a culture of cooperation to Ogoniland in addition to driving improvements in the environmental and health situation on the ground.
Multi-stakeholder response
The majority of UNEP's recommendations require multi-stakeholder efforts coordinated by the Federal Government. The Shell Petroleum Development Company of Nigeria (SPDC) is one of the stakeholders addressed in the UNEP report, although the joint venture it operates has not produced oil or gas in Ogoniland since 1993. SPDC has made progress in addressing all of the recommendations directed to it in the UNEP report.
In July 2014 the Minister of Petroleum recommended the convening of a multi-stakeholder workshop, under the leadership of the Federal Government of Nigeria, to inject fresh urgency into implementation of the UNEP report and deliver a comprehensive remediation programme for Ogoniland. SPDC, as operator of the SPDC Joint Venture, supports this initiative.
Crude oil theft
Crude oil theft, sabotage and illegal refining are the main sources of pollution in the Niger Delta today and accounted for 92% of oil volume spilled from SPDC facilities in 2009-13. Incidents of oil theft and willful damage continue to take place along the Trans-Niger Pipeline in Ogoniland, with severe impacts on the environment.
The UNEP report calls for a coordinated effort between government, oil and gas companies and communities to bring an end to theft and illegal refining and urges communities to take a proactive stand against individuals and groups engaged in these activities.
Frequently Asked Questions on the UNEP Report
- What are Shell's interests in Ogoniland?
- What is the UNEP report?
- What recommendations did the UNEP report make and who is responsible for implementing it?
- Who will pay for the restoration of Ogoniland?
- What actions have been taken by SPDC?
- What progress has SPDC made in restoring the environment of Ogoniland?
- What changes has SPDC made to its oil spill remediation techniques?
- Why is it taking so long to implement the UNEP report?
- What is SPDC doing to prevent new oil pollution in Ogoniland?
Related Links
SPDC and Ogoniland
The UNEP report covers oil spills in Ogoniland, an area covering about 1% of the Niger Delta. In 1993 SPDC shut down all production in Ogoniland due to threats and violence against our staff and facilities.
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The Penningtons Manches travel law team specialises in providing fast, innovative and effective solutions for travel industry clients in this complex and ever-changing area of law. We represent high-profile travel insurers, underwriters, Lloyds syndicates, intermediaries and assistance companies.
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Originally written on Football Nation | Last updated 12/18/12
The 2012 season got off to an embarrassing start, with the replacement refs giving us plenty to complain about, with awful calls, tediously slow-paced games, and general ineptitude. While you could probably make a "most embarrassing moments" list jut of the replacement refs, that would be unfair to the other rest of the people who made themselves look like fools this NFL season. Whether it was a particular player, team, fan base, or commissioner there was plenty of embarrassing moments to go around. The word embarrassing can be interpreted many ways but I chose to look at it as, moments that make you look like a fool and/or utterly incompetent in your NFL related field of work. Under that definition here are the 5 moments that qualify.
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Chicago Fire
If there was ever a game for our schizophrenic 2013 Fire to overcome on what in any other week might have been a highly appealing Friday night home game - this was it.
Squad issues: Hunter Jumper had to replace suspended Bakary Soumare and his calming presence, while new arrivals Arevalo Rios and Juan Luis Anangono are still working to fit neatly into the side.
Opponent: KC, the only team to beat the Fire at Toyota Park in the Mike Magee era, coming to town with Graham Zusi and Teal Bunbury back fit, the team with the most headed goals in MLS against the Fire's makeshift center back pairing.
Off the field: Coach Frank Klopas was suspended, national headlines off the field, time running out on the playoff race.
And then, like they've done time and again this year, the Fire rebounded from a disappointing loss to play up to their potential and not only take all three points, but also show the fans that there's real quality on this team.
Whereas Rios and Jeff Larentowicz seemed out of rhythm in New England, they matched each other swimmingly on Friday, stepping and dropping, playing each other in tight spaces, and frustrating Benny Feilhaber and the rest.
Whereas wide players created next to nothing in New England, Dilly Duka was a force on the right on Friday. Meanwhile, Alex, who seemed out of place as a substitute deployed wide in New England, picked his runs to the middle of the field with considerable vision on Friday, providing support for Magee and Chris Rolfe up top, pushing counter attacks forward, and getting back to help prevent Zusi's service on KC's right side.
So let's give credit to the squad for playing up to their potential in yet another massive game for the Fire. Let's also look briefly at the magic of the 4-4-2 formation, that often-mocked old school set up the Fire rely on because Arrigo Sacchi and (occasionally) Sir Alex Ferguson aside, it's not exactly the formation of kings.
The 4-4-2 is the everyman's formation, the formation you play in your rec league, the most logical way to cover the field and balance attack with defense. Yet at the top level, it's fallen out of fashion in the past decade or so thanks to the emergence of the three man midfield, Vicente Del Bosque's 7-midfielder thing, and the desire to free up superstar players in attacking positions.
But the Fire proved that the 4-4-2 is still a viable formation in the right setting. Unlike complicated, imbalanced, shifting formations, the 4-4-2 is less about creating specific advantages in areas of the field than it is about creating 1v1 situations everywhere. That means it's about winning individual battles, endeavoring for second balls off 50/50s, and that extra 10-yard sprint.
Of course it has its subtler points: overlapping outside backs, the way Magee dropped deeper once Anangono came on to make it more of a 4-4-1-1, etc. But what we saw on Friday night was a team focused on working hard on and off the ball for the entire game. In that way, Hunter Jumper's scrappy goal was a perfect game-winner, because all game the Fire were on the ground, reaching balls just an inch before KC player's could.
The commitment seemed to shoot out from Rios and Larentowicz's eyes. They were everywhere, covering far more space than two men ought to, sliding around, starting counter attacks, holding the ball, and annoying KC all game.
You could say it's a weakness of the 4-4-2, that it takes complete self-sacrifice. But you have only to look at the reaction of Rios at the final whistle to see that the pride in exhaustion is always worth it.
Ben Schuman-Stoler is a contributor to Chicago-Fire.com. Follow him on Twitter @bsto.
Just in case you missed Friday's MLS Insider, Judah Friedlander documents how former Fire forward Roman Kosecki used inspiration from The Three Stooges to provide one of the top moments of comedy every seen... Check out Storytime Theater below...
Catch the full episode of last Friday's MLS Insider here.
Select shots from the Fire's Practice in the Community event.
Select shots from the Fire's 1-0 win over Sporting Kansas City.
CREDIT: Brian Kersey
After a morale sapping 2-0 loss in New England last week, the Fire need to pick themselves up for the visit of Eastern Conference table toppers Sporting KC Friday night. There has been no love lost between the sides over the past few seasons and this one promises to be no different. Here are few things to look out for from a tactical perspective.
Changes to the Fire defense – who will replace Bakary Soumare
Since the return of Bakary Soumare, the Fire's starting back four has remained virtually unchanged despite some less than stellar performances. Soumare's suspension forces Frank Klopas into making a tough decision.
The two most likely options are moving Jalil Anibaba into the middle and replacing him with Logan Pause/Wells Thompson/Mike Videra or keeping Jalil at right back and drafting Hunter Jumper into the middle.
The latter seems the more likely choice, especially considering Jumper's height and the coaching staff's desire to play big men against Sporting KC in the past. Jumper has had limited playing time this season (just one appearance so far) and will need to adjust to a SKC team who started off so well at Toyota Park last time out.
A strong start and scoring first will be a huge boost to the Fire psychologically.
How to break SKC down – target the outside defenders
Kansas City have the second best defensive record in the East thanks in part to a brilliant goalkeeper and rock solid central defense pairing but it's on the outside of the defensive four that some cracks appear.
In SKC's recent loss against New York, more than one of the goals scored by the Red Bulls came from getting in behind the defense. With players like Mike Magee, who is so good at making runs, the Fire need to be trying to play through balls as much as possible Friday night.
Getting into 1v1 situations with the SKC outside backs is another good tactic. Joel Lindpere has made no secret of his desire to play in the middle and not on the wing, where he feels that his lack of place and ability to take a man on are on show.
With that in mind, switching Alex to the wing is a good option. With Alex and Dilly Duka on the wings, the SKC outside defenders would certainly be on the back foot for most of the night.
SKC wing play – don't allow easy crosses
Just as the Fire should be looking to attack down the wings, the Men in Red must also be wary of SKC's wide play. Normally, SKC rely on U.S. international Graham Zusi to create from midfield but in his absence, more emphasis has been put on getting the ball wide and putting crosses into the box for Bieler, Kamara and Saad.
In Sporting's last match against New England, this tactic worked to perfection, with the first two goals of the night coming from crosses. New England allowed the SKC players far too much room to pick people out with crosses.
The Fire must be quicker to close Kansas City down, especially when they get the ball into the wide areas. It is expected that Zusi will be back in the starting lineup tonight but his presence should not distract the Fire from concentrating, not allowing Sporting players time on the ball.
Prediction: It's a must win for the Fire and I expect them to come out on top: 1-0 Fire with a goal from Mike Magee.
Stephen Piggott is a contributor to Chicago-Fire.com. Follow him on Twitter @irish_steve.
Over the weekend, Chicago Fire Season Ticket Holders began receiving #FIREUP renewal packets in the mail regarding 2014 Season Tickets. Chicago-Fire.com did a Q&A with Vice President of Ticket Sales, Service and Operations Mike Ernst to explain the philosophy behind some of the changes to the club's Season Ticket packages next season.
Chicago-Fire.com: Why is there a reduction from a 20 tickets to 18 tickets in the Season Ticket Holder packages?
Mike Ernst: Having discussed the potential move in the past, there are a couple of reasons we decided to make the switch this year.
First, we have seen over the course of the past several years that the Bonus Games were not always popular with our Season Ticket Holders. When we had a match against a big-name team like Manchester United, people were extremely happy, but if the game(s) were against a perceived lesser opponent, people were not as interested and were less likely to attend.
I think this stems from the fact that the games are exhibitions in nature and often times the regular starters did not play due to the competition calendar.
As a Club, we have tried to do our best to balance making sure the First Team is rested and has a competitive advantage in games that count (MLS Regular Season & U.S. Open Cup) while also putting on exhibitions that attract new, prospective fans.
C-F.com: Does the exclusion of Bonus Matches from this year's season ticket packages mean the Fire won't be hosting international friendlies next year?
ME: Far from it, exhibitions against international opponents will continue to be a focus for our Club going forward and we will give Season Ticket Holders the chance to purchase their tickets for any of these games before the general public. In addition, Season Ticket Holders will be able to purchase these tickets at a significant savings off the face value.
These matches give us the opportunity to raise the profile of our Club with the opponent's fan base and the broader general public. The goal of hosting these matches is to attract local fans of another Club to a Fire game with the aim of converting them to supporting their local Club.
It is critical for the continued growth of our Club to recruit new fans and then convert them to Season Ticket Holders over time.
C-F.com: Why has the Club shifted course on U.S. Open Cup games with the offering of the U.S. Open Cup Series Ticket? What does that mean?
ME: The U.S. Open Cup Series ticket will be the 18th game in the season ticket package. That ticket (and parking if applicable) will be good for up to three games if the Fire host the 3rd Round, 4th Round and Quarterfinal at home.
This change is the next step in ownership's commitment to contend for the U.S. Open Cup on an annual basis. In the past, we have and have not included U.S. Open Cup games in our season ticket package. We feel it is important to take this step, so that we give the guys on the field the best possible competitive advantage.
In the event that we do not host a U.S. Open Cup game at home, the Series ticket will be good for exchange to another MLS regular season home match.
C-F.com – What benefits are changing for Season Ticket Holders in 2014?
ME: The Club is committed to providing Fire fans with the best season ticket benefits in Chicago. In 2014, we will continue to offer free parking/$6 parking where applicable, the same exchange program to help you avoid wasting tickets, and a 20% off savings on merchandise at the TOYOTA PARK team store and online. In addition, it is important to note that we are not raising the price of tickets on a per-game basis.
Our goal is to continue to grow the season ticket base, so that we put the Club in a situation to sellout every match at TOYOTA PARK and thereby provide the team on the pitch with a home-field advantage. While that will not happen overnight, we believe that providing all Fire fans with an affordable and flexible season ticket option is critical to achieving our goal.
C-F.com – When can Season Ticket Holders expect to receive tickets for 2014?
We are expecting the 2014 season to begin sometime in early to mid-March, so we are aiming to have Season Tickets out by mid-February. It is important to us to make sure that this process goes as smoothly as possible.
In addition, we are still looking at options on how Season Tickets will be formatted for next year. There will be more information on that in the coming months.
Select shots from the Fire's match vs. New England
CREDIT: USA Today Sports Images
The Fire head east for another six pointer Saturday night, facing a slumping New England Revolution squad in Foxboro. Despite being without key players Mike Magee and Patrick Nyarko, the Men in Red beat Montreal at home last weekend. The Revs got handily beaten 3-0 in KC and are 0-2 in the month of August.
Here are some things to look out for from a tactical perspective.
The Magee/Anangonó partnership – how will it fare?
With Chris Rolfe not training this week and Mike Magee back, it appears the Fire will start with Magee and new DP striker Juan Luis Anangonó up front on the turf against New England.
The U.S. Open Cup semifinal defeat is the only time both players have been on the pitch together and it will be interesting to see how they combine against a New England team that has given up the second least amount of goals in the East.
Anangonó is very mobile for a target forward and is capable of dropping deep, something that Magee is also comfortable doing. On the turf, it will be important to keep the ball on the ground and retaining possession will also be key and I believe it will be up to both Magee and Anangonó to get other players like Dilly Duka and Joel Lindpere involved in the attack.
Any new strike partnership takes time to gel, but I look for Magee and Anangonó to not stray too far from each other and be heavily involved Saturday night.
The Rios/Larentowicz partnership – another potential central midfield pairing
WATCH: Lindpere, Larentowicz preview Revolution
Last weekend, we saw the return of Logan Pause, partnering Jeff Larentowicz in the middle and allowing the Ginger Ninja to get forward and support the attack.
This week, we could see a debut for Uruguayan midfielder Egidio Arevalo Rios, assumingly partnering the former New England man in the center of the park.
Most observers see Rios as a tough tackling midfielder who breaks up opposition attacks. This is certainly the case, but like Larentowicz, the Uruguayan also likes to get forward.
What will surprise some teams and even some Fire fans is Rios's willingness to get forward when possible. Though he won't score many goals (he had five in 53 matches last season) Rios will certainly start quite a few attacks from breaking up play in the opposition's half, something we've seen Patrick Nyarko do a lot of this season.
What will be very important on Saturday night is that both players must know where the other is and not have a situation where they're caught too high up the field. Communication and discipline from both players will be important, but I have no worries considering the wealth of experience the duo possesses.
New England's Attack – who will get the start on Saturday night?
When people look at the Revs attack, Diego Fagundez and Saer Sene immediately spring to mind. In addition, New England have a couple of American strikers that have the ability to change games, namely Juan Agudelo and Charlie Davies.
Agudelo is back to fitness after missing the last eight matches and is a familiar foe for the Fire, scoring in a 4-1 defeat by Chivas USA at Toyota Park back in March. He scored three goals in five games for the Revs before being injured and is certainly a threat.
Davies is looking to get his career back on track with the Revs and has a point to prove in MLS but he hasn't played a competitive match in a few months.
With the addition of the former U.S. international, the Revs have excellent strength in depth at the forward position and have the luxury of bringing on high quality strikers if need be.
I touched on this issue when the Fire played Philly back to back earlier this season and it will be important that the team is prepared to change midway through the game and adjust to whoever comes off the bench. All four strikers bring different qualities and it will be important for the Frank Klopas to adjust his side accordingly.
Prediction: With so many question marks about who will start and new partnerships on the field, this game is very difficult to predict. I am going with 1-0 Fire (first clean sheet in two months!) with a goal from Juan Luis Anangonó.
Stephen Piggott is a contributor to Chicago-Fire.com. Follow him on Twitter @Irish_Steve.


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