Methods for treating peritoneal adhesions by local administration of a Clostridial toxin, such as a botulinum toxin, to a patient with a peritoneal adhesion.

The present invention relates to methods for treating peritoneal adhesions. In particular the present invention relates to methods for treating peritoneal adhesions by administration of a Clostridial neurotoxin, such as a botulinum toxin, to a patient.
Peritoneal Adhesions
Internal organs, such as the stomach, most of the intestine, parts of the female reproductive system and the inside of the abdominal wall are typically covered with a shiny membrane called the peritoneum. A film of fluid called peritoneal fluid coats adjacent layers of peritoneum. The peritoneum and the peritoneal fluid essentially lubricate internal organs and permits them to slip and slide in relation to each other during for example digestion when waves of muscular contraction pass along the gut wall and propel the food within the lumen of the gastrointestinal tract.
Injury to the peritoneum, as can occur due to trauma, surgery, infection and/or inflammation can cause the peritoneum to become sticky and to attach itself to other areas of peritoneum, that is peritoneal adhesions can form. Briefly, peritoneal adhesions are pathological fibrotic bands developing after mesothelial damage. Peritoneal adhesions can be a transient phenomenon, followed after a few days by separation, or they can become a permanent adhesion complete with fibrous scar tissue. The formation of peritoneal adhesions can interfere with normal functions, and can cause pain, intestinal obstruction, and infertility.
There are various types of peritoneal adhesions. For example, pelvic adhesions can occur due to a pelvic inflammatory disease. Vascular adhesions can lie between the omentum (a layer of fatty tissue surrounding the intestines) and the area under the left groin. Peritoneal adhesions can occur between the intestines and the top of the abdomen. Additionally, peritoneal adhesions can occur between the liver and the diaphragm ("violin string" adhesions)
Peritoneal adhesions can occur in response to peritoneal injury and can occur as a result of endometriosis (the spread of endometrial tissue from the lining of the uterus out into the peritoneal cavity), and infections producing peritonitis. But most peritoneal adhesions are the result of procedures that involve handling and incisions made during abdominal surgery. Thus, patients who have never had abdominal surgery have perhaps a 10% chance of developing peritoneal adhesions, while about two thirds of patients who have had an abdominal surgery develop adhesions (Weibel, M. A., et al., Peritoneal adhesions and their relation to abdominal surgery. A postmortem study, Amer. J. Surgery, 126, 345-353 (1973)) and patients who have had two or more abdominal procedures have about a 93% chance of developing peritoneal adhesions. Menzies, D., et al., Intestinal obstruction from adhesions—how big is the problem?, Annals of the Royal College of Surgeons, England, 72, 60-63 (1990).
Adhesion formation is of major concern to the pelvic surgeon. For example, adhesions can be induced when operating on myomas and endometriosis. Most patients develop postoperative adhesions regardless of whether the mode of access to the abdominal cavity is by laparoscopy or laparotomy. Significantly, infertility is related to adhesions in the pelvis in 15-20% of cases. Additionally, peritoneal adhesions are the main cause of mechanical bowel obstruction in 65-80% of cases and contribute to a large extent to health-care expenditures.
There are at least three important consequences of peritoneal adhesions. First, peritoneal adhesions can cause chronic abdominal pain. The pain experienced may be due to traction (pulling) of nerves, distention of an obstructed part of the intestines, and/or the restrictions adhesions place upon organ movement, and the resulting stretching and pulling of smooth muscle of adjacent viscera and/or of the abdominal wall itself. Patients with peritoeneal adhesions often report tenderness at or in the area of the adhesions, indicating that the adhesions themselves can generate pain stimuli. Additionally, it has been reported that sensory nerve fibers presumably capable of nocicoception are present in human peritoneal adhesions. Sulaiman, H. et al, Presence and distribution of sensory nerve fibers in human peritoneal adhesions, Annuals of Surgery, 234(2), August 2001, and; Sulaiman H, et al., Adhesions have feeling, Amer J. Gastroenterology, 97(1):9, January 2002.
Second, peritoeneal adhesions can cause intestinal obstructions. For example, two thirds of all cases of small bowel obstruction involve peritoneal adhesions. Ellis, H., The clinical significance of adhesions: focus on intestinal obstruction. European Journal of Surgery, Suppl (577), 5-9 (1997). Third, adhesions involving the ovaries and fallopian tubes can cause infertility and dyspareunia (painful intercourse).
Adhesiolysis (cutting of adhesions) has been used to treat painful peritoneal adhesions, but has a high risk of the development of new adhesions. For example, when adhesions were cut to relieve intestinal obstruction, obstruction recurs in up to one-fifth of all cases.
Various methods have been tried to reduce the risk of peritoneal adhesion formation. For example, different types of biodegradable or non-biodegradable synthetic membrane (barrier) products can be placed over damaged peritoneum during an operation with the aim of preventing the formation of adhesions. Examples of such products are INTERCEED® (Johnson & Johnson), SEPRAFILM® (Genzyme Corp) and Gore-Tex. Drawbacks of synthetic membrane products can include lack of absorption, occurrence of inflammation, requirement for suturing or stapling to hold the membrane in place, and formation of new peritoneal adhesions after laparoscopy. Other medications that have been studied to try and prevent the occurrence of postoperative peritoneal adhesions include glucocorticoids, heparin, dextran 70, saline solution, antibiotics, promethazine, antihistamines, prostaglandin synthesis inhibitors, Ringer's lactate solution and calcium-channel blockers.
Botulinum Toxin
The genus Clostridium has more than one hundred and twenty seven species, grouped according to their morphology and functions. The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A is the most lethal natural biological agent known to man. About 50 picograms of a commercially available botulinum toxin type A (purified neurotoxin complex)1 is a LD50 in mice (i.e. 1 unit). One unit of BOTOX® contains about 50 picograms (about 56 attomoles) of botulinum toxin type A complex. Interestingly, on a molar basis, botulinum toxin type A is about 1.8 billion times more lethal than diphtheria, about 600 million times more lethal than sodium cyanide, about 30 million times more lethal than cobra toxin and about 12 million times more lethal than cholera. Singh, Critical Aspects of Bacterial Protein Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New York (1976) (where the stated LD50 of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 20 grams each.
Seven generally immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B. Additionally, botulinum toxin type B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD50 for botulinum toxin type A. Moyer E et al., Botulinum Toxin Type B: Experimental and Clinical Experience, being chapter 6, pages 71-85 of "Therapy With Botulinum Toxin", edited by Jankovic, J. et al. (1994), Marcel Dekker, Inc. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine. Additional uptake can take place through low affinity receptors, as well as by phagocytosis and pinocytosis.
Regardless of serotype, the molecular mechanism of toxin intoxication appears to be similar and to involve at least three steps or stages. In the first step of the process, the toxin binds to the presynaptic membrane of the target neuron through a specific interaction between the heavy chain, H chain, and a cell surface receptor; the receptor is thought to be different for each type of botulinum toxin and for tetanus toxin. The carboxyl end segment of the H chain, HC, appears to be important for targeting of the toxin to the cell surface.
In the second step, the toxin crosses the plasma membrane of the poisoned cell. The toxin is first engulfed by the cell through receptor-mediated endocytosis, and an endosome containing the toxin is formed. The toxin then escapes the endosome into the cytoplasm of the cell. This step is thought to be mediated by the amino end segment of the H chain, HN, which triggers a conformational change of the toxin in response to a pH of about 5.5 or lower. Endosomes are known to possess a proton pump which decreases intra-endosomal pH. The conformational shift exposes hydrophobic residues in the toxin, which permits the toxin to embed itself in the endosomal membrane. The toxin (or at a minimum the light chain) then translocates through the endosomal membrane into the cytoplasm.
The last step of the mechanism of botulinum toxin activity appears to involve reduction of the disulfide bond joining the heavy chain, H chain, and the light chain, L chain. The entire toxic activity of botulinum and tetanus toxins is contained in the L chain of the holotoxin; the L chain is a zinc (Zn++) endopeptidase which selectively cleaves proteins essential for recognition and docking of neurotransmitter-containing vesicles with the cytoplasmic surface of the plasma membrane, and fusion of the vesicles with the plasma membrane. Tetanus neurotoxin, botulinum toxin types B, D, F, and G cause degradation of synaptobrevin (also called vesicle-associated membrane protein (VAMP)), a synaptosomal membrane protein. Most of the VAMP present at the cytoplasmic surface of the synaptic vesicle is removed as a result of any one of these cleavage events. Botulinum toxin serotype A and E cleave SNAP-25. Botulinum toxin serotype C1 was originally thought to cleave syntaxin, but was found to cleave syntaxin and SNAP-25. Each of the botulinum toxins specifically cleaves a different bond, except botulinum toxin type B (and tetanus toxin) which cleave the same bond. Each of these cleavages block the process of vesicle-membrane docking, thereby preventing exocytosis of vesicle content.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles (i.e. motor disorders). In 1989, a botulinum toxin type A complex has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus and hemifacial spasm. Subsequently, a botulinum toxin type A was also approved by the FDA for the treatment of cervical dystonia and for the treatment of glabellar lines, and a botulinum toxin type B was approved for the treatment of cervical dystonia. Non-type A botulinum toxin serotypes apparently have a lower potency and/or a shorter duration of activity as compared to botulinum toxin type A. Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months, although significantly longer periods of therapeutic activity have been reported.
Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. Botulinum toxin types B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally, botulinum toxin type C1 has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes. Apparently, a substrate for a botulinum toxin can be found in a variety of different cell types. See e.g. Biochem J 1;339 (pt 1):159-65:1999, and Mov Disord, 10(3):376:1995 (pancreatic islet B cells contains at least SNAP-25 and synaptobrevin).
The molecular weight of the botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum toxin types B and C1 is apparently produced as only a 700 kD or 500 kD complex. Botulinum toxin type D is produced as both 300 kD and 500 kD complexes. Finally, botulinum toxin types E and F are produced as only approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine (Habermann E., et al., Tetanus Toxin and Botulinum A and C Neurotoxins Inhibit Noradrenaline Release From Cultured Mouse Brain, J Neurochem 51(2);522-527:1988) CGRP, substance P and glutamate (Sanchez-Prieto, J., et al., Botulinum Toxin A Blocks Glutamate Exocytosis From Guinea Pig Cerebral Cortical Synaptosomes, Eur J. Biochem 165;675-681:1897. Thus, when adequate concentrations are used, stimulus-evoked release of most neurotransmitters is blocked by botulinum toxin. See e.g. Pearce, L. B., Pharmacologic Characterization of Botulinum Toxin For Basic Science and Medicine, Toxicon 35(9);1373-1412 at 1393; Bigalke H., et al., Botulinum A Neurotoxin Inhibits Non-Cholinergic Synaptic Transmission in Mouse Spinal Cord Neurons in Culture, Brain Research 360;318-324:1985; Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the release of [3H]Noradrenaline and [3H]GABA From Rat Brain Homogenate, Experientia 44;224-226:1988, Bigalke H., et al., Tetanus Toxin and Botulinum A Toxin Inhibit Release and Uptake of Various Transmitters, as Studied with Particulate Preparations From Rat Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 316;244-251:1981, and; Jankovic J. et al., Therapy With Botulinum Toxin, Marcel Dekker, Inc., (1994), page 5.
Botulinum toxin type A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known procedures. All the botulinum toxin serotypes are initially synthesized as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum toxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. In contrast, botulinum toxin serotypes C1, D and E are synthesized by nonproteolytic strains and are therefore typically unactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for example, the botulinum toxin type B serotype only cleave a portion of the toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture. Therefore, a certain percentage of any preparation of, for example, the botulinum toxin type B toxin is likely to be inactive, possibly accounting for the known significantly lower potency of botulinum toxin type B as compared to botulinum toxin type A. The presence of inactive botulinum toxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy. Additionally, it is known that botulinum toxin type B has, upon intramuscular injection, a shorter duration of activity and is also less potent than botulinum toxin type A at the same dose level.
High quality crystalline botulinum toxin type A can be produced from the Hall A strain of Clostridium botulinum with characteristics of ≧3×107 U/mg, an A260/A278 of less than 0.60 and a distinct pattern of banding on gel electrophoresis. The known Shantz process can be used to obtain crystalline botulinum toxin type A, as set forth in Shantz, E. J., et al, Properties and use of Botulinum toxin and Other Microbial Neurotoxins in Medicine, Microbiol Rev. 56;80-99:1992. Generally, the botulinum toxin type A complex can be isolated and purified from an anaerobic fermentation by cultivating Clostridium botulinum type A in a suitable medium. The known process can also be used, upon separation out of the non-toxin proteins, to obtain pure botulinum toxins, such as for example: purified botulinum toxin type A with an approximately 150 kD molecular weight with a specific potency of 1-2×108 LD50 U/mg or greater; purified botulinum toxin type B with an approximately 156 kD molecular weight with a specific potency of 1-2×108 LD50 U/mg or greater, and; purified botulinum toxin type F with an approximately 155 kD molecular weight with a specific potency of 1-2×107 LD50 U/mg or greater.
Botulinum toxins and/or botulinum toxin complexes can be obtained from List Biological Laboratories, Inc., Campbell, Calif.; the Centre for Applied Microbiology and Research, Porton Down, U.K.; Wako (Osaka, Japan), Metabiologics (Madison, Wis.) as well as from Sigma Chemicals of St Louis, Mo. Pure botulinum toxin can also be used to prepare a pharmaceutical composition.
As with enzymes generally, the biological activities of the botulinum toxins (which are intracellular peptidases) is dependant, at least in part, upon their three dimensional conformation. Thus, botulinum toxin type A is detoxified by heat, various chemicals surface stretching and surface drying. Additionally, it is known that dilution of the toxin complex obtained by the known culturing, fermentation and purification to the much, much lower toxin concentrations used for pharmaceutical composition formulation results in rapid detoxification of the toxin unless a suitable stabilizing agent is present. Dilution of the toxin from milligram quantities to a solution containing nanograms per milliliter presents significant difficulties because of the rapid loss of specific toxicity upon such great dilution. Since the toxin may be used months or years after the toxin containing pharmaceutical composition is formulated, the toxin can stabilized with a stabilizing agent such as albumin and gelatin.
A commercially available botulinum toxin containing pharmaceutical composition is sold under the trademark BOTOX® (available from Allergan, Inc., of Irvine, Calif.). BOTOX® consists of a purified botulinum toxin type A complex, albumin and sodium chloride packaged in sterile, vacuum-dried form. The botulinum toxin type A is made from a culture of the Hall strain of Clostridium botulinum grown in a medium containing N-Z amine and yeast extract. The botulinum toxin type A complex is purified from the culture solution by a series of acid precipitations to a crystalline complex consisting of the active high molecular weight toxin protein and an associated hemagglutinin protein. The crystalline complex is re-dissolved in a solution containing saline and albumin and sterile filtered (0.2 microns) prior to vacuum-drying. The vacuum-dried product is stored in a freezer at or below −5° C. BOTOX® can be reconstituted with sterile, non-preserved saline prior to intramuscular injection. Each vial of BOTOX®D contains about 100 units (U) of Clostridium botulinum toxin type A purified neurotoxin complex, 0.5 milligrams of human serum albumin and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative.
To reconstitute vacuum-dried BOTOX®, sterile normal saline without a preservative; (0.9% Sodium Chloride Injection) is used by drawing up the proper amount of diluent in the appropriate size syringe. Since BOTOX® may be denatured by bubbling or similar violent agitation, the diluent is gently injected into the vial. For sterility reasons BOTOX® is preferably administered within four hours after the vial is removed from the freezer and reconstituted. During these four hours, reconstituted BOTOX® can be stored in a refrigerator at about 2° C. to about 8° C. Reconstituted, refrigerated BOTOX® has been reported to retain its potency for at least about two weeks. Neurology, 48:249-53:1997.
It has been reported that botulinum toxin type A has been used in clinical settings as follows:    (1) about 75-125 units of BOTOX® per intramuscular injection (multiple muscles) to treat cervical dystonia;    (2) 5-10 units of BOTOX® per intramuscular injection to treat glabellar lines (brow furrows) (5 units injected intramuscularly into the procerus muscle and 10 units injected intramuscularly into each corrugator supercilii muscle);    (3) about 30-80 units of BOTOX® to treat constipation by intrasphincter injection of the puborectalis muscle;    (4) about 1-5 units per muscle of intramuscularly injected BOTOX® to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.    (5) to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1-5 units of BOTOX®, the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. amount of diopter correction desired).    (6) to treat upper limb spasticity following stroke by intramuscular injections of BOTOX® into five different upper limb flexor muscles, as follows:    (a) flexor digitorum profundus: 7.5 U to 30 U    (b) flexor digitorum sublimus: 7.5 U to 30 U    (c) flexor carpi ulnaris: 10 U to 40 U    (d) flexor carpi radialis: 15 U to 60 U    (e) biceps brachii: 50 U to 200 U. Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX® by intramuscular injection at each treatment session.    (7) to treat migraine, pericranial injected (injected symmetrically into glabellar, frontalis and temporalis muscles) injection of 25 U of BOTOX® has showed significant benefit as a prophylactic treatment of migraine compared to vehicle as measured by decreased measures of migraine frequency, maximal severity, associated vomiting and acute medication use over the three month period following the 25 U injection.
It is known that botulinum toxin type A can have an efficacy for up to 12 months (European J. Neurology 6 (Supp 4): S111-S1150:1999), and in some circumstances for as long as 27 months, when used to treat glands, such as in the treatment of hyperhydrosis. See e.g. Bushara K., Botulinum toxin and rhinorrhea, Otolaryngol Head Neck Surg 1996; 114(3):507, and The Laryngoscope 109:1344-1346:1999. However, the usual duration of an intramuscular injection of BOTOX® is typically about 3 to 4 months.
The success of botulinum toxin type A to treat a variety of clinical conditions has led to interest in other botulinum toxin serotypes. Two commercially available botulinum type A preparations for use in humans are BOTOX® available from Allergan, Inc., of Irvine, Calif., and DYSPORT® available from Beaufour Ipsen, Porton Down, England. A Botulinum toxin type B preparation (MYOBLOC®)) is available from Elan Pharmaceuticals of San Francisco, Calif.
In addition to having pharmacologic actions at the peripheral location, botulinum toxins may also have inhibitory effects in the central nervous system. Work by Weigand et al, Nauny-Schmiedeberg's Arch. Pharmacol. 1976; 292, 161-165, and Habermann, Nauny-Schmiedeberg's Arch. Pharmacol. 1974; 281, 47-56 showed that botulinum toxin is able to ascend to the spinal area by retrograde transport. As such, a botulinum toxin injected at a peripheral location, for example intramuscularly, may be retrograde transported to the spinal cord.
Significantly, it has been reported that local administration of a botulinum toxin can cause the development of certain esophageal adhesions: Gordon J. M., et al., Prospective study of esophageal botulinum toxin injection in high-risk achalasia patients, Am J Gastroenterol 1997 October;92(10):1812-7 1012 (development of mediastinal adhesions around the distal esophagus after botulinum toxin injection); Eaker E. Y., et al., Untoward effects of esophageal botulinum toxin injection in the treatment of achalasia, Dig Dis Sci 1997 April;42(4):724-7 1012 (development of paresophageal adhesions after botulinum toxin injection), and; Bhutani M. S., et al., Botulinum toxin injection in achalasia before myotomy, Am J Gastroenterol 1998 June;93(6):1012 (development of paresophageal adhesions after botulinum toxin injection).
Additionally, a botulinum toxin has been proposed for or has been used to treat skin bone and tendon wounds (U.S. Pat. No. 6,447,787); intrathecal pain (see e.g. U.S. Pat. No. 6,113,915); various autonomic nerve disorders, including sweat gland disorders (see e.g. U.S. Pat. No. 5,766,605 and Goldman (2000), Aesthetic Plastic Surgery July-August 24(4):280-282); tension headache (U.S. Pat. No. 6,458,365); migraine headache pain (U.S. Pat. No. 5,714,468); post-operative pain and visceral pain (U.S. Pat. No. 6,464,986); hair growth and hair retention (U.S. Pat. No. 6,299,893); psoriasis and dermatitis (U.S. Pat. No. 5,670,484); injured muscles (U.S. Pat. No. 6,423,319); various cancers (see e.g. U.S. Pat. Nos. 6,139,845 and 6,063,768), smooth muscle disorders (U.S. Pat. No. 5,437,291); nerve entrapment syndromes (U.S. patent application 2003 0224019); acne (WO 03/011333); neurogenic inflammation (U.S. Pat. No. 6,063,768); otic disorders (see e.g. U.S. Pat. No. 6,265,379); pancreatic disorders (see e.g. U.S. Pat. Nos. 6,143,306 and 6,261,572); prostate disorders, including prostatic hyperplasia, prostate cancer and urinary incontinence (see e.g. U.S. Pat. Nos. 6,365,164 and 6,667,041 [which also disclose treatment of pelvic pain] and Doggweiler R., et al Botulinum toxin type A causes diffuse and highly selective atrophy of rat prostate, Neurourol Urodyn 1998; 17(4):363); fibromyalgia (U.S. Pat. No. 6,623,742); piriformis muscle syndrome (see e.g. Childers et al. (2002), American Journal of Physical Medicine & Rehabilitation, 81:751-759); and various skin disorders (see U.S. patent applications serial numbers 731,973; 814,764, and; 817,036).
U.S. Pat. No. 5,989,545 discloses that a modified clostridial neurotoxin or fragment thereof, preferably a botulinum toxin, chemically conjugated or recombinantly fused to a particular targeting moiety can be used to treat pain by administration of the agent to the spinal cord. Additionally it has been disclosed that targeted botulinum toxins (i.e. with a non-native binding moiety) can be used to treat various conditions (see e.g. WO 96/33273; WO 99/17806; WO 98/07864; WO 00/57897; WO 01/21213; WO 00/10598.
A botulinum toxin has been injected into the pectoral muscle to control pectoral spasm. See e.g. Senior M., Botox and the management of pectoral spasm after subpectoral implant insertion, Plastic and Recon Surg, July 2000, 224-225. Controlled release toxin implants are known (see e.g. U.S. Pat. Nos. 6,306,423 and 6,312,708) as is transdermal botulinum toxin administration (U.S. patent application Ser. No. 10/194,805).
Both liquid stable formulations and pure botulinum toxin formulations have been disclosed (see e.g. WO 00/15245 and WO 74703) as well as topical application of a botulinum toxin (see e.g. DE 198 52 981).
Additionally, a botulinum toxin may have an effect to reduce induced inflammatory pain in a rat formalin model. Aoki K., et al, Mechanisms of the antinociceptive effect of subcutaneous Botox: Inhibition of peripheral and central nociceptive processing, Cephalalgia 2003 September;23(7):649.
Tetanus toxin, as wells as derivatives (i.e. with a non-native targeting moiety), fragments, hybrids and chimeras thereof can also have therapeutic utility. The tetanus toxin bears many similarities to the botulinum toxins. Thus, both the tetanus toxin and the botulinum toxins are polypeptides made by closely related species of Clostridium (Clostridium tetani and Clostridium botulinum, respectively). Additionally, both the tetanus toxin and the botulinum toxins are dichain proteins composed of a light chain (molecular weight about 50 kD) covalently bound by a single disulfide bond to a heavy chain (molecular weight about 100 kD). Hence, the molecular weight of tetanus toxin and of each of the seven botulinum toxins (non-complexed) is about 150 kD. Furthermore, for both the tetanus toxin and the botulinum toxins, the light chain bears the domain which exhibits intracellular biological (protease) activity, while the heavy chain comprises the receptor binding (immunogenic) and cell membrane translocational domains.
Further, both the tetanus toxin and the botulinum toxins exhibit a high, specific affinity for gangliocide receptors on the surface of presynaptic cholinergic neurons. Receptor mediated endocytosis of tetanus toxin by peripheral cholinergic neurons results in retrograde axonal transport, blocking of the release of inhibitory neurotransmitters from central synapses and a spastic paralysis. Contrarily, receptor mediated endocytosis of botulinum toxin by peripheral cholinergic neurons results in little if any retrograde transport, inhibition of acetylcholine exocytosis from the intoxicated peripheral motor neurons and a flaccid paralysis.
Finally, the tetanus toxin and the botulinum toxins resemble each other in both biosynthesis and molecular architecture. Thus, there is an overall 34% identity between the protein sequences of tetanus toxin and botulinum toxin type A, and a sequence identity as high as 62% for some functional domains. Binz T. et al., The Complete Sequence of Botulinum Neurotoxin Type A and Comparison with Other Clostridial Neurotoxins, J Biological Chemistry 265(16);9153-9158:1990.
Acetylcholine
Typically only a single type of small molecule neurotransmitter is released by each type of neuron in the mammalian nervous system, although there is evidence which suggests that several neuromodulators can be released by the same neuron. The neurotransmitter acetylcholine is secreted by neurons in many areas of the brain, but specifically by the large pyramidal cells of the motor cortex, by several different neurons in the basal ganglia, by the motor neurons that innervate the skeletal muscles, by the preganglionic neurons of the autonomic nervous system (both sympathetic and parasympathetic), by the bag 1 fibers of the muscle spindle fiber, by the postganglionic neurons of the parasympathetic nervous system, and by some of the postganglionic neurons of the sympathetic nervous system. Essentially, only the postganglionic sympathetic nerve fibers to the sweat glands, the piloerector muscles and a few blood vessels are cholinergic as most of the postganglionic neurons of the sympathetic nervous system secret the neurotransmitter norepinephine. In most instances acetylcholine has an excitatory effect. However, acetylcholine is known to have inhibitory effects at some of the peripheral parasympathetic nerve endings, such as inhibition of heart rate by the vagal nerve.
The efferent signals of the autonomic nervous system are transmitted to the body through either the sympathetic nervous system or the parasympathetic nervous system. The preganglionic neurons of the sympathetic nervous system extend from preganglionic sympathetic neuron cell bodies located in the intermediolateral horn of the spinal cord. The preganglionic sympathetic nerve fibers, extending from the cell body, synapse with postganglionic neurons located in either a paravertebral sympathetic ganglion or in a prevertebral ganglion. Since, the preganglionic neurons of both the sympathetic and parasympathetic nervous system are cholinergic, application of acetylcholine to the ganglia will excite both sympathetic and parasympathetic postganglionic neurons.
Acetylcholine activates two types of receptors, muscarinic and nicotinic receptors. The muscarinic receptors are found in all effector cells stimulated by the postganglionic, neurons of the parasympathetic nervous system as well as in those stimulated by the postganglionic cholinergic neurons of the sympathetic nervous system. The nicotinic receptors are found in the adrenal medulla, as well as within the autonomic ganglia, that is on the cell surface of the postganglionic neuron at the synapse between the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic systems. Nicotinic receptors are also found in many nonautonomic nerve endings, for example in the membranes of skeletal muscle fibers at the neuromuscular junction.
Acetylcholine is released from cholinergic neurons when small, clear, intracellular vesicles fuse with the presynaptic neuronal cell membrane. A wide variety of non-neuronal secretory cells, such as, adrenal medulla (as well as the PC12 cell line) and pancreatic islet cells release catecholamines and parathyroid hormone, respectively, from large dense-core vesicles. The PC12 cell line is a clone of rat pheochromocytoma cells extensively used as a tissue culture model for studies of sympathoadrenal development. Botulinum toxin inhibits the release of both types of compounds from both types of cells in vitro, permeabilized (as by electroporation) or by direct injection of the toxin into the denervated cell. Botulinum toxin is also known to block release of the neurotransmitter glutamate from cortical synaptosomes cell cultures.
A neuromuscular junction is formed in skeletal muscle by the proximity of axons to muscle cells. A signal transmitted through the nervous system results in an action potential at the terminal axon, with activation of ion channels and resulting release of the neurotransmitter acetylcholine from intraneuronal synaptic vesicles, for example at the motor endplate of the neuromuscular junction. The acetylcholine crosses the extracellular space to bind with acetylcholine receptor proteins on the surface of the muscle end plate. Once sufficient binding has occurred, an action potential of the muscle cell causes specific membrane ion channel changes, resulting in muscle cell contraction. The acetylcholine is then released from the muscle cells and metabolized by cholinesterases in the extracellular space. The metabolites are recycled back into the terminal axon for reprocessing into further acetylcholine.
What is needed therefore is a therapeutically effective method for treating an adhesion, such as a peritoneal adhesion.

Method for treating peritoneal adhesions


A certification method realized by a certification server is applied to a networking system containing at least one local network connecting together terminals that constitute a same group to share a local session therebetween. When one terminal requests certification, the certification server sends an inter-group ID to the terminal while sending an authentication request to each of the other terminals of the same group. Then, the certification server determines to perform certification on the terminal based on results of authentication that is performed by each of the users of the other terminals in a face-to-face manner. Herein, the certification server can determine whether to certify the terminal based on secret information, which are disassembled and allocated to the terminals respectively. Thus, it is possible to reliably perform certification and authentication on terminals and users.

1. Field of the Invention
This invention relates to methods and apparatuses for certification and authentication of users and computers over networks.
2. Description of the Related Art
Conventionally, user IDs and passwords are both used to verify (or authenticate) users over networks, an example of which is described in a book entitled "Introduction To Coding Theory" written by Eishi Okamoto and published by Kyoritsu Shuppan Kabushiki Kaisha in 1993 in Japan (in particular, pages 132-133). Herein, several pieces of information regarding users of personal computers or terminals are registered with servers in advance. That is, the server stores user IDs, which are assigned to users in advance, and passwords that only the users may know in the storage thereof. In order to use online functions over the network, the user inputs his/her identification number (i.e., user ID) and password by operating a terminal connected with the server via the network. Then, the server makes a determination as to whether or not the input information transmitted thereto via the network match the information stored in the storage thereof. Thus, the server can verify the user who is actually and certainly registered therewith.
Recently, electronic certification services using coding techniques (or encryption) are widely spread in the fields of computer communications and networking services, an example of which is described in the aforementioned book (in particular, pages 133 and 134). In order to use the electronic certification service, the user transmits the prescribed information including a public key regarding encryption (or decryption) to an online certification agency (or organization), which in turn issues a digital ID for the user and stores the public key in the storage. When a user wishes another user to be verified the identity of the other via the network, the user transmits to the other user the aforementioned digital ID and public key together with an electronic signature using a private key (or secret key) regarding encryption (or decryption). Then, the other user transmits the received digital ID to the certification agency, which in turn returns the public key that is stored in correspondence with the digital ID. Thus, the other user compares the public key, which is directly received from the user, with the public key that is transmitted thereto from the certification agency. When there is a match, the other user can verify the user as requested.
The aforementioned technology may ensure mutual certification between computers (e.g., server and terminal) over the network. However, there is a problem that certification may not be reliably performed as to whether or not the computers are actually used by the authorized users. In the method using passwords, an unauthorized person, who differs from the authorized user, may be able to obtain an online certification by operating the terminal and inputting private information of the authorized user such as the user ID and password, which may have been obtained unfairly or illegally. That is, there remains a possibility that unauthorized persons may succeed in using online services, which are provided for authorized users, in unfair or illegal ways. In addition, the aforementioned electronic certification using encryption use digital IDs and public (or private) keys, wherein a third party may be able to act as an authorized user by manipulating the computer dishonestly.
In summary, the conventional certification technology may have abilities of certifying computers whose users are registered with servers and the like. However, it cannot reliably perform certification as to whether or not computers are actually being operated by authorized users.

Method and apparatus for certification and authentication of users and computers over networks


A steerable catheter suitable for radiofrequency ablation of cardiac tissue comprises a catheter shaft with a deflectable tip at the distal end of the shaft. The tip is deflected by means of a shapable handle coupled to pull wires fastened to the distal end of the deflectable tip. A core wire extends from the handle to the distal tip, providing fine positioning of the deflectable tip by applying torque through the core wire to the tip. A spring tube is further provided in the deflectable tip for improved torque transmission and kink-resistance. The catheter has an electrode at the distal end of the deflectable tip for positioning at a target site and applying RF power to accomplish ablation.

The present invention relates generally to the field of electrophysiology. More particularly, this invention relates to methods and apparatus for treating cardiac arrhythmias.
Symptoms of abnormal heart rhythm are generally referred to as cardiac arrhythmias, with an abnormally slow rhythm being classified as a bradycardia and an abnormally rapid rhythm being referred to as a tachycardia. The present invention is concerned with the treatment of tachycardias which are frequently caused by the presence of an "arrhythmogenic site" or "accessory atrioventricular pathway" close to the inner surface of one of the chambers of the heart. The heart includes a number of normal pathways which are responsible for the propagation of signals necessary for normal electrical mechanical function. The presence of arrhythmogenic sites or accessory pathways can bypass or short circuit the normal pathways, potentially resulting in very rapid heart contractions, referred to as tachycardias. Tachycardias may be defined as ventricular tachycardias (VT's) and supraventricular tachycardias (SVT's). VT's originate in the left or right ventricle and are typically caused by arrhythmogenic sites associated with a prior myocardial infarction. SVT's originate in the atria and are typically caused by an accessory pathway.
Treatment of both ventricular and supraventricular tachycardias may be accomplished by a variety of approaches, including drugs, surgery, implantable pacemakers/defibrillators, and catheter ablation. While drugs may be the treatment of choice for many patients, they only mask the symptoms and do not cure the underlying cause. Implantable devices only correct the arrhythmia after it occurs. Surgical and catheter-based treatments, in contrast, will actually cure the problem, usually by ablating the abnormal arrhythmogenic tissue or accessory pathway responsible for the tachycardia. The catheter-based treatments rely on the application of various destructive energy sources to the target tissue, including direct current electrical energy, radiofrequency electrical energy, laser energy, and the like.
Of particular interest to the present invention are radiofrequency (RF) ablation protocols which have proven to be highly effective in tachycardia treatment while exposing the patient to minimum side effects and risks. Radiofrequency catheter ablation is generally performed after an initial mapping procedure where the locations of the arrhythmogenic sites and accessory pathways are determined. After mapping, a catheter having a suitable electrode is introduced to the appropriate heart chamber and manipulated so that the electrode lies proximate the target tissue. Radiofrequency energy is then applied through the electrode to the cardiac tissue in order to ablate a region of the tissue which forms part of arrhythmogenic site or the accessory pathway. By successfully destroying that tissue, the abnormal signalling patterns responsible for the tachycardia cannot be sustained. A method and system for performing RF ablation by controlling temperature at the ablation site is described in co-pending application Ser. No. 866,683, entitled "Method and System for Radiofrequency Ablation of Cardiac Tissue," the full disclosure of which is hereby incorporated herein by reference.
Catheters utilized in radiofrequency ablation are inserted into a major vein or artery, usually in the neck or groin area, and guided into the chambers of the heart by appropriate manipulation through the vein or artery. The tip of the catheter must be manipulable by the user from the proximal end of the catheter, so that the distal electrode can be positioned against the tissue region to be ablated. The catheter must have a great deal of flexibility in order to follow the pathway of the major blood vessels into the heart, and the catheter must permit user manipulation of the tip even when the catheter is in a curved and twisted configuration. Because of the high degree of precision required for proper positioning of the tip electrode, the catheter must be manipulable with a high degree of sensitivity and controllability. In addition, the distal portion of the catheter must be sufficiently resilient in order to be positioned against the wall of the ventricle and maintained in a position during ablation without being displaced by the movement of the beating heart. Along with the steerability, flexibility and resiliency, the catheter must have a sufficient degree of torsional stiffness to permit user manipulation from the proximal end.
Steerable catheters are known for use in a variety of medical procedures. See, for example, U.S. Pat. No. 4,998,916 to Hammerslag, U.S. Pat. No. 4,944,727 to McCoy, U.S. Pat. No. 4,838,859 to Strassmann, U.S. Pat. No. 4,826,087 to Chinery, U.S. Pat. No. 4,753,223 to Bremer, U.S. Pat. No. 4,685,457 to Donenfeld, U.S. Pat. No. 3,605,725 to Bentov, U.S. Pat. No. 3,470,876 to Barchilon and U.S. Pat. No. 4,960,134 to Webster, Jr. Typically, such catheters employ a plurality of steering wires, usually three or four, extending from a steering mechanism at the proximal end of the catheter to an anchor point at the distal end of the catheter. By tensioning certain of the steering wires using the control mechanism, the tip of the catheter can be manipulated in a desired direction. See, e.g., U.S. Pat. 3,470,876 to Barchilon or U.S. Pat. No. 3,605,725 to Bentov. In addition to being steerable in the lateral direction, further positioning of known catheters is accomplished by rotating the catheter as a whole about its longitudinal axis, typically by turning or twisting the proximal end of the catheter. This exerts a torque along the length of the catheter which is translated into a rotational motion at the distal end, allowing a laterally deflected distal tip to be rotated.
While radiofrequency ablation using existing catheters has had promising results, such catheters suffer from certain disadvantages. In particular, known catheters lack a sufficient degree of steering sensitivity to accurately position the distal tip electrode at the desired position within the heart. The known technique of achieving rotation of the distal tip by twisting the proximal end of the catheter frequently results in "whipping" of the distal tip in an abrupt and uncontrolled recoiling motion. Such recoiling can occur at unpredictable locations and timings, reducing the success of ablation procedures and potentially risking the health of the patient. Known catheters further suffer from the inability to maintain the position of the distal electrode against the wall of the ventricle the movement of the beating heart. In addition, known catheters suffer from a tradeoff between catheter length and torsional stiffness, with catheters of relatively long length having insufficient torsional stiffness to allow effective positioning by rotating the proximal end of the catheter.
For these and other reasons, it would be desirable to provide a catheter suitable for radiofrequency ablation which is steerable from the proximal end with greater sensitivity and controllability than in known catheters. Further, the catheter should have greater torsional stiffness per unit length than known catheters, so that the relatively long catheters required in certain ablation procedures are sufficiently manipulable from the proximal end. At the same time, such catheters should allow both lateral and rotational manipulation of the distal tip for both "rough" and "fine" positioning. Further, the catheter should have sufficient flexibility to follow the contours of the vessel pathway into the heart without detracting from the catheter's steerability.


The present invention provides a pharmaceutical composition or a solid preparation containing a stabilized pharmaceutically active ingredient and a stabilizing method thereof.

The "nonpeptidic pharmaceutically active ingredient having a primary or secondary amino group" is widely used as a pharmaceutically active ingredient for various diseases. For example, patent document 1 describes a compound represented by the following formula and a salt thereof as agents for the treatment or prophylaxis of peptic ulcer, gastritis, erosive esophagitis and the like.
wherein r1 is a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, the monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle optionally has substituent(s), r2 is an optionally substituted C6-14 aryl group, an optionally substituted thienyl group or an optionally substituted pyridyl group, r3 and r4 are each a hydrogen atom, or one of r3 and r4 is a hydrogen atom, and the other is an optionally substituted lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r5 is an alkyl group.
Patent document 2 describes a proton pump inhibitor (PPI) comprising a compound represented by the following formula or a salt thereof, or a prodrug thereof as an agent for the treatment or prophylaxis of peptic ulcer, gastritis, erosive esophagitis and the like.
wherein Z and W are the same or different and each is a bond or a spacer having 1 to 20 atoms in the main chain, r6 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, r7, r8 and r9 are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted thienyl group, an optionally substituted benzo[b]thienyl group, an optionally substituted furyl group, an optionally substituted pyridyl group, an optionally substituted pyrazolyl group, an optionally substituted pyrimidinyl group, an acyl group, a halogen atom, a cyano group or a nitro group, and r10 and r11 are the same or different and each is a hydrogen atom or an optionally substituted hydrocarbon group.
Patent document 3 describes N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropaneamide (the following formula) or a pharmacologically acceptable salt thereof as an active ingredient of a stabilized pharmaceutical composition containing an indoline compound.

Patent document 4 describes, as an improved preparation for oral use of a compound, a pharmaceutical composition for oral administration, which comprises at least a) ethyl 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzoimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate represented by the following formula or one of the pharmaceutically acceptable salts thereof and b) one or more pharmaceutically acceptable organic acids having water-solubility higher than 1 g/250 ml at 20° C.

On the other hand, regarding a stabilizer of a pharmaceutically active ingredient in a pharmaceutical composition, patent document 5 discloses an aqueous pharmaceutical solution comprising an aqueous solution containing an organic acid salt of a polymyxin antibiotic and carboxylic acid (organic acid, as a stabilizer).
In addition, non-patent document 1 describes, for stabilization of peptide (P66) in a nonaqueous solvent, acidification of peptide by addition of HCl, TFA, H3PO4 and the like.
Beside the above, patent document 6 describes a pharmaceutical composition comprising a proton pump antagonist (acid pump antagonist, APA) and one or more basic excipients to stabilize APA, and patent document 7 describes a sustained-release pharmaceutical composition comprising reversible PPI, wherein APA is stabilized with one or more basic excipients (carbonate, magnesium salt etc.).
Patent document 8 discloses a stabilized pharmaceutical preparation coated with a coating agent containing a) a light shielding agent capable of generating free radical by UV light, and b) a free radical scavenger. In addition, as the light shielding agent capable of generating free radical by UV light, metal oxides such as titanium oxide and the like are described, and as the free radical scavenger, for example, organic acids such as benzoic acid and the like are described.
In addition, non-patent document 2 describes the principles of photocatalytic reaction of titanium oxide, and explains the Honda Fujiyama effect that various substances adsorbed to a photocatalytic surface are oxidized and reduced when titanium oxide, which is one kind of the photocatalysts, is exposed to a light having a wavelength of 380 nm or below.

Abstract: According to the present invention, a pharmaceutical composition can be stabilized by containing a nonpeptidic pharmaceutically active ingredient having a primary or secondary amino group, an excipient and an acidic compound. In addition, a solid preparation containing a pharmaceutically active ingredient, titanium oxide, a plasticizer and a chain organic acid can enhance the stability of the pharmaceutically active ingredient during light irradiation.


A damper device for a refrigerator has a step motor used as the power source for rotating a baffle to open/close the cold air passage of the refrigerator in a more secured manner. The damper device for a refrigerator includes a frame installed in the cold air passage of the refrigerator and provided with an opening at the center thereof, a baffle rotatably installed on the frame to open/close the opening, a gear-equipped step motor installed on a surface of the frame and having a reduction gear and a motor integrally formed therein to transmit a rotation force necessary for opening/closing operation of the baffle, and a stopper adapted to mechanically limit the baffle in such a manner that it can be positioned in the desired opening position.

In general, a refrigerator is provided with a damper device in the cold air passage, such as a duct, to regulate the flow of cold air inside the refrigerator and maintain the temperature within the refrigerator at a preset temperature.
The present invention has been made to improve the prior art disclosed in Korean Registered Utility Model No. 20-0285567 in the name of the present applicant, entitled "REFRIGERATOR DAMPER USING GEAR-EQUIPPED STEP MOTOR", the disclosure of which will now be described with reference to FIG. 1.
As shown in FIG. 1, the refrigerator damper 100 using a gear-equipped step motor a frame 110 installed in the cold air passage and provided with an opening 114, a baffle 130 adapted to regulate the flow of cold air in the opening 114 of the frame 110, and a gear-equipped step motor 120 installed in a motor case formed on a side of the frame 110 to rotate the baffle 130 a predetermined angle based on the temperature condition of the refrigerator.
The baffle 130 is a square plate and is adapted to be rotated a predetermined angle by the gear-equipped step motor 120 to open/close the opening 114 of the frame 110. The baffle 130 has an output shaft cap 132 formed on a side thereof to be inserted into and coupled to the output shaft 122 of the gear-equipped step motor 120 and a rotation support shaft cap 134 formed on the other side thereof into which the rotation support shaft 112 formed on the frame 110 is inserted and coupled to support the rotation of the output shaft.
As currents are applied to the gear-equipped step motor 120, it generates a rotation force which is transmitted to the output shaft cap 132 inserted and coupled to the output shaft 122. The baffle 130 is then reciprocally rotated by the rotation force within a predetermined range of rotation angle to open/close the opening 114 and control the outflow of the cold air.
When the baffle 130 completely closes the opening 114, the flow of cold air is interrupted and, when the baffle 130 completely opens the opening 114, the flow of cold air is maximized. As such, the amount of cold air flowing into the refrigerating chamber or the freezing chamber is regulated.
When the baffle position (rotation angle) of the damper is controlled by the conventional gear-equipped step motor, however, the gear-equipped step motor may operate erroneously and the rotation angle of the baffle may exceed a desired range. Thus, the opening/closing operation of the baffle becomes unreliable frequently.
Particularly, the step motor has a preset rotation angle corresponding to each electrical input signal (pulse) and is suitable for position control. When a predetermined frequency or pulse is applied to the gear-equipped step motor for opening operation of the baffle, the absence of a means for limiting the maximum rotation angle of the baffle generates frequent errors in the baffle position.
Such errors in the baffle position due to the gear-equipped step motor make the opening/closing operation of the baffle inaccurate. When the baffle incompletely opens the opening, the circulation of cold air within the refrigerator is disturbed and, when the baffle incompletely closes the opening, the cold air leaks out and the efficiency of the refrigerator degrades.
When the baffle position of the damper is controlled by the gear-equipped step motor, it is difficult to install a means for limiting the maximum rotation angle of the baffle, e.g., a stopper, inside the gear-equipped step motor. Even when such a means is installed therein, it is not easy to adjust the initial position when the damper is assembled.


The present invention relates to methods for producing a polypeptide, comprising: (a) cultivating a fungal host cell in a medium conducive for the production of the polypeptide, wherein the fungal host cell comprises a nucleic acid construct comprising a first nucleotide sequence encoding a signal peptide operably linked to a second nucleotide sequence encoding the polypeptide, wherein the first nucleotide sequence is foreign to the second nucleotide sequence and the 3′ end of the first nucleotide sequence is immediately upstream of the initiator codon of the second nucleotide sequence. The present invention also relates to the isolated signal peptide sequences and to constructs, vectors, and fungal host cells comprising the signal peptide sequences operably linked to nucleotide sequences encoding polypeptides.

1. Field of the Invention
The present invention relates to methods for producing secreted polypeptides. The present invention also relates to isolated nucleotide sequences encoding signal peptides and nucleic acid constructs, vectors, and host cells comprising the signal peptide sequences operably linked to nucleotide sequences encoding polypeptides.
2. Description of the Related Art
The recombinant production of a heterologous protein in a fungal host cell, particularly a filamentous fungal cell such as Aspergillus or a yeast cell such Saccharomyces, may provide for a more desirable vehicle for producing the protein in commercially relevant quantities.
Recombinant production of a heterologous protein is generally accomplished by constructing an expression cassette in which the DNA coding for the protein is placed under the expression control of a promoter, excised from a regulated gene, suitable for the host cell. The expression cassette is introduced into the host cell, usually by plasmid-mediated transformation. Production of the heterologous protein is then achieved by culturing the transformed host cell under inducing conditions necessary for the proper functioning of the promoter contained on the expression cassette.
Improvement of the recombinant production of proteins generally requires the availability of new regulatory sequences which are suitable for controlling the expression of the proteins in a host cell.
U.S. Pat. No. 6,015,703 discloses genetic constructs comprising a promoter, a xylanase secretion signal, and a mature beta-glucosidase coding region. The disclosed constructs, when expressed in recombinant microbes, dramatically increase the amount of beta-glucosidase produced relative to untransformed microbes.
WO 91/17243 discloses an endoglucanase V and the gene thereof from Humicola insolens DSM 1800.
It is an object of the present invention to provide improved methods for producing a polypeptide in a fungal host cell using signal peptide sequences.

Methods for producing secreted polypeptides


An exemplary method of providing network address translation (NAT) for GPRS tunneling protocol user plane (or GTP-U) traffic on a data center server supporting multiple radio bearers in a mobile network is disclosed. The method includes: receiving packets from a source node via a GTP-U tunnel; filtering ingress GTP-U packets from other types of packets; forwarding a respective ingress GTP-U packet with a public destination IP address to a first queue if a destination IP address matches a defined GTP-U public IP address for the destination node; extracting one or more ingress GTP-U packets and forwarding the packets to a user-land operating system process for inspection; performing NAT of the destination IP address; placing ingress GTP-U packets that have an internal IP address that identifies with a particular radio bearer into a second queue; and forwarding the ingress GTP-U packets via a radio bearer within a network for processing.

The exemplary embodiment relates to a method and apparatus that provides processing, including network address translation, for general packet radio service (GPRS) tunneling protocol user plane traffic on generic data center servers supporting multiple radio bearers in a mobile network. While the exemplary embodiment is particularly directed to the art of wireless telecommunications, and will be thus described with specific reference thereto, it will be appreciated that the exemplary embodiment may have usefulness in other fields and applications.
By way of background, a mobile network operator (also known as a wireless service provider, wireless carrier, cellular company, or mobile network carrier) is a provider of wireless communications services that owns or controls the elements necessary to sell and deliver services to an end user including radio spectrum allocation, wireless network infrastructure, back haul infrastructure, billing, customer care and provisioning computer systems and marketing, customer care, provisioning and repair organization. Mobile network operators' networks are populated with a large and increasing variety of proprietary hardware appliances. To launch a new network service often requires yet another variety of proprietary hardware appliance and finding the space and power to accommodate all these boxes of proprietary hardware appliances is becoming increasingly difficult. This difficulty is often compounded by the increasing costs of energy, capital investment challenges and the rarity of skills necessary to design, integrate and operate increasingly complex hardware-based appliances.
Moreover, hardware-based appliances can rapidly reach their end of life, requiring the procure-design-integrate-deploy cycle of new appliances to be repeated with little or no revenue benefit. Worse yet, hardware lifecycles are becoming shorter as technology and services innovation accelerates, inhibiting the rollout of new revenue earning network services and constraining innovation in an increasingly network-centric connected world.
Thus, there is a need for a method and system that resolves the above-referenced difficulties and others.

Method and apparatus for processing GPRS tunneling protocol user plane traffic in a cloud-based mobile network


An organopolysiloxane emulsion composition produced by the emulsion polymerization of an emulsion that comprises (A) an organopolysiloxane containing a silanol group or an organooxy group, (B) a nonionic surfactant represented by formula (2): R2O(EO)a(PO)bR3 (wherein R2 represents an alkyl group or R4(CO)—; R4 represents an alkyl group; R3 represents an alkyl group or R5(CO)—; R5 represents an alkyl group; EO represents an ethylene oxide group; PO represents an alkylene oxide group; and a and b independently represent 0 to 100, wherein a+b>0 and the sequence of EO and PO may be random or in the form of a block) and (C) a surfactant other than the component (B), and may additionally comprise (D) a polymerization catalyst and (E) water if required. According to the present invention, it becomes possible to produce an extremely stable organopolysiloxane emulsion composition without inhibiting polymerization during the emulsion polymerization of an organopolysiloxane having condensation reactivity. Further, it also becomes possible to reduce the amount of octamethylcyclotetrasiloxane produced during the emulsion polymerization.

In a variety of fields including cosmetics, household agents and parting agents, it is required that an organopolysiloxane having a high degree of polymerization or organopolysiloxane having a branched silicone chain be available in emulsion form. However, when such organopolysiloxane is directly emulsified, a particle size of several microns becomes the limit. So studies were made on the preparation method via emulsion polymerization. For example, it is known from Patent Documents 1 and 2: JP-B S34-2041 and JP-B S41-13995 that cyclic siloxane oligomers are emulsified before emulsion polymerization is conducted in the presence of strong acids or strong bases.
Recently, octamethylcyclotetrasiloxane becomes a matter of concern as environmental loading substance. Samples having a reduced content of octamethylcyclotetrasiloxane are required. It is known that the siloxanes in the above-cited patent documents contain 40,000 ppm or more of octamethylcyclotetrasiloxane. Studies have been made on the method of suppressing the amount of octamethylcyclotetrasiloxane formed.
As one exemplary method, it is known from Patent Document 3: JP 3145394 that a condensation reactive organopolysiloxane having a silanol group at the end of the molecular chain and containing up to 5,000 ppm of a non-condensation reactive organosiloxane oligomer of up to 20 silicon atoms is subjected to emulsion polymerization at 40° C. or lower for a polymerization time within 40 hours. However, an ordinary nonionic surfactant of the structure having a hydroxyl group at the end, which is used to enhance the stability of emulsion, inhibits condensation of silanol. Even after emulsion polymerization is continued for 40 hours, the ultimate viscosity is several million mm2/s. The emulsion polymerization time must be further prolonged before a higher degree of polymerization can be reached.

This patent is subject to a terminal disclaimer.


A wind power and hydrogen power complex generating device includes a fan assembly having a blade unit and a demultiplexer connected to the blade unit. A heating unit is connected to a first output end of the demultiplexer. A pump is connected to a second output end of the demultiplexer. The pump pressurizes liquid water. A heating assembly is connected to the pump and the heating unit. The heating assembly heats the liquid water into a critical state. An electrolyzing unit includes an input end, a hydrogen output end, and an oxygen output end. The input end is connected to the heating assembly. The electrolyzing unit electrolyzes the liquid water in the critical state into gaseous hydrogen and gaseous oxygen. A fuel cell unit includes an anode passage connected to the hydrogen output end and a cathode passage connected to the oxygen output end.

1. Field of the Invention
The present invention relates to a generating device and, more particularly, to a wind power and hydrogen power complex generating device using a fuel cell unit.
2. Description of the Related Art
FIG. 1 shows a conventional wind power generating device 9 including a post 91, a blade unit, 92, a generator set 93 and a gear box. The blade unit 92 is rotatably mounted to a top end of the post 91. The generator set 93 is connected via the gear box to the blade unit 92. When the blade unit 92 is driven by wind to rotate, the gear box regulates the rotating speed and then drives the generator set 93 to generate electricity.
Generally, the wind power generating device 9 captures the wind power by using lift-type or drag-type blades. A rotating shaft and a gear train of the generator set 93 convert the wind power into mechanical energy, which, in turn, is converted into electrical energy. However, the conversion coefficient during conversion from the wind power to the mechanical energy is about 0.52 according to the Betz's law; namely, only about a half of the wind power is converted by the wind power generating device 9, and the other half of the wind power is lost during the conversion, causing limitation to the amount of electricity generated by the generator set 93 through conversion from the mechanical energy to the electrical energy. The amount of electricity generated is also limited by the operating capacity of the generator set 93. Thus, the electricity generating effect of the wind power generating device 9 is not good. Improvement to the wind power generating device 9 is, thus, required.

Wind power and hydrogen power complex generating device

NATIONAL PINGTUNG UNIVERSITY OF SCIENCE & TECHNOLOGY


The present invention provides methods and compositions for amplifying the detection signal in surface plasmon resonance (SPR)-based flow systems. The signal amplification methods comprise the use of well established marker systems that provide a precipitate. The marker systems include, for example, enzyme and nucleation systems. Enzymes suitable for use as a marker system include peroxidases and phosphatases. The amplification system is useful in any SPR-based detection system including microfluidic systems, e.g., “lab on a chip” systems and the like. The methods can comprise any SPR-based assay format, including typical immunoassay formats. The immunoassay formats can include competitive and sandwich assays. Analyte capture agents can include antibodies, lectins, carbohydrates, polynucleotides, receptor proteins, and the like.

The present invention relates generally to microfluidic devices and flow-based methods for performing analytical testing and analysis and, more specifically, the present invention provides compositions and methods for signal enhancement of surface plasmon resonance-based chemical detection in flow-based systems, such as microfluidic flow devices.
Surface plasmon resonance (SPR) is a general spectroscopic method for sensing refractive index changes near the surface of a metal film. Its sensitivity to these changes provides a versatile platform for the observation and quantitation of chemical reactions and intermolecular binding at the metal/solution interface. The generality of the technique has led to its application to a variety of chemical systems, including biological interactions and reactions. Several specifically designed commercial instruments are currently available for these types of assays.
SPR allows detection of small changes in refractive index that result from interactions between surface-bound biomolecules and a solution-borne binding partner. For example, immobilization of a protein to the sensor surface allows for detection of protein binding events manifested by a change in refractive index that is measured as a change in the angle-dependent (or wavelength-dependent) reflectance of the metal film. This type of SPR sensing is typically carried out on commercial instruments that can use, for example, a binding or immobilization layer, such as a carboxylated dextran gel, in addition to a gold film as the sensor surface. Where the dextran gel is used, the gel acts as a host for the surface-immobilized binding partner. However, SPR has also been applied in a number of other formats, including imaging SPR where a large number of chemistries can be rapidly interrogated simultaneously. Also, a variety of other surface chemistries have been used to immobilize and pattern biomolecules for interaction with their binding partners.
SPR relies on the optical excitation of surface modes (plasmons) in a free electron metal, e.g., gold (Au), silver (Ag), aluminum (Al), or copper (Cu) anchored to a glass substrate. Methods for attaching or anchoring the metal to the glass substrate are well known in the art and can include adhesion with a thin layer of, for example, mercaptosilane, titanium, or chromium. Back-side, p-polarized illumination of a prism-coupled film at a specific angle greater than the critical angle for total internal reflection results in plasmon excitation at the metal-solution interface. SPR is most easily observed as a reduction in the intensity of reflected light as measured at the detector (located in the path of the reflected light). The experimental condition (angle or wavelength) of minimum reflectivity, denoted as the SPR angle, shifts to a different position as material is adsorbed onto the metal layer. The shift in the resonance position can be converted to a measure of the thickness of the adsorbed material using various calculations, e.g., complex Fresnel calculations. Adsorption, desorption, and molecule-molecule interactions that occur within the sensing region of about 300 nm adjacent to the metal-solution interface, can thus be monitored in real-time, making SPR suitable for dynamic sensing.
In using SPR to test for biological, biochemical, or chemical substances, a beam of light from a laser source is directed through a prism onto a biosensor consisting of a transparent substrate, usually glass, which has one external surface covered with a thin film of a noble metal, which in turn, is covered with an organic film that interacts strongly with an analyte, such as a biological, biochemical, or chemical substance. The organic film can contain substances, such as antibodies or antigens, that can bind with an analyte in a sample solution to cause an increase in the refractive index in the sample sensing region and shift the SPR resonance. By monitoring either the position of the SPR resonance (as a function of the experimental parameter angle or the wavelength) or the reflectivity at fixed experimental parameters near the SPR resonance, the presence or absence of an analyte in the sample can be detected. Typically, labeling of biomolecules is not required, nor has it been desired. However, this limits the changes in refractive index produced by the binding of both analytes and secondary reagents, which, in turn, limits the speed and sensitivity of SPR detection.
Materials and products have been proposed to enhance the signal from standard SPR-detection methods. One such method is described in WO 01/09388 (incorporated herein by reference), wherein metal nanoparticles are used as optical tags.
The present invention provides additional compositions and methods for signal enhancement of surface plasmon resonance-based chemical detection systems. In the methods an enzyme precipitation signal-enhancement protocol that is well established for use in optical absorption assays is shown to increase the signal associated with reflectivity changes in chemical assays, especially biomolecular recognition assays on planar SPR surfaces coated with a capture reagent. The methods are generally applicable to all detection schemes in which an enzyme label can be used. Commonly used detection schemes in which this method is applicable include, but are not limited to: i) a competition or displacement assay with an enzyme labeled ligand, ii) a sandwich assay in which the enzyme is linked to an agent that binds specifically to the analyte of interest, i.e., an antibody, and iii) a nucleic acid assay in which the enzyme is linked to a nucleic acid probe fragment.

Signal amplification method for surface plasmon resonance-based chemical detection

University of Washington UW Tech Transfer - Invention Licensing


In one embodiment, a light-emitting device having a reflector cup, a light source die, a wavelength-converting layer, an optical structure, and an encapsulant is disclosed. The wavelength-converting layer may be configured to convert a narrow band light emitted from the light source die into a broad band light before the light is directed towards a first direction. The optical element may be an air ring embedded within the encapsulant and may be arranged circumscribing the wavelength-converting layer. In another embodiment, a light-emitting device with extended wavelength-converting layer in place of the air ring is presented.

A light-emitting diode ("LED") represents one of the most popular light-emitting devices today. In recent years, the luminous efficacy of LEDs, defined in lumens per Watt, has increased significantly from 20 lumens per Watt (approximately the luminous efficacy of an incandescent light bulb) to over 500 lumens per Watt, which greatly exceeds the luminous efficacy of a fluorescent light at 60 lumens per Watt. In addition to the luminous efficacy, LEDs may be superior or preferable compared to traditional light sources because of their small form factor, which enables an optical lens may be placed in close proximity to the light sources. Various optical designs that were not possible with traditional light sources may become possible with LEDs. With new optical designs, LEDs are poised to become one of the most appealing light sources.
Usually, color and brightness consistency requirements in LEDs are demanding. Generally speaking, LEDs are susceptible to yellow ring effect, in which light output of an LED may appear yellowish at outer ring. The yellow ring effect may be one of the main reasons why LEDs fail in the uniformity requirements.

Avago Technologies General IP (Singapore) Pte. LM.


A face-image area is decided with comparatively good accuracy. An (N−1)th frame of a subject image α1 and an Nth frame of a subject image α2 are obtained by sensing the image of a subject successively. Face-image detection processing is applied to the frames of the subject images α1 and α2 to detect face-image areas C1, C2 and C3. The face-image area C2 is construed to be linked to the face-image area C1, which is the corresponding face-image area. Since a face-image area that corresponds to the face-image area C3 does not exist, the face-image area C3 is construed as not being linked. The linked face-image area C2 in the Nth frame of the subject image α2 is decided upon as a face-image area. Thus, face areas can be decided with comparatively good accuracy.

1. Field of the Invention
This invention relates to an apparatus and method for detecting the position of a target image, and to a program for controlling this apparatus.
2. Description of the Related Art
When the subject of photography is a person, often it is desired that the portion of the subject image that is the face be imaged attractively. In order to accomplish this, there are instances where the face-image portion is detected from within the image of the subject. There are cases where a plurality of face detections are performed with regard to the same image in order to raise the accuracy of face detection (see the specification of Japanese Patent Application Laid-Open No. 2003-216935).
Further, in a situation in which images of a subject are applied one after another, there are instances where an area in the vicinity of a face image detected in the immediately preceding frame of the subject image is stipulated as an area for detecting the face image portion in the present frame of the subject image (see the specification of Japanese Patent Application Laid-Open No. 11-15979).
However, if erroneous detection is performed in the preceding frame of the image of the subject, this may have an effect upon detection in subsequent frames of subject images. The detection accuracy may become low.

Target-image position detecting apparatus, method and program for controlling said apparatus


A liquid discharging device includes: a discharge head mounting unit having first and second electrical terminals; a power source; a switch controlling connection between the power source and the electrical terminals; and a control unit controlling the switch; wherein a driving circuit driving a liquid discharge head is closed by attachment thereof to the mounting unit; the power source can selectively output multiple voltages; and the control unit selectively effects a state for supply of a discharge electrical power, in which electric power sufficient for a discharging actuator of the discharge head to discharge liquid is supplied thereto by controlling the switch, and a state for diagnosis, in which, wherein electric power insufficient for the discharging actuator to discharge liquid is supplied thereto by controlling the switch, and in which the voltage of at least one of the terminals is measured, and information of the state of the power source, discharging actuator, and driving circuit, is obtained.

1. Field of the Invention
The present invention relates to a liquid discharge device having diagnostic functions of diagnosing the discharge functions of a driving circuit for driving a discharge actuator of a liquid discharge head for discharging a liquid, and to a self-diagnosis method of the liquid discharge device. The present invention particularly relates to the art of a function for confirming that the driving circuit is in a normal state capable of discharging, before actually discharging a liquid such as medical substances, ink, or the like.
2. Description of the Related Art
Conventionally, with inhalers wherein a person inhales a substance sprayed into the throat or mouth, there have been cases wherein the following operation is necessary as a preparation of inhaling the substance, for example. That is to say, a replaceable cartridge integrally configured of a liquid tank and liquid discharging portion, detachably mounted to the inhaler main unit, is mounted to the main unit following which confirmation is made regarding whether or not the mounting has been properly made such that the liquid can be correctly discharged. There has also been cases wherein confirmation is necessary to confirm that the discharge driving circuit for discharging at the main unit side functions properly. One conceivable method for preparation before discharging and inhaling the liquid is to cause a smaller amount of liquid, such as around 1/10 the actual amount to be inhaled, to be discharged, and to visually confirm the state of the mist discharged therefrom.
Such confirmation is also performed with printing apparatuses and the like for discharging ink, and a printing apparatus has been proposed having a function for detecting whether a printing head has been mounted or not mounted, by checking the contact state of electrical terminals.
However, such a method for visually confirming the mist state of the substance wastes the substance. Also, the method for detecting whether or not the discharge head is mounted by the state of contact at the electrical terminals only detects whether or not the discharge head is mounted, and cannot perform an overall check regarding, for example, the actuators themselves within the discharge head, such as heaters or piezoelectric elements, or the state of the driving circuit.

Liquid discharge device capable of self-diagnosis of discharge functions


Methods and apparatuses for embolizing an artery in a living subject using a catheter are disclosed. The catheter has a lumen and also has a balloon located near the distal end of the catheter. The distal end of the catheter is introduced into the artery, and the balloon is inflated to form a seal that prevents blood in the artery from flowing past the balloon. A mixture that includes embolic particles and contrast agent is injected through the lumen into the portion of the artery that is distally beyond the balloon. The subject's own blood or another fluid that contains platelets is injected through the lumen into the portion of the artery that is distally beyond the balloon. Subsequently, the balloon is deflated and the distal end of the catheter is withdrawn.

Obesity is widely recognized as a major public health issue resulting in decrease of quality of life and development of chronic diseases, such as metabolic syndrome, diabetes, hypertension, congestive heart failure, atherosclerosis, sleep apnea, etc. Lifestyle changes can be used to treat obesity, but lifestyle changes are not always achievable, especially in long term prospect. Drug therapy is one conventional treatment for obesity, but it is often accompanied by various complications and adverse side effects.
Bariatric surgery is another conventional treatment for obesity. One of the recognized benefits of bariatric surgery is the decreased production of ghrelin. Ghrelin, a neuropeptide which is predominantly produced in the gastric fundus, is the only known hormone that stimulates food intake (orexigenic hormone). It is believed that the decreased production of ghrelin that is associated with bariatric surgery helps promote weight loss. But bariatric surgery is invasive and can be accompanied by considerable surgical complications and/or adverse side effects.

Selectively delivering particles into the distal portion of the left gastric artery


An apparatus and method related to performing Remote Direct Memory Access Request (“RDMA”) is presented. In one embodiment, the apparatus comprises Remote direct memory access (“RDMA”) logic that executes a direct memory access (“DMA”) request from the remote peer. The apparatus further comprising a protection checking logic to verify a key and a target address in the DMA request and conversion logic to convert the target address to an input/output virtual address (“IOVA”) if the conversion is required. The IOVA is to be translated to the host physical address by an address translation unit at another hardware subsystem.

Computer systems often define several address spaces to store various types or classes of data. For example, executable instructions may be stored in a code segment, while non-executable data may be stored in a data segment. Sometimes address spaces overlap, so that the same data may be referenced through two different addresses; other address spaces are entirely distinct, so that data located within one address space does not appear anywhere within the other space.
Separate (or separable) address spaces provide a powerful programming tool, and serve as a foundation for many advanced computing paradigms. Pre-emptive multitasking and virtual memory systems depend on hardware that permits the establishment of separate, protected memory spaces. Each process or thread in such a system can be provided with an execution environment that appears to contain memory and other resources dedicated solely to that process. An operating system ("OS") keeps track of the physical resources in the system (e.g. memory and devices) and arranges for the hardware to translate virtual addresses ("VA") used by the processes and threads into physical addresses ("PA") that the hardware can use.
Virtual machine systems add another level of abstraction to this model. In some virtual machine systems, low-level software called a "hypervisor" controls the system's physical resources and uses virtualization features of the processor(s) to create one or more virtual machines, each of which appears to be an independent computer with its own physical resources. A "guest" operating system can be started on each of these virtual machine. The guest OS manages the resources supplied by the hypervisor and doles them out to processes and/or threads running under the guest OS.
Several different address spaces are present in this three-level virtual machine model. At the lowest level, the hypervisor deals with physical addresses of real resources present in the host system—"Host Physical Addresses" ("HPA"). The guest OSs are presented with virtual resources that the hypervisor has arranged at locations within the address space of a virtual machine. Each guest OS uses "guest physical addresses" ("GPA") to refer to these resources. Finally, the guest OS prepares virtual execution environments for its threads and processes; the threads and processes use virtual addresses ("VA") to refer to resources the guest OS has allocated to them.
Modern central processing units ("CPUs") contain dedicated circuitry to translate between these addresses, so that a thread or process can quickly access data stored in a physical memory, when the thread has only a virtual address of the data. However, peripheral hardware units may not have ready access to these translation facilities, so it may be difficult or time-consuming for a non-CPU hardware device to access data stored in a physical memory when the software task controlling the device cannot provide a HPA. This situation may arise in the virtual machine environment described: a guest OS may only be able to provide GPAs to a peripheral, but the peripheral needs a HPA to transfer data to or from the intended memory location (such a transfer from device to memory is called a direct memory access, or "DMA.")

Method and apparatus by utilizing platform support for direct memory access remapping by remote DMA (“RDMA”)-capable devices


Systems and methods for denying access to a data processing system by an intruder are provided. Input/output (I/O) on the intruder's connection may be taken over and responses mimicking a local terminal session passed back. On an attempted reconnect by the intruder, the user name and password used by the intruder to access the system may be captured. The password may then be changed on the edge system and the intruder's terminal session disconnected, or alternatively, continue to log the intruder's activity.

In modern data processing systems, particularly with respect to enterprise networks, attacks against the network by unauthorized intruders are a continuing problem. This problem is made particularly acute by the Internet, and the necessity for enterprises to have Internet connectivity. Typically, enterprise networks employ an intrusion detection system (IDS) to monitor the network. Typically an IDS will simply page a system administrator or log the incident. More sophisticated systems may terminate the unauthorized connection and deny future logins. However, such intrusion prevention schemes are unworkable if the compromised login happens to be "root."
Moreover, typical IDS operate on a system-by-system basis. That is, each system attached to the enterprise network performs its own IDS function. However, an intruder may have broken into an edge node, snooped passwords on the enterprise network, and then connected to the next node via a Telnet session. (It would be recognized by those of ordinary skill in the art that Telnet is the protocol within the TCP/IP suite of protocols that establishes a emulated terminal session between two network systems.) Thus, although an intruder may be denied access to the most sensitive nodes via their respective IDS, the intruder may still have access to a multiplicity of nodes on the enterprise system.
Therefore, there is a need in the art for systems and methods to deny access to potential intruders at the edge node. As described further hereinbelow in conjunction with FIG. 1, an edge node connects the enterprise network to an external network such as the Internet.

System and method for denying unauthorized access to a private data processing network

International Business Machines Corporation