A grip heater has a tubular insulator that is designed to slip over a handlebar and has two interposed pairs of helical recesses. Each pair of helical recesses is formed by two parallel helical grooves and accommodates a heating element; the heating elements can have different resistances to provide differing degrees of heat when selectively connected to a voltage source. Preferably, the pairs of recesses overlap such that the heating elements reside in alternating grooves and cross over each other. The heating elements can be connected to a common ground to allow replacement of existing three-wire grip heaters. When a common ground is employed, the heating elements are preferably isolated where they cross.

Grip heaters are employed to heat the hand grips of motorcycles, snowmobiles, and similar equipment which are operated in cold weather but which require sufficient dexterity on the part of the user to make the wearing of bulky mittens or gloves impractical. Such grip heaters are particularly beneficial in alleviating the effect of wind chill, especially when used on vehicle handgrips. These grip heaters have an electrical heating element which is embedded in the handgrip and is powered by a voltage supply of the equipment, such as a battery or a magneto. Examples of such grip heaters are taught in U.S. Pat. Nos. 4,471,209; 4,937,429; and 4,990,753 of the present inventor. These grip heaters have a single heating element of resistive wire wrapped over a tubular insulator having a pair of helical recesses in which the heating element resides. This structure is subsequently covered with a soft grippable material such as rubber to form a composite grip; the helical recesses serve to maintain the heating element in place as the soft grippable material is molded onto the wire-wound insulator. When an electrical current is passed through the wire of the composite grip, the grip is heated.
Since equipment with grip heaters are typically operated under a wide range of temperature and operating conditions, there is frequently a desire to adjust the amount of heat provided, such as providing both a low heat setting and a high heat setting. One approach to providing different degrees of heating is to provide two different heating elements in the handgrip, each element generating a different amount of heat when powered by the equipment battery. This has been achieved through the use of heating elements fabricated with printed circuits, where a pattern of conductors can be printed so as to form two interleaved but electrically isolated circuits on a substrate, which is then formed into a tube and incorporated into a grip. The printed circuits maintain reasonable grip thickness since the conductors are thin and flat; however, these conductors tend to break down at one or more locations along the conduction during use. These breakdowns may result from damage to the printed circuits due, in part, to mechanical straining of the circuit by the user applying force or torque to the grip to maneuver the device to which it is attached. The mechanical strains introduce irregularities which in turn causes the temperature to spike, causing local deterioration of the circuit and ultimately failure; this limits the useful life of such devices. Two additional problems that have been found in printed circuit grip heaters are delamination and heat loss. Over time, the circuit substrate delaminates from the underlying structure, apparently due to thermal degradation of the laminating adhesive, again reducing the life of the grip. The printed circuit also results in excessive heat loss since it resides in close proximity to a metal handlebar and employs flat conductors wrapped around the handlebar, which will increase heat radiation toward the handlebar.
U.S. Pat. No. 6,686,572 teaches a grip heater having two heat levels which does not require the use of printed circuits. The '572 patent teaches a heated handle having a tubular insulator with two interposed helical coils wound thereon, the coils having different heating efficiencies. The coils reside in a pair of parallel helical recesses in the tubular insulator and are subsequently covered with a rubber jacket to form the handle. The '572 patent does not disclose how the individual heating coils are connected to form a circuit, thus raising the issue of whether the '572 patent provides an enabling disclosure. However, while not taught in the '572 patent, it appears that a circuit could be formed if each of the coils is connected to a metal handlebar which in turn is connected to the ground terminal of the battery. In fact, this approach has been commercially used in dual-coil heated handgrips offered by Polly Heaters, Inc. of Franklin Park, Ill., at least as early as 1998. The Polly Heaters handgrips employ two heating elements that are connected to a switch for power from the equipment battery at one end of the handgrip and connected to a central metal sleeve at the other end, which provides a ground through the metal handlebar of the equipment. The switch allows either of the heating elements to be energized, to provide either a low or high heat output. A limitation of such grip heaters is that they depend on the central metal sleeve and metal handlebar to complete the electrical circuit, and thus cannot be used on equipment which has handlebars that are electrically insulated from the battery. Additionally, the metal sleeve tends to act as a heat sink, drawing heat towards the metal handlebars.
An alternative approach to provide a grip with a variable heat output is to control the amount of heat generated by a single heating element. This has been achieved either by limiting the electrical voltage available to the heating element or by varying the amount of time that the heating element receives power. Limiting the voltage available to the heating element, so as to provide a low heat setting, is accomplished by a resistor and a switch. When the switch is in its low heat position, the resistor is in series with the heating element, and when the switch is in the high heat position, it bypasses the resistor. The inclusion of a resistor complicates the wiring and results in wasted electrical power output. Furthermore, the resistor must be fairly large to dissipate a large amount of energy and must be mounted in an exposed location to allow the heat to be dissipated, complicating installation of the grip heater. Controlling the amount of time that the heating element is energized is typically achieved by use of a Pulse Width Modulator, where the electrical current is rapidly pulsed on and off, with the proportion of time on determining how much heat is provided. This approach requires complicated circuitry to switch the current on and off.
Thus, there is a need for a grip heater that allows selecting between high and low heat output while avoiding the disadvantages of the prior art.


An injection stretch blow-molded (ISBM) container prepared by way of injection molding a tubular preform followed by reheating and concurrently stretching and blow-molding the heated preform into the container. The container and preform comprise from 70 wt. % to 97.5 wt. % of a semi-crystalline polyolefin composition comprising one or polymers selected from polyethylene polymers and polypropylene polymers and from 2.5 wt. % to 30 wt. % of an alicyclic polyolefin composition, wherein the alicyclic polyolefin composition has a glass transition temperature, Tg, of from 80° to 145° C.

Monolayer extrusion blow-molding (EBM) of HDPE containers have reached practical limits for light-weighting, that is, reduction of container weight without sacrificing performance. HDPE container manufacturers, for applications such as shampoo and soap bottles, face considerable commercial pressure to lower cost (PET containers may be less expensive), improve performance and improve sustainability, which encompasses container weight reduction, enhanced recyclability and recovery and increased recycle content in new containers.
Polyethylene terephthalate (PET) containers, such as soda and water bottles, are manufactured by way of ISBM. ISBM offers many advantages versus EBM, especially considerably faster production time, significant light-weighting and greater toughness.
ISBM is practiced in so called single-step and two-step processes. In a single-step process, preforms are injection molded, cooled and conditioned, reheated and blown into a bottle on one machine. In a two-step process, (also called reheat stretch blow-molding), preforms are injection molded and cooled. Preforms are taken to a second machine where they are reheated and blown into bottles. PET has crystalline structure which enables PET polymer to strain harden well at elevated temperatures during the stretch and blow process. HDPE is also a crystalline polymer, but it does not strain harden at the required stretch and blow process temperature window of 120° C.-130° C. HDPE melts just above these temperatures. Lack of strain hardening of the HDPE constrains the blow-molding process window and prevents efficient manufacture of HDPE containers using this method.
While the ISBM process has met with tremendous commercial success for making PET containers, one skilled in the art appreciates that semi-crystalline polyethylenes including HDPE generally lack strain hardening behavior which is critical to efficient ISBM processing. See Brandau, O., Stretch Blow Moulding, 3rd Ed., Chapter 2, pp. 18-20, Elsevier, 2017.
Blends of bimodal HDPE and cycloolefin copolymers have been disclosed for injection molding applications, See EP 2 891 680 A1; however, their potential in connection with ISBM processes and products has not been realized.
Manufacturers have explored ISBM of bimodal HDPE with somewhat better success than typical unimodal HDPE as is seen in United States Patent Application Publication No. US 2012/0282422, entitled "Bimodal Polyethylene for Injection Stretch Blow Moulding Applications", of Boissiere et al. However, the HDPE ISBM process window is too narrow to enable the required container quality and prevents widespread commercial adoption.
While there has been passing disclosure of the use of cycloolefin polymers in connection with ISBM processes and semicrystalline olefins, little practical guidance and indeed no recognition at all of the potential of amorphous cycloolefin polymers to improve polyethylene or polypropylene ISBM container manufacture exists in the literature. United States Patent Application Publication No. US 2006/02550499, entitled "Stretch Blow-Molded Stackable Tumbler", of McCarthy et al. mentions stretch blow-molding with blends of polyethylenes in general but provides no specifics or examples. Note ¶[0064]. Likewise, U.S. Pat. No. 6,544,610, entitled "Container and Blow-Molded Product", to Minami et al. discloses a layered product with PE/cycloolefin polymer. See Abstract. U.S. Pat. No. 7,871,558, entitled "Container Intended for Moisture-Sensitive Products", to Merical et al. is relevant to layered products as well; while United States Patent Application Publication No. US 2002/0088767, entitled "Plastic Bottle and Method of Producing the Same", of Saito et al. is of more general interest. See also U.S. Pat. No. 9,272,456 to Etesse which discloses ISBM polyethylene containers.

Injection stretch blow-molding (ISBM) enhancement for semi-crystalline polyolefin containers utilizing alicyclic polyolefins


An apparatus and method of use or treatment are disclosed for creating intrauterine adhesions resulting in amenorrhea. In particular, the apparatus relates to an easily deployed intrauterine implant that readily and consistently reduces or eliminates abnormal intrauterine bleeding. In addition, the apparatus is also used as a uterine marker device for visualizing endometrial tissue thickness and potential changes. The method of the present invention serves as a supplement to or a replacement for conventional hysterectomy or ablation/resection procedures used to treat menorrhagia.

Menstrual bleeding is a part of normal life for women. The onset of menstruation, termed menarche, usually occurs at the age of 12 or 13. The length of a woman's monthly cycle may be irregular during the first one to two years. Once the menstrual cycle stabilizes, a normal cycle may range from 20 to 40 days, with 28 days commonly being an average. Age, weight, athletic activity and alcohol consumption are several factors that affect menstrual cycles. For example, younger women (under the age of 21) and older women (over the age of 49) tend to have longer cycle times, generally averaging 31 days and over. Similarly, women who are very thin or athletic also have longer cycles. In contrast, women who consume alcohol on a regular basis tend to have shorter cycle times.
Nearly all women, at some time during their reproductive life, experience some type of menstrual disorder. These disorders range from mild to severe, often resulting in numerous lost work hours and the disruption of personal/family life each month. In general, physical symptoms such as bloating, breast tenderness, severe cramping (dysmenorrhea) and slight, temporary weight gain frequently occur during most menstrual cycles. In addition to physical symptoms, emotional hypersensitivity is also very common. Women report a wide range of emotional symptoms, including depression, anxiety, anger, tension and irritability. These symptoms are worse a week or so before a woman's menstrual period, generally resolving afterward.
Many women also suffer from a condition called menorrhagia (heavy bleeding). Menorrhagia is a clinical problem characterized by extremely heavy flow/bleeding and major discomfort characterized by blood loss exceeding 80 cc/month. It is estimated that 1 in 5 women between the ages of 35 and 50, or approximately 6.4 million women in the United States alone, are affected by menorrhagia. Fibroids, hormonal imbalance and certain drugs, such as anticoagulants and anti-inflammatory medications, are common causes of heavy bleeding.
Women diagnosed with menorrhagia or dysmenorrhea have limited treatment options available to them. Currently, other than hormone therapy and a few experimental pain management techniques, hysterectomy (removal of the uterus) and endometrial ablation/resection (destruction of the lining of the uterus) are the clinically accepted treatment modalities for menorrhagia. Both of these surgical procedures eliminate the possibility of childbearing. Further, hysterectomy requires up to a six week recovery time and a lifetime of hormone therapy when the ovaries are removed. Endometrial ablation has a low success rate at achieving amenorrhea (cessation of menstrual bleeding). As a result, many of the women affected by menorrhagia are driven to make lifestyle-altering decisions.
Over 600,000 hysterectomies are performed each year in the United States. It is estimated that 1 in 3 women in the U.S. have a hysterectomy before the age of 65. Menorrhagia is the most common reason why hysterectomies are performed. Several studies have estimated that menorrhagia is the cause of 30% (some studies as high as 50%) of the 600,000 annual hysterectomies, resulting in a basis of 180,000 to 300,000 procedures annually. Financially, these numbers translate into annual hospital costs that exceed $5 billion per year.
Based on these statistics, hysterectomy is a very common operation. In general, there are three types of hysterectomies: partial, total and radical. As shown in FIG. 1, a partial hysterectomy involves removal of the upper portion 10 of the uterus 12 (whereby the dotted lines in the figure indicated the area removed), leaving the cervix 14 and the base 16 of the uterus 12 intact. FIG. 2 illustrates a total hysterectomy whereby the entire uterus 12 and cervix 14 are removed. A radical hysterectomy, shown in FIG. 3, entails removal of the uterus 12, both Fallopian tubes 18, both ovaries 20, and the upper part of the vagina 22. Each of the above three procedures may be performed via an abdominal incision (abdominal hysterectomy) or through a vaginal incision (vaginal hysterectomy).
After the operation, the hospital stay is generally less than a week, depending on the type of hysterectomy and whether there are any complications. Since a hysterectomy is a major operation, discomfort and pain from the surgical incision are most pronounced during the first few days after surgery. Medication is available to minimize these symptoms. By the second or third day, most patients are up walking. Normal activity can usually be resumed in four to eight weeks and sexual activity can usually be resumed in six to eight weeks.
Since the 1800's, attempts using various treatments have been made to control uterine bleeding by means other than hysterectomy. Alternative methods include chemicals, steam, ionizing radiation, lasers, electrocautery, cryosurgery and others. The long-term risk for such procedures is quite high and may lead to other more serious complications such as mixed mesodermal tumors or uterine cancer.
Typical therapy or treatment options include drug therapy followed by dilation and curettage (D & C) and, as a last resort, hysterectomy. Drug therapy is generally the first treatment option employed to treat excessive bleeding. Birth control pills, progestin, danazol and gonadotropin-releaseing hormone (GnRH) are a few examples of drug treatments prescribed to reduce bleeding. In general, birth control pills contain synthetic forms of estrogen and progesterone, which prevent ovulation and, thereby, reduce endometrial build-up or thickness. As a result, pill users normally have lighter or minimal menstrual bleeding. Progestin, another synthetic form of progesterone, balances the effects of estrogen normally produced by the body and, similar to the pill, reduces endometrial growth. Often, Danazol and other GnRH agents are prescribed to suppress estrogen production and ovulation. As a result, menstrual bleeding stops or is significantly reduced. However, side-effects of such treatments may include bloating, breast tenderness, increased risk of osteoporosis and high cholesterol.
D & C, frequently a second treatment option for excessive bleeding, is a very common, minor surgical procedure that is generally performed on an outpatient basis in a hospital. Usually, the patient is given a general anesthetic, although the procedure occasionally is performed using only a local anesthetic. The dilation step of the procedure involves dilating or stretching the cervix, which is the lower part of the uterus. Once the cervix is appropriately dilated, the curettage step can then be performed. During curettage, a curette (a spoon-shaped instrument) is inserted through the vagina, past the cervix and into the uterus. The curette is then used to scrape and/or collect tissue from the inside surfaces of the uterus.
Endometrial ablation has become more popular and has been offered as another alternative treatment to hysterectomy for patients suffering from menorrhagia. In 1996, 179,000 ablation procedures were performed, up from 49,000 in 1993. This technique is intended to permanently ablate all layers of the endometrium and allow the cavity to become lined with fibrous tissue.
In general, endometrial ablation is less costly and requires less recovery time for the patient. However, the procedure has received mixed results for controlling bleeding, depending on the technique used, and has a limited success rate of no greater than 20% when defined as complete cessation of bleeding. During one five-year study of 525 women with an average age of 42, endometrial ablation completely stopped uterine bleeding only 26% to 40% of the time. However, approximately 79% to 87% of the women were satisfied with the surgery. About 16% of the women required a repeat ablation to stop bleeding and 9% of the women ultimately opted for a hysterectomy. Research has also shown that the effectiveness of endometrial ablation may decline over years, with menstruation returning in about one-third of women.
It should be noted, however, that the goal of endometrial ablation was never to create amenorrhea (cessation of menstrual periods). This procedure was originally developed as a less invasive alternative to hysterectomy in order to return women with menorrhagia to a normal menstrual flow.
In either endometrial ablation or resection, an attempt is made to remove or destroy the entire lining of the uterus (the endometrium). Endometrial resection, first described in 1983 by De Cherney et al., involves the use of a resectoscope-cutting loop to perform endometrial ablation to remove the lining of the uterus. In contrast, ablation generally uses either vaporization, coagulation or some other thermal energy source to destroy the uterine lining.
Although ablation and resection procedures are often discussed as if they are the same, they differ significantly. For example, some physicians argue that resection is more difficult. However, when it is performed skillfully, resection has much better results (control of bleeding in up to 88% of patients) than roller ball ablation (40% to 55%) and newer ablation techniques (3% to 30%).
There are various methods by which an endometrial ablation procedure may be performed. These methods include roller ball electrocautery, cryo-cauterization, microwave, free circulating water, vaporization, balloon ablation and photodynamic therapy. In general, these procedures are performed in a hospital or surgery center, not in the physician's office, due to the need for anesthesia.
Referring to FIG. 4, conventional endometrial ablation, commonly referred to as "roller ball" ablation, uses a device 24 that looks like a tiny steamroller. This device 24 applies heat and, thereby, destroys endometrial tissue 26 (whereby the destroyed tissue is shown in the figure by a dotted line) as it rolls across the uterine wall 28. Endometrial ablation usually takes 15 to 45 minutes and the patient can go home the same day, although a general anesthetic is usually required.
Another type of ablation procedure is vaporization. This technique involves vaporizing uterine tissue using a thin powerful laser beam or high electric voltage. Visualization of the uterine cavity is made possible by filling the cavity with fluid. If any resection or cauterization is performed, a special substance, such as glycine, sorbitol or mannitol, is used so that the fluid does not conduct electricity. This prevents accidental burn injuries to the rest of the uterus. Because this procedure involves removing or destroying the endometrium using a simple, rapid technique, it is often referred to as "global" endometrial ablation.
The NovaSure System is one example of a global endometrial ablation device used to perform ablation via controlled vaporization of the endometrium. The patient is sedated using a local anesthesia with IV sedation and the cervix is dilated. A gold-plated mesh triangle is delivered via a slender tube and expanded into the uterus of the patient. The shape of the mesh is configured to generally resemble the profile of the uterine cavity. Prior to energizing the mesh, suction is applied to bring the uterine cavity into close contact with the mesh. After energy has been delivered to the endometrial lining via the mesh for one to two minutes, the mesh is retracted and the tube removed from the patient's body.
In 1994, Singer et al. reported preliminary experience with an ablation system incorporating an intrauterine balloon. As shown in FIG. 5, balloon ablation utilizes a balloon 30 at the tip 32 of a catheter tube 34 that is filled with fluid and inflated until it conforms to the walls of the uterus 28. A probe in the balloon (not shown) heats the fluid to destroy the endometrial lining. After eight minutes, the fluid is drained out and the balloon 30 is removed. Pregnancy is possible if some of the lining is maintained, but the risk to mother and child is considerable.
Photodynamic therapy is another type of ablation method. A light-sensitive agent (photofrin II) that contains a cell-killing substance is given intravenously and is absorbed by the endometrium. A light anesthetic is administered and the physician then inserts a small probe into the uterine cavity, through which laser light is transmitted for a few minutes. The light activates the photofrin II, which causes destruction of the endometrium. Early results show reduced bleeding without significant side effects.
Other ablation methods to treat menorrhagia, such as microwave and freezing (cryoablation) techniques, are currently being investigated. However, long-term studies using these treatments to determine their effectiveness at producing amenorrhea and any potential side effects are still needed.
Although ablation and resection procedures are less invasive than hysterectomies, there are various complications that may occur. Examples of possible complications include perforation of the uterus, injury to the intestine, hemorrhage or infection. Another concern associated with ablation treatment involves the risk of cancer. Since ablation does not remove the uterus, women still are at risk for developing endometrial cancer (although the risk is reduced; however, no clinical proof is currently available). Further, because endometrial ablation alters the wall of the uterus, early detection of cancerous changes may be difficult to identify.
Other potential side effects of ablation procedures are infections caused by ablation or similar procedures and intrauterine adhesions. Intrauterine adhesions or synechiae are described as scar tissue inside the uterine cavity. Termed Asherman's Syndrome, intrauterine adhesions 36, as shown in FIG. 6, are band-like formations that develop as a result of injury or trauma to the uterus 12 (due to, for example over-vigorous curettage to the uterus 12) or can also happen simultaneously.
In 1894, Heinrich Fritsch was the first to describe amenorrhea resulting from traumatic obliteration of the uterine cavity following puerperal curettage. However, it was not until 1948, that knowledge about uterine adhesions was first disseminated in medical journals by Joseph G. Asherman, for whom the condition is named. In 1957, the 17th Congress of the Federation of French Speaking Societies of Gynecology and Obstetrics proposed the following classification of uterine synechiae:                Traumatic Synechiae connected with surgical or obstetrical evacuation of the uterus        Spontaneous synechiae of tuberculosis origin        Synechiae occurring after myomectomy        Synechiae secondary to the attack of chemical or physical agents and likewise those resulting from atrophic changes
In general, two types of traumatic synechiae are currently recognized. The first type is stenosis or obliteration of the cervical canal. The second type of traumatic synechiae is partial or complete obliteration of the uterine cavity by conglutination of the opposing walls.
Other terms, such as endometrial sclerosis, traumatic uterine atrophy, uterine artesia, uterine synechiae and adhesive endometriosis, have also been used to describe the phenomena of Asherman's Syndrome. The severity of adhesion is generally classified into one of the following three groups or classes: Class I represents adhesions occurring in less than one-third of the uterine cavity with both ostia (i.e. openings of the Fallopian tubes) visible; Class II represents adhesions occurring in one-third to one-half of the uterine cavity with one ostium visible; and Class III represents adhesions occurring in greater than one-half of the uterine cavity with no ostium visible.
Although Asherman's Syndrome has been studied extensively and numerous articles and papers have been written on the topic, uncertainty still exists as to the predominant causative factor(s) and biological mechanism(s). A general diagram illustrating the process of adhesion formation after trauma is illustrated in FIG. 7. It is believed that if the endometrium is severely damaged, it may be replaced by granulation tissue. When this happens, the opposing uterine walls adhere to one another and form scar tissue. In particular, adhesions form and transluminally bridge the anterior and posterior surfaces of the uterus. The adhesions or tissue that is formed between the walls comprises connective tissue that is, typically, avascular. Soon after, the tissue may be infiltrated by myometrial cells and, later, covered by endometrium.
Conventionally, intrauterine adhesions have been regarded as undesirable conditions (for example U.S. Pat. No. 6,211,217, issued to Spinale et al, U.S. Pat. No. 6,136,333, issued to Cohn et al. and U.S. Pat. No. 6,090,997, issued to Goldbert et al.). Indeed, in several known treatment methods for menorrhagia, it has been encouraged to avoid the creation of adhesions. Even in those circumstances where clinicians have experimented with adhesion formation, the results have not proved promising. For example, in the March 1977 edition of the Israel Journal of Medicine, an article by J. G. Schenker, entitled Induction of Intrauterine Adhesions in Experimental Animals and Women, described an experiment in which surgical sponges were implanted into the subcutaneous wall of the patient. The sponges remained in the subcutaneous wall until fibroblasts, or connective-tissue cells, were formed within the sponges. Next, the sponges were then removed and implanted into the uterus of the same patient.
Schenker observed that, after a period of time, adhesions were formed in the areas adjacent to the location of the implanted fibroblast bearing sponge. No adhesions were observed in areas that did not have contact with the fibroblast bearing sponge. These experiments were carried out in several animal models (for example, rabbit, rat and primates) and humans. Schenker concluded that it was possible to artificially create adhesions within the uterus, but that such a procedure was not practical.
In view of the above, there is a need for a minimally invasive device and method to treat abnormal intrauterine bleeding. In particular, it is desirable that the device have a high success rate at treating menorrhagia and have minimal to no side-effects or related complications. Such a device must also be biocompatible and non-toxic. In addition, the related treatment methods should reduce patient recovery times and hospital costs. Overall, the method of treatment should also improve the quality of life for patients.

Method and apparatus for creating intrauterine adhesions


A process for preparing ondansetron by transamination of an ondansetron structural analog that can be readily prepared conveniently by a Mannich reaction is provided. The process represents an improvement upon known procedures for making ondansetron by transamination because of its rapid rate, selectivity and the ease with which the product can be isolated from the reaction mixture.

Ondansetron, whose systematic chemical name is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, and whose molecular formula is
is the active ingredient of FDA approved antiemetic drugs that are indicated for treatment of nausea and vomiting associated with some cancer chemotherapy and radiotherapy and for the prevention of postoperative nausea and/or vomiting. Ondansetron is commercially available in orally disintegrating tablets and ondansetron hydrochloride dihydrate is commercially available in tablets and in oral solution, each under the brand name Zofran®.
Ondansetron has one chiral center. Ondansetron was first disclosed as a racemate in the patent literature in U.S. Pat. No. 4,695,578 ("the '578 patent") in 1987. The '578 patent describes several ways by which ondansetron can be made. In Example 7 of the '578 patent, ondansetron was prepared by treating a 0.34 M solution of the hydrochloride salt of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (IIa):
in water with 2.9 equivalents of 2-methylimidazole of formula (III):
The reaction was conducted at about 100° C. and required 20 hours to go to completion. Ondansetron was obtained in 82% yield after a single recrystallization. According to a general discussion of this reaction contained in the '578 patent, it may be carried out in a suitable solvent such as water or an alcohol, e.g. methanol, or mixtures thereof and at a temperature of from 20° to 150° C.
In Example 4 of the '578 patent, ondansetron was prepared by N-methylation of 1,2,3,9-Tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of formula (IV):

A solution of the formula (IV) compound in dry N,N-dimethylformamide was added to a solution of sodium hydride in dry dimethylformamide to deprotonate the 1,2,3,9 tetrahydrocarbazol-4-one ring nitrogen and then the resulting anion was reacted with dimethylsulfate. The yield of the reaction was only about 21%. According to a general discussion of this reaction contained in the '578 patent, the reaction can be carried out in an inert organic solvent such as an amide, e.g. dimethylformamide; an ether, e.g. tetrahydrofuran; or an aromatic hydrocarbon, e.g. toluene.
Other preparations of ondansetron disclosed in the '578 patent include Example 8, where ondansetron was prepared by Michael-type addition of 2-methylimidazole to 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one of formula (V)
The reaction was conducted in refluxing water over a 20 hour period and occurred in 44% yield. According to a general discussion of this reaction in the '578 patent, suitable solvents include water; esters, e.g. ethyl acetate; ketones, e.g. acetone, or methylisobutylketone; amides, e.g. dimethylformamide; alcohols, e.g. ethanol; and ethers, e.g. dioxane or tetrahydrofuran; or mixtures thereof.
In Example 18(ii) of the '578 patent, ondansetron was prepared by substitution of 2-methyl-1H-imidazole for chloride in 3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (VI):

The reactants were stirred in dry DMF under nitrogen at 90° C. for 3.75 hours. The reaction occurred in about 72% yield. According to a general discussion of this reaction contained in the '578 patent, it can be carried out in an amide solvent, e.g. dimethylformamide; an alcohol, e.g. methanol or industrial methylated spirit; or a haloalkane, e.g. dichloromethane.
In Example 19 of the '578 patent, 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-carbazole maleate of formula (VII):
was oxidized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dry THF and the counterion was separated to give ondansetron in 55% yield.
In Example 20, DDQ was used to oxidize 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-carbazol-4-ol of formula (VIII):
in 41% % yield (the '578 patent actually reports a yield corresponding to a 413% theoretical yield. The most likely explanation for the error is omission of a decimal place after the decimal point of the mass yield. Thus, we infer that the actual yield was 41%). According to a general discussion in the '578 patent, the oxidation reactions of Examples 19 and 20 may be conducted in ketones, e.g. acetone or butanone; ethers e.g. tetrahydrofuran or dioxane; amides, e.g. dimethylformamide; alcohols, e.g. methanol; hydrocarbons, e.g. benzene or toluene; halogenated hydrocarbons, e.g. dichloromethane; and water or mixtures thereof.
U.S. Pat. No. 5,478,949 discloses a multistep process for preparing ondansetron that concludes with the step of N-alkylating the methylene group alpha to the oxo group of the 1,2,3,9 tetrahydrocarbazol-4-one ring system of the compound of formula (IX)
with 2-methylimidazole to give a compound of formula (X):
which is converted in situ to ondansetron by cleaving the oxalate group with a second nucleophile (EtO−) that also is present in the reaction mixture. The calculated theoretical yields ranged from 75% to 87.3%.
U.S. Pat. No. 6,388,091 discloses a process for preparing ondansetron wherein the silyl enol ether of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one of formula (XI):
is alkylated with a 1-(N,N-dialkylaminomethyl)-2-methylimidazole of formula (XII):
where substituent R is N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, morpholin-4-yl, piperidin-1-yl or pirrolidin-1-yl. According to the '091 patent, the reaction can be performed in an organic solvent such as methylene chloride, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, N,N-dimethylformamide, ethanol and a mixture thereof, or in a mixture of one of the above organic solvents and water to induce precipitation of the product. In the Examples, ondansetron was recovered in 81–86% yield.
U.S. Pat. No. 4,957,609 describes a process for preparing ondansetron and related compounds wherein the last step is closure of the central ring of the 1,2,3,9-tetrahydrocarbazol-4-one ring system starting with a compound of formula (XIII):
wherein X is a hydrogen or a halogen atom using a copper or palladium catalyst depending upon the identity of substituent X. When a palladium catalyst is used, suitable solvents include nitrites, e.g. acetonitrile, alcohols e.g. methanol or ethanol, amides, e.g. dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, and water. When a copper catalyst is used, suitable solvents include amides, e.g. dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, nitrites, e.g. acetonitrile, and alcohols, e.g. ethanol.
U.S. Pat. No. 4,739,072 describes another cyclization process for preparing ondansetron and related compounds. In this process, cyclization of the starting material, a hydrazine of formula (XIV),
is induced with an acid. The Lewis acid ZnCl2 was used in the examples. According to the '072 patent, the reaction can be performed in an aqueous medium, which may be aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.g. dioxane or tetrahydrofuran) as well as mixtures of such solvents. Anhydrous reaction media in which the cyclization can be conducted include one or more alcohols or ethers, carboxylic acids (e.g. acetic acid) or esters (e.g. ethyl acetate).
Chinese Patent Application No. 11143234 discloses additional one-step processes for preparing ondansetron which are related in that they install the (2-methyl imidazolyl)methylene group on the 1,2,3,9-tetrahydrocarbazol-4-one ring system.
It will be appreciated that considerable effort has been expended by synthetic chemists to discover a process for preparing ondansetron that represents an improvement over the processes described in the '578 patent. In fact, the preceding discussion of ondansetron preparation processes focuses on the final step of what, in many instances, are lengthy synthetic sequences from commercially available starting materials to ondansetron. The present invention arose out of our efforts to achieve improved results over those obtained in the '578 patent with a process that was well suited for scale up and industrial production of ondansetron without abandoning the basic synthetic strategies offered in the '578 patent. Accordingly, disclosed herein are improvements to the transamination process of compound (IIa) and related compounds that increase the reaction rate, yield and the general economic efficiency of producing ondansetron from such compounds.

Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-YL)methyl]-4H-carbazol-4-one

TEVA Gyógyszergyár Zárkörüen Müködö Részvénytársaság


A system, method and article of manufacture are provided for use in playing back content. Some embodiments provide a method for use in content playback by accessing an embedded object embedded within object oriented programming stored on a portable storage media where the embedded object controls playback of content, communicating a navigation command from the embedded object within the object oriented programming to the content, altering a register in response to the navigation command communicated, and controlling the playback of the content in response to the altering of the register.

Multimedia computer systems have become increasingly popular over the last several years due to their versatility and their interactive presentation style. A multimedia computer system can be defined as a computer system having a combination of video and audio outputs for presentation of audio-visual displays. A modern multimedia computer system typically includes one or more storage devices such as an optical drive, a CD-ROM, a hard drive, a videodisc, or an audiodisc, and audio and video data are typically stored on one or more of these mass storage devices. In some file formats the audio and video are interleaved together in a single file, while in other formats the audio and video data are stored in different files, many times on different storage media. Audio and video data for a multimedia display may also be stored in separate computer systems that are networked together. In this instance, the computer system presenting the multimedia display would receive a portion of the necessary data from the other computer system via the network cabling.
Graphic images used in Windows multimedia applications can be created in either of two ways, these being bit-mapped images and vector-based images. Bit-mapped images comprise a plurality of picture elements (pixels) and are created by assigning a color to each pixel inside the image boundary. Most bit-mapped color images require one byte per pixel for storage, so large bit-mapped images create correspondingly large files. For example, a full-screen, 256-color image in 640-by-480-pixel VGA mode requires 307,200 bytes of storage, if the data is not compressed. Vector-based images are created by defining the end points, thickness, color, pattern and curvature of lines and solid objects comprised within the image. Thus, a vector-based image includes a definition which consists of a numerical representation of the coordinates of the object, referenced to a corner of the image.
Bit-mapped images are the most prevalent type of image storage format, and the most common bit-mapped-image file formats are as follows. A file format referred to as BMP is used for Windows bit-map files in 1-, 2-, 4-, 8-, and 24-bit color depths. BMP files contain a bit-map header that defines the size of the image, the number of color planes, the type of compression used (if any), and the palette used. The Windows DIB (device-independent bit-map) format is a variant of the BMP format that includes a color table defining the RGB (red green blue) values of the colors used. Other types of bit-map formats include the TIF (tagged image format file), the PCX (Zsoft Personal Computer Paintbrush Bitmap) file format, the GIF (graphics interchange file) format, and the TGA (Texas Instruments Graphic Architecture) file format.
The standard Windows format for bit-mapped images is a 256-color device-independent bit map (DIB) with a BMP (the Windows bit-mapped file format) or sometimes a DIB extension. The standard Windows format for vector-based images is referred to as WMF (Windows meta file).
Full-motion video implies that video images shown on the computer's screen simulate those of a television set with identical (30 frames-per-second) frame rates, and that these images are accompanied by high-quality stereo sound. A large amount of storage is required for high-resolution color images, not to mention a full-motion video sequence. For example, a single frame of NTSC video at 640-by-400-pixel resolution with 16-bit color requires 512K of data per frame. At 30 flames per second, over 15 Megabytes of data storage are required for each second of full motion video. Due to the large amount of storage required for full motion video, various types of video compression algorithms are used to reduce the amount of necessary storage. Video compression can be performed either in real-time, i.e., on the fly during video capture, or on the stored video file after the video data has been captured and stored on the media. In addition, different video compression methods exist for still graphic images and for full-motion video.
Examples of video data compression for still graphic images are RLE (run-length encoding) and JPEG (Joint Photographic Experts Group) compression. RLE is the standard compression method for Windows BMP and DIB files. The RLE compression method operates by testing for duplicated pixels in a single line of the bit map and stores the number of consecutive duplicate pixels rather than the data for the pixel itself. JPEG compression is a group of related standards that provide either lossless (no image quality degradation) or lossy (imperceptible to severe degradation) compression types. Although JPEG compression was designed for the compression of still images rather than video, several manufacturers supply JPEG compression adapter cards for motion video applications.
In contrast to compression algorithms for still images, most video compression algorithms are designed to compress full motion video. Video compression algorithms for motion video generally use a concept referred to as interframe compression, which involves storing only the differences between successive frames in the data file. Interframe compression begins by digitizing the entire image of a key frame. Successive frames are compared with the key frame, and only the differences between the digitized data from the key frame and from the successive frames are stored. Periodically, such as when new scenes are displayed, new key frames are digitized and stored, and subsequent comparisons begin from this new reference point. It is noted that interframe compression ratios are content-dependent, i.e., if the video clip being compressed includes many abrupt scene transitions from one image to another, the compression is less efficient. Examples of video compression which use an interframe compression technique are MPEG, DVI and Indeo, among others.
MPEG (Moving Pictures Experts Group) compression is a set of methods for compression and decompression of full motion video images that uses the interframe compression technique described above. The MPEG standard requires that sound be recorded simultaneously with the video data, and the video and audio data are interleaved in a single file to attempt to maintain the video and audio synchronized during playback. The audio data is typically compressed as well, and the MPEG standard specifies an audio compression method referred to as ADPCM (Adaptive Differential Pulse Code Modulation) for audio data.
A standard referred to as Digital Video Interactive (DVI) format developed by Intel Corporation is a compression and storage format for full-motion video and high-fidelity audio data. The DVI standard uses interframe compression techniques similar to that of the MPEG standard and uses ADPCM compression for audio data. The compression method used in DVI is referred to as RTV 2.0 (real time video), and this compression method is incorporated into Intel's AVK (audio/video kernel) software for its DVI product line. IBM has adopted DVI as the standard for displaying video for its Ultimedia product line. The DVI file format is based on the Intel i750 chipset and is supported through the Media Control Interface (MCI) for Windows. Microsoft and Intel jointly announced the creation of the DV MCI (digital video media control interface) command set for Windows 3.1 in 1992.
The Microsoft Audio Video Interleaved (AVI) format is a special compressed file structure format designed to enable video images and synchronized sound stored on CD-ROMs to be played on PCs with standard VGA displays and audio adapter cards. The AVI compression method uses an interframe method, i.e., the differences between successive frames are stored in a manner similar to the compression methods used in DVI and MPEG. The AVI format uses symmetrical software compression-decompression techniques, i.e., both compression and decompression are performed in real time. Thus AVI files can be created by recording video images and sound in AVI format from a VCR or television broadcast in real time, if enough free hard disk space is available.
As discussed above, such audio and video content is often stored on media such as CD-ROM or digital video disc (DVD). However, once a vendor has delivered such content to a customer, the vendor loses any practical control over the product. Even if the product is delivered under license rather than out right sale, it has traditionally been difficult to prevent a customer from copying the content or providing the content to any number of friends so that they might illegally copy the content.
Another problem which arises from the vendors loss of control of the content maintenance and updating of the software. If content is to be added or modified, the vendor must send a new disc to the customer In addition, the vendor can not control the amount of data which the customer can access. In other words, once the disc is delivered, the customer will have access to all of the content on the disc and only that content. Time sensitive content, such as advertising, can become obsolete but will still be accessible on the disc.
Therefore, there remains a need for a system method or apparatus allowing flexible control of content delivered to a client. Such a system, method or apparatus would preferably allow content to be initially delivered on a traditional recording medium such as a CD-ROM or DVD but would allow a vendor to remote control the access of a user to the content stored thereon. Furthermore, such a system would preferably allow a vendor supplement and/or modify the content and could allow the vendor to limit a client's access to certain portions of the locally stored content if desired. Furthermore, remote control of navigation would be preferably and could facilitate simultaneous access by a controlled number of multiple clients if desired.

System, method and article of manufacture for remote control and navigation of local content


A system and method includes acquisition of a plurality of images depicting a respective scintillator crystal, determination of a plurality of categories based on the plurality of images, determination of a crystal quality value associated with each of the plurality of categories, training of a network to receive an input image and output an indication of one of the plurality of categories based on the input image, the training based on the plurality of images and the at least one category associated with each pf the plurality of images, operation of the trained network to receive a first image of a first scintillator crystal and output a first one of the plurality of categories based on the first image, and determination of a quality of the first scintillator crystal based on the first one of the plurality of categories and a first crystal quality value associated with the first one of the plurality of categories.

A gamma photon detector (also, a gamma camera) typically consists of a scintillator crystal and light sensors optically coupled thereto. In operation, the scintillator crystal receives (i.e., absorbs) a gamma photon and emits a number of visible light photons in response. The light photons are in turn detected by the light sensors, which absorb the light photons and produce corresponding electrons via the photoelectric effect. The magnitude of the resulting electrical pulse is proportional to the energy of the original gamma photon received by the scintillator crystal.
Since these electrical pulses are used to generate images, the quality of the images depends in part on the scintillation properties of the scintillation crystal. More specifically, the sensitivity of the scintillation crystal to gamma photons should be suitable for the imaging system in which it is to be employed and the scintillation properties should be suitably consistent throughout the scintillation crystal (i.e., regardless of where a gamma photon is absorbed). Currently, the adequacy of a scintillation crystal is evaluated visually and subjectively, and becomes sufficiently known only after it is incorporated into an imaging system. The lack of efficient crystal evaluation systems results in excessive discarding of suitable scintillation crystals and manufacturing of then-discarded imaging systems using unsuitable crystals. Systems are desired to efficiently reduce this waste.


A non-linear electrosurgical electrode extender is disclosed. The extender includes a shaft at a proximal end thereof, a receiver at a distal end thereof, and a curved body portion extending between the shaft and the receiver. The shaft fits in an electrosurgical handpiece that defines a handpiece central axis. The receiver receives the electrosurgical electrode. The curved body portion is disposed outside the handpiece central axis and positions the receiver at a converging angle relative to the handpiece central axis such that when the electrosurgical electrode is disposed in the receiver, a surgically active distal end of the electrode intersects the handpiece central axis. The electrode extender is adapted for use with wire loop gynecologic electrosurgical electrode in gynecologic procedures. The extender maintains the tactility and control of a straight electrode extender while permitting the handpiece to be disposed outside the cervix view axis.

This disclosure relates to a non-linear electrosurgical electrode extender. More specifically, the disclosure relates to an electrode extender which is curved to orient an electrosurgical electrode coupled to the extender in a manner that the surgically active end of the electrode falls within a handpiece central axis, as if the electrode extender were linear. The curved electrode extender positions the electrode handpiece away from a colposcope to avoid interference with a colposcope body in gynecologic procedures where a colposcope is used.
Electrosurgical electrodes are used in many different surgical procedures. The electrodes may have a specialized shape and configuration adapted for a particular surgical procedure, such as certain gynecologic procedures. One such procedure is Loop Excision of the Transformation Zone (LETZ). Medical literature also refers to the LETZ procedure as the Loop Electrosurgical Excision Procedure (LEEP). The LETZ procedure uses a thin wire loop electrode to remove cervical lesions. The wire loop may have various sizes and shapes. One commercially available electrode is the UtahLoop® round loop electrode available from Utah Medical Products, Inc., Midvale, Utah. The wire loop electrode is attached to a handpiece (sometimes referred to as an electrosurgical pencil, pen, or chuck), which is a hand-held device that holds the electrode. The handpiece is coupled to an electrosurgical generator which generates an electric current that heats and cuts cervical tissue cells close to the wire loop. A colposcope is often used to allow the gynecologist to clearly see the cervix during the electrosurgical procedure.
Cervical depth varies among patients. Gynecologic electrosurgical electrode lengths that are appropriate for one patient may be insufficient to reach another patient's cervix. A traditional straight electrode extender can provide adequate reach, but the additional length may cause handpiece interference with the colposcope body or block the cervical view. In some cases, the handpiece, without an extender, can be obstructed by the colposcope body. In other cases visual obstruction of the cervix can occur during direct visualization when a colposcope is not used. Moreover, sometimes other equipment and instruments, or even the clinician's hand, may block the cervical view.
Accordingly, it would be an improvement in the art to provide an electrosurgical electrode extender that avoids handpiece interference with the colposcope body. It would be a further advancement in the art to provide an electrosurgical electrode extender that does not block the cervical view axis.

Non-linear electrosurgical electrode extender


Computing devices may implement dynamic transitions from video messages to video communications. Video communication data for a video message may be received at a recipient device. The video communication data may be displayed as it is received, and recorded for subsequent playback. An indication of a selection to establish a video communication with the sender of the video message may be received, or an indication that display of the video communication is to be ceased may be received. If a video communication is to be established, then a video communication connection with the sender of the video message may be created so that subsequent video communication data may be sent via the established connection.

The advent of mobile computing combined with more powerful networking capabilities has changed the ways in which individuals communicate. Formerly, specialized networks had to be configured with particular equipment to provide different types of communication. Video conferencing, for instance, relied upon specialized telephone networks, radio frequencies, or closed-circuit television systems to provide two-way or multi-way video communications between users at different (and often fixed) locations. As broadband or other high-capacity networking technologies have allowed greater and more flexible access to a variety of different systems or devices, via the Internet for instance, different types of communication have developed or evolved to take advantage of these more powerful networking capabilities. For example, instant messaging technologies may provide real-time transmission of text messages over the Internet, allowing participants to chat between two Internet-enabled devices.
Video conferencing has also evolved to facilitate video communication between network-connected devices. Video communication data may be transmitted over networks, such as the Internet, to other participants, providing a video conference-like user experience, without being subject to the limitations of older and more static communication technologies. However, as many devices, such as laptops, mobile phones, tablet computers, or other mobile computing devices now facilitate multiple programs or functions operating simultaneously, video communications may be subject to disruption, inattention, or competition for computing resources of the device performing video communication, dulling the reach or effectiveness of new video communication technologies.

Dynamic transition from video messaging to video communication


A method of controlling the population of a first microorganism at a foliar locus by preferentially enhancing the population of a second microorganism at said locus, comprises applying to the locus an amount of a durable selective habitat enhancer which substantially preferentially potentiates growth of said second microorganism with respect to said first microorganism. The durable selective habitat enhancer preferably comprises a substantially water-insoluble, weather resistant polymeric substrate and a binder which increases the durability of the habitat enhancer. The second microorganism can be endogenous to the foliar locus or exogenously applied. Chitin and cellulose are preferred habitat enhancers.

This invention relates to a method of controlling the population of a first microorganism at a foliar locus by preferentially enhancing the population of a second microorganism at said locus.
Microbiological plant pathogens and insect pests of plants represent a major source of loss of agricultural productivity throughout the world. Research on the biological control of foliar pathogens is limited when compared with studies concerning this form of control for soilborne pathogens. However, as restrictions on the use of chemical pesticides increase, biological control of foliar pathogens is becoming more important.
The ecosystems which exist on above-ground plant surfaces are complex, and the microbial interactions which occur on it are poorly understood. Plant pathogens and their interactions with the host plant have been influenced under limited circumstances by the population of microbial epiphytes which exist in the foliar phylloplane. The introduction of organisms that exhibit antagonism towards foliar pathogens in this environment has been successful in controlling certain pathogens by several mechanisms, which include direct parasitism of the pathogen by the epiphyte, competition for nutrients and space, the production of antibiotics and/or lytic enzymes by the antagonist, and stimulation of a host resistance response.
Recently, there have been several reported successes using introduced antagonists for the control of foliar diseases in the field. Spurr (1981) used Pseudomonas cepacia to inhibit the germination of Alternaria alternata and thereby control Alternaria leaf spot of tobacco in field tests by repeated applications over a period of three years. Limited but significant control of Cercospora leaf spot on peanut was achieved in field tests using aqueous suspensions of P. cepacia applied to foliage at two week intervals. In later experiments by Bailey and Spurr (1984), P. cepacia and Bacillus thuringiensis (Bt) were formulated as wettable powders and sprayed onto peanut foliage using xanthan gum, a water-soluble polysaccharide, as a sticking agent. A decrease in Cercospora leaf spot with both P. cepacia and Bt was observed. Knudsen and Spurr (1987) formulated several bacteria including B. cereus and P. cepacia into wettable powders and dusts and applied them to peanuts in the field. Limited control of Cercospora arachidicola a was achieved using P. cepacia although B. cereus survived in greater number, perhaps due to its resistant spores.
An isolate of Bacillus subtilis was found to produce a compound that inhibits urediniospore germination in Puccinia pelargonii-zonalis, the causal agent of geranium rust (Rytter and Lukezic, 1986). A culture filtrate applied to leaves prior to inoculation with the pathogen reduced the number of rust pustules by 75% compared to controls. The decrease in disease incidence resulting from the application of culture filtrate indicated antibiotic activity. A fluorescent Pseudomonas isolated from the phylloplane of cacao (Theobroma cacao) exhibited antagonism to Monilia roreri in vitro (Jimenez et al., 1986). When tested in the field it achieved control similar to that obtained with fungicide treatments. Lindow (1983) has successfully used a genetically engineered ice-minus form of Pseudomonas syringae to compete with naturally occurring ice nucleation-active bacteria and prevent frost damage. The ice-minus mutant lacks the gene necessary to produce a large surface protein that acts as an initiator for ice crystal formation. Mild frost damage, induced by nucleation-active bacteria, is a precursor for many diseases. Thus, excluding the bacteria from the microenvironment that they normally occupy reduces disease incidence.
The use of fungi as foliar biocontrol agents has received less attention than that of bacteria. There has, however, been success using Trichoderma, which produces an array of potent antibiotics, and has been shown to control Botyris bunch rot and Phomopsis viticola, the cause of dead arm disease of grape (Gullino and Garibaldi, 1986). Five applications of Trichoderma spores beginning at dormant bud stage were found to be equivalent to the control obtained by a commercial fungicide.
It is to be noted that in each of these attempts at bacteriological biocontrol of these various diseases, the introduced microorganism showed poor long-term survivability. It is likely that the limited successes achieved utilizing these techniques were probably the result of antibiotics present in the cultural filtrates coapplied to the plants with the microorganisms.
The chemical environment encountered at the surface of a plant may govern the degree of aggressiveness of virulence a pathogen exhibits. One focus of plant disease control using biological agents has been the introduction of organisms capable of preempting the nutrient supply of a pathogen (Baker and Cook, 1974). It has been shown that if an established epiphytic (foliar) ecosystem is continuously supplied with a source of nutrition, it becomes difficult for a newly introduced pathogen to compete and growth of the pathogen is limited accordingly (Warren, 1972).
Bashi and Fokkema (1977) showed that populations of Sporobolomyces roseus, an epiphytic yeast, increased when a 2% sucrose solution was applied to leaves as a food base. This indicated that the amount of nutrients present on the leaf was a limiting factor with respect to the growth of these organisms. By monitoring the growth of yeasts on wheat leaves after the application of nutrients, Fokkema et al. (1975) demonstrated that epiphytic bacteria compete effectively for nutrients. They found that yeast populations increased only after antibiotics to limit bacterial growth are applied with the nutrients. The ability of bacteria to utilize certain nutrients varies. Danilewicz (1980) found that epiphytic bacteria capable of utilizing lignin precursors were abundant where the precursors were available. The amount and type of nutrients available on the leaf surface play an important role in influencing the growth of epiphytic bacteria. By studying the effect of nutrients on the epiphytic bacteria of bean leaves, Morris and Rouse (1985) found that the application of low concentrations of nutrients affected the composition of the bacterial community by increasing the proportion of those bacteria able to utilize the nutrient applied.
In regard to disease control, addition of nutrients to aqueous bacterial suspensions enhances survival of the bacterium. Control of northern leaf blight of corn and early blight of tomato was thereby obtained in greenhouse tests (Leben and Daft, 1965). Control of Phytophthora infestans on tomato leaves in the greenhouse was achieved using water extracts from composted organic wastes (Weltzien and Ketterer, 1986). Sterile-filtered or heat-treated extracts were ineffective. The use of nitrogen-containing compounds such as urea and lecithin has also been investigated. Burchill and Cook (1971) found that in apple leaves infected with Venturia inaequalis, treatment with 5% urea resulted in the fungus producing fewer ascospores. However, this was likely a result of the urea promoting the rotting of the fallen leaves on the ground, thereby suppressing growth of the fungus. Ammonia, the breakdown product of urea, is toxic to some organisms and caused a rapid increase and significant shifts in the microbial populations from gram positive chromogens to gram negative nonchromogens. In vitro tests showed gram positive organisms stimulated growth of the scab fungus, while gram negative organisms inhibited its growth. Boudrea and Andrews (1987) had little or no success controlling V. inaequalis by the application of Chaetomium globosum ascospores to field-grown trees. The fact that few C. globosum ascospores germinate in the absence of nutrients in the form of complex media was suggested as a possible explanation for its poor performance.
With the exception of the lower fungi and yeasts, the most important structural component of the fungal cell wall is chitin (Lopez-Romero and Ruiz-Herera, 1986). In the fungal cell wall, polymers of chitin are embedded in an amorphous matrix composed of .beta.-1,3-glucans and are susceptible to degradation by chitinases in the thin primary wall formed at the growing tip of the hyphae. Ordentlich et al. (1988) in in vitro studies found that chitinolytic enzymes produced by the bacterium Serratia marcescens caused degradation of 60% of the hyphal tip cells of Sclerotium rolfsii, a soil-borne pathogen.
Chitin has been used as a soil amendment for controlling plant parasitic nematodes and soil-borne pathogens with some success. The addition of chitin to soil stimulates the growth of bacteria, actinomycetes, and fungi capable of producing chitinolytic enzymes (Brown et al., 1979; Godoy et al., 1983; Mitchell and Alexander, 1962). Godoy et al. found that the addition of chitin to soil stimulated the growth of organisms capable of degrading chitin, a component of the middle layer of egg shells in tylenchoid nematodes, through the production of chitinases. The study supported earlier results by Mian et al. (1982) that demonstrated the development of a particular soil microflora in response to the addition of chitin. Many fungi, including species of Aspergillus, Chaetomium, Fusarium, and Verticillium, showed enhanced growth after the addition of chitin to the soil and have been shown to be actively involved in cyst and egg wall degradation of species of Heterodera and Meloidogynee (Godoy et al., 1982; Godoy et al., 1983; Morgan-Jones and Rodriguez-Kabana, 1981; Ownley-Gintis et al., 1982).
In regard to the control of soil-borne fungal pathogens, Chet et al. (1986) have shown that chitin amendments stimulate the growth of the fungus Trichoderma harzianum which produces enzymes capable of degrading the cell walls of Sclerotium rolfsii, Rhizoctonia solani, and Fusarium spp., giving it great potential as a means for controlling soil-borne plant pathogenic fungi.
Each of the approaches to microbiological biocontrol of plant diseases discussed above has demonstrated only a limited success. In particular, it is noted that long term survival and reproduction of the microorganisms was not shown to be enhanced by these approaches, despite the number of years that biocontrol has been considered an ecologically and commercially important goal.

Method of controlling foliar microorganism populations


The invention obtains a controller and a control method capable of improving safety by automatic emergency deceleration action while suppressing a motorcycle from falling over. The invention also obtains a brake system that includes such a controller.

The present disclosure relates to a controller and a control method capable of improving safety by automatic emergency deceleration action while suppressing a motorcycle from falling over, and to a brake system that includes such a controller.
As a conventional technique related to a motorcycle, a technique of improving driver safety has been available.
For example, a driver assistance system is disclosed in JP-A-2009-116882. Based on information detected by a sensor device that detects an obstacle present in a travel direction or substantially in the travel direction, the driver assistance system warns a driver of the motorcycle that the motorcycle inappropriately approaches the obstacle.

Controller, control method, and brake system

Abstract: In the controller, the control method, and the brake system according to the invention, a control mode that causes the motorcycle to take the automatic emergency deceleration action is initiated in response to trigger information generated in accordance with peripheral environment of the motorcycle. In the control mode, automatic emergency deceleration that is deceleration of the motorcycle generated by the automatic emergency deceleration action is controlled in accordance with a change rate of a state amount that is related to posture of the motorcycle during turning travel.


According to one embodiment, a wireless apparatus includes an antenna, a semiconductor chip and a board. The antenna comprises a radiating element includes a main radiating part. The semiconductor chip is connected with the antenna. The board has a first surface and a second surface, terminals are arranged on the first surface, and the semiconductor chip is arranged on the second surface. The main radiating part is arranged outside a first region and a second region, the first region is defined by imaginary lines passing through centers of peripheral terminals of the terminals, the second region is defined as a region where the first region is orthogonally projected onto the second surface.

There is a technique of forming an antenna element by solder balls on a ball grid array package as a semiconductor package with build-in antenna. In this technique, the volume (scale) of a wireless apparatus can be made small as compared with a case in which an external antenna is added. Furthermore, additional steps are not required for a manufacturing process, thereby reducing the manufacturing cost of the wireless apparatus.


Cache and architectural functions within a cache controller are layered and provided with generic interfaces, isolating controller logic from specific architectural complexities. Controller logic may thus be readily duplicated to extend a nonshared cache controller design to a shared cache controller design, with only straightforward modifications required. Throttling of processor-initiated operations handled by the same controller logic resolves operation flow rate issues with acceptable performance trade-offs.

1. Technical Field
The present invention relates in general to cache controllers in data processing systems and in particular to cache controllers which layer cache and architectural specific functions. Still more particularly, the present invention relates to supporting straightforward extension of nonshared cache controller implementations to shared implementations, with simple resolution of associated flow rate issues.
2. Description of the Related Art
Data processing systems which utilize a level two (L2) cache typically include a cache controller for managing transactions affecting the cache. Such cache controllers are conventionally implemented on a functional level, as depicted in FIG. 7. For example, a cache controller 702 may include logic 704 for maintaining the cache directory, logic 706 for implementing a least recently used (LRU) replacement policy, logic for managing reload buffers 708, and logic for managing store-back buffers 710. In traditional implementations, the cache is generally very visible to these and other architectural functions typically required for cache controllers, with the result that cache controller designs are specific to a particular processors such as the PowerPC.TM., Alpha.TM., or the x86 family of processors.
The basic controller structure depicted in FIG. 7 is employed in both nonshared and shared cache controller designs. Nonshared cache controllers manages transactions between a single upstream processor and a nonshared cache. Shared cache controllers, which manage transactions to a cache shared by two or more processors, are difficult to design but have been successfully implemented. Because of the extensive interlocks required, controller designs for a single upstream processor are virtually useless when designing a controller for a shared cache. The logic required for nonshared cache controllers is already complex for many processors and bus architectures because of the numerous special cases which must be accommodated. The logic complexity increases exponentially as additional upstream processors are added and additional interlock logic for coordination becomes necessary. In particular, a substantial portion of the complexity in a shared cache design derives from the requirement--unique to shared cache designs--that the cache controller be capable of responding to a plurality of operations initiated by different processors in the same cycle. For a nonshared cache, only one operation may be initiated within a given cycle. Under the prior art approach, nonshared cache controller designs may not be easily reused in shared cache controllers, but require extensive and laborious design modifications and enhancements for successful transition to a shared controller design.
An additional problem with prior art designs relates to operation flow rate. Typically operations are initiated at a certain rate. In traditional implementations, operations initiated by an upstream processor or processors generally cannot be cancelled or ignored by the cache controller. The cache controller must respond to the operation, even if only to indicate that the operation should be retried later. Therefore, cache controllers are designed to respond to operations at the rate at which they are initiated by an upstream processor or processors. Thus, if a controller supports a single upstream processor which initiates operations at a given flow rate, cache controller 702 must respond to operations at that flow rate. For example, where a bus is defined to be capable of producing an operation once every three cycles, the cache controller is also designed to respond to operations at a rate of one every three cycles. Similarly, shared cache controllers are designed to respond to operations at a cumulative flow rate for upstream processors (that is, equal to the flow rate of all operations initiated by processors sharing the subject cache). Such operational speed requirements, imposed on necessarily complex logic, present a substantial design obstacle.
It would be desirable, therefore, to implement a cache controller which permits straightforward extension of a nonshared controller design to a shared design. It would further be advantageous to provide a cache controller design permitting uncomplicated resolution of the operation flow rate issues associated with implementing a shared cache controller.

Apparatus and method for separately layering cache and architectural specific functions in different operational controllers to facilitate design extension

International Business Machines Corporation


A printer comprises a feed roller to which driving force is transmitted from a motor via a reducer. While the feed roller moves a recording paper, an image is recorded by a line print head one line by one line. The feed roller is provided with a rotary encoder. A controller counts encoder pulses (measured EP) of the rotary encoder to measure an actual feed amount of the recording paper. Whenever five lines are recorded, the measured EP is compared with predetermined reference encoder pulses to detect a feed error of the recording paper. In case that slipping or the like occurs on the reducer, delay in feeding the recording paper is caused. A printing cycle of the next five lines is adjusted so as to eliminate the feed error. In this way, a printing length of one frame is adjusted to a target printing length.

A color thermal printer using a color thermosensitive recording paper is known. The color thermosensitive recording paper comprises three thermosensitive coloring layers which are formed on a support to color in yellow, magenta and cyan respectively. The color thermal printer colors the color thermosensitive recording paper by heating it with a thermal head. The color thermal printer records images of the respective colors in a frame sequential manner so that a full-color image of one frame is obtained. In the thermal head, for example, a plurality of heating elements corresponding to pixels are aligned in a scanning direction. Thermal recoding is performed while the color thermosensitive recording paper is moved in a feeding direction in a condition that the thermal head is pressed against the color thermosensitive recording paper.
The color thermosensitive recording paper is moved by a feed roller. For example, the feed roller is driven by a stepping motor, rotation of which is transmitted to the feed roller via a reducer. As to this reducer, a traction-driven type (see Japanese Patent Laid-Open Publication No. 11-146676) is used for instance. As is well known, the reducer of the traction-driven type comprises a sun roller to which the rotation of the motor is inputted, and planetary rollers disposed around the sun roller. The planetary rollers slide on and revolve about the sun roller. The reducer of the traction-driven type further comprises an output shaft driven by the revolution of the planetary rollers.
The reducer of the traction-driven type has lesser backlash in comparison with a reducer of a gear type. In addition, speed fluctuation is also lesser. Consequently, when the reducer of the traction-driven type is employed in a system for driving the feed roller of the printer, speed fluctuation of the recording paper is restrained. Thus, there is an advantage that color unevenness is restrained. Meanwhile, in the above-mentioned Publication No. 11-146676, a roller to which the motor transmits the rotational force via the reducer is provided with a rotary encoder. Encoder pulses generated by the rotary encoder are detected to perform feedback control for a rotating speed of the motor so that rotational unevenness of the roller is restrained.
As for the reducer of the traction-driven type, although the rotational unevenness is restrained, there is a problem in that reduction ratios of the respective reducers are likely to be different due to variation in accuracy of the sun roller and the planetary rollers, wherein the variation in accuracy is caused at a time of production. Moreover, if load fluctuation occurs, there arises another problem in that the reduction ratio is likely to be changed due to slipping caused between the sun roller and the planetary roller. When the reduction ratios of the reducers are different, a feed amount of the recording paper becomes different in the perspective printers. In this case, variation in printing length of a print image is caused. Further, if the reduction ratio is changed due to the load fluctuation, variation of the printing length is caused relative to the print images printed by a single printer.

Printer and printing method for recording image during movement of recording paper


A rewinding reel for rewinding a carbon ribbon or a label carrier in a label printer is provided, including a shaft, a gear, at least two sliding bases, at least two outer casing members, a resilient element, and a knob. The gear is mounted to the shaft to mate a transmission of the label printer for driving rotation of the shaft. The sliding bases are mounted to the shaft and are rotatable by the shaft. The sliding bases include movable portions that form camming projections and follower projections respectively in camming engagement with follower projections and camming faces formed on the outer casing members to radially move the outer casing members away from and toward the sliding bases for expanding and contracting the outer casing members in order to selectively loosen the carbon ribbon or the label carrier wound around the outer casing members. The knob is fixed to the movable portions and is manually depressible to move the movable portions. The resilient element provides a biasing force that sets the movable portions at a position where the outer casing members expand.

1. Field of the Invention
The present invention relates to a rewinding reel for rewinding a carbon ribbon or a label carrier in a label printer, and in particularly to a rewinding reel that is operable by manually depressing a knob to release or loosen the wound carbon ribbon or label carrier for easy removal thereof.
2. The Related Arts
A conventional label printer receives and fixes labels to be printed and a carbon ribbon for printing therein. The labels are carried by a carrier. The label carrier and the carbon ribbon must be rewound for collection after the printing operation is done and in this respect, rewinding reels are provided to rewind and collect the carbon ribbon and the label carrier. The conventional rewinding reel suffers difficulty of removal of the wound carbon ribbon or label carrier due to the tight engagement of the wound carbon ribbon or label carrier around the reel. Thus, the carbon ribbon or the label carrier must be removed forcibly and this causes certain problems and troubles to a user of the label printer. A conventional solution to this problem is to provide a paper spool as a base for rewinding and the paper spool together with the wound carbon ribbon or the label carrier is then disposed of together. This is also troublesome.

Rewinding reel for carbon ribbon/label carrier of label printer


A golf club head cover is provided with an essentially flexible, non-rigid material construction forming a cavity therein. An elongate opening is provided to the cavity, wherein the opening has a non-linear configuration when the opening is in either the open position, closed position, or both. A seam extends adjacent both edges of the opening forming piping edges next to the opening. A flexible magnetic strip is positioned within the entire length of each of the piping edges adjacent the opening. The flexible magnetic strips are a continuous flat or cylindrical strip that curve around the non-linear configuration of the opening. The strips having magnetic properties along the entire length of the strips.

Golf club head covers have been used for numerous years to protect the head of golf clubs, especially the wood clubs, from hitting other clubs within the golf bag during the transport of the golf clubs. Typically, the head cover is made of a soft, plush or padded material that extends over and around the golf club head. The golf club head cover may also extend over a portion of the shaft or may be connected to a narrow band of highly elasticized material that extends over a portion of the shaft. One purpose of the narrow band of highly elasticized material that extends over a portion of the shaft is to provide a closure means for the golf club head so that it cannot easily or inadvertently be removed from the golf club head cover. Although a portion of the shaft is also protected by the narrow band of highly elasticized material of the golf club head cover, in many cases this protection is not necessary. Thereby eliminating this narrow band of highly elasticized material helps to minimize the cost of the golf club head cover. However, it presents another problem of how to prevent the golf club head from being inadvertently dislodged from the head cover by providing a closure that is aesthetic and allows for quick and easy storage and retrieval of the golf club head.

Golf club head cover with magnetic closure


Embodiments of the present invention provide a pixel cell for an image sensor that includes a photodiode, which provides high gain, low noise, and low dark current. The pixel cell includes a photodiode comprising layers of a first material and at least a second material in contact with one another. The photodiode generates charge in response to light and also amplifies the charge. The layers may be configured to promote impact ionization by a first carrier type and suppress impact ionization by a second carrier type. The pixel cell also includes a gate of a transistor adjacent to the photodiode and may include readout circuitry for reading out the charge generated and amplified by the photodiode.

CMOS image sensors are increasingly being used as low cost imaging devices over Charge Coupled Device (CCD) image sensors. A conventional CMOS image sensor circuit includes a focal plane array of pixel cells, each one of the cells includes a photo-conversion device for generating charge in response to light incident on the pixel cell. Each pixel cell typically includes a transistor for transferring charge from the photo-conversion device to a sensing node, and a transistor, for resetting a sensing node to a predetermined charge level prior to charge transference. The pixel cell also typically includes a source follower transistor for receiving and amplifying charge from the sensing node and an access transistor for controlling the readout of the cell contents from the source follower transistor.
In a conventional CMOS image sensor, the photo-conversion device converts photons to charge and accumulates the photo-generated charge, while other active elements of the pixel cells, such as transistors, amplify the charge.
CMOS image sensors of the type discussed above are generally known as discussed, for example, in Nixon et al., "256×256 CMOS Active Pixel Sensor Camera-on-a-Chip," IEEE Journal of Solid-State Circuits, Vol. 31(12), pp. 2046-2050 (1996); and Mendis et al., "CMOS Active Pixel Image Sensors," IEEE Transactions on Electron Devices, Vol. 41(3), pp. 452-453 (1994). See also U.S. Pat. Nos. 6,177,333 and 6,204,524, which describe operation of conventional CMOS image sensors, the contents of which are incorporated herein by reference.
The basic structure of a photodiode conventionally used in CMOS image sensors includes a p-n junction typically formed as doped regions in a silicon substrate, wherein the p-n junction is operated under a reverse-biased electrical field. The photon to charge conversion occurs as the photons are absorbed into the photodiode and the energy from the light induces ionization in the depletion region at the p-n junction by causing the electrons of the ionized atoms to move from the valence band to the conduction band, leaving behind a hole. The amount of charge generated is proportional to the intensity of the incident light on the photodiode.
Other optoelectronic devices use different types of photodiodes. For example, avalanche photodiodes have been used in light detectors to convert incident light into electrical charge. In addition to photon-to-charge conversion, avalanche photodiodes amplify the photo-generated charge. An example of an avalanche photodiode (APD) is shown in FIG. 1, and includes a light absorbing layer 2, a multiplication layer 4, and a substrate 6. Electrodes 8 and 10 are placed in contact with the light absorbing layer 2 and the substrate 6, respectively, and a bias source 12 connected between the electrodes 8, 10 to create an electric field through the entire APD structure. The layers of the APD are typically materials which consist of Group III and V elements of the periodic table.
Light 14 is directed onto the light absorbing layer 2 and the energy from the photons generates the initial charge carriers by creating a number of electron-hole pairs in the previously neutral atoms of the material of the light absorbing layer. The initially created carriers, electrons and holes, are moved by the electric field into the multiplication layer 4. The holes and electrons generated by the incident light may gain energy as they move to layer 4. When a hole or electron has acquired sufficient energy it may subsequently undergo impact ionization collisions and create a second generation of electrons and holes. Additionally, carriers of the first generation as well as subsequent generations, may then gain energy to ionize, generating more carriers, and so forth. In this manner, the electrical charge generated by the incident light is amplified.
The secondary and subsequent generations of charge carriers may acquire sufficient energy to impact ionize by drifting through the material in the presence of the electric field, as described by R. J. McIntyre, "A New Look at Impact Ionization—Part I: A Theory of Gain, Noise, Breakdown Probability, and Frequency Response," IEEE Transactions on Electron Devices, vol. 46, No. 8, August 1999, the disclosure of which is hereby incorporated by reference.
Avalanche photodiodes amplify charge, but the amplification process may also produce significant noise, typically referred to as the excess noise factor F. In the well recognized article entitled "Multiplication Noise in Uniform Avalanche Diodes," IEEE Transactions on Electron Devices, vol. 13, pp. 164-168, 1966, which is incorporated herein by reference, R. J. McIntyre demonstrates that the excess noise factor can be minimized by maximizing the number of ionizing collisions by one type of carrier and minimizing impact ionizations by the other.
The excess noise factor, F, can be described by the following equation:F(M)=kM+(2−1/M)(1−k),where M is the current multiplication factor, and k is the ratio of a first carrier type ionization rate to the second carrier type ionization rate. In the presence of a relatively low electric field, k is a function of the magnitude of the electric field and the rate of change of the electric field. The higher the electric field in a region that a carrier has moved from, the more likely it is that the carrier will ionize.
It would be advantageous to provide a CMOS image sensor that includes a photo-conversion device capable of charge amplification and with reduced noise for minimized dark current.

High gain, low noise photodiode for image sensors and method of formation