A method for administering nerve growth factor to treat cravings is provided. Pharmaceutical compositions for the treatment of cravings comprising nerve growth factor are also provided.

The present invention provides methods for treatment of psychological conditions. Such psychological conditions, including major depression, hypomania, cyclothymia, anxiety, bipolar disorder, insomnia and other sleep disorders, hyperactivity, attention deficit disorder, chronic fatigue syndrome, premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and agoraphobia, take an enormous toll on people's ability to work, maintain relationships, communicate effectively, think properly, perform physical activity, and sense the environment around them.
The most common of these psychological conditions is depression, which ranks first among all causes of disability in the United States and second after heart disease, as a cause of healthy years lost to premature mortality and disability (Regier et al., Arch Gen Psychiatry 45:977 (1988). Depression can be divided into several types. Major depression is the most severe form of depression characterized by a severe, persistent depressed mood and loss of interest or pleasure in normal activities accompanied by decreased energy, changes in sleep habits, restless behavior, difficulty concentrating, loss of appetite, feelings of guilt or hopelessness, and in severe cases, psychotic symptoms such as hallucinations, delusions, and even suicidal thoughts. An individual must have a history (greater than 2 weeks) of persistent sad moods, loss of interest or pleasure in activities once enjoyed, and feelings of guilt or hopelessness, restless behavior, difficulty concentrating, and even suicidal thoughts in order to make a diagnosis of major depression. The Beck's Depression Scale Inventory, or other screen tests for depression, can be helpful in diagnosing depression.
Major depression can be treated with medications and/or counseling. Studies have shown that antidepressant drug therapy combined with psychotherapy appears to have better results than either therapy alone (Elkin et al., Arch Gen. Psychiatry 46:971 (1989). Medications used include, but are not limited to, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitor (SSRIs), and some new antidepressant drugs such as bupropion, reboxetine, trazodone, venlafaxine, and mitrazapine. Antipsychotic medications are needed for patients suffering from more severe forms of psychotic symptoms, such as delusions or hallucinations. Types of psychotherapy that have proven to be particularly effective for treating depression include interpersonal therapy, group therapy, and cognitive/behavioral therapy. Often experimenting with the right combination of these drugs and therapy is required by the treating physician. Unfortunately, up to 30% of patients with major depression do not gain substantial benefit from initial antidepressant treatments. Often, it is recommended that if one drug does not improve the mood of a patient after 4-6 weeks of treatment, the drug should be changed (Potter et al., N. Eng. J. Med. 325:633 (1991)). Finally, electroconvulsive therapy (ECT), which is a treatment that causes a central nervous system seizure by means of an electric current, is often reserved as a treatment of last resort, in order to improve the mood of severely depressed or suicidal people who do not respond to other treatments. ECT, however, is accompanied by severe side effects, such as long-lasting memory impairment (Hyman et al., Merks Manual of Medicine, Chapter 13 page 13 (2000)).
Alternative therapeutic methods include the use of herbal products for management of chronic conditions, such as psychiatric disorders, including anxiety and depression. In addition, St. John's Wort (hypericum) has recently gained popularity as an adjunct antidepressant in the United States. The National Institute of Health has recently sponsored a Hypericum Clinical Trial comparing 50 to 150 mg/day of sertraline (Zololoft), 900 to 1800 mg/day of St. John's Wort, and placebo in 300 patients with major depression. The conclusion of the study was St. John's Wort was no more effective for treating major depression of moderate severity than a placebo (NIH News Release, Apr. 9, 2002). Side effects of St. John's Wort are mild and primarily include gastrointestinal symptoms and fatigue. Therefore, there is a need in the art for alternative treatments, which are more effective and are associated with fewer side effects for treating major depression.
A second form of depression is chronic low-grade depression, also known as dysthymia. Dysthymia is present most of the time for a period of two or more years wherein an individual experiences a decrease in his/her overall level of energy, appetite, and sleep, as well as has feelings of low self-esteem and hopelessness. These symptoms cause distress and the individual has difficulty functioning in everyday activities. These symptoms, however, are not as severe as those symptoms experienced in major depression. The cause and maintenance of these symptoms are often due to one of the following problems: loss of a friend, substantial disappointment at work or home, prolonged or chronic illness, and alcohol or drug abuse. People who suffer from dysthymia are at an increased risk for episodes of major depression. This produces a behavioral pattern called "double depression," wherein the individual is mildly depressed most of the time, with periodic symptoms of major depression.
Treatments for mild depressive disorders include improving health habits like acquiring adequate, regular sleep and good nutrition. Also, decreasing the use of alcohol and other drugs and becoming involved in healthy activities such as recreation and creative endeavors will relieve depressed feelings. In cases where a subject is unable to shake these "depressed" feelings within a few weeks, the subject may be suffering from major depression and should contact their physician.
The least severe form of depression is a depressed mood. This is an emotional state dominated by feelings of sadness, gloominess, or emptiness, which may be associated with lack of energy. Depressed moods are usually temporary responses to an unhappy or stressful event. Treatments for such conditions are the same as discussed above in treatments for mild depressive disorders.
Finally, diagnosis of depression is different for the different stages in one's life. Elderly depression is one such example. Elderly patients, who present excessive concerns about bodily aches and pains, fatigue, loss of appetite, and sleeping difficulties, are demonstrating, in reality, secondary affects of depression. Depression in the elderly is infrequently diagnosed and untreated due to the fact many older individuals do not admit to the signs or symptoms of depression. Depression in adolescents also requires careful examination. For example, physical examination is used to rule out other medical causes for depressive symptoms. Careful psychiatric evaluations are required to assess the history of the persistent sad, empty, or irritable state of the adolescent patient, along with obtaining information about whether other family members have a history of depression.
Bipolar Disorders
Bipolar disorder is a chronic disease affecting over 2 million Americans at some point in their lives. Bipolar disorder affects men and women equally and appears between the ages of 15 and 25. As opposed to unipolar major depression, the incidence of biopolar disorder does not vary widely around the world. The exact cause is unknown, but it is linked to areas of the brain which regulate mood, and has a strong genetic component. The American Psychiatric Association's "Diagnostic and Statistical Manual of Mental Disorders" describes two types of biopolar disorder, type I and type II. In type 1 (formerly known as manic depressive disorder), there has been at least one full manic episode. People with this type, however, may also experience episodes of major depression. In type II disorder, periods of "hypomania" involve more attenuate (less severe) manic symptoms that alternate with at least one major depressive episode. When the patients have an acute exacerbation, they may be in a manic state, depressed state, or mixed state. The manic phase is characterized by elevated mood, hyperactivity, over-involvement in activities, inflated self-esteem, a tendency to be easily distracted, and little need for sleep. In the depressive phase, there is loss of self-esteem, withdrawal, sadness, and a risk of suicide. Either the manic or the depressive episodes can predominate and produce a few mood swings, or the patterns of the mood swing may be cyclic. While in either phase, patients may abuse alcohol or other substances, which worsens the symptoms.
Methods for treating bipolar disorders differ depending upon the state of the patient. During an acute phase, hospitalization may be required to control the symptoms. In order to reduce the risk of switching into mania, hypomania or rapid cycling, a combination of a mood stabilizer (e.g. lithium; valproate) and antidepressants (e.g., bupropion) is effective for controlling bipolar disorders. Even though lithium is effective in controlling manic and depressive relapses, careful medical supervision along with maintaining salt intake, avoiding nonsteroidal anti-inflammatory drugs, and undertaking weight-reduction diets are all required in order to reduce possible renal failure. Valproate also is characterized by severe side effects including nausea, vomiting, anorexia, heartburn, and diarrhea. Finally, the use of antidepressants for suppressing bipolar disorder must also be carefully monitored in order to achieve full symptomatic remission. Therefore, safer therapeutic methods are needed in the art in order to reduce the severe side effects associated with current treatments of bipolar disorders.
Cyclothymic disorders are similar to bipolar disorders, but less extreme. Cyclothymic disorders are characterized by stages of mild mood changes with stages of mild depression and excitement (hypomania). The changes in mood are very irregular and abrupt, but the severity of the swings is less. Cyclothymia is treated like biopolar disorders, though often not as aggressively. Thus, safer treatments are needed in the art.
Anxiety Disorders
Anxiety disorders, panic attacks, and agoraphobia are conditions that occur as a manifestation of primary mood disorders such as depression. Anxiety is a feeling of apprehension or fear that lingers due to an individual's perception of persistent and unrelenting stress. Anxiety is accompanied by various physical symptoms including twitching, trembling, muscle tension, headaches, sweating (e.g., night sweats), dry mouth, or difficulty swallowing. Some people also report dizziness, a rapid or irregular heart rate, increased rate of respiration, diarrhea, or frequent need to urinate when they are anxious. Fatigue, irritable mood, sleeping difficulties, decreased concentration, sexual problems, and nightmares are also common. Some people are more sensitive to stress and are thus more likely to develop anxiety disorders. The propensity to succumb to anxiety attacks may be due to genetic predisposition or by previous (e.g. childhood) exposure to certain stresses.
Treatment of anxiety disorders includes diagnostic tests for blood differential and thyroid function as well as an electrocardiogram (EKG). If any worrisome physical signs or symptoms do not accompany the anxiety, a referral to a mental health care professional is recommended. Psychotherapy such as cognitive-behavior therapy (CBT) along with the medication benzodiazepines, which facilitate the actions of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the nervous system, are the most effective in severe cases of anxiety. In addition to these treatments, use of antidepressants such as imipramine and the selective serotonin re-uptake inhibitor (SSRI) paroxetine have been shown to produce antianxiety benefit to anxiety patients (Rocca et al., Acta Psychiatr Scand 95:444 (1997)). Treatment with benzodiazepines, however, is accompanied by fatigue, drowsiness, and unsteadiness. After successive treatments with benzodiazepines, patients often develop dependence to the drug and, therefore, careful medical monitoring is required. Thus, there is a need in the art for treatments that provide less drug dependence along with a reduction in side effects and costs.
Panic disorder, one of the anxiety disorders, is characterized by repeated and unexpected attacks of intense fear and anxiety. Panic attacks are usually not related to a particular situation and typically "peak" within ten minutes of their onset. The exact cause of panic disorder is unknown, but it is associated with multiple physiological factors. Panic disorder can occur with or without agoraphobia, but agoraphobia develops in one-third of cases. Agoraphobia is a disorder characterized by avoidance of crowds, and open and public places, particularly if escape or assistance is not immediately available. The development of agoraphobia may involve learned behavior, since it reflects a fear of experiencing panic attacks in unprotected settings, and sometimes the association of panic attacks with areas where they have occurred. The prevalence rate of panic attacks in the population is as high as 1.5 to 5% (Cruz, et al). Panic disorder can occur in children, but the average age of onset is 25 years old. Panic disorder affects middle-aged and older adults as well. Studies have shown that women are 2 to 3 times more likely to be affected (Cruz, et al.).
Symptoms of panic disorder include shortness of breath, dizziness, palpitations, trembling, sweating, choking, nausea, numbness, chest pain, hot flashes or chills, fear of dying, fear of losing control, and fear of going insane. Symptoms of agoraphobia include anxiety about being in places where escape might be difficult, fear of being alone, fear of losing control in a public place, feeling of helplessness, and feelings of detachment. Treatments for both disorders are similar to treatment of anxiety. Antidepressant medicines are effective for treatment of many people with panic disorder and agoraphobia including SSRIs such as Paxil. Behavior therapies are also used in conjunction with drug therapy including relaxation techniques, pleasant mental imagery, and cognitive behavioral therapy to restructure distorted and harmful interpretations of particular situations. As discussed above, the disadvantage of these therapies is possible drug dependence, harmful side effects, and costs. Therefore, there is a need in the art to develop novel methods for treating panic disorders and agoraphobia.
Premenstrual Syndrome (PMS)
Woman's physical, emotional, and behavioral changes associated with phases of their menstrual cycle may worsen mental disorders such as depression and bipolar disorder (discussed below). These changes are referred to as premenstrual syndrome (PMS). In some women, these changes occur regularly, are sometimes severe, and are characterized as feelings of depression, irritability, and other emotional and physical changes. These changes typically begin after ovulation and become gradually worse until menstruation starts. PMS is estimated to affect 70% to 90% of women during their childbearing years. Thirty to forty percent of women suffer from PMS symptoms severe enough to interfere with daily living activities. Wide ranges of physical and emotional symptoms are associated with PMS. By definition, such symptoms must occur during the second half of the menstrual cycle (14 days or more after the first day of the menstrual cycle) and be absent for about 7 days after a menstrual period ends. Symptoms of PMS include, but are not limited to the following: headache, swelling of ankles, feet, and hands, backache, abdominal cramps, breast tenderness, weight gain, bloating, anxiety, confusion, depression, forgetfulness, irritability, fatigue, low self-esteem, and paranoia.
Current treatments for PMS include self-care methods such as exercise and dietary measures wherein nutritional supplements such as vitamin B6, calcium, and magnesium are used. In addition, prostaglandin inhibitors may be prescribed for women with significant pain including headache, backache, menstrual cramping, and breast tenderness. Diuretics can be prescribed for women found to have significant weight due to fluid retention. Psychiatric medications and/or therapy may be used for women who exhibit a moderate to severe degree of anxiety, irritability, or depression. Finally, oral contraceptives may decrease PMS symptoms. Although these treatments provide relief to most women, more effective treatments that eliminate or reduce side effects and costs are still needed in the art.
Premenstrual Dysphoric Disorder (PMDD)
An estimated 3-4% of women suffer severe premenstrual mood symptoms that significantly interfere with work and social functioning. These severe premenstrual symptoms are diagnosed as premenstrual dysphoric disorder (PMDD) or mid-cycle dysphoria. The occurrence of PMDD is higher in women in their late 20s and early 40s, those with at least one child, those with a family history of major depression disorder, or women with a past medical history of either post-partum depression or an affective mood disorder. PMDD differs from PMS in that prospective premenstrual mood symptoms described above occur across multiple menstrual cycles rather than the latter half of the menstrual cycle. Adequate diagnosis is important, because PMDD symptoms may be severe enough to prevent women from maintaining normal function. These symptoms, combined with a patient already suffering from depression, place these patients at a significantly higher risk of committing suicide during the latter half of their menstrual cycle.
Treatments for PMDD include hormone agonist therapy (gonadotropin-releasing hormone (GNRH) agonist leuprolide), and serotoninergic antidepressant therapy (clomipramine, fluoxetine, sertraline, and citalopram). These therapies have demonstrated efficacy in controlling PMDD, but require continuous pharmacotherapy throughout the menstrual cycle, which increases the side effects and costs of these treatments. Intermittent treatments of PMDD with medication administered daily only during the luteal phase (e.g. for 14 days premenstrually) is being studied, but at present has not been implemented. Thus, there is a need in the art for a therapeutic method for treating PMDD and PMS wherein the side effects and costs are reduced and continuous pharmacotherapy is not required.
Other Psychological Disorders
Attention Deficit Disorder (ADD) is the most commonly diagnosed psychological disorder of childhood, affecting 3% to 5% of school aged children. Symptoms include developmentally inappropriate levels of attention, concentration, activity, distractibility, and impulsivity. There are three sub-categories of attention deficit disorder: (1) attention deficit/hyperactivity disorder of the combined type; (2) attention deficit/hyperactivity disorder of the predominantly inattentive type; and (3) attention deficit/hyperactivity disorder of the predominantly hyperactive or impulsive type. Despite much progress in the diagnosis and treatment of ADD, the treatment for this disorder remains highly controversial. While the cause of attention deficit disorder is unknown, scientists have determined a neurological basis for the disease and genes have been identified that are thought to be involved in ADD.
The most effective treatment strategy for ADD is using psychotropic medications such as Dexedine (dextroamphetamine), Ritalin (methylphenidate), and Cylert (magnesium pemoline). Antidepressants (such as amitriptyline or fluoxetine), tranquilizers (such as thioridazine), alpha-adrenergic agonist (clonidine), and caffeine have also been tried to treat ADD. The disadvantage of these drugs is the lack of long term information on the affect these drugs have on the cognitive and emotional development of ADD children. In addition, medications such as antidepressants, tranquilizers, and caffeine have met with little success. A significant amount of research has been carried out studying psychological therapeutic treatments such as contingency management (e.g. time out), cognitive-behavioral treatment (e.g. self monitoring, verbal self instruction, problem solving strategies, and self reinforcement), parent counseling, and individual psychotherapy. Studies using these techniques have yielded mixed results and no studies have been carried out combining psychological interventions with stimulant medications. Therefore, parents are directed to manage the symptoms and direct the child's energy to constructive and educational paths.
Exacerbations of Depression or Other Psychological Conditions
If untreated, depression or other psychological conditions can lead to further complications over a period of time directly dependent upon the severity of depression or psychological condition. There is usually an increased risk of problems with physical and emotional health, which can lead to premature death due to an accentuated medical illness. In turn, physical and emotional maladies such as chronic fatigue syndrome, constipation, tension headaches, and various sleep disorders perpetuate the depressive state of an individual (along with anxiety and bipolar disorders). Depression also increases the risk of tobacco dependence and/or alcohol abuse and/or drug-related problems. Finally, risk of committing suicide is increased up to as much as 15% of those people who suffer from depressive disorders such as major depression. Therefore, there is a need in the art for more improved treatments of depression, which will lead to improvement of other physical, emotional, and substance abuse maladies and vice versa.
Sleep Disorders
Another secondary effect of depression and other psychological conditions is sleep disorders. A sleep disorder is a disruptive pattern of sleep that may include difficulty falling or staying asleep, falling asleep at inappropriate times, excessive total sleep time, or abnormal behaviors associated with sleep. There are more than 100 different disorders of sleeping and waking. They can be grouped into four main categories: problems with staying and falling asleep (insomnia, e.g.), problems with staying awake (sleep state misperception, e.g.), problems with adhering to a regular sleep schedule (hypersomnias such as narcolepsy, e.g.), and sleep disruptive behaviors (sleep walking, e.g.). Both insomnia and sleep disruptive behaviors could be direct results of a patient suffering from a psychological disorder such as depression or anxiety.
Insomnia includes any combination of difficulty with falling asleep, staying asleep, intermittent wakefulness, and early-morning awakening and can lead to the following disorders: psychophysiological, delayed sleep phase syndrome, hypnotic dependent disorder, and stimulant dependent sleep disorder. Episodes may be either transient (2-3 weeks) or chronic. Common factors associated with insomnia are depression, anxiety, stress, illness, caffeine, abuse of alcohol, medication, illness, physical discomfort, and counterproductive sleep habits such as early bedtimes and daytime napping. Treatment of insomnia is related to the cause. If there is an obvious physical or psychological cause (such as depression), it is the first focus of treatment.
Sleep disruptive behaviors include sleep terror disorder, sleep walking or REM behavior disorders (a type of psychosis related to lack of REM sleep and lack of dreaming). Symptoms of sleep disruptive behaviors are depressed mood, anxiety, apathy, difficulty concentrating, irritability, daytime fatigue, drowsiness, and difficulty falling asleep. Again, treatment of sleep disruptive behaviors is often related to the cause. If there is an obvious physical or psychological cause, it is the first focus of treatment.
Tension Headaches
A tension headache is one of the most common forms of headache. It can occur at any age, but is most common in adults and adolescents. If headaches occur two or more times weekly for several months or longer, the condition is considered chronic. Tension headache is a result of contraction of the neck and scalp muscles. One cause of this muscle contraction is a response to stress, depression, or anxiety. Any activity that causes the head to be held in one position can cause a headache. Other causes include eye-strain, fatigue, alcohol use, excessive smoking, excessive caffeine use, or conditions such as sinus infection, nasal congestion, overexertion, colds, influenza, etc. Tension headaches are not associated with structural lesions in the brain. Current treatment is aimed at relieving symptoms and preventing reoccurrence of the headache. Stress management is one such treatment aimed at removal and control of precipitating factors such as anxiety or depression. There is a need, however, in the art for more effective treatments for tension headaches.
Chronic Fatigue Syndrome
Chronic fatigue syndrome is a condition of prolonged and severe tiredness and weakness (fatigue) that is not relieved by rest and is not directly caused by other conditions. Recent studies have shown that chronic fatigue syndrome may be caused by inflammation of pathways in the nervous system; and that this inflammation may be some sort of immune response or autoimmune process. Chronic fatigue syndrome may occur when a viral illness is complicated by an inadequate or dysfunctional immune response. Other factors such as age, prior illness, stress, environment or genetic disposition and depression may also play a role in the disease. Although depression is indirectly related to chronic fatigue syndrome, it may contribute to the unusual nervous system symptoms associated with this disease. Many people with chronic fatigue syndrome experience depression and other psychological problems that may improve upon treatment. There is no current treatment that has proven to be effective in curing chronic fatigue syndrome. Some proposed treatments are antiviral drugs, medications to treat depression, medications to treat anxiety, and medications to treat pain, discomfort, and fever. Even though depression and anxiety may not be directly linked to chronic fatigue syndrome, depression and other psychological disorders are intricately interrelated with this disease and, therefore, there is a need in the art to find new innovative ways for treating these diseases.
Constipation
Constipation is a relative term. When the stool is hard, infrequent, and requires significant effort to pass, the person has constipation. Constipation may cause discomfort with passage of stools, and passage of large, wide stools may tear the mucosal membrane of the anus, especially in children, causing bleeding and the possibility of an anal fissure. Constipation can be caused by changes in diet, decrease in physical activity, diseases of the bowel, congenital diseases, medications, dehydration, behavior and psychological problems such as depression and anxiety, and neurological diseases. Depression and anxiety are again aggravating factors that contribute to a person suffering from constipation. There is a need in the art to focus on treatment of the depression or anxiety disorder in order to overcome the secondary effects of conditions like constipation.
A patient is considered to have chronic (long duration) constipation if (1) for at least 12 months, patients not taking laxatives report two or more of the following: fewer than three bowel movements per week; excessive straining during at least 25% of bowel movements; passage of hard or pelletlike stool during at least 25% of bowel movements; a feeling of incomplete evacuation for at least 25% of bowel movements; or (2) for at least 12 months, patients have an average of fewer than two bowel movements per week.
Cravings
Substance-related disorders appear to be caused not by a single agent but by a combination of social, biological, and psychological factors. Stress can serve as an inducement for craving or addictive behavior, especially chronic stress, and with continued or repeated use of the substance in question, a dependency of physiological and/or psychological origin. Simple habituation can be complicated by a growing dependency, especially if the substance craved provides a sense of happiness or pleasure via the dopamine or other pathway. Often depression is thought to be a prelude to craving or dependence, although it has likewise been argues that craving leads to depression.
Regardless of origin, craving reflects a biochemical process which, in theory, if interrupted could lead to correction of the malady by regulating those bio-active molecules associated with addiction pathways in such a manner as to restore relative homeostasis at a molecular, or sub-molecular level. Accordingly, there remains a desire for methods and compositions for the treatment of cravings.
Nerve Growth Factor
Nerve growth factor (NGF), a prototypical neurotrophic factor and member of the neurotrophin family, promotes a wide range of responses in target cells. These responses include, but are not limited to, neuron differentiation, maintenance of neuronal survival, and regulation of metabolic activities. Nerve growth factor is well-characterized neurotrophic factor that is essential for the normal development and function of basal forebrain cholinergic neurons in the central nervous system (CNS) (Ghahn et al., 1983; Thoenen and Edgar, 1985). A central area of research in application of nerve growth factor has been its application to age-related cognitive impairments due to the atrophy or loss of basal forebrain cholinergic neurons (Armstrong et al., Neurobiol. Aging 14:457-470 (1993)). For example, studies have shown the intraventricular infusion of NGF can reduce cholinergic neuron atrophy and improve spatial learning or memory retention in aged rats (Scali et al., Neurosci Lett 170:117-120 (1994); Markowska et al., J. Neurosci 14:4815-4825 (1994)). Due to studies indicating decreased immunoreactivity for the NGF receptor in basal forebrain of aged rodents, neural growth factor appears to be linked to spatial learning and memory retention (Fischer et al., Neurobiol. Aging 13:9-23 (1992)). One example of therapeutic uses of NGF includes administering NGF to patients with senile dementia of the Alzheimer's type (SDAT). The problem of such treatment is NGF does not pass through the blood-brain barrier in physiologically relevant amounts and treatments required intracranial surgery (Kordower et al., Exp. Neurol. 124:21-30 (1993). Novel carrier systems consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26) have been able to cross the blood-brain barrier.
Despite these recent applications of nerve growth factor, there remains a desire to use NGF to remedy other neurological disorders. Moreover, there exists a growing concern over the widespread use of psychotropic drugs for treating disorders such as depression, anxiety, bipolar disorder. Accordingly, there remains a desire in the art for improved treatment of various psychological conditions by administration of safer compounds that are relatively inexpensive, safe without accompanying side effects, and that can easily be administered.

Method of treating cravings by administration of nerve growth factor


The present invention refers to an exchangeable crimping die insert for a crimping die for crimping electrical contact terminals to electrical cables. The exchangeable crimping die insert includes a first and second crimp profile integrated in one part, the first crimp profile having an essentially identical profiles with the second crimp profile. Furthermore, the exchangeable crimping die insert includes an indicator to differentiate the first crimp profile from the second crimp profile.

Crimping is extensively used for joining two pieces of metal or other ductile materials by deforming one or both pieces. For example, in the automotive industry, the crimping technique has replaced soldering to a large extent. In an exemplary crimping process a stripped wire is inserted in correctly sized crimping vanes of a terminal, and a crimping tool or a crimping die is used to tightly squeeze the crimping vanes of the terminal against the wire. In order to fulfil predetermined requirements for a crimped product, the terminal, the crimping material, for example the stripped wire, and a crimping tool have to be tailored to each other. For this purpose, crimping tools or crimping dies have specific crimp profiles adapted to specific terminals and crimping materials.
European Patent Application EP 1503454 A1 describes a typical crimping process for joining a contact terminal to a respective electrical wire for generating wire harnesses used in vehicles. U.S. Patent Application Publication 2005/0050940 A1 describes an example of a crimping tool as it is applied in automated mass production.
As already mentioned, the crimping die has to deform in a defined manner at least one of the two components to be combined in the joining process, typically the terminal. This means that usually the material of the crimping tool has to be harder than the material of both the materials to be joined. In order to increase the lifetime of the crimping die, these tools preferably have an exchangeable or changeable crimping die insert of hard material, preferably a hard metal or a hard metal alloy. Nevertheless, exchangeable crimping die inserts wear off rapidly during thousands or hundreds of thousands of crimping processes performed by a crimping die or crimp tool designed for mass production. Hence, the crimping die insert is a wearing part. The usage of the crimping tool for many joining processes gradually changes the crimp profile of the crimping die insert. This may lead to the result that the crimped product does no longer meet predetermined requirements with respect to the reliability and/or durability. Therefore, it is necessary to periodically replace the crimping die insert, i.e. after having performed a predetermined number of crimps.
To optimize the lifetime of a crimping die insert, it would be beneficial that a crimping die insert has more than one identical crimp profile. For example, in case a crimping die insert has two identical crimp profiles, the lifetime of the crimping die would double. The German patent application DE 4427306 A1 describes an exchangeable contour insert for an automated strand placement machine, wherein the exchangeable contour insert includes two identical crimp profiles arranged on the top and bottom face of the contour insert.
However, the two identical crimp profiles of DE 4427306 A1 are integrated in an exchangeable contour insert carry the risk that one of the crimp profiles is excessively used, whereas the other one is hardly used. This may occur, since it is difficult to determine the degree of wear and tear of several identical crimp profiles of an exchangeable crimping die insert. In particular, it is not possible to reliably identify the condition of a crimp profile with the naked eye, so that it is not readily possible to identify whether a crimp profile has already been used or not. For this purpose, it is either necessary to steadily control the quality of the crimped product and/or to apply expensive measurement tools to periodically investigate the crimp profiles of the crimping die inset in a time-consuming process.
The subject matter discussed in the background section should not be assumed to be prior art merely as a result of its mention in the background section. Similarly, a problem mentioned in the background section or associated with the subject matter of the background section should not be assumed to have been previously recognized in the prior art. The subject matter in the background section merely represents different approaches, which in and of themselves may also be inventions.

Exchangeable crimping die insert for a crimping die


A semiconductor integrated circuit device is arranged to have a plurality of logic circuit blocks, a data signal path for interconnecting logic circuit blocks and for providing a function of interfacing a current-driven signal. The logic circuit block on a signal output side includes an output circuit connected to the data signal path and a switching element formed of an NMOS transistor for controlling current flowing through the data signal path in response to an input signal applied to an input terminal of the output circuit. The logic circuit block on a signal input side includes an input circuit connected to the data signal path. The input circuit includes a bipolar transistor having an emitter connected to a constant current source, a collector forming an output terminal, and a base set at a fixed potential. The data signal path led from the output circuit is connected to the emitter of the bipolar transistor. The arrangement results in reducing a signal amplitude on the signal bus, thereby speeding up the transmission of the data signal and reducing noise of the signal.

The present invention relates to a semiconductor integrated circuit device having a plurality of MOS field-effect transistors and bipolar transistors and its applied circuit device, and more particularly to a hardware arrangement of a current-driven type signal interface for speeding up the signal interface and a carry propagation device having a hardware arrangement applied thereto.
As the hardware arrangement for speeding up a signal interface, which is comprised of a semiconductor integrated circuit device having a plurality of MOS field-effect transistors and bipolar transistors integrated thereon, a BiCMOS tri-state buffer circuit has been disclosed in JP-A-59-28726. The speed-up concept this circuit is to amplify the current of the CMOS circuit through the effect of the bipolar transistors for enhancing the driving capability of a load and driving the load at a higher speed.
In addition, as an example, a current-driven circuit applied to a wiring driver and a receiver connecting for effecting interconnection of the LSI blocks has been disclosed in JP-A-61-20346.
The foregoing prior arts have the same signal amplitude as a voltage difference between a supply voltage and a grounding voltage such as, used in a CMOS circuit. Since the signal amplitude is large, therefore, a large amount of charges to be charged or discharged is needed for inverting the signal. This puts a limitation to speeding up the circuit. Further, since the signal amplitude is large, the larger amount of current flows through the circuit within a unit time. This results in causing more noise.
The problems associated with the prior arts have will be described in detail with reference to FIGS. 19A to 19B. FIGS. 19A to 19B show a tri-state output buffer circuit and an input circuit used for the interface between logic blocks, respectively. In FIG. 19A, 201 is an input terminal. Numeral 202 is an enable terminal. When the voltage of the terminal 202 is at a high logical level "H", the output of the circuit has a high impedance. When it is at a low logical level "L", the circuit outputs an inversion signal of the input signal at the terminal 201. The output circuit has such a fundamental concept that the logic circuit is comprised of MOS transistors and the current is amplified with bipolar transistors for driving the heavy load depending on the wiring and fanout at a high speed. The output circuit can supply a signal whose amplitude is the substantially the same as that of the CMOS circuit, that is, the potential difference between a power supply potential 1 and a grounding potential 2. More strictly, the amplitude V of the output signal of such a circuit can be derived as V=VDD-GND-2Vbe, wherein VDD is a power supply potential, GND is a grounding potential, and Vbe is a potential between a base and an emitter of the bipolar transistors 203 and 204. As an example, VDD=5 V, GND=0 V and Vbe=0.7 V are referred. In this example, the amplitude of the output signal is V=3.6 V. That is, since the signal amplitude has such a high value as V=3.6, the foregoing problems may be brought about.
FIG. 20 shows a conventional BiCMOS I/O circuit. A BiCMOS output circuit 211, a CMOS output circuit 212 and a BiCMOS input circuit 213 are connected through a bus 214. When an input terminal 202 is at "L" and an input terminal 215 is at "L", the BiCMOS output circuit 211 is selected so that the output of the CMOS output circuit 212 has a high impedance. At this condition, the bus 214 is at 0 V or 3.6 V depending on the state of the input terminal 201. When the input terminal 202 is at "H" and the input terminal 215 is at "H", the CMOS output circuit 212 is selected so that the output of the BiCMOS output circuit 211 has a high impedance. In this condition, the bus is at 0 V or 5 V depending on the state of the input terminal 216. As mentioned above, the conventional circuit provides such a high signal amplitude of the bus as 5 V or 3.6 V.
The conventional data processing apparatus employs a semiconductor element with a high-speed operating capability. This is not fast enough to process a signal at high speed. The main factor greatly controlling the performance of such a data processing apparatus is a carry delay in an adder. As a word length of the input data is made longer, the carry delay of the adder is increased linearly. To improve such a delay, a proposal has been made that a carry of each stage is calculated in parallel. Such an improving method, which is well known , is "Principles of CMOS VLSI Design: A systems Perspective", by Neil H. E. Weste and Kamran Eshraghian, published 1985.
In the writing, an i-th carry Ci is represented by the following expression. EQU Ci=Gi+Pi.multidot.Ci-1 (1)
wherein EQU Gi=Ai.multidot.Bi (Generation Signal) (2) EQU Pi=Ai.sym.Bi (Propagation Signal) (3)
The expansion of those expressions results in obtaining the following expression. EQU Ci=Gi+Pi.multidot.Gi-1+Pi.multidot.Pi-1.multidot.Gi-2+. . . +Pi.multidot.Pi-1. . . P1.multidot.C0 (4)
The sum Si can be generated by the following expression. ##EQU1##
For the first four gates, the terms indicated below can be obtained. EQU C.sub.1 =G.sub.1 +P.sub.1 C.sub.0 ( 6) EQU C.sub.2 =G.sub.2 +P.sub.2 G.sub.1 +P.sub.2 P.sub.1 C.sub.0 ( 7) EQU C.sub.3 =G.sub.3 +P.sub.3 G.sub.2 +P.sub.3 P.sub.2 G.sub.11 +P.sub.3 P.sub.2 P.sub.1 C.sub.0 ( 8) EQU C.sub.4 =G.sub.4 +P.sub.4 G.sub.3 +P.sub.4 P.sub.3 G.sub.2 +P.sub.4 P.sub.3 P.sub.2 C.sub.1 +P.sub.4 P.sub.3 P.sub.2 P.sub.1 C.sub.0 ( 9)
With respect to C.sub.4, the expression of C.sub.4 can be represented by the following expression. EQU C.sub.4 =G.sub.4 .multidot.P.sub.4 .multidot.(G.sub.3 +P.sub.3 .multidot.(G.sub.2 +P.sub.2 .multidot.(G.sub.1 +P.sub.1 .multidot.C.sub.0))) (10)
As one example of a circuit for realizing the foregoing operational expression, a Manchester carry adder shown in FIG. 27 has been known. This adder is arranged as a Manchester carry propagating circuit composed of MOS transistors only. When each MOS transistor operates on a clock signal, the transistor at an output stage changes between 0 V and 5 V. That is, the amplitude of the propagation signal is so large as to restrict the speed-up of the signal processing. Further, in this circuit, when the clock signal CK is at a logic "0", the node is pre-charged so that the output C4 is fixed at a logic "0". When the clock signal CK is at a logic "1", depending on the logic condition, the charges are discharged from the node for defining the output C4. This means that the signal is allowed to be propagated only when the clock signal CK remains at "1".
To improve this disadvantage, as described in JP-A-61-194529, there has been proposed a carry propagating device arranged to have bipolar transistors and CMOS transistors in combination. As shown in FIG. 28, this device is arranged to have a Manchester carry propagating circuit composed of the MOS transistors only and a sensing circuit composed of a bipolar transistor. The output signal of the Manchester carry propagating circuit is applied to between a base and an emitter of the bipolar transistor. Hence, the carry signal is allowed to be transmitted in the range of 0.8 V. This makes it possible to reduce the amplitude of the carry signal for speeding up the signal processing.
The prior arts, however, are designed so that the transistors may operate on a clock signal. Hence, these prior arts need a half cycle for pre-charging a node and a half cycle for determining a logic, so that the propagating period of the signal is limited to a half cycle of the clock signal. Besides, the amplitude of the carry signal cannot to be limited to 0.8 V or less.

Current-driven signal interface implemented in semiconductor integrated circuit device


The present application discloses a method for manufacturing a gate-all-around field effect transistor, comprising the steps of: forming a suspended fin in a semiconductor substrate; forming a gate stack around the fin; and forming source/drain regions in the fin on both sides of the gate stack, wherein an isolation dielectric layer is formed in a portion of the semiconductor substrate which is adjacent to bottom of both the fin and the gate stack. The present invention relates to a method for manufacturing a gate-all-around device on a bulk silicon substrate, which suppress a self-heating effect and a floating-body effect of the SOI substrate, and lower a manufacture cost. The inventive method is a conventional top-down process with respect to a reference plane, which can be implemented as a simple manufacture process, and is easy to be integrated into and compatible with a planar CMOS process. The inventive method suppresses a short channel effect and promotes miniaturization of MOSFETs.

1. Field of Invention
The present invention relates to semiconductor technology, and more particularly, to a method for manufacturing a suspended fin and a gate-all-around field effect transistor on a bulk silicon.
2. Description of Prior Art
The integrated circuit industry continues developing according to Moore's law and the feature size of CMOS devices is becoming smaller and smaller. A planar CMOS device on a bulk silicon is facing with severe challenges, such as a short channel effect (SCE), leakage current between the source and the drain, a drain induced barrier lowering effect (DIBL), and the like. To solve the above problems, many novel device structures are proposed, in which a gate structure of the device is changed from the initial single-gate structure to a double-gate structure (i.e. FinFET), a multi-gate structure, or even a surrounding gate which surrounds the channel completely. With an increase of the number of the gate, the gate controllability and the capability of suppressing the short channel effect are enhanced. The above novel device structures, such as a double-gate (FinFET), a multi-gate, or even a gate-all-around device, all involve the fabrication of a channel having a fin structure. Specifically, a suspended fin structure should be fabricated for a gate-all-around device.
Up to now, an SOI substrate is used for manufacturing a gate-all-around device. Since an SOI substrate has a natural buried oxide layer (BOX) which can be used as a sacrificial layer, it facilitates the manufacture of a gate-all-around device. The SOI substrate has the following beneficial effects: easily isolating the devices by a natural buried oxide layer in the SOI substrate, which avoids a latch up effect in a bulk silicon substrate; simplifying the manufacturing process; easily suppressing a parasitic transistor at the bottom; smaller parasitic capacitance; high speed; and good anti-radiation performance. However, there are still many problems in manufacturing a gate-all-around device with an SOI substrate. For example, since the SOI substrate has a self-heating effect and a floating-body effect, complicated source/drain engineering should be introduced into the manufacture process so as to decrease parasitic resistance between the source and the drain.
Since a bulk silicon substrate is still used in a mainstream semiconductor manufacture process at present, researches are focused on forming a gate-all-around device in a bulk silicon substrate, which has important significance in application of a gate-all-around device and the development of the semiconductor industry. To manufacture a gate-all-around device in a bulk silicon substrate, one should first consider how to fabricate a suspended fin structure in a bulk silicon substrate.

Method for manufacturing suspended fin and gate-all-around field effect transistor

Institute of Microelectronics, Chinese Academy of Sciences


The order of messages in an asynchronous message system is preserved, by generating a message and tagging the generated message with a sequence identifier and a sequence number. The order of messages is further preserved by processing the tagged message by checking a log to determine whether the sequence identifier is in the log, sending the tagged message to a selected consumer if the sequence identifier is not in the log and sending the tagged message to a particular consumer if the sequence identifier is in the log. Still further, the order of messages is preserved by writing an entry to the log having the sequence identifier and the sequence number of the tagged message and a consumer identifier of the selected consumer if the sequence identifier of the tagged message is not in the log.

Various aspects of the present invention relate generally to preserving message order in an asynchronous messaging system.
With reference to FIG. 1, in an asynchronous messaging system (100), a sending application (termed "producer" (105) herein) sends a message to a queue (115) of a receiving application (termed "consumer" (110) herein) for processing.
When using an asynchronous messaging system, there is often a need for messages from a producer to be processed in the order in which they were sent. For example, if a set of messages represent inserts, updates, deletes etc. for a database, the results can be disastrous if the messages are processed out of order. For example, if an operation to insert a row, followed by an operation to delete a row is processed in the wrong order (i.e. the delete operation is processed before the insert operation), the result leaves a row that should have been deleted as remaining inserted.
A producer naturally orders messages as they are produced. To assure the order is maintained, the most common solution is to configure a producer to send all its messages to a single queue associated with a single consumer. The single consumer processes all messages from the queue in the order in which the messages were placed in to the queue.
Unfortunately, the consumer of such messages becomes a single point of failure. Furthermore, since only a single consumer is used, the system is not scalable. This solution restricts the ability to build dynamic, flexible, messaging architectures which can support different numbers of consumers. Advantageously, multiple consumers can aid with load balancing requirements, can be utilized to route around a failed consumer etc.
Thus, to provide scalability in some asynchronous messaging systems, multiple consumers are employed to process messages stored in a shared queue. There is no guarantee that different consumers will process messages taken from a shared queue at the same rate. With reference to an asynchronous messaging system (200) in FIG. 2, if two consumers (210, 220) listen on a single queue (215), one consumer may process messages faster than the other consumer.
For example, if Consumer 1 (210) executes operations at half the speed of Consumer 2 (220), Consumer 1 (210) can take twice as long as Consumer 2 (220) to process some messages. Furthermore, typically, Consumer 1 has no knowledge of the existence of Consumer 2. Thus a message sequence m1, m2, m3 may actually be processed in the order m1, m3, m2 if Consumer 2 (220) retrieves and processes message m1; Consumer 1 (210) retrieves m2; Consumer 2 (220) retrieves and processes message m3 before Consumer 1 (210) completes its processing of m2.
In one prior art solution, a system is disclosed that can be used when multiple consumers process messages from a shared queue. In the prior art, messages of a particular kind are marked (e.g. by a producer, a filtering application etc.) with a globally unique sequence number (GUS). The multiple consumers must have access to a first relational database that stores data (e.g. GUS, message payload) associated with a last message that was processed and a second relational database that stores data (e.g. GUS) associated with an out of sequence message. Thus if produced messages m1, mn2 and m3 are received in the order m1, m3″ m2, then m1 is processed first and is inserted in the first relational database. When m3 is received, a query against the first relational database determines that m3 is out of order. Message m3 is inserted in the second relational database until m2 is received. When m2 is received, a query is executed against the first relational database to determine that m1 has been processed. Thus, m2 and m3 can then be processed. The first relational database is then updated to reflect that m2 and m3 have been processed.
The prior art solution allows messages to become out of order in transit and then allows for the order to be re-established by utilizing GUS and relational databases. However, there is a requirement for message payload to be stored, which creates resource-consuming overhead. There is also a requirement for consumers to share access to the relational databases—this can cause overhead and reduce scalability, since the number of consumers that can share access to the relational databases is limited.
In some asynchronous messaging systems, multiple consumers are "clustered", wherein each consumer has an associated queue. To preserve message ordering, some systems typically provide a feature wherein a producer can select a single instance of a consumer to which to send messages. However, if the message is to be sent via a chain of different, clustered, consumers, either the message ordering requirement must be sacrificed (i.e. allow later messages to overtake earlier messages so that each consumer in the chain can be selected dynamically for each message) or the ability to build dynamic, flexible, messaging architectures is sacrificed (i.e. wherein each component explicitly specifies the next component to which the message must be sent).

International Business Machines Corporation


A disposable absorbent article, such as a diaper, is disclosed. The diaper has two lengthwise extending longitudinal marginal portions, each longitudinal marginal portion having two elastically extensible leg cuffs, a barrier cuff and a gasket cuff. The leg cuffs serve to help contain body exudates within the disposable article. Each leg cuff is elasticized to provide a relatively low ultimate contact force against the skin of the wearer at relatively high elongations. This arrangement provides a diaper with leg cuffs which can be elongated to conform to the shape of the wearer, without causing undue discomfort or irritation to the legs of the wearer. The relatively low ultimate contact force at relatively high elongations may be accomplished either through a low contact force differential material, or through a material which exhibits stress relaxation over a relatively short period of time.

Disposable absorbent articles, such as diapers, frequently utilize one or both of two types of leg cuffs, gasket leg cuffs and barrier leg cuffs. Gasket leg cuffs are used to seal the leg openings of the article about the wearer and to help prevent the leakage of body exudates from the article at the leg openings. For example, U.S. Pat. No. 3,860,003 issued Jan. 14, 1975 to Buell teaches a diaper having an elastically contractable side portion. U.S. Pat. No. 4,333,782 issued June 8, 1982 to Pieniak and U.S. Pat. No. 4,450,026 issued May 22, 1984 to Pieniak et al. teach diapers having an elastic film ribbon incorporated into the marginal edges of the diapers.
Barrier leg cuffs are utilized to provide improved containment of body exudates within the disposable absorbent article. For example, U.S. Pat. No. 4,704,115 issued Nov. 3, 1987 to Buell teaches a disposable garment having side edge leakage guard gutters which obviate inversion and unfolding during use by not encircling the thighs of the wearer. U.S. Pat. No. 4,808,178 issued Feb. 28, 1989, to Aziz et al. teaches a disposable article having leakage resistant flaps which are non-absorbent and liquid-impermeable.
Other variations of barrier cuffs have been proposed, such as U.S. Pat. No. 4,795,452 issued Jan. 3, 1989 to Blaney et al. This reference teaches a disposable article having a cuff member with a cantilevered flap which provides a liquid-impermeable seal, a barrier wall which retards the flow of exudates and gasketing action about the legs of the wearer. U.S. Pat. No. 4,795,454 issued Jan. 3, 1989 to Dragoo teaches a disposable absorbent article having a barrier cuff with a distal edge and a proximal edge, with spacing means disposed at the distal edge and a seal formed at the proximal edge.
While many of the leg cuffs of the prior art are elasticized and elastically contractible, the prior art does not address how such elastication affects the comfort of the wearer, particularly with regard to red marking and the associated epidermal irritation, or how such leg cuffs may be utilized to advantageously shape the diaper. Therefore, it is an object of this invention to provide a diaper having leg cuffs which are leakage resistant and yet optimize wearer comfort. In accordance with one aspect of the present invention, a diaper having leg cuffs is provided, which leg cuffs have an ultimate contact force of less than about 270 grams per centimeter (1.5 pounds per inch) of width when elongated about 50 to about 350 per cent, and which have an incremental differential force of less than about 14 grams per centimeter of cumulative width of the elastic members.

Disposable absorbent article having improved leg cuffs


A heat-assisted magnetic recording (HAMR) head has a protective film confined to a window of the disk-facing surface of the slider than surrounds the near-field transducer (NFT) and write pole end. Materials for the protective film include TiO2, ZrO2, HfO2, Nb2O5, Ta2O5, Sc2O3, Y2O3, MgO SiN, BN, SiBN and SiBNC. The slider overcoat is located in the non-window region on the slider's disk-facing surface and optionally also on the window region, with the outer surface of the overcoat forming the slider's ABS. An optional recess may be formed on the disk-facing surface of the slider in the window region, with the protective film located in the recess.

In conventional magnetic recording, thermal instabilities of the stored magnetization in the recording media can cause loss of recorded data. To avoid this, media with high magneto-crystalline anisotropy (Ku) are required. However, increasing Ku also increases the coercivity of the media, which can exceed the write field capability of the write head. Since it is known that the coercivity of the magnetic material of the recording layer is temperature dependent, one proposed solution to the thermal stability problem is heat-assisted magnetic recording (HAMR), wherein high-Ku magnetic recording material is heated locally during writing to lower the coercivity enough for writing to occur, but where the coercivity/anisotropy is high enough for thermal stability of the recorded bits at the ambient temperature of the disk drive (i.e., the normal operating or "room" temperature of approximately 15-30° C.). In some proposed HAMR systems, the magnetic recording material is heated to near or above its Curie temperature. The recorded data is then read back at ambient temperature by a conventional magnetoresistive read head. HAMR disk drives have been proposed for both conventional continuous media, wherein the magnetic recording material is a continuous layer on the disk, and for bit-patterned media (BPM), wherein the magnetic recording material is patterned into discrete data islands or "bits".
In a typical HAMR write head, light from a laser diode is coupled to a waveguide that guides the light to a near-field transducer (NFT) (also known as a plasmonic antenna). A "near-field" transducer refers to "near-field optics", wherein the passage of light is through an element with subwavelength features and the light is coupled to a second element, such as a substrate like a magnetic recording medium, located a subwavelength distance from the first element. The NFT is typically located at the air-bearing surface (ABS) of the air-bearing slider that also supports the read head and magnetic write pole and rides or "files" above the disk surface. NFTs are typically formed of a low-loss metal (e.g., Au, Ag, Al, Cu) shaped in such a way to concentrate surface charge motion at a notch or tip located at the slider ABS when light is incident. Oscillating tip charge creates an intense near-field pattern that heats the recording layer on the disk. The magnetic write pole is then used to change the magnetization of the recording layer while it cools. Sometimes, the metal structure of the NFT can create resonant charge motion (surface plasmons) to further increase intensity and disk heating. For example, when polarized light is aligned with an E-antenna type of NFT, an intense near field pattern is created at the notch or tip of the E-antenna. Resonant charge motion can occur by adjusting the E-antenna dimensions to match a surface plasmon frequency to the incident light frequency. A NFT with a generally triangular output end, sometimes called a "nanobeak" type of NFT, is described in US 2011/0096639 and US 2011/0170381, both assigned to the same assignee as this application. In this type of NFT an evanescent wave generated at a surface of the waveguide couples to surface plasmons excited on the surface of the NFT and a strong optical near-field is generated at the apex of the triangular output end.
As part of the development of this invention, it has been discovered that the reliability of the NFT is much worse under actual recording conditions on a disk than under similar optical power in vacuum or ambient air conditions. This may be due to degradation or oxidation of the slider's protective overcoat, which is formed of amorphous diamond-like carbon (DLC). It may also be due to "back-heating" of the NFT as a result of slider-disk frictional heating, conduction from the disk and/or the accumulation of carbonaceous material near the NFT. Back-heating, i.e., heating of the NFT in addition to the normal optical heating from the laser radiation, can cause diffusion of the NFT metal until the NFT tip rounds and recording degrades.
What is needed is a HAMR head that is not impacted by degradation of the slider's DLC overcoat and which is protected from back-heating.

Heat-assisted magnetic recording (HAMR) write head with protective film for near-field transducer


Provided herein are peptide inhibitors of the interaction between End Binding Protein 3 (EB3) and Inositol 1,4,5-Trisphosphate Receptor Type 3 (IP3R3). Also provided are methods and materials for treating lung injury, including acute lung injury, which may include hyperpermeability of lung vessels, vascular leakage, the development of edema, asthma, anaphylaxis, angioedema, systemic vascular permeability syndromes, and nasal congestion.

Microtubule (MT) cytoskeleton provides an important control-point of endothelial barrier regulation; however, the role of this key cytoskeleton element has not been well studied. The MT stabilizing drug taxol has been shown to attenuate the lung injury in mice models suggesting that MTs may be important in mediating increased lung vascular permeability. However, taxol displays a general toxicity that makes it an inconvenient drug for doctors and their patients.
Microtubule end binding proteins are highly conserved microtubule plus-end tracking accessory factors that bind to growing microtubules (MTs) and suppress MT catastrophic events. Two such end binding proteins, EB1 and EB3, play roles in regulating endothelial cytoskeletal dynamics and cell shape change, the primary determinants of the permeability of endothelial barrier.
Ca2+ is a highly versatile second messenger that regulates endothelial permeability and vascular homeostasis. The activation of phospholipase C β (PLCβ), downstream of PAR-1 activation mediates hydrolysis of phosphotidyl inositolbisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates Ca2+ release from IP3-sensitive intracellular stores, i.e., the endoplasmic reticulum (ER). The depletion of Ca2+ from ER stores is mediated by activation of IP3R on the ER membrane and leads to transient increase in intracellular Ca2+. Ca2+ entry or "influx" is mediated by transient receptor potential canonical (TRPC) channels that are permeable to various cations including Ca2+ and Mg2+. TRPC1 and 4 are store-operated Ca2+ channels (SOC) in endothelial lung microvascular cells that are activated by depletion of ER.
The increase in intracellular concentration of Ca2+ up-regulates activity of protein kinase Cα (PKC α). PKC α is a key regulator of the endothelial permeability response to multiple mediators 2. PKC α phosphorylates p120-catenin and mediates its dissociation from VE-cadherin, thus resulting in VE-cadherin internalization. PKC α also acts upstream of RhoA activation by phosphorylating p115RhoGEF and GDI-1. RhoA in turn facilitates phosphorylation-induced inhibition of myosin light chain phosphatase (MLCP) by activating Rho kinase (ROCK). The inhibition of MLCP is accompanied by the Ca2+/calmodulin-dependent activation of MLCK that leads to phosphorylation of MLC and induces acto-myosin contraction in response to pro-inflammatory mediators such as thrombin and histamine.
The integrity of MT cytoskeleton is required for IP3-induced Ca2+ release from ER stores. Alteration of MT dynamics by MT destabilizing or MT stabilizing agents nocodazole, colchicine and taxol inhibits IP3-gated release of Ca2+, suggesting that MT dynamics are required for full activation of IP3R. The MT cytoskeleton is involved in remodeling of ER, thus ensuring organization and propagation of Ca2+ waves in response to external stimuli. The ER attaches to and elongates together with MT growing ends though direct interaction of EB1 and EB3 with stromal interaction molecule 1 (STIM1). Depletion of EB1 in HeLa (HeLa cells do not express EB3) decreases ER protrusion events, however does not inhibit activation of SOC by thapsigargin suggesting that some other mechanisms are involved in activation of SOC and propogation of calcium signaling in epithelial cells. In endothelial cells, the localization of IP3R in caveolae is critical for both ER Ca2+ store depletion and SOC activation. This indicates that activation of IP3R and/or its responsiveness to IP3 is important element of calcium signaling. It is proposed that MT cytoskeleton positively regulates IP3R activation in response to IP3 and thus transmits extracellular signals throughout the cell, eliciting a physiological response.
Despite the advanced supportive care in the United States, about 100,000 patients die annually from Acute Lung Injury (ALI), a complex inflammatory response associated with neutrophil infiltration and release of cytokine and pro-inflammatory mediators during sepsis. Hyper-permeability of lung vessels, a characteristic feature of the disease, leads to the formation of pulmonary edema. Novel therapies are needed to prevent or treat dysfunction of endothelial barrier.

This patent is subject to a terminal disclaimer.

Peptide compositions and methods for treating lung injury, asthma, anaphylaxis, angioedema, systemic vascular permeability syndromes, and nasal congestion

The Board of Trustees of the University of Illinois


Digital documents are pre-loaded with expressions of underlying data in a plurality of output languages. Expressions of the underlying data are alternatively presented to users to facilitate data collection and information transfer between people who do not share a common language.

The following relates to the facilitation of communications between two people who do not share a common language. It may be applied to hospital communications between doctors and patients, and will be described with particular reference thereto. The following may also be applied to any type of inter-language communication, data collection, and a variety of similar applications. For example, "doctor" shall be read to include doctors, nurses, any type of health care provider, and any type of person or system that needs to collect data and/or provide instructions; "hospital" shall be read to include any type of health care institution, and any institution that collects data and keeps records; and "patient" shall be read to include hospital patients, as well as any other type of person or system that is required to provide data and/or receive instructions.
Hospitals typically use hundreds of different forms to gather medical data from their patients, additional forms to provide instructions, and still other forms to collect patient signatures. These forms may cover anything from administration of medicine, to proper diet, to the acknowledgement of informed consent. Hospitals expend significant resources keeping these forms in stock, organized, and readily accessible. Inventory complexity increases significantly when forms are required in multiple languages.
In addition to the inventory and organizational problems, there are inter-language communication problems. If the doctor and patient do not share a common language, the doctor will have trouble explaining the form to the patient, and may be unable to elicit a meaningful response. Patients may describe their conditions more accurately in response to diagnosis forms in their own language. Likewise, printed health care instructions are nearly useless if written in a language the patient cannot understand.
Although a variety of "on the fly" or "real time" software based translation solutions exist, their translations are prone to errors. Translation accuracy is critical for medical diagnosis and patient instruction.
Hospitals often employ human translators. While expert human translators provide accurate translations, they are expensive, and often unavailable (especially at night).
Therefore, there is a need for a system to keep an inventory of documents in a plurality of languages in stock and readily accessible. Furthermore, there is a need for a high-accuracy system to facilitate the explanation and discussion of such forms and documents between people who do not share a common language.


A bone screw includes a screw shaft with an external thread. The screw shaft anchors the bone screw in a bone. A proximal end of the screw shaft includes a screw head. The ratio between the outer thread diameter and the thread core diameter increases toward the screw head in a proximal screw shaft portion or in the area of the thread's run-out.

Pedicle screws usually serve for the dorsal stabilization of the spinal column in the event of fractures, tumors, inflammations, deformities and degeneratively induced instabilities by means of a transpedicular screw connection. In doing so, pedicle screws are placed in the pedicles of neighboring vertebrae, creating an angularly stable connection between the pedicle screws arranged axially one above the other and an axially extending longitudinal member or bar. In such an arrangement, the pedicle screws and the longitudinal member constitute a vertebral stabilization system.
The pedicle screws are screwed through the pedicle into the vertebral body (corpus vertebrae) between the transverse process (processus transversus) and the spinous process (processus spinosus). To this end, a pedicle screw usually comprises a screw head and an elongated screw shaft provided with an external thread. Whereas the screw head is formed like a tulip for the fixation of the longitudinal member or carries a so-called tulip, the screw shaft serves for anchoring the pedicle screw in the vertebra.
Various geometries are known with regard to the design of the screw shaft.
By way of example, screws are used which have a cylindrical thread and in which both the core diameter and the outer or flank diameter remain constant over the entire longitudinal extension of the screw shaft (cf. FIG. 4A). These screws have a very high pull-out strength which is hardly affected even in the event of turning back the screw in order to correct the position of the screw head, for instance. It is a disadvantage of constant external diameters and core diameters that the thread—which is cut into the bone by the external thread in the entry area between the transverse process and the spinous process—may wear out in case of further driving in the screw, possibly reducing the support in the area of the proximal shaft portion. A further disadvantage lies in the fact that a cylindrical thread, in particular a constant core diameter, is not capable of compacting the cancellous bone material, which is present in the vertebra, between the thread flanks.
Further, it is also known that there are screws comprising a fully conical thread in which both the outer thread diameter and the core diameter uniformly increase from the screw tip up to the screw head. The advantage of this screw geometry is to see in the fact that they have a good grip in the bone and even the proximal shaft portion cuts further into the bone; in this way, a good support is also ensured in the proximal area. However, screws comprising a fully conical thread do not allow for their subsequent fine adjustment, as otherwise the contact of the thread flanks of the screw with the bone's thread which has been excessively widened beforehand in radial direction would get lost over the entire length even in the case of only slightly turning back the screw.
This is why screws comprising a partially conical thread are frequently used, in which the core is conical and the thread is formed to be cylindrical (cf. FIG. 7A). The cylindrical thread ensures a high pull-out strength. Due to the increasingly larger core diameter, a radial pressure on the cancellous bone material is produced between the thread flanks and said bone material is compacted, improving the support. What is more, a screw comprising a partially conical thread also has a higher fatigue strength than a screw with a constant core diameter which is due to the increasing core diameter.
In the case of screws comprising a partially conical thread, however, the thread flanks become increasingly broad and dull toward the screw head; this is why said flanks do not have a cutting effect any more in the proximal area of the screw shaft, but are pressed into the thread turn in radial and axial directions and possibly expand or even burst the thread turn in the proximal area. Also in this case, a slight backward turn may result in the screw becoming loose, as the thread flanks lose the contact with the thread turn (which is expanded in axial direction).
As each of these geometries has advantages and disadvantages, combinations of these geometries are also known, such as e.g. a screw comprising a cylindrical external diameter and a core with alternating cylindrical and conical core diameter portions (cf. FIGS. 5A and 6A).
As already mentioned above, the entry point of a pedicle screw is situated between the transverse process and the spinous process, then extends through the pedicle in the axial direction of the relatively narrow pedicle and opens out into the vertebral body. In the area of the vertebral body and in the area between the entry point and the pedicle, there mainly is soft cancellous bone material, whereas dense cortical bone material can be found in the slim area of the pedicle immediately in the area of the entry point. None of the thread shapes known hitherto satisfies this bone structure of a vertebra and the inhomogenous bone strength.