The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and materials for treating seizure and seizure disorders, epilepsy, status epilepticus, migraine, spreading depression, intracranial hypertension; for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia; for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol; and for treating neurophsyciatric disorders and central nervous system edema by administering agents that modulate ionic concentrations and/or ionic gradients in the brain, particularly ion-dependent or cation-chloride cotransporter antagonists. Ion-dependent cotransport antagonists and combinations of such compositions with other agents for treating various conditions are disclosed. The present invention also relates to methods and compositions for treating pain by administering ion-dependent cotransporter antagonists. Methods and compositions for enhancing cortical function, for example, in centers of cognition, learning and memory, by administering ion-dependent cotransporter agonists are disclosed. Methods and systems for screening drug candidate compounds for desired activities using in vitro and in vivo systems are disclosed.

The present invention relates to methods and compositions for treating selected conditions of the central and peripheral nervous systems employing non-synaptic mechanisms. More specifically, one aspect of the present invention relates to methods and materials for treating seizures and seizure disorders, epilepsy, status epilepticus, migraine headache, cortical spreading depression, intracranial hypertension, neuropsychiatric disorders, central nervous system edema; for treating or protecting from the pathophysiological effects of toxic agents such as ethanol and certain infectious agents; for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia; and for improving certain brain functions, such as cognition, learning and memory by administering agents that modulate ionic concentrations and ionic balances in the central nervous system. Specific treatment compositions, including loop diuretics, analogs and derivatives of such compositions, as well as combinations of such compositions with other agents for modulating ionic concentrations and gradients, and for treating various conditions, are disclosed. Materials and methods for treating pain by administering agents that modulate ionic concentrations and gradients in the peripheral nervous system are also disclosed. Methods and systems for screening drug candidate compounds for desired activities using in vitro and in vivo systems are described.
Conventional treatments for neuronal disorders, such as seizure disorders, epilepsy, and the like, target synaptic mechanisms that affect excitatory pathways, such as by modulating the release or activity of neurotransmitters or inhibitors. Conventional treatment agents and regimen for seizure disorders diminish neuronal excitability and inhibit synaptic firing. One serious drawback of this approach is that while seizures are generally localized, the treatment affects (diminishes) neuronal activity indiscriminately. For this reason, there are serious side effects and repeated use of conventional medications may result in unintended deficiencies in normal and desirable brain functions, such as cognition, learning and memory. More detailed information concerning particular disorders of interest is provided below.
Epilepsy
Epilepsy is characterized by abnormal discharges of cerebral neurons and typically manifested as various types of seizures. Epileptiform activity is identified with spontaneously occurring synchronized discharges of neuronal populations that can be measured using electrophysiological techniques. This synchronized activity, which distinguishes epileptiform from non-epileptiform activity, is referred to as xe2x80x9chypersynchronizationxe2x80x9d because it describes the state in which individual neurons become increasingly likely to discharge in a time-locked manner with one another.
Epilepsy is one of the most common neurological disorders, affecting about 1% of the population. There are various forms of epilepsy, including idiopathic, symptomatic and cryptogenic. Genetic predisposition is thought to be the predominant etiologic factor in idiopathic epilepsy. Symptomatic epilepsy usually develops as a result of a structural abnormality in the brain.
Status epilepticus is a particularly severe form of seizure, which is manifested as multiple seizures that persist for a significant length of time, or serial seizures without any recovery of consciousness between seizures. The overall mortality rate among adults with status epilepticus is approximately 20 percent. Patients who have a first episode are at substantial risk for future episodes and the development of chronic epilepsy. The frequency of status epilepticus in the United States is approximately 150,000 cases per year, and roughly 55,000 deaths are associated with status epilepticus annually. Acute processes that are associated with status epilepticus include intractable epilepsy, metabolic disturbances (e.g. electrolyte abnormalities, renal failure and sepsis), central nervous system infection (meningitis or encephalitis), stroke, degenerative diseases, head trauma, drug toxicity and hypoxia. The fundamental pathophysiology of status epilepticus involves a failure of mechanisms that normally abort an isolated seizure. This failure can arise from abnormally persistent, excessive excitation or ineffective recruitment of inhibition. Studies have shown that excessive activation of excitatory amino acid receptors can cause prolonged seizures and suggest that excitatory amino acids may play a causative role. Status epilepticus can also be caused by penicillin and related compounds that antagonize the effects of xcex3-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain.
One early diagnostic procedure for epilepsy involved the oral administration of large quantities of water together with injections of vasopressin to prevent the accompanying diuresis. This treatment was found to induce seizures in epileptic patients, but rarely in non-epileptic individuals (Garland et al., Lancet, 2:566, 1943). Status epilepticus can be blocked in kainic acid-treated rats by intravenous injection of mannitol (Baran et al., Neuroscience, 21:679, 1987). This effect is similar to that achieved by intravenous injection of urea in human patients (Carter, Epilepsia, 3:198, 1962). The treatment in each of these cases increases the osmolarity of the blood and extracellular fluid, resulting in water efflux from the cells and an increase in extracellular space in the brain. Acetazolamide (ACZ), another diuretic with a different mechanism of action (inhibition of carbonic anhydrase), has been studied experimentally as an anticonvulsant (White et al., Advance Neurol., 44:695, 1986; and Guillaume et al., Epilepsia, 32:10, 1991) and used clinically on a limited basis (Tanimukai et al., Biochem. Pharm., 14:961, 1965; and Forsythe et al., Develop. Med. Child Neurol., 23:761, 1981). Although its mechanism of anticonvulsant action has not been determined, ACZ does have a clear effect on the cerebral extracellular space.
Traditional anti-epileptic drugs exert their principal effect through one of three mechanisms: (a) inhibition of repetitive, high-frequency neuronal firing by blocking voltage-dependent sodium channels; (b) potentiation of xcex3-aminobutyric acid (GABA)-mediated postsynaptic inhibition; and (c) blockade of T-type calcium channels. Phenytoin and carbamazepine are examples of sodium channel antagonists, which exert their effect at the cellular level by reducing or eliminating sustained high-frequency neuronal depolarization while not appreciably affecting regular firing rates of neurons. Barbiturates, such as Phenobarbital and benzodiazepines, act by enhancing GABA-mediated synaptic inhibition. Both classes of compounds increase the hyperpolarization of the postsynaptic membrane, resulting in increased inhibition. Ethosuximide and valporate are examples of drugs that decrease calcium entry into neurons through T-type voltage-dependent calcium channels.
Current anti-epileptic drug therapies exert their pharmacological effects on all brain cells, regardless of their involvement in seizure activity. Common side effects are over-sedation, dizziness, loss of memory and liver damage. Additionally, 20-30% of epilepsy patients are refractory to current therapy.
Focus on synaptic hyperexcitability has been a guiding principle in basic research on the mechanisms of epileptogenesis and in the design and discovery of new anti-epileptic drugs. One of the shortcomings of this approach is that most current anti-epilepsy drugs exert their influence in an indiscriminate manner, in both the epileptogenic and normal areas in the brain. The compositions of the present invention offer a novel approach to the treatment of seizures, in part because they act via a non-synaptic pathway.
Migraine
Migraine headaches afflict 10-20% of the U.S. population, with an estimated loss of 64 million workdays annually. Migraine headache is characterized by pulsating head pain that is episodic, unilateral or bilateral, lasting from 4 to 72 hours and often associated with nausea, vomiting and hypersensitivity to light and/or sound. When accompanied by premonitory symptoms, such as visual, sensory, speech or motor symptoms, the headache is referred to as xe2x80x9cmigraine with aura,xe2x80x9d formerly known as classic migraine. When not accompanied by such symptoms, the headache is referred to as xe2x80x9cmigraine without aura,xe2x80x9d formerly known as common migraine. Both types evidence a strong genetic component, and both are three times more common in women than men. The precise etiology of migraine has yet to be determined. It is theorized that persons prone to migraine have a reduced threshold for neuronal excitability, possibly due to reduced activity of the inhibitory neurotransmitter xcex3-aminobutyric acid (GABA). GABA normally inhibits the activity of the neurotransmitters serotonin (5-HT) and glutamate, both of which appear to be involved in migraine attacks. The excitatory neurotransmitter glutamate is implicated in an electrical phenomenon called cortical spreading depression, which can initiate a migraine attack, while serotonin is implicated in vascular changes that occur as the migraine progresses.
Cortical spreading depression (CSD) is characterized by a short burst of intense depolarization in the occipital cortex, followed by a wave of neuronal silence and diminished evoked potentials that advance anteriorly across the surface of the cerebral cortex. Enhanced excitability of the occipital-cortex neurons has been proposed as the basis for CSD. The visual cortex may have a lower threshold for excitability and therefore is most prone to CSD. Mitochondrial disorders, magnesium deficiency and abnormality of presynaptic calcium channels may be responsible for neuronal hyperexcitability (Welch, K. M. A., Pathogenesis of Migraine, Seminars in Neurobiology, vol. 17:4, 1997). During a spreading depression event, profound ionic perturbations occur, which include interstitial acidification, extracellular potassium accumulation and redistribution of sodium and chloride ions to intracellular compartments. In addition, prolonged glial swelling occurs as a homeostatic response to altered ionic extracellular fluid composition and interstitial neurotransmitter and fatty acid accumulation. Studies have shown that furosemide inhibits regenerative cortical spreading depression in anaesthetized cats (Read, S J, et al, Cephalagia, 17:826, 1997).
A study of eighty-five patients with refractory transformed migraine type of chronic daily headache (CDH) concluded that acute headache exacerbations responded to specific anti-migraine agents such as ergotamine, dihydroergotamine (DHE), and sumatriptan, and addition of agents such as acetazolamide and furosemide, after diagnosis of increased intracranial pressure, resulted in better control of symptoms (Mathew, N. T. et al. Neurology 46:(5), 1226-1230, May 1996). The authors note that these results suggest a link between migraine and idiopathic intracranial hypertension that needs further research.
Drug therapy is tailored to the severity and frequency of migraine headaches. For occasional attacks, abortive treatment may be indicated, but for attacks occurring two or more times per month, or when attacks greatly impact the patient""s daily life, prophylactic therapy may be indicated. Serotonin receptor agonists, such as sumatriptan, have been prescribed for abortive therapy. Serotonin receptor agonists are thought to constrict dilated arteries of the brain and thereby alleviate the associated pain. Side effects associated with this therapy include tingling, dizziness, warm-hot sensation, land injection-site reactions. Intravenous administration is contraindicated as a consequence of the potential for coronary vasopasms. Ergotamine-based drugs are classified as vasoconstrictors that specifically counteract the dilation of some arteries and arterioles, primarily the branches of the external carotid artery. To prevent ergotamine rebound phenomena, ergotamine should not be repeated on the second or third day of a migraine attack. Yet, if the drug is stopped abruptly, the patient will experience a severe rebound headache. Excessive consumption of ergotamines may cause symptoms of vasoconstriction, such as cold clammy extremities, and may lead to ergotism.
Drugs used for prophylactic indications include andrenergic beta-blockers such as propranolol, calcium channel blockers, or low-dose anti-epileptics. In particular, anti-epileptic drugs that increase brain levels of GABA, either by increasing GABA synthesis or reducing its breakdown, appear to be effective in preventing migraine in certain individuals. In some patients, tricyclic analgesics, such as amitriptline, can be effective. NMDA receptor antagonist, acting at one of the glutamate receptor subtypes in the brain, inhibits CSD. Drugs or substances currently believed to function as weak NMDA receptor antagonists include dextromethoraphan, magnesium and ketamine. Intravenous magnesium has been successfully used to abort migraine attacks.
Neurotoxicity
A variety of chemical and biological agents, as well as some infectious agents, have neurotoxic effects. A common example is the pathophysiological effect of acute ethanol ingestion. Episodic ethanol intoxications and withdrawals characteristic of binge alcoholism result in brain damage. Animal models designed to mimic the effects of alcohol in the human have demonstrated that a single dose of ethanol given for 5-10 successive days results in neurodegeneration in the entorhinal cortex, dentate gyrus and olfactory bulbs, accompanied by cerebrocortical edema and electrolyte (Na+ and, K+) accumulation. As with other neurodegenerative conditions, research has focused primarily on synaptically based excitotoxic events involving excessive glutamatergic activity, increased intracellular calcium and decreased xcex3-aminobutyric acid. Co-treatment of brain damage induced by episodic alcohol exposure with an NMDA receptor antagonist, Non-NMDA receptor and Ca2+ channel antagonists with furosemide reduces alcohol-dependent cerebrocortical damage by 75-85%, while preventing brain hydration and electrolyte elevations (Collins, M., et al, FASEB, vol.12 February 1998). The authors observed that the results suggest that furosemide and related agents might be useful as neuroprotective agents in alcohol abuse.
Cognition, Learning and Memory
The cognitive abilities of mammals are thought to be dependent on cortical processing. It has generally been accepted that the most relevant parameters for describing and understanding cortical function are the spatio-temporal patterns of activity. In particular, long-term potentiation and long-term depression have been implicated in memory and learning and may play a role in cognition. Oscillatory and synchronized activities in the brains of mammals have been correlated with distinct behavioral states.
Synchronization of spontaneous neuronal firing activity is thought to be an important feature of a number of normal and pathophysiological processes in the central nervous system. Examples include synchronized oscillations of population activity such as gamma rhythms in the neocortex, which are thought to be involved in cognition (Singer and Gray, 1995), and theta rhythm in hippocampus, which is thought to play roles in spatial memory and in the induction of synaptic plasticity (Heurta and Lisman 1995; Heurta and Lisman 1996; O""keefe 1993). To date, most research on the processes underlying the generation and maintenance of spontaneous synchronized activity has focused on synaptic mechanisms. However, there is evidence that nonsynaptic mechanisms may also play important roles in the modulation of synchronization in normal and pathological activities in the central nervous system.
Screening of Candidate Compounds and Evaluating Treatment Efficacy
Drug development programs rely on in vitro screening assays and subsequent testing in appropriate animal models to evaluate drug candidates prior to conducting clinical trials using human subjects. Screening methods currently used are generally difficult to scale up to provide the high throughput screening necessary to test the numerous candidate compounds generated by traditional and computational means. Moreover, studies involving cell culture systems and animal model responses frequently don""t accurately predict the responses and side effects observed during human clinical trials.
Conventional methods for assessing the effects of various agents or physiological activities on biological materials, in both in vitro and in vivo systems, generally are not highly sensitive or informative. For example, assessment of the effect of a physiological agent, such as a drug, on a population of cells or tissue grown in culture, conventionally provides information relating to the effect of the agent on the cell or tissue population only at specific points in time. Additionally, current assessment techniques generally provide information relating to a single or a small number of parameters. Candidate agents are systematically tested for cytotoxicity, which may be determined as a function of concentration. A population of cells is treated and, at one or several time points following treatment, cell survival is measured. Cytotoxicity assays generally do not provide any information relating to the cause(s) or time course of cell death.
Similarly, agents are frequently evaluated based on their physiological effects, for example, on a particular metabolic function or metabolite. An agent is administered to a population of cells or a tissue sample, and the metabolic function or metabolite of interest is assayed to assess the effect of the agent. This type of assay provides useful information, but it does not provide information relating to the mechanism of action, the effect on other metabolites or metabolic functions, the time course of the physiological effect, general cell or tissue health, or the like.
U.S. Pat. Nos. 5,902,732 and 5,976,825 disclose methods for screening drug candidate compounds for anti-epileptic activity using glial cells in culture by osoniotically shocking glial cells, introducing a drug candidate, and assessing whether the drug candidate is capable of abating changes in glial cell swelling. This patent also discloses a method for screening drug candidate compounds for activity to prevent or treat symptoms of Alzheimer""s disease, or to prevent CNS damage resulting from ischemia, by adding a sensitization agent capable of inducing apoptosis and an osmotic stressing agent to CNS cells, adding the drug candidate, and assessing whether the drug candidate is capable of abating cell swelling. A method for determining the viability and health of living cells inside polymeric tissue implants is also disclosed, involving measuring dimensions of living cells inside the polymeric matrix, osmotically shocking the cells, and then assessing changes in cell swelling. Assessment of cell swelling activity is achieved by measuring intrinsic optical signals using an optical detection system.
Selected treatment compositions and methods of the present invention are useful for treating central nervous system conditions, including seizures and seizure disorders, epilepsy, including status epilepticus, migraine headaches, cortical spreading depression, intracranial hypertension, neuropsychiatric disorders, and central nervous system edema. Selected treatment compositions and methods of the present invention are also suitable for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol and certain infectious agents, and for treating the pathophysiological effects of head trauma, stroke, ischemia and hypoxia. According to another embodiment, treatment agents and methods of the present invention improve function in certain cortical tissue, such as in cortical centers of cognition, learning and memory. Additionally, treatment agents and methods of the present invention are useful for treating pain by affecting or modulating the conduction of impulses associated with pain in the peripheral nervous system. Treatment compositions and methods of the present invention may be used episodically or prophylactically and are suitable for both human and veterinary applications.
Methods and compositions of the present invention involve treatment of various conditions of the central and peripheral nervous systems by means of non-synaptic mechanisms and, more specifically, by modulating the synchronization of neuronal population activity. According to a preferred embodiment, the synchronization of neuronal population activity is manipulated by modulating anionic concentrations and gradients in the central and/or peripheral nervous systems. Ion dependent cotransporter antagonists are suitable treatment compositions, anion cotransporter antagonists are preferred treatment compositions, and cation-chloride cotransporter antagonists are especially preferred treatment compositions. According to one embodiment, Na+,K+,2Clxe2x88x92 chloride cotransporter antagonists are especially preferred treatment agents for modulating the synchronization of neuronal population activity. Anion cotransporter antagonists are useful for treating conditions such as seizures, epilepsy and status epilepticus, cortical spreading depression and migraine headaches, intracranial hypertension, neuropsychiatric disorders, central nervous system edema, for treating or protecting from the pathophysiological effects of neurotoxic agents such as ethanol and certain infectious agents, and for reducing the perception of pain. Chloride cotransporter agonists are preferred treatment agents, and cation-chloride cotransporter agonists are especially preferred treatment agents for improving function in cortical areas associated with cognition, learning and memory, for example. Methods for screening candidate compounds for ion-dependent cotransporter agonist and antagonist activity, and for efficacy in treating various conditions and disorders are also provided.
Reference to the methods and compositions of the present invention using xe2x80x9cnon-synapticxe2x80x9d mechanisms means that mechanisms associated with neuronal excitability, such as the release or activity of transmitters, or the release or activity of inhibitors, are not affected by methods and agents of the present invention. Similarly, ion channels and receptors are not directly affected by methods and compositions of the present invention. Rather, the methods and treatment agents of the present invention affect the synchronization, or relative synchrony, neuronal population activity. Preferred methods and treatment agents of the present invention modulate the extracellular anionic chloride concentration and/or the ion gradients in the central or peripheral nervous system without substantially affecting neuronal excitability.
One aspect of the present invention relates to treatment agents and methods for modulating the synchronization of neuronal discharges by diminishing or eliminating hypersynchronization of neuronal population activity associated with seizures and other pathophysiologies of the central nervous system. In one embodiment, the treatment composition is capable of modulating the anion concentration, preferably the chloride concentration, in the extracellular space in the central nervous system. In a preferred embodiment, the treatment agent is a chloride cotransporter antagonist, and in another preferred embodiment, the treatment agent is a cation chloride cotransporter antagonist, and in an especially preferred embodiment, the treatment composition is a glial cell Na+,K+,2Clxe2x88x92 cotransporter antagonist. According to yet another preferred embodiment, the treatment agent has a high level of cation-chloride cotransporter antagonist activity,in glial cells, and has a lower level of ion-dependent cotransporter activity in neuronal and kidney cells. Preferred agents for treatment of central nervous system conditions are preferably capable of crossing the blood brain barrier, or are administered using delivery systems that facilitate delivery of agents to the central nervous system.
In general, loop diuretics, such as furosemide, bumetanide, ethacrynic acid, and the like, exhibit ion-dependent cotransporter antagonist activity and are suitable for use as treatment compositions of the present invention. Although such loop diuretics produce the desired modulation of the extracellular anionic chloride concentrations and ionic gradients and, hence, modulation of synchronization of neuronal population activity, they may also produce other, undesired effects. Furosemide, for example, acts as a cation-chloride cotransporter antagonist in both glial and neuronal cells, as well as in the kidney. Especially preferred treatment agents of the present invention, exhibiting ion-dependent cotransporter antagonist activity, exhibit a high degree of activity in glial cell populations, and exhibit a lesser degree of activity in neuronal and renal cell populations.
Methods for treating status epilepticus involve administering an ion-dependent cotransporter antagonist, preferably a cation-chloride cotransporter antagonist, in combination with another treatment agent. Furosemide and other loop diuretics are suitable cation-chloride cotransporter antagonists. Experimental studies have shown that furosemide treatment produces a transient and early increase in synchronization of neuronal population activity, followed by a persistent and complete disruption of the hypersynchronization characteristic of epileptiform activity. Treatment of status epilepticus, according to the present invention, involves administration of an ion-dependent cotransporter antagonist, preferably a cation-chloride cotransporter antagonists, such as furosemide, in combination with another agent, such as a barbiturate, that is capable of treating the symptoms associated with the transient and early increase in synchronization of neuronal population activity observed upon administration of furosemide.
Methods and treatment compositions for treating seizures and seizure disorders, epilepsy, migraine headaches, cortical spreading depression intracranial hypertension, neuropsychiatric disorders, and for treating or protecting from the pathophysiological effects of neurotoxic agents, head trauma, stroke, ischemia and hypoxia involve modulating the synchronization of neuronal population activity, preferably by modulating ion gradients in the central nervous system. Ion-dependent cotransporter antagonists are preferred treatment compositions, and cation-chloride cotransporter antagonists are especially preferred treatment compositions. If the ion-dependent cotransporter antagonist treatment composition has activity, for example, with respect to glial cells, but has lower or substantially no activity with respect to neuronal cells, it is suitable for administration alone. If the ion-dependent cotransporter antagonist treatment composition has activity with respect to neuronal as well as other types of cells, it is preferably administered in combination with another agent, such as conventional anti-epleptic or anti-convulsant agent.
Another aspect of the present invention relates to methods and agents for relieving pain, or the perception of pain, by effecting or modulating propagation of action potentials or conduction of impulses in certain nerve fibers in the peripheral nervous system. More specifically, changes in extracellular ionic concentrations and ionic gradients in cells in the peripheral nervous system, affected by ion-dependent cotransporters, diminishes the perception or sensation of pain. Ion-dependent cotransporter antagonists and, preferably, cation-chloride cotransporter antagonists, delivered to the peripheral nervous system, are preferred treatment compositions for the reduction of pain.
Yet another aspect of the present invention relates to methods and agents for enhancing the function of cognitive, learning and memory centers in the central nervous system. Enhanced synchronization of neuronal population activity improves function in centers associated with cognitive abilities, learning and memory in central nervous system cortex. Treatment compositions and methods of the present invention for enhancing cognitive, learning and memory functions involve modulating the synchronization and timing of neuronal population activity, preferably by enhancing synchronization and coordinating timing. According to one embodiment, enhancement of synchronization is achieved by administering an agent capable of modulating extracellular anionic chloride concentrations and ionic gradients in the brain. Ion-dependent cotransporter agonists are preferred treatment agents, and cation-chloride cotransporter agonists are especially preferred. Methods for screening candidate compounds for ion-dependent cotransporter agonist activity are also provided.
Screening methods and systems of the present invention employ optical, or spectroscopic, detection techniques to assess the physiological state of biological materials including cells, tissues, organs, subcellular components and intact organisms. The biological materials may be of human, animal, or plant origin, or they may be derived from any such materials. Static and dynamic changes in the geometrical structure and/or intrinsic optical properties of the biological materials in response to the administration of a physiological challenge or a test agent, are indicative and predictive of changes in the physiological state or health of the biological material.
Two different classes of dynamic phenomena are observed in viable biological materials using optical detection techniques: (1) geometrical changes in the diameter, volume, conformation, intracellular space of individual cells or extracellular space surrounding individual cells; and (2) changes in one or more intrinsic optical properties of individual cells or of cell populations, such as light scattering, reflection, absorption, refraction, diffraction, birefringence, refractive index, Kerr effect, and the like. Both classes of phenomena may be observed statically or dynamically, with or without the aid of a contrast enhancing agent. Geometrical changes may be assessed directly by measuring (or approximating) the geometrical properties of individual cells, or indirectly by observing changes in the optical properties of cells. Changes in optical properties of individual cells or cell populations may be assessed directly using systems of the present invention.
Observation and interpretation of geometrical and/or intrinsic optical properties of individual cells or cell populations is achieved in both in vitro and in vivo systems without altering characteristics of the sample by applying physiologically invasive materials, such as fixatives. Physiologically non-invasive contrast enhancing agents, such as vital dyes, may be used in desired applications to enhance the sensitivity of optical detection techniques. In applications employing contrast enhancing agents, the optical detection techniques are used to assess extrinsic optical properties of the biological materials.
Detection and analysis of the geometrical and/or intrinsic optical properties of individual cells or sample cell populations provides information permitting classification of the physiological state of individual cells or sample cell populations. Based on analysis of the geometrical and/or optical properties of a sample cell population, the sample may be classified as viable or non-viable, apoptotic, necrotic, proliferating, in a state of activity, inhibition, synchronization, or the like, or in any of a variety of physiological states, all of which produce distinct geometrical and/or optical profiles. The methods and systems of the present invention therefore provide for identification of the physiological state of a sample population and differentiation among various physiological states.
An important application of the methods and systems of the present invention involves screening cell populations to assess the effect(s) of exposure to various types of test agents and test conditions. The effect of various test agents and conditions may be evaluated on both normal and pathological sample populations. Safety and cytoxicity testing is conducted by exposing a sample population to a test agent or test condition and assessing the physiological state of the sample population using optical techniques at one or more time points following administration of the test agent or test condition. Such testing may be conducted on various sample populations to determine how a test agent or condition affects a desired target sample population, as well as to predict whether a test agent or condition produces physiological side effects on sample populations that are not the target of the test agent or condition.
According to a preferred embodiment, a pathological condition is simulated in biological materials prior to administration of a test agent or test condition to assess the suitability of the test agent or condition for treating the disease state or compromised condition. Exposure of sample populations to a physiological challenge, such as a change in extracellular osmolarity or ion concentration, altered oxygen or nutrient or metabolite conditions, drugs or diagnostic or therapeutic agents, a disturbance in ion homeostasis, electrical stimulation, inflammation, infection with various agents, radiation, and the like, may simulate a pathological state at a cellular or tissue level. Subsequent exposure of the sample populations a test agent or condition and detection and analysis of changes in geometrical and/or optical properties of the sample populations provides information relating to the physiological state of the sample populations produced by the test agent or condition. Screening techniques may be adapted for use with various types of cell sample populations maintained in vitro under appropriate cell culture conditions to provide a high throughput, automated screening system. Alternatively, screening techniques may be adapted to examine cell and tissue populations using various animal models to assess the effect of a physiological challenge and/or administration of a test agent on various cell populations in animal models in situ. Moreover, because the screening techniques of the present invention are physiologically non-invasive and use spectroscopic techniques, they may be adapted to examine cell and tissue populations in humans, in situ, to assess or monitor a patient""s condition, and to assess or monitor the efficacy of a treatment agent or regimen.
Changes in geometrical and/or optical properties of individual cells or cell populations may be determined by reference to empirically determined standards for specific cell types, cell densities and various physiological states, or appropriate controls may be run in tandem with the test samples to provide direct comparative data. Data is collected and, preferably, stored at multiple time points to provide data relating to the time course of the effect of a test agent or condition on sample populations. Strategies for designing screening protocols, including appropriate controls, multiple samples for screening various dosages, activities, and the like, are well known in the art and may be adapted for use with the methods and systems of the present invention.

Methods and compositions for treating conditions of the central and peripheral nervous systems using non-synaptic mechanisms


A file folder conveyor which comprises a rotatable spiral mounted in a base that has opposite ends and has a back wall which extends higher than the front wall such that as the spiral is rotated, files can be moved which rest in the spiral and extend out of the front of the base so that they can be easily removed by a user. The spiral may be driven manually or by a motor means.

1. Field of the Invention
This invention relates in general to office equipment and particularly to a novel file folder conveyor for storing and moving files.
2. Description of Related Art
U.S. Pat. No. 2,279,643 discloses a non-rotating spiral which is used for a mail dispenser, but it does not rotate. U.S. Pat. No. 4,969,561 discloses a diary reminder, but it does not have a base with different heights with continuously rotating dispensing device with side walls. See also U.S. Pat. Nos. 2,619,233, 5,070,986, 5,064,092, 4,757,915, 4,844,294, 4,600,119, 1,134,988, 4,312,460 and 2,867,161.


A lift attached to a truck has a tail gate supported by at least one hydraulic lift and at least one tilt cylinder for respectively lifting the tail gate as a whole and rotating it for opening and closing. A control system for moving such a tail gate up and down as a whole and rotating it to open and close it is provided with a power unit including a hydraulic pump, an electric motor for the hydraulic pump, and a plurality of valves for selectably allowing or not allowing transport of a hydraulic liquid by the hydraulic pump into the hydraulic cylinders, a sensor for measuring the slope angle of the tail gate, external switches, and a controller which serves to transmit output signals to the motor and to the valves in response to input signals from the sensor and the external switches and is capable of stopping rotary motion of the tail gate at a horizontal position irrespective of the slope of the vehicle and starting and stopping the rotary motion of the tail gate gradually.

This invention relates to the control of a lift of the kind attached to a back part of a freight truck for transporting freight up into and down from the truck. More particularly, the invention relates to a mechanism and a method of control for the opening and closing of the truck's tail gate.
FIGS. 2A and 2B show a lift of this general type attached to a back part of a freight truck. Such a lift generally makes use of a parallel link mechanism comprising a plurality of cylinders to open and close a freight-receiving table (herein referred to as the tail gate), as well as moving it up and down as a whole.
Explained more in detail with reference to FIGS. 3A, 3B, 3C and 3D, a gate-opening mechanism 30 of such a lift for opening and closing a tail gate 31 (that is, a mechanism for rotating the tail gate 31 around an axis between a closed position and an open position), a tilt cylinder 32 with a piston, a main arm 36 and an attachment bracket 38. The tip of the piston of the tilt cylinder 32 is axially connected to the tail gate 31 through a pin 34, and the other end of the tilt cylinder 32 is axially connected to the bracket 38 through another pin 39. Similarly, one end of the main arm 36 is axially connected to the tail gate 31 through a pin 33, and the other end is axially connected to the bracket 38 through another pin 35. The attachment bracket 38 is welded to the chassis 37 of the truck.
The aforementioned rotary (or tilting) motion of the tail gate 31 is generally effected by means of a pair of left-hand and right-hand tilt cylinders, of which only one is shown in FIGS. 3A, 3B, 3C and 3D. Their motion is controlled by a power unit comprising hydraulic pumps, electric motors for operating these pumps and solenoid valves, as well as an electric control unit.
The tail gate of a kind structured as generally shown in FIGS. 2, 3A, 3B, 3C and 3D is usually designed so as to be parallel to the ground when it is stopped at its opened position. When the truck is parked on the ground which is sloped in the forward or backward direction, therefore, not only is it difficult but also dangerous to load or unload a cargo by using such a tail gate remaining parallel to the sloped ground. In other words, loading and unloading could not be done with high efficiency by using such a lift unless the ground was flat.
The tail gate of a prior art lift is adapted to rotate at a same speed whether it is opening or closing. This means that it starts and stops its motion suddenly, making it likely to damage a fragile cargo. Sudden movements of the tail gate are also a problem to be considered from the point of view of safety to the workers.
Another disadvantage of a prior art lift of this type has been the lengths of the oil pipes between the cylinders and the valves. If there is a damage to a pipe, the loss of pressure inside a cylinder cannot be prevented even if valves are closed, and this could lead to a serious accident.


A disposable hand tool of the compressed air drive type is disclosed for use in performing dental procedures on a workpiece. An elongated body has conduits penetrating a base at one end of the body. The conduits allow entry of a light beam, a pressurized water stream, and a compressed air stream into the body. The base includes attachment threads for securing the body to a source of the light beam, pressurized water stream, and compressed air stream. A plurality of passageways are in communication with the conduits for conducting the light beam, the water stream, and the air stream through the body. A head at the opposite end of the body contains bearings attached to a supporting shaft. The shaft includes a turbine impeller and a clamping hole for removable attachment of a dental bur to the shaft. The air stream drives the impeller at a high speed for rotating the bur about a rotational axis. An opening in the body adjacent to the head allows release of the light beam, the pressurized water stream, and a portion of the compressed air stream in a direction toward the distal end of the bur so that the bur, the light beam, the water stream, and the air stream may all converge on the workpiece.

It is well known that infectious agents such as viruses and bacteria can be transmitted from one person to another through re-use of incompletely sterilized medical instruments, such as dental hand tools, syringes, and the like. As it is difficult to completely sterilize complex tools, such as air-driven dental hand tools, an effort has been made to make available disposable dental hand tools that are to be used with only one patient and then discarded. It is argued that such hand tools, if made of inexpensive plastic and not designed for an extended life, would become practical and inexpensive enough for use in many common dental procedures.
For example, U.S. Pat. No. 3,955,284 to Balson on May 11, 1976, discloses a disposable dental drill assembly. The advantages of such a disposable drill assembly, as disclosed, are based on economics, as opposed to patient and practitioner safety, and are motivated by the relatively high cost of purchasing a plurality of expensive, machined, extended-life hand tools. It is argued that such a disposable dental assembly, while not as durable as an expensive machined dental drill assembly, is more economical due to its inexpensive manufacturing cost. No mention is made, however, of using one such disposable drill assembly per patient to avoid infection.
As the concern over infectious disease has become more prominent, and injection molding techniques have become more refined and less expensive, other disposable dental hand tools have become available. U.S. Pat. Nos. 4,795,343 and 4,842,516, both to Choisser on Jan. 3, 1989 and Jun. 27, 1989, respectively, are examples of such disposable hand tools meant for use on a single patient specifically to reduce the risk of spreading disease. While such devices can be manufactured relatively inexpensively, such devices are also quite limited in their functionality.
For example, dental burs or diamond cutting tools of such devices are permanently mounted to a drive turbine, necessitating the use of as many such devices as dental burs are required for a particular patient. As single dental procedure may easily require five or more different types of dental burs, such as drill bits of varying sizes and shapes, polishers, prophylactic angles, and the like, a practitioner may have to use five or more such disposable hand tools for a single patient, subsequently discarding all of them.
Moreover, such devices are limited to supplying an air stream for driving a turbine attached to the bur. Frequently, however, it is necessary to flush the work site with air and water. Consequently, using such devices requires additional water and air supplying implements, and causes further congestion in the already crowded working environment of a person's mouth. Further, the means by which rotation is imparted to the turbines of such devices provides less torque than many conventional hand tools.
A further drawback of such disposable devices is evident in that it is often difficult to properly illuminate a person's mouth when a number of implements are inserted in the mouth. Yet such disposable dental hand tools provide no means of illuminating the work site. Consequently, while devices of this type do help reduce the risk of spreading diseases between patients, the lack of functionality inherent in such devices requires additional expense, equipment, and time on the part of the dental practitioner and, therefore, the patient.
Clearly, a disposable dental hand tool is needed that overcomes the drawbacks of those devices found in the prior art. Such a needed device would be inexpensive to manufacture, thereby making it practical to dispose of after use with one patient. Moreover, such a needed device would allow the replacement of different dental burs, making it unnecessary to use more than one such device for each patient. Further, such a needed device would allow the insertion of burs of various sizes and shapes, and would make removal and insertion of such burs easy to accomplish without significantly increasing the size of the device. Still further, such a needed device would provide means of delivering water, air, and light to the work site. Such a needed device would additionally provide a high degree of torque and control to the dental bur, making it easy for the dental practitioner to use. Still further, such a needed device would be light weight, easy to grasp and manipulate, and easy to connect to a standard source of air, water, and light. The present invention fulfills these needs and provides further related advantages.

Disposable handpiece for dental procedures


A method includes tagging, by at least one processor, one or more three-dimensional assets with a unique identifier and storing the one or more three-dimensional assets in a database, creating, by the at least one processor, a three-dimensional model based on the one or more three-dimensional assets and loading the three-dimensional model in a simulator, generating, by the at least one processor, a two-dimensional image that is a representation of the three-dimensional model in the simulator, the two-dimensional image comprising metadata that includes each unique identifier for each three-dimensional asset of the three-dimensional model displayed in the two-dimensional image, and assigning, by the at least one processor, the two-dimensional image with a unique identifier and storing each unique identifier for each three-dimensional asset of the three-dimensional model displayed in the two-dimensional image in metadata for the two-dimensional image.

Neural networks may utilize a large amount of data to train. Privacy and ownership may mandate that any data used in the training be verifiably owned or correctly licensed by the user of the network. In addition, any real world data is to be used with permission. The process of assembling training datasets is complex and ill-structured. Data may be from many different sources and may undergo many changes before being used in a given training. In order to satisfy requirements, there should be a chain linking the data used in the training back to the source data. While it is possible to maintain traceability within a closed system, network training can result in data being detached from the system. There should be a way of tracing data that is embedded in the data itself. Additionally, synthetic data presents additional problems. Simulated environments can make use of source materials and assets that exist separately from synthetic images but ownership of and rights to the assets should be provable.
It is with these issues in mind, among others, that various aspects of the disclosure were conceived.


A gas sensor system includes a gas sensor capable of producing an output signal responsive to the concentration of a specific gas component in measurement gas, a gas concentration determination device that makes electrical connections to the gas sensor and determines the concentration of the specific gas component according to the output signal of the gas sensor, a failure detection device that detects a potential failure in any one of the electrical connections, a sensor temperature determination device that judges whether the gas sensor has been cooled to a predetermined temperature or lower with reference to a sensor temperature parameter and a failure identification device that, when the gas sensor has been cooled to the predetermined temperature or lower, outputs a diagnosis signal to the gas sensor, measures potentials of the electrical connections under the diagnosis signal and identifies in which of the electrical connections the potential failure is occurring based on the measured potentials.

The present invention relates to a gas sensor system with a failure diagnostic function and a failure diagnosis method for a gas sensor system.
Heretofore, an internal combustion engine such as a gasoline engine has adopted, as a combustion control technique for reductions in automotive CO, NOx and HC emissions, air-fuel ratio feedback control by regulating fuel injection in accordance with the concentration of a specific gas component in exhaust gas. There are various exhaust gas sensors for use in air-fuel ratio control. One example of exhaust gas sensor is an oxygen sensor having a single electrochemical cell, which consists of a solid electrolyte layer and a pair of electrodes arranged on opposite sides of the solid electrolyte layer and exposed to measurement gas and reference gas, respectively, so as to detect the concentration of oxygen in the measurement gas based on a potential difference between the measurement gas and the reference gas. Another example of exhaust gas sensor is an air-fuel ratio sensor (also called a "full-range oxygen sensor") having two electrochemical cells with a measurement gas chamber defined between these two cells to introduce measurement gas into the measurement gas chamber through a gas diffusion material and detect the concentration of oxygen in the measurement gas linearly over rich and lean ranges. A NOx sensor with three electrochemical cells is also known as the exhaust gas sensor. Each of these exhaust gas sensors is generally equipped or combined with a heater in order to activate the electrochemical cell irrespective of the exhaust gas temperature.
It has recently become common practice to form an automotive gas sensor system with a gas sensor and a sensor control unit and to diagnose the occurrence of a failure in the gas sensor or the sensor control unit automatically during engine combustion control. Japanese Laid-Open Patent Publication No. 11-107830 and No. 2003-097342 propose gas sensor systems of such failure diagnostic type, each of which is configured to diagnose a system failure e.g. a short-circuit or wire breakage and then inform a vehicle driver of the diagnosis result.

Gas sensor system with failure diagnostic function and failure diagnosis method for gas sensor system


An actuator assembly for a disc drive includes an E-block supported by a spindle for rotation about an axis and having an actuator arm supporting a transducer. An elongated yoke arm extends from the E-block. A motor rotates the E-block about the axis to position the transducer adjacent a selected track on the recording disc. The motor includes a voice coil supported by the yoke arm. A stop mechanism defines at least one of the inner and outer tracks of the disc and comprises at least one stop pin mounted to the disc drive housing and a stop surface on a distal end of the yoke arm for engaging the stop pin.

This invention relates to magnetic disc drive assemblies of the class employing one or more rigid discs.
Magnetic disc drive assemblies employing rigid, or hard, discs are commonly used in desktop and other computer mainframes as a principal memory for the computer. There is a continuing need for disc drives with greater capacity. This need is met by a combination of factors, including increasing the number of tracks on a given disc. The number of tracks on a disc is established by the track density, usually measured by the number of tracks per radial inch, and the radial position of the inner and outer tracks. If the inner track is as close to the disc spindle as possible and the outer track is as close to the outer edge of the disc as possible, a maximum number of tracks for a given track density is achieved.
Present disc drives employ stop mechanisms that establish the limits of rotation of the head/actuator assembly, thereby defining stop positions of an E-block of the head/actuator assembly, thereby defining the inner and outer track positions on the disc(s). Typically, the stop mechanism employs one or more stop arms on the E-block arranged to engage one or more pins fixed to the disc drive housing. The position of the stop arm(s) to the stop pin(s) is established during manufacture of the disc drive housing, based on calculations dictated by the geometry of the actuator assembly.
In the prior art, the stop arms were mounted close to the spindle axis. Any error in the positioning of the stop surfaces (e.g., the pins and/or the engaging surfaces on the stop arm) was magnified over the longer distance between the spindle axis and the transducing heads. As a result, positioning of the inner and outer tracks was not altogether accurate.

Positioning inner and outer tracks on a recording disc


An outdoor weatherproof protective electrical outlet cover adapted to be attached in weatherproof connection to an electrical outlet comprising a base plate adapted to be attached in weatherproof connection with the electrical outlet, the base plate having an aperture of sufficient size to accommodate the electrical outlet positioned in a first orientation and a second orientation wherein only one electrical outlet orientation can be accommodated at a given time, an insert sized and adapted to fit within the aperture of the base plate in a first orientation and a second orientation, the aperture being of sufficient size to accommodate one electrical outlet orientation, and a protective housing defining a closed space enclosing the electrical outlet with at least one electrical plug present, the protective housing adapted to be mounted to the base plate. Also included is a latching mechanism for an outdoor outlet cover adapted to secure the housing in a closed position with respect to the base and having an optionally removable release button to facilitate opening of the cover.

It is commonplace to have electrical outlets placed outdoors in order to supply the electricity required by outdoor lighting, outdoor yard equipment, outdoor recreation equipment, and the like. Where electrical outlets are placed outdoors, the damaging effects of weather conditions require a weather-resistant outdoor electrical outlet cover.
Certain types of outdoor electrical outlet covers provide weather resistant protection not only for the outlet receptacle, but also provide for an appliance to be plugged into the outdoor receptacle while maintaining weather-resistant protection to both the receptacle and the appliance plug. This feature is convenient because it is sometimes preferred to leave certain outdoor appliances plugged into an outdoor outlet for extended periods of time. Examples of such appliances include outdoor lighting such as spotlights. Even when an appliance is not intended to be left plugged in for an extended period of time, it is also sometimes preferred to provide weather resistant protection for the appliance plug during use.
One type of outdoor electrical outlet cover is designed for use with a vertically aligned electrical outlet. For example, U.S. Pat. No. 4,424,407 describes a weatherproof outdoor electrical outlet cover secured to an electrical outlet. The outlet cover described in the '407 patent is a rectangular structure with a gap in the bottom wall through which an electrical cord may pass.
One of the disadvantages of this type of device is that only a vertically aligned electrical outlet may be satisfactorily protected from varying weather conditions. If the device described in the '407 patent were to be placed on a horizontally aligned electrical outlet, the opening for the appliance cord would no longer be oriented downward thereby creating a greater likelihood that water, moisture or other substances would enter the protected area. Accordingly, such a cover would be unsuitable for protecting horizontally aligned electrical outlets.
Even if the outlet cover, such as the one described in the '407 patent were to be adapted for use with a horizontally aligned electrical outlet, it would require a manufacturer to make an entirely separate line of outlet covers, one for horizontal outlets and one for vertical outlets. Also, retailers would have to stock both types. This could lead to greater costs associated with manufacturing and stocking more product lines. Moreover, when a consumer is considering purchase of an outlet cover, he must remember the orientation of the outlet for which the cover is intended.
Another example of a outlet cover for outdoor applications is shown in U.S. Pat. No. 4,109,095. The device described in the '095 patent is a more complex weatherproof electrical outlet box cover. The box cover contains a pair of spring biased lids which fit together to seal an electrical cord extending out of the cover. The two lids contain an interlocking gear mechanism in order to synchronize the movement of the two lids. While this '095 device is capable of enclosing a horizontally or vertically aligned outlet, this outlet cover is relatively complicated and requires a large number of parts. Moreover, the outlet cover described in the '095 patent prevents easy accessibility for the insertion of an electrical plug.
Another disadvantage of prior outdoor outlet covers is that the outlet covers described above are designed for use with only one specific electrical outlet configuration, i.e., a standard duplex or a Decora style outlet. Even if the cover were a broad enough design to protect more than just one style, it would not be capable of use with both single-gang and/or double-gang size outlet boxes.
Therefore, a simple and more versatile weatherproof outdoor electrical outlet cover is needed.


An assisted rescue system to extract a seatbelt harnessed person from a vehicle. The system comprises a seatbelt harness and seat liner which together form a sling. The seatbelt harness is connected at anchor points with a releasable securing mechanism that is operable with a single release action.

One option for removal of an injured person from an armoured vehicle is via the roof hatch. This first requires that the seatbelt be unfastened or cut away from the casualty. Thereafter the casualty is moved using whatever means possible through the hatch opening or any other point of egress.
During rescue operations, time is of course of the essence. Attempting to undo the seatbelt and/or trying to cut away the various sections of the seatbelt, or parts thereof, can be time consuming. It also requires the rescuer to access, reach and apply forces in awkward and tight quarters and from difficult angles in a vehicle already damaged in the attack.
The casualty may have suffered back, neck, spinal cord injuries or other grievous bodily harm. Moving the deadweight of the casualty is difficult, and may additionally cause damage and trauma. There is accordingly a need for extracting a seatbelt harnessed person from the vehicle quickly and efficiently for evacuation to medical faculties.


A silver halide color photosensitive material comprising a support and, superimposed thereon, a blue-sensitive layer unit, a green-sensitive layer unit and a red-sensitive layer unit, each of these light-sensitive layer units composed of at least one silver halide emulsion layer, together with at least one non-sensitive layer, wherein compound (A) is contained in at least one layer in the silver halide color photosensitive material, compound (A) being a compound capable of releasing compound (Ac1) by oxidation coupling reaction with a color developing agent, compound (Ac1) being a heterocyclic compound which when added, is capable of enhancing the sensitivity of the photosensitive material as compared with that exhibited when not added, provided that the heterocyclic ring of the heterocyclic compound has 1 or 2 hetero atoms.

1. Field of the Invention
The present invention relates to a silver halide color photosensitive material. More specifically, the present invention relates to a silver halide color photosensitive material with high sensitivity minimal in graininess and excellent in storability.
2. Description of the Related Art
For a long time there has been a desire to make a silver halide color photosensitive material highly sensitive without increasing graininess. In general, sensitivity is dependent on the size of silver halide emulsion grains. The larger the emulsion grain, the greater the sensitivity is. However, since the graininess is increased in accordance with the increase in the size of the silver halide emulsion grains, there is a trade-off between sensitivity and graininess. In the industry, it is the most basic and important matter from the viewpoint of improving the image quality of a photosensitive material to increase the sensitivity without increasing the graininess.
There has been disclosed a technique of increasing the sensitivity without increasing the graininess by containing a compound having at least three hetero atoms in a silver halide color photosensitive material (see, for example, Jpn. Pat. Appln. KOKAI Publication No. (hereinafter referred to as JP-A-)2000-194085, JP-A-2003-156823 and JP-A-2004-226971).
In contact, the present inventors have found that a compound having one or two hetero atoms obtains preferably better effect for improving the sensitivity than the above-mentioned compound at least of three hetero atoms and have extensively studied Improvement.
However, although the increase in sensitivity is obtained by the above-mentioned method, it has been clarified that the storability of a raw photosensitive material is occasionally degraded extremely. In particular, the storability of a photosensitive material in an environment of high temperature and low humidity such as the inside of an automobile left alone in the sun, occasionally a serious situation provokes, and it has been clarified that fog increase and sensitivity decrease are problems when the material is left alone at a temperature of 80° C. or more and a humidity of 10% or less.

Silver halide color photosensitive material


A system (20; 300) has: a compressor (22) having a suction port (40) and a discharge port (42); an ejector (32) having a motive flow inlet (50), a suction flow inlet (52), and an outlet (54); a separator (34) having an inlet (72), a vapor outlet (74), and a liquid outlet (76); a first heat exchanger (24); an expansion device (28); and a second heat exchanger (26; 302). Conduits and valves are positioned to provide alternative operation in: a cooling mode; a first heating mode; and a second heating mode. In the cooling mode and second heating mode, a needle (60) of the ejector is closed.

The disclosure relates to heat pumps. More particularly, the disclosure relates to heat pumps featuring an ejector.
Vapor compression systems have long been used for air conditioning. An exemplary vapor compression air conditioner comprises a refrigerant compressor, an outdoor heat exchanger downstream of the compressor along a refrigerant flowpath, an expansion device downstream of the outdoor heat exchanger, and an indoor heat exchanger downstream of the expansion device prior to the refrigerant flowpath returning to the compressor. Refrigerant is compressed in the compressor. Refrigerant then rejects heat in the outdoor heat exchanger and loses temperature. An exemplary outdoor heat exchanger is a refrigerant-air heat exchanger wherein fan-forced outdoor air acquires heat from refrigerant. By rejecting heat, the refrigerant may condense from vapor to liquid in the heat rejection heat exchanger. Accordingly, such exchangers are often referred to as condensers. In other systems, the refrigerant remains vapor and such are referred to as gas coolers.
The refrigerant expands in the expansion device and decreases in temperature. The reduced temperature of the refrigerant thus absorbs heat in the heat absorption heat exchanger (e.g., evaporator). Again, the evaporator may be a refrigerant-air heat exchanger across which a fan-forced interior/indoor airflow is driven with the interior/indoor airflow rejecting heat to the refrigerant.
Such vapor compression systems may also be used to heat interior spaces. In such cases, the refrigerant flow direction is altered to pass first from the compressor to the indoor heat exchanger and return from the outdoor heat exchanger to the compressor. Such arrangements are referred to as heat pumps.
In addition to simple expansion devices such as orifices and valves, ejectors have been used as expansion devices. Ejectors are particularly efficient where there is a large temperature difference between the indoor and outdoor environments.
An exemplary ejector is formed as the combination of a motive (primary) nozzle nested within an outer member or body. The ejector has a motive flow inlet (primary inlet) which may form the inlet to the motive nozzle. The ejector outlet may be the outlet of the outer member. A motive/primary refrigerant flow enters the inlet and then passes into a convergent section of the motive nozzle. It then passes through a throat section and an expansion (divergent) section and through an outlet of the motive nozzle. The motive nozzle accelerates the flow and decreases the pressure of the flow. The ejector has a secondary inlet forming an inlet of the outer member. The pressure reduction caused to the primary flow by the motive nozzle helps draw a suction flow or secondary flow into the outer member through the suction port. The outer member may include a mixer having a convergent section and an elongate throat or mixing section. The outer member also has a divergent section or diffuser downstream of the elongate throat or mixing section. The motive nozzle outlet may be positioned within the convergent section. As the motive flow exits the motive nozzle outlet, it begins to mix with the suction flow with further mixing occurring through the mixing section which provides a mixing zone.
Ejectors may be used with a conventional refrigerant or a CO2-based refrigerant. In an exemplary operation with CO2, the motive flow may typically be supercritical upon entering the ejector and subcritical upon exiting the motive nozzle. The secondary flow is gaseous (or a mixture of gas with a smaller amount of liquid) upon entering the secondary inlet. The resulting combined flow is a liquid/vapor mixture and decelerates and recovers pressure in the diffuser while remaining a mixture.
U.S. Pat. No. 6,550,265 of Takeuchi et al., issued Apr. 22, 2003, and entitled "Ejector Cycle System" discloses switching arrangements for use of an ejector in a cooling mode and a heating mode. US Patent Application Publication 2012/0180510A1 of Okazaki et al., published Jul. 19, 2012, and entitled "Heat Pump Apparatus" discloses a configuration with ejector and non-ejector heating modes and a non-ejector defrost mode. Additionally, PCT/US2015/030709 of Feng et al., filed May 14, 2015, and entitled "Heat Pump with Ejector" discloses a configuration with alternative ejector and non-ejector heating modes and a non-ejector cooling mode.


The apparatus for ion beam fabrication, which has been able to detect any anomalous condition of ion beams only by means of the current irradiated on the specimen, could not compensate the failure by investigating the cause and could not realize stable processing. To solve the problem described above, the present invention includes the first and second blankers and Faraday cups switches ON and OFF the first and second blankers and monitors beam current at two positions above and below the projection mask. By adopting this configuration, it will be possible to acquire the information on failure in ion beam, sort out the cause of the failure and to compensate the failure while limiting damages to the projection mask. As a result, it will be possible to realize stable processing by means of ion beam, and to use the ion beam fabricating device on a stable basis.

The needs are rising for tests and analyses of semiconductor devices that are becoming progressively minute. In failure analyses for specifying the cause of failure, in particular, the direct observation of defects within devices has become an indispensable technology. For these observations, it is necessary to precisely microfabricate the position of observation objects of the device. So far, this precise miocrofabrication has been carried out by means of a tool called "focused ion beam (hereinafter referred to as "FIB") processing device." As this FIB enables to work precisely on the target position by irradiating the specimen with ion beam focused to the submicron order and electrostatically deflecting the same, this is used for shaping the section for analysis and for fabricating specimens for analysis.
And in this failure analysis processing, the needs are rising for fabricating specimens for analysis in a short period of time. As an improvement in yield is directly connected with the device cost, the identification of the cause of the failure in a short period of time will have a great impact on the reduction of cost. Therefore, a rapid processing of specimens for analysis is expected. As a processing device for realizing this, there is, for example, a projection ion beam (hereinafter referred to as "PJIB") processing device described in JP-B No. 3542140. Unlike the FIB processing device described above that processes to shape the intended form by focusing, deflecting ion beams and scanning the specimen with the same, this device enables to process the specimens in block by projecting mask patterns of shapes similar to the intended shapes predetermined in advance on the specimen. The processing speed is determined roughly by how much ions are irradiated on the area to be processed. In other words, the larger the ion beam current is, higher the processing speed rises. In terms of simple ion beam current density in the ion diameter, the FIB is greater than the PJIB. However, in the processing of an area where the PJIB ion beam current is greater than the FIB ion beam current, the PJIB processing is simply faster. In fact, in the case of processing used for the failure analysis of devices, there is hardly any processing in the submicron range, and in most cases processing in the range of several to several tens of microns is required. And in such cases, the PJIB processing has the merit of being faster.
Since the analyses of failures by using these apparatus for ion beam fabrications were often conducted in the past by specialized operators, even if an anomalous event has occurred in the device, it was possible to cope with such an event by the skill of the operators. Lately however, devices capable of automatically processing without the attendance of any specialized operator have increased. As a result, it has become important to secure the stability of beams in particular in these devices. In order to secure stability of beams, it is effective to monitor beams. For example, JP-B No. 3567749 describes an example of the method of monitoring beam current by an ion implantation equipment. This describes the method of measuring the distribution of current at two points before and after the item processed by means of multipoint Faraday cups, and interpolating or extrapolating the current density distribution of ion beams at the position of the processed item (specimen). It also states that, in view of such a presumed current density distribution, the distribution of beams can be compensated by for example extending the scanning irradiation time in an area with a low current density and by curtailing the scanning irradiation time in an area with a high current density.


An electro-hydraulic actuation system (901) includes an unbalanced hydraulic actuator (902) capable of motion in retraction and extension directions during movement of a load (904). A pump (204) provides a flow of fluid to the actuator. A displacement of the pump controls a velocity of the actuator during motion in the retraction and extension directions. An electric motor (202) drives the pump. Speed and direction of the electric motor affects the displacement of the pump. A controller (802) controls the speed and direction of the electric motor. A feedback device (228,248) is operable for sensing a system condition and for providing a feedback signal indicative of the sensed system condition to the controller. The controller is responsive to the feedback signal for determining an occurrence of an over-center load condition and for modifying the speed of the electric motor in response to the occurrence in an attempt to maintain the velocity of the actuator.

Hydraulic actuators in many machines are subjected to varying loads. The loads may be overrunning loads or resistive loads. An overrunning load is a load that acts in the same direction as the motion of the actuator. Examples of overrunning loads include lowering a wheel loader boom or lowering an excavator boom, each with gravity assistance. A resistive load is a load that acts in the opposite direction as the motion of the actuator. Examples of resistive loads include raising a wheel loader boom or raising an excavator boom, each against the force of gravity. In certain applications, hydraulic actuators can be subjected to both an overrunning load and a resistive load in the same extend or retract stroke. As an example, when a wheel loader bucket that is curled in is given a command to curl out (generally, a retraction of the actuator), the motion may begin with a resistive load applied to the actuator and, at some point in the stroke, typically due to the force of gravity, the load on the actuator becomes an overrunning load. The transition between the resistive load and the overrunning load without a change in the direction of motion is referred to herein as an "over-center load condition." An over-center load condition may occur during a transition from a resistive load to an overrunning load and during a transition from an overrunning load to a resistive load.
It is desirable that an over-center load condition not affect the velocity of retraction or extension of the actuator. Such velocity control is particularly difficult when the hydraulic actuator is an unbalanced actuator of an electro-hydraulic actuation (EHA) system. An unbalanced actuator has unequal cross-sectional areas on opposite sides of the piston, generally as a result of the rod being attached to only one side of the piston. An EHA system is a system in which a reversible, variable speed electric motor is connected to a hydraulic pump, generally fixed displacement, for providing fluid to an actuator for controlling motion of the actuator.

Velocity control of unbalanced hydraulic actuator subjected to over-center load conditions


An edge detection system and method implement a recursive polar algorithm process to generate an edge image from an input image. The edge detection system may include a polar filter to recursively perform low-pass filtering along edge contours of a gradient pixel grid and generate a gradient image output. An edge thinner may be included to find gradient field peaks along a direction of gradient vectors of the gradient image output and generate thinned gradient pixels. An edge path segmenter may group the thinned gradient pixels into edge segments, and a segment classifier may determine whether the edge segments are edge paths or clutter. The edge detection system and method may improve automated image processing in medical diagnostics, reconnaissance, missile guidance, hazard or threat warning systems, security systems, access control systems (e.g., face recognition), navigation, geographic mapping, manufacturing quality inspection, robot vision, and search and rescue.

Locating features within an image is fundamental to computer vision applications. The edges (or outline) of objects within the image are frequently the most useful features since the edges typically provide object shape information. The shape information facilitates subsequent object acquisition or recognition processing. The rapid increase in microprocessor throughput capabilities in recent years has fueled proliferation of computer vision applications in many diverse fields. Examples include automated processing of images in medical diagnostics, reconnaissance, missile guidance, hazard or threat warning systems, security systems, access control systems (e.g. face recognition), navigation, geographic mapping, manufacturing quality inspection, robot vision, search and rescue, etc.
One problem with conventional image processing systems is that the methods employed for edge detection and generation of edge images are not very tolerant to noise. Another problem with convention image processing systems is that significant throughput time is required for improved noise tolerance. Another problem with convention edge detection systems is that conventional methods may not achieve optimal edge filtering along arbitrary paths.
Thus, there is a general need for an improved image processing system and method. Thus, there is also a need for improved systems and methods for edge detection and generation of edge images. There is also a need for an improved edge detection and edge image generation system and method that provides improved noise tolerance and lowers the cost of imaging equipment greatly improving the affordability of an image processing system. Thus, there is also a need for an improved edge detection and edge image generation system and method with improved noise tolerance without significant throughput increases. Thus there is also a need for an edge detection system that may automatically adjust to any edge orientation or shape rather than being constrained to a discrete set of straight edge orientations to help achieve optimal edge filtering along arbitrary paths.

System and method for detection of image edges using a polar algorithm process


The invention relates to a container, such as a saucepan, pot, coffee pot or similar item, that is intended for keeping a content of the container (2) warm. The arrangement (1) has a container (2) that is enclosed by a heat insulating fabric part (3) that with the help of an adjustable band (18) is wrinkled at an upper part (5) around an area of an upper edge (6) of the container (2). This fixates the position of the fabric part (3) while at the same time providing a protection of the upper edge (6) of the container (2). An upper part (7) of the fabric part (3) is pivotably attachable to a heat insulating fabric part (9) that completely or partially encloses or covers a lid (8).

When food is served today, the contents of saucepans are often transferred to serving pots and put on the table. In this way, the food cools rapidly which leads to, after serving the food in portions, the food gets a temperature that makes the food less tasty. Alternatively, the item, such as saucepan, is put directly on the table but in certain circles this is not seen as polite and is therefore not recommended when guests are served.
The purpose of the present invention is to accomplish an arrangement with which one can place different saucepans, pots or similar items directly on the table so that they are clothed with a fabric pullover that hides the saucepan or the pot in question and therefore the actual saucepan or pot on the table is used while at the same time providing an effective maintenance of the warmth of the food. The distinguishing features of the present invention are outlined in the claims below.
Thanks to the invention, an arrangement is available for keeping the content of saucepan, pot, coffee pot or similar items warm. The arrangement fulfills its purpose in an effective way while at the same it is inexpensive and easy to manufacture. According to the arrangement of the present invention the contents of containers such as potatoes, rice, pasta, coffee, tea, etc. are kept warm partially by keeping the container warm when it is brought from the stove and no heat is lost when the content is poured to a serving pot that usually is only at room temperature and needs to be heated up. The serving pots often lack lids. By providing the container with the arrangement according to the invention the user saves on both dishes and time because only the container itself needs washing and no special serving pots are used. By using the arrangement of the present invention both the container and its content are hidden although the actual container is on the table and this is more evident if the warming arrangement is made of a fabric that is adapted to today's fashion and trends. It may perhaps also be adapted to table cloths, napkins and seat covers that are available on the market. Another advantage of the arrangement of the present invention is that it also protects the table and also the surrounding, such as persons and especially children, who otherwise can easily get burned and also when it is used on a lake. Furthermore, a container with a warm keeping arrangement according to the present invention is easier to move around on the table because it is attached to the actual container which an ordinary coaster or potholder does not do. Finally, the warm keeping arrangement of the present invention is washable which all coasters are not such as the most common cork coasters.


A method is used for recovering misdischarge of liquid in an on-demand type liquid jet recording apparatus. The apparatus comprises a recording head having a discharge port for discharging liquid, a liquid path communicating with the discharge port and energy generating means provided in response to the liquid path so as to generate energy utilized for discharging liquid, and exhausting means for exhausting liquid in the liquid path. Drive of the energy generating means is performed in synchronism with drive of the exhaust means at least in a predetermined time period.

1. Field of the Invention
The present invention relates to a method for recovering misdischarge is an ink jet recorder which eliminates non-discharge or misdischarge of ink to permit stable discharge of ink, and an ink jet recording apparatus using the same.
2. Related Background Art
In a prior art ink jet recorder such as that disclosed in U.S. Pat. No. 4,045,802, capping means for closing a periphery of an discharge orifice of a record head is provided to close the periphery in a non-record mode so that the record head is isolated from surrounding atmosphere while the record head is capped, and air layer in the capping means is filled with vapor of ink to keep a saturated vapor pressure so that drying and increase of viscosity of the ink in the discharge orifice are prevented.
However, in such a recorder, in a low humidity environment or when recording is paused for a long time it is not possible to sufficiently prevent the increase of viscosity of ink even if drying is prevented by the capping means, and hence it is difficult to completely prevent non-discharge or misdischarge of the ink from the nozzle in a record mode.
When a fine air bubble or dust is present in the ink in the discharge orifice, it causes disturbance of discharge of the ink in the record mode and it significantly deteriorates an image quality.
In order to solve such a problem, U.S. Pat. No. 4,600,931 discloses an ink jet recorder which renders the air layer in the capping means to be of low pressure so that the ink in the discharge orifice of the record head is sucked. U.S. Pat. No. 4,123,761 disclosed an ink jet recorder which has pumping means for an ink supply system including the record head and it is automatically or manually activated to pressurize the ink so that the ink is discharged from all nozzles of the record head. U.S. Pat. No. 4,176,363 discloses an ink jet recorder which effects pre-discharge in order to prevent non-discharge of the ink.
However, even such ink jet recorders are not always sufficient in that the recorders are always operable in a best condition regardless of a surrounding environment or recording condition. It is particularly difficult to completely eliminate fine air bubbles in the ink. Even if there is no fine air bubble at the start of recording, fine air bubbles may be generated and grown by cavitation during continuous recording operation, or ink droplets including air bubbles therein may be discharged from the discharge orifice to cause disturbance in the discharge of the ink.

Ink jet misdischarge recovery by simultaneously driving an ink jet head and exhausting ink therefrom


A system for creating an augmented reality display coupled with a firefighter's self-contained breathing apparatus (SCBA) mask. The invention combines a camera, motion tracking sensor, head-mounted display, SCBA mask, and optional head phones into a display suitable for performing exercises, such as training of firefighters or other emergency first responders, in augmented reality.

Augmented Reality (AR) is emerging as a technology for assistance in performing a variety of tasks. AR systems can be used to allow firefighters and other emergency first responders to train using real equipment and virtual fire and smoke. As part of making the experience realistic for firefighter trainees, it is important that the AR experience resemble the real experience as closely as possible. Therefore, it is important to integrate an AR system into real or mockup fire fighting equipment.

Augmented reality display integrated with self-contained breathing apparatus


A radiometric data acquisition and display system is provided. The system has a detector assembly with a boom. A radiometer is connected at an end of the boom. The radiometer has a sensor head including an antenna horn to acquire radiometric data from an area of interest. A rangefinder is constructed and arranged to provide location data indicative of a position of the sensor head, and a data processor is connected to receive the location data from the rangefinder and the radiometric data from the radiometer. The data processor includes signal processing circuitry and a display connected to the computer. A method of acquiring and displaying a radiometric image of an object is also provided. The method has the steps of: randomly sweeping a radiometer detector over an area of interest; detecting an object in a portion of the area of interest; sweeping the radiometer detector over the object to acquire radiometric image data; processing the data to construct an image from the radiometric image data; and displaying the image. In an embodiment, the method distributes the radiometric data over an antenna pattern to construct an image using the location data.

The present invention is directed generally to mine detection and more specifically to a method and apparatus for acquiring and displaying a radiometric image of a mine.
The detection of land mines and other ordnance on the battlefield has grown in importance with their increased use, not only for military personnel, but also for civilians after hostilities have ceased. The need for new approaches and sensors to increase the speed and efficiency of methods to clear mines is an issue that must be addressed.
The detection of land mines has been an important part of battlefield management since the first use of mines. Similarly, the detection of unexploded ordnance (UXO) for clean-up of long-used test ranges is of concern. The importance of both has grown with time and the task has not become easier. The long term danger posed by mines and UXO to both military personnel and displaced civilian populations during wars was illustrated most recently by experiences during the Gulf War and continues today around the world.
As a further example, the dangers posed by metal and plastic land mines is an everyday issue facing the United States military and others in regions such as Bosnia-Herzegovina. Techniques currently being used are relatively crude and labor intensive. The difficulty in locating these and other mines and UXO throughout the world begs the development of improved sensors to speed the process of clearing them to reduce casualties, injuries, and other costs.
Sensors in the millimeter wave region of the electromagnetic spectrum (typically from 30 to 300 GHz) have been shown to be capable of detecting metal above and under dry sand. For example, the inventors of the present application co-authored an article entitled, "Passive millimeter wave sensors for detection of buried mines," SPIE Vol. 2496, April 1995, incorporated in its entirety herein by reference. The detection capabilities disclosed point to new possibilities for improving mine detection techniques. Passive millimeter wave sensors (or radiometers) provide day/night operation, have good spatial resolution, good signal-to-noise ratio (SNR) providing good target contrast, and clutter is benign compared to the situation with ground penetrating (GPEN) radar and infrared (IR) sensors.
For greater ground penetration, extension of the spectrum to lower frequencies is desirable. For example, in the detection of buried mines, lower frequencies have better ground penetration capability and are expected to give improved detection of such targets. The reduced fill factor (discussed below) and lower resolution that follows from the use of lower frequencies forces the use of large apertures or detection at shorter ranges.
Further, it has been shown that metal targets such as mines placed above soil, under an open sky, stand out clearly against the soil background when using a millimeter wave radiometer as an imaging device. There are three basic factors that allow this to happen.
First, the sky above has a very low brightness temperature (.ltoreq.40K) which means that it acts like a very cold, low power illuminator that bathes the scene with a very low level of millimeter wave radiation. This occurs at certain spectral windows where emissions from the atmospheric oxygen and water are relatively low (for example, below.apprxeq.20 Ghz, and around 35, 94, and 140 GHz).
Second, the soil typically has a high emissivity (or low reflectivity), and thus emits millimeter wave radiation corresponding to its physical temperature (.apprxeq.295K).
Third, the metal target has low emissivity (or high reflectivity). Thus, its own physical temperature is unimportant in terms of its appearance in the millimeter wave regime. The appearance of the metal target is determined by what the target reflects.
These three factors combine as follows: the metal target reflects the low level radiation from the sky and looks like a "cold" object surrounded by the "hot" soil which is emitting a higher level of millimeter wave radiation. This high contrast (295K-40K=255K), combined with typical modem millimeter wave radiometer sensor temperature resolutions of 1K, allows a high signal-to-noise ratio (SNR).
However, the high contrast described above occurs on a clear day, and cloud cover will raise the effective sky temperature, thereby reducing the contrast of the target with its background. A heavy overcast situation can cause the effective sky temperature to rise to about 200K, but this still leaves plenty of contrast.
Similarly, burying the metal target under soil will reduce the target contrast due to the obvious obscuring nature of the soil, but also because of the hot millimeter wave emissions from the overburden. The amount of contrast reduction will vary with the depth of soil coverage, the type of soil, the amount of water content in the soil, and the temperature of the soil.
Another consideration in determining the target contrast in a mine detector system is the "fill factor," a measure of the extent to which the detector's field of view is filled by the reflective target. The smaller the fill factor, the smaller the target contrast. Remote mine detection, as from an airborne platform, requires a sufficiently high resolution sensor to maintain an adequate fill factor.
The effect of the detection frequency on the ability of radiometric techniques to detect buried metal targets has been demonstrated. For example, the inventors of the present application co-authored an article entitled, "Detection of metal and plastic mines using passive millimeter waves," SPIE Vol. 2765, April 1996, incorporated in its entirety herein by reference. Typically the results are plotted as the absolute value of the radiometric temperature difference .vertline..DELTA.T.vertline. between an infinitely thick sand layer and a sand layer of varying thickness over the metal target, versus the thickness of the sand layer. The general trend is that .vertline..DELTA.T.vertline. increases (the sand appears colder than an infinitely thick sand layer) as the sand layer decreases in thickness, until it reaches a maximum value corresponding to the sky temperature directly reflected off the metal target without any obscuring sand. As the sand layer increases in thickness, .vertline..DELTA.T.vertline. approaches zero (the presence of the metal target is totally masked).
The detectability of targets (larger .vertline..DELTA.T.vertline.) improves with lower frequencies and lower water content. For a given minimum resolvable temperature that a detector can resolve (based on its noise characteristics) and a given water content, a lower frequency allows detection to a greater depth.
On the other hand, a plastic target, given its much lower reflectivity and its transparency to radiation rising from below it, produces a much smaller .vertline..DELTA.T.vertline. than a metal target. To quantify the degree of detectability of metal and plastic mines using radiometric techniques, measurements have been performed using some typical mines under varying conditions and detection frequencies. The above articles demonstrate that metal and plastic mines can be detected both on the surface and under soil with varying moisture content.
Past detection techniques involve mechanically scanning the scene by passing the radiometer over the scene in a set pattern, and dwelling a long time at each spot to get a good enough integration time, and then forming the image after the fact. Such a technique is an organized, systematic way of generating an image. However, such a process is time-consuming and wasteful. For instance, the radiometer spends an equally long time over areas without a mine, as it does over areas with a mine. Such a system scans the scene back and forth in an orderly manner using a precise system for moving the radiometer back and forth. The radiometer was mounted on an azimuth elevation platform which uses a motorized system with gears and an apparatus to move the radiometer back and forth.
Thus, the radiometer was moved back and forth in a fixed pattern. As the radiometer was moved across the scene, the system recorded the data and its position, but no display was immediately generated. Also, the system did not have the capability for the operator to move the head to an area of interest and scan over that area for a longer period of time.
Thus, the above described detection system operated by scanning to the left, moving forward, scanning to the right, and moving forward again and repeating the process over and over. A raster scan image of the scene was generated showing a two-dimensional image indicating a mine buried under the soil.
The detection of inert metal and plastic mines at the surface or under dry sand or soil, and leaves, has been demonstrated at both 12 and 44 GHz. Soil with a high water content drastically affects the detectability of the mines. Also, modeling predicts that better performance is possible at lower frequencies. A need therefore exists for a method and apparatus for acquiring and displaying a radiometric image of a buried mine which allows an operator to concentrate on a particular region of interest.

Method and apparatus for detecting mines using radiometry