The present invention is directed to methods of treating movement disorders by administering an effective amount of one or more adenosine A2A receptor antagonists to a patient in need thereof. The present invention also provides methods of decreasing the adverse effects of L-DOPA in patients receiving L-DOPA therapy in the treatment of Parkinson's disease. The present invention further provides methods and compositions for treating Parkinson's disease patients with sub-clinically effective doses of L-DOPA by combining L-DOPA treatment with an effective amount of one or more adenosine A2A receptor antagonists (i.e., L-DOPA sparing effect). The present invention further provides methods of effective treatment of Parkinson's disease by co-administering at least one adenosine A2A receptor antagonist, L-DOPA and a dopamine agonist and/or a COMT inhibitor and/or a MAO inhibitor. The present invention further provides methods of prolonging effective treatment of Parkinson's disease by administering an adenosine A2A receptor antagonist singly or together with a dopamine agonist, and/or a COMT inhibitor, and/or a MAO inhibitor without prior or subsequent administration of L-DOPA, delaying or removing on-set of L-DOPA motor complication.

Movement Disorders are neurological conditions characterized by either a paucity or lack of movement (such as Parkinson disease) or excessive movement (such as dystonia, dyskinesia, tremor, chorea, ballism, akathisia, athetosis, bradykinesia, freezing, rigidity, postural instability, myoclonus, and tics or Tourette syndrome). See, Watts and William eds. (1997); and Shulman and Weiner (1997).
Parkinson's Disease and Motor Complication
Parkinson's disease (paralysis agitans) is a disorder of the brain characterized by shaking and difficulty with walking, movement, and coordination. The disease is associated with damage to a part of the brain that controls muscle movement.
Parkinson's disease was first described in England in 1817 by James Parkinson. The disease affects approximately 2 out of 1,000 people, and most often develops after age 50. The symptoms first appear, on average, at about age 60, and the severity of Parkinson's symptoms tends to worsen over time. It affects both men and women and is one of the most common neurologic disorders of the elderly. The term "parkinsonism" refers to any condition that involves a combination of the types of changes in movement seen in Parkinson's disease. Parkinsonism may be genetic, or caused by other disorders or by external factors (secondary parkinsonism).
In the United States, about a million people are believed to suffer from Parkinson's disease, and about 50,000 new cases are reported every year. Because the symptoms typically appear later in life, these figures are expected to grow as the average age of the population increases over the next several decades. The disorder is most frequent among people in their 70s and 80s, and appears to be slightly more common in men than in women.
The dopaminergic neurons of the substantia nigra pars compacta and ventral tegmental area play a crucial role in regulating movement and cognition, respectively. Several lines of evidence suggest that the degeneration of dopaminergic cells (i.e. dopamine-producing cells) in the substantia nigra produces the symptoms of Parkinson's disease. Dopaminergic cells, concentrated in the region of the substantia nigra, are the fastest aging cells in the body. As dopaminergic cells decay, control over movement is diminished and Parkinson's disease develops.
Usually the first symptom of Parkinson's disease is tremor (trembling or shaking) of a limb, especially when the body is at rest. The tremor often begins on one side of the body, frequently in one hand. Other common symptoms include other movement disorders such as slow movement (bradykinesia), an inability to move (akinesia), rigid limbs, a shuffling gait, and a stooped posture. Parkinson's disease patients often show reduced facial expression and speak in a soft voice. The disease can cause secondary symptoms of depression, anxiety, personality changes, cognitive impairment, dementia, sleep disturbances, speech impairments or sexual difficulties. There is no known cure for Parkinson's disease. Treatment is aimed at controlling the symptoms. Medications control symptoms primarily by controlling the imbalance between the neurotransmitters. Most early Parkinson's disease patients respond well to symptomatic treatment with dopamine replacement therapy, but disability increases with progression of the disease.
The medications used, the dose and the amount of time between doses vary, depending on the case. The combination of medications used may need to be adjusted as symptoms change. Many of the medications can cause severe side effects, so monitoring and follow-up by the health care provider is important.
Although currently available medications for Parkinson's disease generally provide adequate symptomatic control for a number of years, many patients develop motor fluctuations and dyskinesias that compromise clinical response. Rascol et al. (2000); and Parkinson Study Group (2000). Once this occurs, increasing dopaminergic therapy is likely to worsen dyskinesias and decreasing dopaminergic therapy is likely to worsen motor function and increase OFF time. In light of this problem, attention has turned to potential therapeutic manipulation of non-dopaminergic neurotransmitter systems.
Most Parkinson's disease symptoms arise from a deficiency of dopamine and most anti-Parkinson drugs restore dopamine or mimic dopamine's actions. However, the drugs do not permanently restore dopamine or exactly mimic dopamine's actions. While a loss of dopamine cells in the substantia nigra is the main feature of Parkinson's disease, non-dopamine nerve cells are also lost. Moreover, dopamine-responsive cells are present not only in the substantia nigra but in other brain regions. Thus drugs that are effective in Parkinson's disease can, by stimulating these cells, cause side effects such as nausea, hallucinations, and confusion.
In 1967, L-DOPA was introduced and remains the most effective anti-Parkinson drug. Symptoms most likely to benefit from L-DOPA include bradykinesia, rigidity, resting tremor, difficulty walking, and micrographia. Symptoms least likely to benefit from L-DOPA include postural instability, action tremor, and difficulty swallowing. L-DOPA may worsen dementia. Although L-DOPA provides robust and rapid therapeutic benefits in Parkinson's disease, eventually, severe adverse reactions to dopamine emerge, including motor complications such as wearing off phenomenon, ON-OFF fluctuations, and dyskinesia. Marsden et al. (1982). Once established, motor complications are not typically controllable with manipulation of L-DOPA or other dopaminergic drugs.
Early in Parkinson's disease L-DOPA is taken 3 times per day. Peak concentrations in the brain occur 1 to 2 hours after administrations. Although the drug has a short half-life (0.5 to 1 hour) there are sufficient remaining dopamine cells in the brain to store dopamine and maintain its activity over several hours. As Parkinson's disease progresses, more dopamine cells die and the remaining cells cannot store sufficient dopamine to maintain its benefits: the duration of action of each dose decreases and patients need higher or more frequent doses. After 2-5 years as many as 50-75% of patients experience fluctuations in their response to L-DOPA: ON/OFF periods. Associated with the fluctuations, patients develop dyskinesias. The dyskinesias usually occur at the peak effect of L-DOPA but can also occur as the drug wears off, or at stressful times. The fluctuations and dyskinesias can seriously impact the patient's life. If L-DOPA is given continuously (through an intravenous pump) ON/OFF effects disappear and dyskinesias decrease. However, it is impractical to give L-DOPA intravenously.
When L-DOPA is taken alone part of it is changed outside the brain to dopamine by dopa-decarboxylase. The dopamine so produced cannot enter the brain and causes side effects such as nausea, vomiting, and appetite loss. Therefore L-DOPA is often combined with carbidopa or benserazide. Carbidopa blocks dopa-decarboxylase outside the brain allowing more L-DOPA to enter the brain without causing nausea, vomiting, and appetite loss. Atamet or Sinemet are tablets containing both carbidopa and L-DOPA. In combination with carbidopa, the half-life of L-DOPA is 1.2 to 2.3 hours.
Thirty years after its discovery, L-DOPA is still the best treatment for Parkinson's disease. In the early stages of the disease, patients usually enjoy a good response to L-DOPA, but as the disease progresses L-DOPA-tends to become less helpful. This is not due to loss of L-DOPA efficacy, but rather to development of motor complications such as adverse fluctuations in motor response including end-of-dose deterioration or "wearing-off", and the "ON/OFF" fluctuations and dyskinesias. ON/OFF fluctuations are a sudden, unacceptable loss of therapeutic benefit of a medication ('ON' state, during which the patient is relatively free from the symptoms of Parkinson's disease) and onset of the parkinsonian state ('OFF' state). Wearing off phenomenon is a decrease in the duration of L-DOPA action, and characterized by the gradual reappearance of the 'off' state, and shortening the 'on' state. Dyskinesia can be broadly classified as chorea (hyperkinetic, purposeless dance-like movements) and dystonia (sustained, abnormal muscle contractions). In 1974, Duvoisin first focused on these abnormal involuntary movements, and found that over half of patients with Parkinson's disease developed dyskinesia within six months of treatment. With increasing duration of treatment, there is an increase in both the frequency and severity of dyskinesia. In a seminal study of the potential benefits of possible neuroprotectants in Parkinson's disease—the DATATOP trial-L-DOPA induced dyskinesia was observed in 20-30% of patients who received L-DOPA treatment for a mean of 20.5 months. Ultimately, most L-DOPA treated patients experienced dyskinesia; up to 80% of patients developed dyskinesia within five years of treatment. Parkinson Study Group (1996); and Rascol et al. (2000). Treatment-related dyskinesias are not solely a problem of L-DOPA, as dopamine receptor agonists are also capable of eliciting dyskinesia. Thus, the common term "L-DOPA-induced dyskinesia" could be used to describe dopamine-treatment-related dyskinesia in general terms. Most dyskinesias occur when levodopa or other dopamine receptor agonists have a concentration in the brain that is sufficient to overactive dopamine receptors in the putamen (peak-dose-dyskinesia). However, dyskinesia also occurs when dopamine concentration is low (OFF dystonia) or in stages when the concentration of dopamine rises or falls (biphasic dyskinesia). Other movement disorders, such as myoclonus and akathisia, might also be components of the L-DOPA induced dyskinesia spectrum.
The biological basis of L-DOPA motor complications in Parkinson's disease is still far from clear. It has been suggested that they may involve not only advancing disease and continued loss of nigral neurons, but also changes of dopamine receptor sensitivity and their downstream expression of proteins, and genes, the sequence of events of which relate, at least in part, to the dose and method of administration of L-DOPA or dopamine agonists. Changes in non dopamine systems such as glutamate-mediated neurotransmission, GABA-mediated neurotransmission, and opioid peptide mediated transmission, might also be involved in the neuronal mechanisms that underlie L-DOPA motor complications in Parkinson's disease. Bezard et al. (2001). Notably, it seems that the short plasma half-life and consequent short duration of action of dopaminergic agents and the pulsatile stimulation of dopamine receptors by dopaminergic agents are associated with motor fluctuations and peak-dose-dyskinesias. All these events combine to produce alterations in the firing patterns that signal between the basal ganglia and the cortex.
Originally introduced as adjunctive therapy to L-DOPA in patients with fluctuations, dopamine agonists are now increasingly proposed as monotherapy in early patients. The antiparkinsonian effects of dopamine agonists, however, are usually less than those of L-DOPA, and after two to four years their efficacy wanes. When more potent treatment is required, low doses of L-DOPA can be "added on" to the agonist. An alternative strategy is to combine an agonist with low doses of L-DOPA from the beginning. Both strategies are purported to be as effective as L-DOPA and to have the advantage of significantly reducing the risk of motor fluctuations and dyskinesias. These claims, however, are based upon a small number of pilot studies, all of which suffer from methodological shortcomings.
Additionally, dopamine receptor agonists are also capable of eliciting dyskinesia. Dopamine agonists also provoke dyskinesia in parkinsonian animals previously exposed by L-DOPA. Neuropsychiatric side effects, especially hallucination and psychosis, often limit the use of dopamine agonists. Despite the potential benefits provided by the adjunctive use of dopamine agonists, L-DOPA motor complications can thus be extremely difficult or even impossible to control. See, Olanow, Watts and Koller eds. (2001). Finally, dopamine agonists are sometimes used in monotherapy as substitutes for L-DOPA in patients with advanced Parkinson's disease and severe motor fluctuations and dyskinesias.
More recently, catecholamine-O-methyltransferase (COMT) inhibitors such as tolcapone and entacapone have been proposed as adjunctive therapy to L-DOPA. These compounds extend the plasma half-life of L-DOPA, without significantly increasing Cmax. Thus, they decrease the duration of wearing-off but tend to increase the intensity of peak-dose side effects including peak-dose-dyskinesias. Tolcapone appears to induce significant liver toxicity in a small percentage of patients.
Anti-cholinergics such as tri-hexiphenidyl (Artane) and piperidine (Cogentin) block the actions of acetylcholine in the brain. This may result in a mild to moderate degree of improvement in symptoms such as drooling and tremor. Patients above age 65 are likely to experience side effects such as dry mouth, blurred vision, constipation, confusion and hallucinations when treated with anti-cholinergics.
Dystonias
The term dystonia refers to a movement disorder characterized by sustained muscle contractions resulting in a persistently abnormal posture. Based on this definition, there are a number of dystonic syndromes, which can be subdivided according to their clinical features as: generalized (affecting all body parts); segmental (affecting adjacent body parts); or focal (restricted to a single body part). Focal dystonias include spasmodic torticollis, blepharospasm, hemifacial spasm, oromandibular dystonia, spasmodic dysphonia, and dystonic writer's cramp.
There are several degrees of dystonia. Some people can maintain a relatively normal life-style, while others are permanently hindered, often needing full time assistance.
Symptoms may be focal or limited to one region of the body, such as the neck or an arm or a leg. There are many different types of focal dystonia. Blepharospasm is marked by involuntary contraction of the muscles that control the movement of the eyelids. Symptoms may range from intermittent, painless, increased blinking to constant, painful, eye closure leading to functional blindness. In patients with cervical dystonia (CD), also known as spasmodic torticollis, muscle spasms of the head and neck may be painful and cause the neck to twist. These sometimes painful spasms may be intermittent or constant. Oromandibular and lingual dystonia is characterized by forceful contractions of the lower face causing the mouth to open or close. Chewing and unusual tongue movements may also occur. In spasmodic dysphonia (SD), also known as laryngeal dystonia, the muscles in the voice box (larynx) are affected. SD is marked by difficulties either opening or closing the vocal cords, causing the voice to have either a strained, hoarse, strangled, or whispering quality. In limb dystonia, there are involuntary contractions of one or more muscles in the arm, hand, leg, or foot. These types of focal dystonias include writer's cramp and other occupational dystonias.
Some patients have symptoms that are segmental or involve two adjacent areas of the body, such as the head and neck or arm and trunk. In other patients, symptoms may be multifocal or appear in two areas of the body that are not next to each other, such as the two arms, or an arm and a leg. In generalized dystonia, symptoms begin in an arm or a leg and advance, becoming more widespread. Eventually, the trunk and the rest of the body are involved.
Most cases of primary or idiopathic dystonia are believed to be hereditary and occur as the result of a faulty gene(s). In these patients, dystonia occurs as a solitary symptom and is not associated with an underlying disorder. For example, most cases of early-onset primary dystonia are due to a mutation in the DYT-1 gene. Early-onset dystonia that occurs as a result of this disease gene is the most common and severe type of hereditary dystonia. Other genetic causes of primary dystonia are rare.
Diseases involving dystonias include hereditary spastic paraplegia (HSP), a group of genetic, degenerative disorders of the spinal cord characterized by progressive weakness and stiffness of the legs; Huntington's disease (HD) a hereditary progressive neurodegenerative disorder characterized by the development of emotional, behavioral, and psychiatric abnormalities and movement abnormalities; multiple system atrophy (MSA) a neurodegenerative disease marked by a combination of symptoms affecting movement, blood pressure, and other body functions; pathologic myoclonus; progressive supranuclear palsy; restless legs syndrome; Rett syndrome; spasticity; Sydenham's chorea; Tourette syndrome; and Wilson disease.
Dystonia may occur because of another underlying disease process such as Wilson disease, multiple sclerosis, stroke, etc.; trauma to the brain, such as injury during a vehicular accident or anoxia during birth; or as a side effect of a medication. This type of dystonia is termed secondary or symptomatic dystonia. In adults, the most common type of secondary dystonia is tardive dystonia, which occurs as a result of the use of certain neuroleptic or antipsychotic drugs (used to treat psychiatric disorders). These drugs include haloperidol (Haldol®) or chlorpromazine (Thorazine®). Other drugs that block central dopamine receptors may also cause tardive dystonia. In most patients, symptoms occur some time after ongoing exposure to the drug. Table 1 provides a list of drugs that can cause dystonia.
TABLE 1Generic(Trade Names)Acetophenazine(Tindal ®)Amoxapine(Asendin ®)Chlorpromazine(Thorazine ®)Fluphenazine(Permitil ®, Prolixin ®)Haloperidol(Haldol ®)Loxapine(Loxitane ®, Daxolin ®)Mesoridazine(Serentil ®)Metaclopramide(Reglan ®)Molindone(Lindone ®, Moban ®)Perphenazine(Trilafon ® or Triavil ®)Piperacetazine(Quide ®)Prochlorperazine(Compazine ®, Combid ®)Promazine(Sparine ®)Promethazine(Phenergan ®)Thiethylperazine(Torecan ®)Thioridazine(Mellaril ®)Thiothixene(Navane ®)Trifluoperazine(Stelazine ®)Triflupromazine(Vesprin ®)Trimeprazine(Temaril ®)
There are a number of options available to treat dystonia. Drugs may be used alone or in combination. In addition, they may be combined with other forms of treatment. Drugs currently in use include botulinum toxin (BTX), benzodiazepines, Baclofen, anticholinergics and dopamine-blocking agents/dopamine-depleting agents. Surgical treatment is also available and includes thalamotomy, pallidotomy, deep brain stimulation, myectomy (myotomy), ramisectomy, rhizotomy and peripheral denervation.
Tardive Dyskinesia and other Extrapyramidal Syndromes
The extrapyramidal system of the nervous system is centered on the basal ganglia and influences motor control through pyramidal pathways, generally by means of input to the thalamus. When the extrapyramidal system is disturbed, motor control is affected and patients suffer extrapyramidal syndromes. These are a combination of neurological effects that include tremors, chorea, athetosis, and dystonia. This is a common side effect of neuroleptic agents. Other medications known to cause these reactions include haloperidol, molindone, perphenazine and aminotriptyline, loxapine, pimozide, and rarely, benzodiazepines.
Tardive dyskinesia is an involuntary neurological movement disorder. Depending upon the type of onset, a differential diagnosis might include Sydenham's chorea, Huntington's chorea, congenital torsion dystonia, hysteria, and the stereotyped behavior or mannerism of schizophrenia. American College of Neuropsychopharmacology-FDA Task Force (1973). Tardive dyskinesia results from the use of neuroleptic drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions. Long-term use of these drugs may produce biochemical abnormalities in the striatum. Tardive dystonia is believed to be the more severe form of tardive dyskinesia.
Other closely related, untreatable neurological disorders have now been recognized as variants of tardive dyskinesia. Tardive akathisia involves painful feelings of inner tension and anxiety and a compulsive drive to move the body. In the extreme, the individual undergoes internal torture and can no longer sit still. Tardive dystonia involves muscle spasms, frequently of the face, neck and shoulders, and it too can be disfiguring, disabling and agonizing.
Treatment of tardive dyskinesia has been unsatisfactory. Removal of the antipsychotic agent is often advocated (Baldessarini (1990)) but often results in more severe forms of the movement disorder. Various pharmaceutical agents have been tried with some reported success; early investigators in this area turned their attention to reserpine (Serpasil®), tradename of Ciba-Geigy a compound known to deplete dopamine levels. Reserpine and α-methyldopa (Aldomet®) in the treatment of long-standing tardive dyskinesia showed that both compounds were statistically more effective than placebo in reducing symptomatology. Huang et al. (1981). However, another study showed that, catecholamine synthesis blockers such as α-methyldopa have not demonstrated a beneficial effect on tardive dyskinesia. AMPT, an experimental agent that inhibits tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine and norepinephrine, has shown partial reduction of dyskinesia.
Formerly, tardive dyskinesia was often treated by increasing the dose of the neuroleptic. This initially treats the pathophysiology of tardive dyskinesia but can aggravate the pathogenesis by further denervation and subsequent hypersensitivity. Thus, the movements may decrease or disappear initially but then reappear later. The use of the atypical neuroleptic, clozapine may be useful in certain situations in which patients with disfiguring tardive dyskinesia need neuroleptic treatment alternative.
Lithium interferes with the presynaptic release of monoamines as well as having other actions on the CNS. Two studies report mild improvement in tardive dyskinesia with lithium while two others report no improvement or exacerbation. Tepper and Haas (1979).
Oral pimozide caused improvement in degree of movement. Clayeria et al. (1975). Buspirone (BuSpar®), a partial serotonin receptor agonist, may also be useful in treating the condition. Moss et al. (1993). In rats, buspirone reverses the DA receptor subsensitivity induced by chronic neuroleptic administration, and it is this effect that may also occur in humans due to partial agonist effects at D2 receptors. Reports have associated tardive dyskinesia with reserpine, tetrabenazine, metoclopramide, tricyclic antidepressants, benztropine, phenyloin and amphetamines.
Other than neuroleptics, the drug that regularly produces dyskinesia is L-DOPA and other dopaminergic agents, in patients receiving these drugs for Parkinson's diseases. L-DOPA actually can improve neuroleptic-induced tardive dyskinesia.
There is no accepted treatment for tardive dyskinesia. Casey (1999). Either discontinuing the offending antipsychotic or switching a patient to an atypical antipsychotic (with the possible exception of risperidone) may alleviate the movement disorder. The treatment of tardive dyskinesia has been recently reviewed. Egan et al. (1997). Most pharmacologic treatment strategies are directed toward reducing dopamine activity or enhancing CNS cholinergic effect. If the etiology of tardive dyskinesia relates to chronic dopaminergic receptor site blockade and the pathophysiology relates to the denervation hypersensitivity, agents that interrupt this sequence would, theoretically, be of potential benefit.
Many drugs have been tried in treating neuroleptic-induced tardive dyskinesia. Because of differences in patient populations, study design, and doses of agents used, the results for individual agents are conflicting. Baldessarini and Tarsy (1978); and Klawans et al. (1980).
Amine depleting agents e.g., reserpine and tetrabenazine, act by blocking the reuptake of dopamine, norepinephrine, and serotonin into the presynaptic neuronal storage vesicles, thereby depleting the brain of these substances. Studies with these agents have indicated improvement in tardive dyskinesia but side effects have limited their use and the studies are of short duration. Short-term suppression may occur as reported with neuroleptics.
Several cholinergic agonists have been administered to patients with tardive dyskinesia. Choline chloride and phosphatidylcholine (lecithin), which are orally bioavailable precursors of acetylcholine, have been reported to be useful in short-term studies. Deanol acetaminobenzoate was originally reported to be efficacious in the treatment of tardive dyskinesia, but other studies have not confirmed these findings. Gelenberg et al. (1990).
There have been several attempts to treat tardive dyskinesia with drugs believed to potentiate central GABA mechanisms. Thaker et al. (1990). In a study involving 10 patients with tardive dyskinesia of greater than a 6 month duration, benztropine 2 mg IV increased dyskinetic movements in 7 patients and reduced them in the remaining three. Moore and Bowers (1980). In a preliminary report the β-adrenergic blocking agent propranolol (Inderal®) in a dose of 30-60 mg/day produced marked resolution of tardive dyskinesia within 1 to 10 days of treatment in four patients. Wilbur and Kulik (1980).
Several studies have examined the effectiveness of treating tardive dyskinesia with vitamin E. Adler et al. (1999); Lohr and Caligiuri (1996); Lohr et al. (1988); Elkashef et al. (1990); Shriqui et al. (1992); Egan et al. (1992); Adler et al. (1993a); Adler et al. (1993b); Goldberg (1996); McCreadie et al. (1994); Dabiri et al. (1993); Bischot et al. (1993); Akhtar et al. (1993); and Dabiri et al. (1994).
It was previously thought that in the majority of patients, tardive dyskinesia is permanent or irreversible. However, this is not necessarily the case. The earlier tardive dyskinesia is diagnosed and the neuroleptic discontinued, the better the prognosis for disorder reversal. In young adults, tardive dyskinesia disappears within several weeks after early drug withdrawal. Uhrbrand and Faurbye (1960); Itoh et al. (1981); Driesens (1988); and Gardos et al. (1994).
Table 2 summarizes various agents that have been used to treat tardive dyskinesia.
TABLE 2Classes of AgentsSpecific agentsDopamine antagonistsButyrophenones, clozapine, metoclopramide (Karp et al.(1981)), papaverine (mechanism uncertain),phenothiazines, bromocriptine, pimozideDopamine D2 AgonistsBuspironeAmine-depleting agentsReserpine, tetrabenzineBlocker of catecholamineα-methyldopa, α-methyltyrosine (AMPT)synthesisCatecholamine release blockerLithium saltsCholinergic agentsDeanol, physostigmine, choline and lecithinGABA agonistsProgabide (Bartholini (1983)), valproic acid, baclofen,iazepam, clonazepamAnticholinergic agents.Benztropine, trihexyphenidylMoore et al. (1980)Agents with variable,α-methyldopa, amantadine, anticholinergicsnegligible, or uncertain effectsantihistamines, apomorphine, barbiturates,benzodiazepines, methylphenidate, penicillamine,physostigmine, pyridoxine (B6), tryptophan,α-tocopherol (Vitamin E)Agents that worsen tardiveAnticholinergic agents, antiparkinson agents (e.g.,dyskinesiabenztropine), dopamine agonists, amphetamines,L-DOPANewer investigational agentsendopioids, Substance P, Cholecystokinin, Ceruletide,(peptides). Blurn et al. (1983)Neurotensin, Cyclo-Leucine-Glycine
Other motor syndromes caused by the effects of neuroleptic drugs on the extrapyramidal system include drug induced parkinsonism, akathisia, dystonia, oculogyric crisis, and opisthotonus. Akathisia is a condition that is characterized by motor restlessness, which may range from anxiety to an inability to lie or sit quietly, or to sleep, and possible causes include a toxic reaction to neuroleptics such as phenothiazine. An oculogyric crisis is the paroxysmal, involuntary upward deviation of the eyes. The eyelids are often retracted. Attacks last from a few minutes to a few hours. It may occur in patients sensitive to phenothiazines, haloperidol, and metoclopramide. Opisthotonus is a form of spasm in which head, neck and spine are arched backwards
Adenosine A2A Receptors
Adenosine is known to act via four major receptor subtypes, A1, A2A, A2B, A3, which have been characterized according to their primary sequences. Fredholm et al. (1994). Adenosine A2 receptors are further divided into A2A (high-affinity) and A2B (low-affinity) subtypes. Daly et al. (1983); and Burns et al. (1986). In contrast to the widespread distribution of A1, A2B, and A3 receptors in the brain, A2A receptors are highly localized to the basal ganglia, especially to the caudate-putamen (striatum), nucleus accumbens and globus pallidal, and the olfactory tubercles. Jarvis et al. (1989); and Schiffmann (1991b). The basal ganglia are located in the telencephalon and consist of several interconnected nuclei: the striatum, globus pallidus external segment (GPe), globus pallidus internal segment (GPi), substantia nigra pars compacta (SNc), substantia nigra pars reticulata (SNr), and subthalamic nucleus (STN). The basal ganglia are a critical component of subcortical circuits involved in the integration of sensorimotor, associative, and limbic information to produce motor behavior. A major component of basal ganglia is the striatum, where GABAergic medium spiny neurons, which represent more than 90% of striatal neuronal population, are the only projection neurons.
The medium spiny neurons receive massive glutamatergic inputs from the cortex and thalamus, and project their GABAergic output onto the major output nuclei of basal ganglia, i.e. GPi and SNr, via the striatopallidal medium spiny neurons in an "indirect pathway" and the striatonigral medium spiny neurons in a "direct pathway." Alexander et al. (1990); Gerfen (1992); and Graybiel (1990). The medium spiny neurons also receive intrastriatal GABAergic, cholinergic, and nigrostriatal dopaminergic modulatory inputs. Neurons of the striatonigral direct pathway contain GABA plus substance P/dynorphin and directly project from the striatum to GPi/SNr. These neurons provide a direct inhibitory effect on GPi/SNr neurons. Striatal neurons in the striatopallidal indirect pathway contain GABA plus enkephalin and connect the striatum with the GPi/SNr via synaptic connections in the GPe and STN. In these neurons, A2A receptors are located almost exclusively on striatopallidal medium spiny neurons in the striatum and globus pallidus of the indirect pathway [Schiffmann et al. (1991a)], and acetylcholine-containing large aspiny interneurons in the striatum [Dixon et al. (1996)], and have been shown to modulate the neurotransmission of GABA, acetylcholine and glutamate. Kurokawa et al. (1996); Mori et al. (1996); Shindou et al. (2001); Ochi et al. (2000); Richardson et al. (1997); and Kase (2001).
Recent advances in neuroscience together with development of selective agents for the A2A receptors have contributed to increased knowledge about adenosine and the adenosine A2A receptor. Behavioral studies show that adenosine A2A receptor antagonists improve motor dysfunction of several parkinsonian animal models (e.g., MPTP-treated monkeys), but also reveal features of A2A receptor antagonists distinctive from dopaminergic agents. Richardson et al. (1997); Kase et al. (2000); and Kase (2001).
The antiparkinsonian effects of the selective adenosine A2A receptor antagonist KW-6002 have been studied in MPTP-treated marmosets and cynomologus monkeys. Kanda et al. (1998a); Grondin et al. (1999); and Kanda et al. (2000). In MPTP-treated marmosets, oral administration of KW-6002 induced an increase in locomotor activity lasting up to 11 hours in a dose-related manner. Kanda et al. (1998a). Locomotor activity was increased to the level observed in normal animals whereas L-DOPA induced locomotor hyperactivity. Furthermore, in L-DOPA-primed MPTP-treated marmosets, treatment with KW-6002 for 21 days induced little or no dyskinesias whereas under the same conditions, treatment with L-DOPA induced marked dyskinesias. When KW-6002 (20 mg/kg) was administered once a day for 5 days with a threshold dose of L-DOPA to MPTP-treated marmosets primed to exhibit dyskinesias, antiparkinson activity was potentiated without an increase in dyskinesia. Kanda et al. (2000). KW-6002 also additively increased the antiparkinsonian effect of quinpirole, a dopamine D2 receptor agonist but not SKF80723, a dopamine D1 receptor agonist. Taken together, these findings suggest that adenosine A2A antagonists might provide antiparkinsonian benefit as monotherapy in patients with early Parkinson's disease and might be able to improve antiparkinsonian response without increasing dyskinesia in L-DOPA-treated patients with motor complications.
Although the mechanisms by which adenosine A2A antagonists exert an antiparkinsonian effect remain to be fully elucidated, the following mechanism is now proposed.
In either Parkinson's disease or MPTP treatment of primates, following destruction of the nigro-striatal dopaminergic pathway, the most relevant alteration is hyperactivity in the striatopallidal pathway, and such hyperactivity is attributed to an imbalance between the direct striatonigral pathway and the indirect striatopallidal pathway to give rise to parkinsonian state. DeLong (1990); and Obeso et al. (2000). It is noted that A2A receptors are specifically expressed on a subpopulation of medium spiny neurons, the striatopallidal medium spiny neurons but not the striatonigral medium spiny neurons.
The GABAergic striatopallidal medium spiny projection neuron was found as one of major target neurons of A2A receptor-mediated modulation. Kase (2001). Thus, in the striatum, A2A receptors control excitability of the projection neurons through the intrastriatal GABAergic feedback/feedforward inhibition network [Mori et al (1996)], and in the globus pallidus (GPe), A2A receptor activation enhances GABA release from the nerve terminals and might suppress excitability of GPe projection neurons, which project to subthalamus nucleus (STN) [Shindou et al. (2001)]. A2A receptor antagonists selectively block the dual modulation mechanism in the striatopallidal system, leading to suppression of the excessive activation in the striatopallidal medium spiny neurons. This might shift the striatopallidal/striatonigral neuronal imbalance towards the normal state, resulting in recovery of the motor function in parkinsonean state. Ochi et al (2000); Kase (2001), Aoyama et al (2002).
The action mechanism via A2A receptors could work independently of dopamine D2 receptors (Aoyama et al. (2000)), which are co-localized with A2A receptors in the striatopallidal medium spiny neurons. Gerfen et al. (1990). D2 receptor knockout mice (D2R−/−) presented a locomotor phenotype with analogies to Parkinson's disease and significantly altered in the levels of neuropeptide genes expressed in the striatal medium spiny neurons. No difference in the distribution and level of expression of A2A receptor mRNA and the binding properties of the receptor were found between D2R−/− and wild type mice, indicating that D2 receptor absence had no influence on A2A receptor properties. Blockade of A2A receptors by KW-6002 reestablished their locomotor activity and coordination of movement and lowered the levels of striatal enkephalin expression to those in normal mice. Aoyama et al. (2000). The results indicate that A2A and D2 receptors have antagonistic but independent activities in controlling neuronal and motor function in the basal ganglia. Independent functioning of A2A receptors from the dopaminergic system was confirmed by studies using A2A and D2 receptor knockout mice. Chen et al. (2001b).
Physiological and pathophysiological functions of A2A receptors in L-DOPA motor complications in Parkinson's disease are far from clear. Neuronal mechanisms of L-DOPA induced dyskinesia are generally thought to involve the indirect rather than the direct pathway. Crossman (1990). L-DOPA-induced dyskinesias arise when the activity in the STN or GPi falls below a given level as a consequence of excessive inhibition from the GPe. Obeso et al. (1997). Another hypothesis that abnormalities primarily in the direct pathway might contribute significantly to the genesis of L-DOPA-induced dyskinesia isproposed.
The neuroprotective effect of A2A receptor antagonists has been demonstrated in neurotoxin (MPTP or 6-hydroxydopamine)-induced dopaminergic neurodegeneration in rats and mice and A2A receptor knock-out mice. Ikeda et al. (2002); and Chen et al. (2001a). To date, no treatment has been successful in interfering with the basic pathogenic mechanism, which results in the death of dopaminergic neurons.
Therefore, non-dopaminergic drug therapies, which effect an adenosine A2A receptor blockade, offer a means to treat Parkinson's disease. Moreover, adenosine A2A receptor antagonists, which provide antiparkinsonian effects with little or no risk of typical dopaminergic drug adverse effects, i.e., increasing or developing motor complications, are desirable.
Some xanthine compounds are known to show adenosine A2A receptor antagonistic activity, anti-Parkinson's disease activity, antidepressant activity, inhibitory activity on neurodegeneration, or the like (U.S. Pat. Nos. 5,484,920; 5,587,378; and 5,543,415; EP 1016407A1; etc.)

Methods of treating patients suffering from movement disorders


A patient (7) is irradiated by an X-ray source (1) in a computed tomography apparatus. The radiation is subsequently detected by the detector cells (5) of a position-sensitive X-ray detection system (4) and the intensities detected are applied to a computing device (16). Absorption as well as elastic and inelastic scattering of X-rays occur within the patient (7). The data acquired is corrected for elastic (coherent) scatter by deriving a deconvolution function from the elastic scatter function, which deconvolution function is applied to the data. The elastic scatter function is determined, for example by a computer simulation.

1. Field of the Invention
The invention relates to a method of computed tomography in which X-rays from an X-ray source irradiate an object to be examined and are detected by means of a position-sensitive X-ray detector array which occupies a substantially fixed position relative to the X-ray source, the X-ray source and the X-ray detector array being moved together in a number of orientations relative to the object to be examined in order to pick up a number of X-ray images, a density distribution of the object being reconstructed by means of the detected X-ray images and unsharpness in the reconstructed image being reduced by means of deconvolution. The invention also relates to an apparatus for carrying out such a method.
2. Description of the Related Art
Such an apparatus and method are known from EP-A 0 353 299, which corresponds to U.S. Pat. No. 5,120,520. The cited publication describes a method of processing data acquired by means of a computed tomography apparatus (CT scanner) in which the X-ray source emits radiation which originates not only from a focal point but also, unintentionally, from the surroundings of the focal point. These undesirable X-rays are caused by scattering of electrons within the X-ray tube and, consequently, the X-rays originate from an extensive area. Because the X-ray source is no longer substantially punctiform, the reconstructed image contains unsharp edges and artefacts. In the known method the image artefacts caused by the source are reduced by deconvolution with a PSF (point spread function) describing the characteristics of the X-ray source.
In CT scanners in which the problem described in EP-A 0 353 299 does not occur, or in which this problem has been adequately mitigated, unsharpness and artefacts still occur in the reconstructed images. Notably a loss of contrast occurs. These image artefacts can be attributed partly to incoherent (Compton) scattering. Incoherent scattering is uniformly distributed in space and the effects thereof can be removed during reconstruction by subtracting a constant value from the signal measured by each cell in the detector. Said constant value is dependent on the dimensions of the object to be examined. Taking incoherent scatter into account in this manner results in a substantial improvement of the reconstructed image.
However, it has been found that a given degree of unsharpness and artefacts remain in the reconstructed image also after the above correction.

Method of and apparatus for computed tomography


A testing circuit measures a center frequency of a clock signal outputted by a clock generator. The clock generator has a frequency modulator capable of (1) performing a frequency sampling accurately for the duration of modulation frequency and reducing the duration for frequency measurements, and (2) implementing proper testing of the down-spread controlling feature as one of the SSCG modulation functions by accurately determining the center frequency of the clock signal. The testing circuit measures a center frequency of a clock signal outputted by a clock generator by converting an analog modulation signal into a digital signal and outputting the digital signal, counting the period of the clock signal to obtain a count according to the digital signal outputted by the clock generator, and comparing the count with the predetermined specification values related to the center frequency of the clock signal to obtain and output a comparison result.

A testing circuit is known for measuring the frequency of signal output from a clock generator as illustrated in the diagrammatic block diagram of FIG. 7.
Referring to FIG. 7, the testing circuit 100 for the frequency measurement includes a clock generator 101 configured to generate and output a clock having a predetermined frequency, and a frequency counter 102 configured to count a frequency of the clock outputted by the clock generator 101 to obtain frequency data and output resulting data to a counter memory 103.
The counter memory 103 subsequently sends the frequency data to a comparator circuit 104 and a specification memory 105 is configured to output the data on the upper and lower limits to the comparator circuit 104.
The comparator circuit 104 is configured to determine whether the frequency data sent from the counter memory 103 falls within the upper and lower limits and output a decision signal representative of the result obtained from the determination.
Therefore, the frequency testing can be properly implemented with the abovementioned configuration of the output frequency testing circuit 100.
In addition, another clock generator is disclosed in Japanese Laid-Open Patent Application No. 63-187949, for example. This clock generator is capable of automatically testing a variety of frequencies by counting by a frequency counter a frequency of the signal modulated by a frequency modulation circuit.
On the other hand, SSCG (spread spectrum clock generation) technique has been developed recently for suppressing EMI (electromagnetic interference) noises which are radiated from various electronic instruments.
The SSCG technique is configured to apply the frequency modulation to clock signals and disperse the frequency range of EMI noise emission, whereby the level of radiated EMI can be reduced.
In respect to the modulation, several waveforms are utilized such as, for example, either triangular or sinusoidal wave having a constant period, and a triangular waveform synthesized from a plurality of waves each having different modulation periods.
The output frequency of SSCG is generally in the range from several MHz to several hundreds Hz, while a modulation frequency in use for modulating the SSCG output ranges approximately 30 kHZ which is considerably smaller than the SSCG frequency.
FIG. 8 is a diagrammatic block diagram illustrating the configuration of an SSCG circuit previously known.
Referring to FIG. 8, a frequency divider 111 included in the SSCG circuit 110 is configured to implement multiplication setting on the clock signal So outputted by the SSCG circuit 110 such that a phase comparison is made by a phase comparator 112 between a reference input signal Sr and a feedback signal Sf formed by dividing by the frequency divider 111, and that a pulse signal corresponding to the phase difference resulted from the comparison is generated and then outputted by a charge-pump circuit 113.
An output signal from the charge-pump circuit 113 is subjected to the process of removing noises by a low-pass filter 114 and of smoothing, and subsequently outputted to an adder 115.
On the other hand, a modulated signal generator 116 is configured to generate a predetermined modulated signal for the SSCG circuit 110, and output a resulting signal to adder 115.
The adder 115 is configured to add two signals, one outputted by a low-pass filter 114 and the other outputted by a modulated signal generator 116, and then output to VCO (voltage control oscillator) 117 as a control voltage Vcnt.
The VCO 117 is configured to generate and output a clock signal So, which is modulated according to the control voltage Vcnt outputted by the adder 115.
FIGS. 9A through 9C illustrate modulation waveforms of clock signals So outputted by the SSCG circuit 110 such as a triangular wave, a sinusoidal wave, and another triangular wave synthesized from plural waves each having different modulation frequencies.
FIG. 10 illustrates another modulation waveform of clock signal So outputted by the SSCG circuit 110.
As illustrated in FIG. 10, the waveform of the clock signal So outputted by the SSCG circuit 110 is assumed to be triangular, having a center frequency fo and a frequency spread ±Δf.
When the frequency measurement on this signal is carried out for duration, t1˜t2, the increase in the integral of the waveform for one half of the duration ranging from t1 to ta is obtained to be equal to the decrease for the other half of the duration ranging from ta to t2. Therefore, the center frequency of the clock signal So is obtained to be fo.
However, another case may be considered in which the value of the center frequency is influenced by several factors.
For example, assuming the case in which (1) a scattering arises in modulation frequency caused by fluctuation during forming process, (2) the waveform of the clock signal So outputted by the SSCG circuit 110 is triangular, having a center frequency fo, and (3) the period of the modulation is larger than that of FIG. 10.
When a frequency count of the clock signal So is then carried out for the duration, t1˜t2, as shown in FIG. 11, the amount of increase in the integral of the waveform is obtained to be smaller than that of decrease. As a result of the smaller amount in integral, the center frequency is obtained as f1 which is smaller than fo.
That is, a difficulty in the previous method is encountered in that a center frequency is measured by being shifted from the actual frequency.
Therefore, in measuring the center frequency of the modulated clock signal outputted by the SSCG circuit by a previous counter and method, the difficulty such as above has been encountered in that its center frequency may be obtained as one shifted from the actual frequency depending on measurement timing.
In addition, if the frequency of modulated signal outputted by the SSCG circuit is scattered from one sample to another, the frequency count of the clock signal may be obtained to be different even among plural samples having the same center frequency even when the measurements are carried out for the same duration.
In the case of a triangular wave generator used as the means for generating modulated signals, in particular, a considerable scattering in modulation frequency may arise from one testing sample to another due to fluctuation during the process for forming the capacitance incorporated on the output side of the generator.
Moreover, although the accuracy of frequency measurement may increase in general with increasing the duration for the measurements, which may not be advantageous in the present frequency measurements, since the modulation frequency is considerably smaller than the SSCG output frequency and the increased duration has to lead to a considerably prolonged measurement period, whereby the increase is incurred in the number of counter bits as well as process costs.
It is therefore desirable to provide a testing circuit having improved capability of accurately measuring a center frequency of the signals outputted by a clock generator.

Testing circuit for measuring a frequency of signal output from clock generator


A self supporting curved laminate product resulting from curving of a planar precursor, wherein the planar precursor is a self supporting laminate of two sheets of an acrylic thermoplastic, or of sheets including an acrylic thermoplastic, spaced by, but attaching to, an interposed thermoset polyester system, and wherein curving has involved heating of the laminate sufficient to allow its curving without any substantial degradation of the lamination or its component layers.

In one aspect the invention relates to the technology of building materials. Glass is a very common such material. Although it has a number of advantages, transparency being an obvious one, it has a number of disadvantages. Glass is heavy, breakable and can be difficult to manufacture and to form. The problems associated with glass include the weight, lack of insulating and sound proofing properties.
We propose the use of an acrylic. Many variations and types are used, mainly in signage, walkways building canopies and skylights, for example. It has medium to high impact resistance, and has good resistance to scratching. However it is still inferior to glass in a number of areas. Greater thickness is required over certain dimensions and spans in comparison to glass.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention, as it existed before the priority date.
It is an object of the present invention to provide a laminate material of self-supporting character and preferably having one or more superior properties over glass, particularly when used as a construction or manufacturing material.
Additionally or alternatively it is an object of the present invention to provide a laminate material, which can be shaped or formed.
Additionally or alternatively it is an object of the present invention to provide a novel method of preparing a laminate material.
Additionally or alternatively it is an object of the present invention to provide a laminate material that at least provides the public with a useful choice.
Other objects of the invention may become apparent from the following description, which is given by way of example only.


In a process for the preparation of poly-o-hydroxyamides and poly-o-mercaptoamides, a bis-o-aminophenol or a bis-o-aminothiophenol is reacted with a dicarboxylic acid derivative of the following structure: ##STR1## with D=O, S, or NH and where R* is the parent body of the dicarboxylic acid and at least one of the groups R.sup.1 and R.sup.2 is CN or NO.sub.2.

Highly thermoresistant polymers are required in microelectronics, particularly as protective and insulating coatings and as dielectrics (see, for example, "SAMPE Journal" 25, No. 6, pp. 18-23 (1989) and "Proceedings of the 1992 International Conference on Multichip Modules", pp. 394-400). Some of the polymers used, such as homo- and copolymers of aromatic polyethers and precursors of polyimides (PI) and polybenzoxazoles (PBO) show a good solubility in organic solvents and good film-forming properties and can be applied to electronic components by means of spin-coating technology (see, for example, "High Performance Polymers" 4, No. 2, pp. 73-80 (1992) and "Polymers for Advanced Technologies" 4, pp. 217-233 (1993).
By means of a temperature treatment, polymer precursors of the above-mentioned type are cyclized, i.e., converted to the corresponding polymers (PI or PBO); this results in the final properties. This is because, as a result of the cyclization, the hydrophilic groups of the poly-o-hydroxyamide disappear, i.e., the NH, OH, and CO groups, which would have a negative effect on the dielectric properties and the water absorption. This is, for example, a significant advantage of the polybenzoxazoles as compared with the polyimides (with two CO groups per imide unit) and, in particular, as compared with the hydroxypolyimides (with two CO groups and one OH group per imide unit). In addition, the cyclization is important not only for the good dielectric properties and the low water absorption of the end product but also for its high temperature stability.
PI and PBO precursors can, for example, be adjusted photosensitively by the addition of suitable photoactive components and can then be structured directly, i.e., without the use of an auxiliary resist. This is important for the reason that direct structuring--as compared with indirect structuring--offers considerable cost advantages.
In contrast to most photosensitive PI precursors, photosensitive PBO precursors offer the advantages of a positive structurability, such as a lower defect density in the structuring of the so-called "via holes", because--in comparison with negative operating systems--only a fraction of the surface is exposed to light. The use of alkali-soluble PBO precursors also results in the possibility of an aqueous alkaline development. After the photostructuring, the cyclization of the precursors is then carried out by annealing.
PBO precursors that can be developed in aqueous alkaline medium are already known (see European Patent 0 023 662, European Application 0 264 678, and European Patent 0 291 779). The photolithographic process used, except for the cyclization, is the same as in the structuring of known positive resists based on novolaks and quinone azides, a process that is used in numerous production lines worldwide (see, for example, D. S. Soane and Z. Martynenko: "Polymers in Micro-electronics--Fundamentals and Applications", Elsevier, Amsterdam (1989), pp. 77-124).
The solubility of the PBO precursors in alkalies is an important requirement for their use as base polymers for photosensitive dielectrics that can be developed in aqueous alkalies. For microelectronic uses, the precursors must be soluble in developers free of metal ions, so that developers of this type can also be used in the photostructuring. This is because developers containing metal ions can have a negative effect on the electrical operation of the components.
The most common method for the preparation of alkali-soluble PBO precursors, i.e., of poly-o-hydroxyamides, is the reaction of a dicarboxylic acid chloride with a suitable bis-o-aminophenol. To capture the hydrogen chloride formed in the reaction, a soluble base, such as pyridine, is added, as a rule (see European Application 0 264 678 and European Patent 0 291 779). Although it is possible, by means of this method, to prepare precursors that are soluble in aqueous alkaline developers free of metal ions, there is the disadvantage that chloride ions remain in the polymer. However, a polymer of this type can not be used as a coating material for microelectronic components, because the chloride ions cause corrosion and can thus strongly impair the operation of the components. A purification of the polymer by means of ion exchangers is therefore required. However, this purification is time-consuming and expensive, as it includes additional process stages, such as the preparation of the ion-exchange column, dissolution of the polymer, passage of the solution through the column and rewashing, and repetition of the precipitation and drying.
In the preparation of poly-o-hydroxyamides, it is also necessary to meet the requirement that the dicarboxylic acid chloride react predominantly with the amino groups of the bis-o-aminophenol (with amide formation), but not with its hydroxy groups (with ester formation), i.e., the reaction selectivity of the amide formation must be high as compared with that of the ester formation. If the ester formation can not be excluded or strongly suppressed, then this will lead to insufficiently alkali-soluble polymers. A low reaction selectivity can also lead to a gel formation in the polymer solution, as a result of which the poly-o-hydroxyamide produced then becomes unfilterable and thus useless.
Processes for the chloride-free synthesis of poly-o-hydroxyamides--and also of poly-o-mercaptoamides--have also already been described. Thus, it is known, from European Application 0 158 726, to react dihydroxy- and dimercaptodiamino compounds with a dicarboxylic acid in the presence of a carbodiimide. However, in this reaction, urea residues remaining on the resin as a result of a rearrangement reaction frequently present problems. This is because they reduce the thermal stability of the polybenzoxazole or polybenzothiazole and the quality of the coatings prepared from these. In addition, the polymers produced by this process are not sufficiently soluble in aqueous alkaline developers free of metal ions.
An alternative chloride-free production process for poly-o-hydroxyamides consists of using condensation reagents, such as 1-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline and 1,1'-carbonyldioxydi-1,2,3-benzotriazole (see European Application 0 391 196) for the reaction of the dicarboxylic acid with the bis-o-aminophenol. However, the polymers produced in this manner also show an insufficient solubility in aqueous alkaline developers free of metal ions.
Processes are also known in which the amide formation takes place by means of phosphorus compounds (see: European Application 0 481 402, U.S. Pat. No. 4,331,592, and German Application OLS 3,716,629). However, in the case of poly-o-hydroxyamides, syntheses of this type lead either to cyclized, i.e. alkali-insoluble, products, or phosphorus-containing, in part also chemically bonded, residues remain in the polymer, as a result of which the polymer, because of the doping properties of phosphorus, becomes unusable for microelectronic applications. This is because, in contrast to ionic impurities, residues of this type can not be removed, e.g., by means of ion exchangers.

Preparation of poly-o-hydroxyamides and poly o-mercaptoamides


Concentrated perfume compositions are useful for incorporating perfume into fabric care compositions.

Fabric care compositions comprising dispersed lamellar phases are typically not miscible with perfume oils. However, perfuming the fabric compositions is essential to secure high consumer acceptance. Fabric care compositions with a pleasant neat product odor that also deliver a pleasant odor through the wash process and ultimately to dry fabrics are far more desirable to the consumer than un-perfumed fabric care products. The typical and conventional method of perfuming a fabric care composition comprising dispersed lamellar phases is to combine the perfume and the fabric care composition and apply a high level of mechanical energy until the perfume oil is subdivided and adsorbed by the lamellar species. The need to use a high level of mechanical energy leads to several problems. Compositions comprising lamellar phases are typically colloidal dispersions that are not thermodynamically stable. It is desirable for the fabric care composition comprising dispersed lamellar phases to be homogeneous in order to provide the consumer with uniform, acceptable performance with minimal consumer intervention (e.g. shaking the product to recombine phases). When such colloidal dispersions of lamellar phases are exposed to high mechanical energy to incorporate perfume, these compositions may become unstable and separate or form a high viscosity composition. Compositions that separate or form high viscosity phases are unacceptable because these compositions often have poor pour properties, inconsistent performance and/or an undesirable visual appearance.
Additionally the equipment needed to apply high mechanical energy is capital intensive and so such equipment is not always available to provide the level of energy needed to incorporate perfume, especially in economically developing geographies.
Alternately, in place of high mechanical energy, the process engineer may employ the tactic of adding perfume into the front end of product making or increase the residence time of the product in the mixing tank to thoroughly incorporate the perfume. While both approaches will increase the likelihood of perfume incorporation even with many perfumes that are difficult to incorporate, these approaches introduce other problems. Incorporating perfume at the beginning of product making of processing reduces flexibility and introduces a need for increased capital for storage of product variants. Also when perfume is incorporated in the front-end of a process, it is often introduced when other components are still hot and thus, a portion of the perfume volatiles can be lost resulting in sub-optimal product and wasted perfume materials. Increased residence time in the mixing tank is not a desirable solution as it reduces the product making capacity leading to shortfalls in shipping and increased manufacturing costs. Increasing the residence time in mixing tanks increases cycle time to make the product which effectively increases the costs associated with product making.
In today's marketplace, the consumer demands increased customization. This requires processing facilities to be more flexible than ever. Thus it is important to have the capability to differentiate a basic (or base) fabric care formulation just prior to packaging in order to simultaneously achieve maximum efficiency and customization capability. The present invention introduces a method of incorporating perfume at the back-end of product making that requires only simple low-energy mixing (e.g., static mixer).
An additional problem faced when making perfumed fabric care products is that some perfumes are much more difficult to incorporate into fabric care compositions comprising dispersed lamellar phases. Such perfumes are typically less polar perfumes (as further herein described below) are poorly incorporated or impossible to incorporate even after very high levels of mechanical energy are applied. Alternately, certain perfumes can be excluded from use based on poor incorporation related to the perfume's physical properties, but this approach limits the perfumer's and formulator's ability to make the best product and it limits the range of offerings available to satisfy the consumer's demands for customization in fabric care products.
Other challenges are presented by compositions comprising low level of dispersed lamellar phases. Such compositions are exceptionally difficult to perfume because the perfume must be adsorbed by the dispersed lamellar phase(s). When the percentage of dispersed lamellar phase(s) is lowered, without wishing to be bound by theory, less surface area is present for the adsorption of perfume oil. To further complicate this challenge, one skilled in the art may increase the perfume oil in such compositions to compensate for the reduced perfume deposition on fabrics. Thus the amount of oil that must be adsorbed is increased while the amount of surface area in the form of dispersed colloidal particles is decreased resulting in a situation wherein perfume incorporations is poor or near impossible even upon application of high mechanical energy.
There is a need for a wide range of perfume oils to be easily incorporated into compositions with very low to very high percents of dispersed lamellar phase(s) with little to no mechanical energy applied. There is a need to incorporate levels of perfume in fabric care products that require little or no mechanical energy.
There is a need for the concentrated perfume composition to have low flammability and/or low levels of water. One skilled in the art will appreciate that to maintain low costs in a product making environment, it is advantageous to utilize compositions that have low flammability, i.e., a high flash point (e.g., above 38° C.). Minimizing the water content (e.g., less than 10% water by weight of the composition) of the concentrated perfume composition is also advantageous. When water is present in the concentrated perfume composition, often mixing is necessary to maintain a homogeneous concentrated perfume composition.
There is also a need to provide a concentrated perfume composition that, in turn, can be added to an un-perfumed fabric care composition base as part of a late product differentiation processes.


A fluid feeding apparatus capable of excluding the outer environmental influences in feeding a fluid susceptible to contamination, decomposition or denaturation on contact with the outer environment. The includes comprises at least one liquid source container, a cleaning and/or diluting liquid container, a waste liquid collection container, an inert gas feed pipe A, an inert gas feed pipe B, an evacuation pipe connecting to a vacuum source, and a fluid feed pipe for introducing the fluid to a process. The source container has two pipes. The first pipe has valves arranged therein at positions nearer to and farther from the source container, respectively. The second pipe has two valves arranged therein at positions nearer to and farther from the container, respectively. The path between the valves 1 and 4 and the path between the valves 2 and 5 are connected via a connecting pipe C having a valve 3.

1. Field of the Invention
This invention relates to an apparatus for feeding, in fluid form, a compound or composition source which is susceptible to contamination, decomposition or denaturation on contact with the outer environment such as the atmosphere or light. More particularly, it relates to a raw material feeding apparatus capable of protecting the raw material against influences of the outer environment through cleaning and drying operations.
2. Description of the Related Art
Raw materials used in chemical vapor deposition (CVD) or atomic layer deposition (ALD) processes, which are called precursors, are reactive with water, oxygen, carbon dioxide or light, including silicon compounds, phosphorus compounds, boron compounds, metal compounds, and mixtures thereof. Such a raw material easily produces a solid phase deposit in pipes and valves on contact with the outer environment when the container of the raw material is attached or detached. The solid phase deposit influences vapor delivery and vapor phase growth reaction or adversely affects semiconductor thin film quality. A solid phase deposit of highly reactive materials such as alkyl metal compounds can ignite or explode. In analysis processes, such as liquid chromatography and gas chromatography, if a substance under analysis undergoes the outer environmental influences markedly, accurate analysis is not expected.
In the above-exemplified processes for production or analysis dealing with a fluid form source susceptible to contamination, decomposition or denaturation on contact with the outer environment, it has been demanded to establish a method of preventing the source from generating a decomposition or reaction product harmful to the process or a method of completely removing the decomposition or reaction product.
To address the problem, the following techniques have been proposed. JP-A-2001-108199 discloses a method in which a container for raw material delivery is used with a piping and valving configuration designed to enable purging any raw material remaining in the system with a fluid. JP-A-6-244120 also proposes a raw material feed system with a piping and valving configuration designed to enable purging and evacuation of the system. JP-A-2002-343719 discloses a feed system comprising a raw material container, a cleaning fluid container, and a container for a used cleaning fluid, the piping of which is easily purged and evacuated. These related techniques, however, do not bring about satisfactory solutions to the outstanding problem.

Adeka Engineering & Construction Co., Ltd


A novel platinum (II) complex represented by the following formula (A): ##STR1## wherein R.sub.1 represents C.sub.1 -C.sub.5 lower hydrocarbon group, R.sub.2 and R.sub.3 represents hydrogen atom or C.sub.1 -C.sub.3 lower hydrocarbon group, the configuration of 1,2-diaminocyclohexane being cis, trans-l- or trans-d-. Since the platinum (II) complex has a strong anti-tumor activity and its toxicity is low, it is useful as an agent for treating malignant tumor.

A number of organic acid platinum (II) complexes wherein the ligand component is 1,2-diaminocyclohexane have been reported. However, many of them have low solubility so that they cannot be intravenously administered (e.g., cyclobutane-1,1-dicarboxylate disclosed in Japanese Laid Open Patent Application (Kokai) No. 60-10952) while the intravenous administration is the administration route of platinum complexes or, in the alternative, their stabilities in aqueous solutions are low although their solubilities are large (e.g., trimellitate disclosed by P. J. Andrulis et al., Proceedings of the Fifth International Symposium and Other Metal Compounds in Cancer Chemotherapy, p.450 (1987)).
On the other hand, there is a problem in seeking a platinum complex with anti-tumor activity that an impurity contaminated in the synthesized platinum complex often shows anti-tumor activity. Therefore, it is necessary to appropriately purify the platinum complex. Recently, James D. Hoeschele and N. Farrel reported examples wherein the anti-tumor activity of a platinum complex disappeared after an appropriate purification of the platinum complex in Inorg. Chem., 27, 4106-4113 (1988). That is, they reported that among the 1,2-diaminocyclohexane Pt(II) complexes which were reported to be water-soluble and to have high anti-tumor activities, some complexes lost their anti-tumor activities after purification. Thus, they emphasized the importance of obtaining a sample with a high purity for the evaluation of the anti-tumor activities.
The present inventors previously discovered that the platinum (II) complexes containing 1 mole of 1,2-diaminocyclohexane and 2 moles of 3-acetyl-6-methyltetrahydropyran-2,4-dione or its analogue have anti-tumor activities (EP 337,459). However, it turned out that these complexes do not show anti-tumor activities when they are highly purified. Thus, it is important for an industrial preparation that the synthesized complex can be purified easily and the complex with a high purity can be obtained easily.
The object of the present invention is to provide a novel platinum (II) complex with a strong anti-tumor activity, which may easily be purified, which has a solubility that enables intravenous administration, and which is stable in aqueous solution.

Platinum (II) complex and agent for treating malignant tumor


Compounds of formula I are provided where X1, X2 and X3 are independently selected from H or hydroxy protecting groups. Such compounds are used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions.

The natural hormone, 1α,25-dihydroxyvitamin D3 (also referred to as 1α,25-dihydroxycholecalciferol and calcitriol) and its analog in the ergosterol series, i.e. 1α,25-dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and their activity in cellular differentiation has also been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain homologated vitamins, and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity is useful in the treatment of a variety of diseases as established in the art, such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies (see for example, Zemplar, Calcipotriol, MC-903, Dovonex, 22-oxa-1α, 25-(OH)2D3) Slatopolsky, E., Finch, J., Ritter, C., Denda, M., Morrissey, J., Brown, A. & DeLuca, H. (1995) Am. J. Kidney Dis. 26, 852-860; Kubodera, N., Sato, K. & Nishii, Y. (1997) in Vitamin D, eds. Feldman, D., Glorieux, F. H. & Pike, J. W. (Academic, New York), Vol. 63, pp. 1071-1086; Calverley, M. J. (1987) Tetrahedron Lett. 43, 4609-4619; Uskokovic, M. R., Studzinski, G. P. & Reddy, S. G. (1997) in Vitamin D, eds. Feldman, D., Glorieux, F. H. & Pike, J. W. (Academic, New York), Vol. 62, pp. 1045-1070; Kensler, T. W., Dolan, P. M., Gange, S. J., Lee, J.-K., Wang, Q. & Posner, G. H. (2000) Carcinogenesis 21, 1341-1345; Binderup, L., Binderup, E. & Godfredsen, W. O. (1997) in Vitamin D, eds. Feldman, D., Glorieux, F. H. & Pike, J. W. (Academic, New York), Vol. 61, pp. 1027-1043; Jones, G. (1997) in Vitamin D, eds. Feldman, D., Glorieux, F. H. & Pike, J. W. (Academic, New York), Vol. 58, pp. 973-994; Brown, A. J. & Slatopolsky, E. (1997) in Vitamin D, eds. Feldman, D., Glorieux, F. H. & Pike, J. W. (Academic, New York), Vol. 59, pp. 995-1009; Shankar, V. N., Propp, A. E., Schroeder, N. S., Surber, B. W., Makin, H. L. J. & Jones, G. (2001) Arch. Biochem. Biophys. 387, 297-306. All these references are incorporated herein by reference for all purposes.
As discussed above, renal osteodystrophy is a bone disease that occurs when the kidneys fail to maintain the proper levels of calcium and phosphorus in the blood. Renal osteodystrophy is a common problem in people with kidney disease and affects 90 percent of dialysis patients.
Renal osteodystrophy is most serious in children because their bones are still growing. The condition slows bone growth and causes deformities. One such deformity occurs when the legs bend inward toward each other or outward away from each other; this deformity is referred to as "renal rickets." Another important consequence is short stature. Symptoms can be seen in growing children with renal disease even before they start dialysis.
The bone changes from renal osteodystrophy can begin many years before symptoms appear in adults with kidney disease. The symptoms of renal osteodystrophy are not usually seen in adults until they have been on dialysis for several years. Older patients and women who have gone through menopause are at greater risk for this disease because they're already vulnerable to osteoporosis, even without kidney disease. If left untreated, the bones gradually become thin and weak, and a person with renal osteodystrophy begins to experience bone and joint pain and an increased risk of bone fractures.
In healthy adults, bone tissue is continually being remodeled and rebuilt. The kidneys play an important role in maintaining healthy bone mass and structure because it balances calcium and phosphorus levels in the blood. If calcium levels in the blood become too low, the parathyroid glands release parathyroid hormone (PTH). This hormone draws calcium from the bones to raise blood calcium levels. Too much PTH in the blood causes disturbances in calcium and phosphorus homeostasis. This in turn removes too much calcium from the bones; over time, the constant removal of calcium weakens the bones.
Secondary hyperparathyroidism is characterized by an elevation PTH associated with inadequate levels of active vitamin D hormone. Typically, Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to activate the Vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2 D3] is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. Phosphorus also helps regulate calcium levels in the bones. Healthy kidneys remove excess phosphorus from the blood. When the kidneys stop working normally, phosphorus levels in the blood can become too high, leading to lower levels of calcium in the blood and resulting in the loss of calcium from the bones.
Healthy kidneys produce calcitriol to help the body absorb dietary calcium into the blood and the bones. If calcitriol levels drop too low, PTH levels increase, and calcium is removed from the bones. Calcitriol and PTH work together to keep calcium balance normal and bones healthy. In a patient with kidney failure, the kidneys stop making calcitriol, dietary calcium is not absorbed and calcium is removed from the bones.
Controlling PTH levels prevents calcium from being withdrawn from the bones. Usually, overactive parathyroid glands are controllable with a change in diet, dialysis treatment, or medication. The drug cinacalcet hydrochloride (Sensipar), approved by the Food and Drug Administration in 2004, lowers PTH levels by binding to the calcium receptor that controls PTH release. If PTH levels cannot be controlled, the parathyroid glands may need to be removed surgically. Other treatments for the condition include taking synthetic calcitriol as a pill or in an injectable form.
Renal osteodystrophy can also be treated with changes in diet. Reducing dietary intake of phosphorus is one of the most important steps in preventing bone disease. Often, medications such as calcium carbonate (Tums), calcium acetate (PhosLo), sevelamer hydrochloride (Renagel), or lanthanum carbonate (Fosrenol) are prescribed with meals and snacks to bind phosphorus in the bowel, which decreases the absorption of phosphorus into the blood.
Other treatment choices for renal osteodystrophy include Paricalcitol, the active ingredient of Zemplar (paracalcitol injection, USP), which is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's actions are mediated through binding to the VDR, resulting in the selective activation of Vitamin D response pathways. Calcitriol and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

The structure of 1α,25-dihydroxyvitamin D3 and the numbering system used to denote the carbon atoms in this compound are shown below.


A dedicated processing module includes an input for data to be processed and an output for processed data. A block input and a block output are also included. A processing component for the module performs a digital processing operation on the data present at the data input and applies the processed data at the data output. The processor may further generate a block request. A control device within the module reproduces, at the block output, a block request applied to the block input or generated by the processing component. The control device thus may operate to block the application of processed data at the data output upon receipt of a block request at the block input. Two or more dedicated processing modules may be connected in series with each other to form a processing flow chain with the data output of one module connected to the data input of a subsequent module. Additionally, the block output of the subsequent module is connected to the block input of the preceding module.

1. Technical Field of the Invention
The present invention relates in general to data processing flows, and in particular to the adaptation of a bit rate in a data processing flow.
2. Description of Related Art
A bit rate adaptation takes place when a function implemented in the data processing flow modifies the data rate, i.e., when the average amount of data varies between the input and the output of the function. The presence of functions for bit rate adaptation in a processing flow makes its time behavior unpredictable. When the processing flow involves a plurality of bite rate adaptation functions in series, it is difficult to implement at the hardware level. Indeed, a large number of possible configurations must be tested in order to provide an interruption-free processing flow.
Software management of the processing flows is generally used for reduced rates, for example less than one Mbit/s. FIGS. 1 and 2 diagrammatically show such an operation. A general use processor 1, a storage 2 and an interface 4 communicate via the bus 3. The processor 1 is used to sequentially process all of the functions required by the processing flow. Each function of the processor 1 is assigned a dedicated storage location 2. The interface 4 transmits, to the processor 1, a data block to be processed by a function. The function then processes the data block in the processor 1 (for example, by modification, addition or deletion of data). When the function has completed the processing of the block, the modified data block is placed in the dedicated storage location 2. Another function of the processing flow is then launched. A data block is transferred from a dedicated storage location 2 to the processor 1, processed by the function in the processor 1, then transferred to the dedicated storage location. This software solution is relatively easy to debug and develop.
However, the software solution increases the cost of hardware components: this solution requires a processor that is effective enough to implement all of the functions of the flow: such a processor is generally optimized for the specific applications intended by the processing flow. In addition, the amount of memory must be adequate to store a complete data block for each of these functions.
According to an improvement, the storage 2 consists of a small internal cache and a slower, less expensive, larger external storage. Contiguous program data blocks are stored in the internal cache. However, the response time and the power dissipation are generally increased due to the additional transfers caused between the cache and the external storage.
For apparatuses requiring high processing speeds with lower power dissipation (for example, portable apparatuses such as mobile telephones according to the 3GPP standard), a mixed software/hardware solution is preferred. FIGS. 3 and 4 show its operation. The processing of specific functions is thus allocated to an acceleration circuit 5. The acceleration circuit 5 communicates with the general use processor 1 and the storage 2 by means of the bus 3. The processor 1 implements a software processing of a certain number of functions, while other critical functions are processed as desired in the acceleration circuit 5. For example, for a video restitution application, a function associated with the image decompression will be considered to be a critical function.
In a first step, a first block is transferred from the interface 4 to the processor 1. In a second step, a function processes this block in the processor 1. In a third step, this block is transferred to the storage 2. In a fourth step, a block associated with a critical function is transferred from the storage 2 to the acceleration circuit 5. In a fifth step, the critical function processes the block in the acceleration circuit 5. In a sixth step, this block is transferred from the acceleration circuit 5 to the storage 2. Depending on the case, a certain number of transfers between the storage and the acceleration circuit 5 or the processor 1 are performed for the processing of critical or non-critical functions.
When all of the functions are considered to be critical, a hardware solution is adopted. The operation of this solution is shown in FIGS. 5 and 6. When the processing flow is in series (i.e., when the operation sequence can be determined in advance, even if some functions are short-circuited so as to comply with certain operation requirements), the processing operations are performed only by one or more dedicated acceleration circuits 5 forming a processing flow chain by means of intermediate buffer storages 2.
The performance of this solution is superior to that mentioned above. Moreover, its power consumption is lower because only the functions required by the processing flow are integrated into the chain.
However, the development of such a chain is costly. Its architecture is more difficult to develop and may make it necessary to redefine the design of the integrated circuits when they do not have enough available surface. Moreover, as this solution is only hardware transcription of a software solution, significant amounts of memory and data transfers between the acceleration circuits and the storages are still necessary. A functional analysis shows that such an architecture has an amount of intermediate buffer storage that is not essential for the implementation of the functions, but that facilitates the hardware design and development. This memory amount occupies a substantial circuit surface and generates an unnecessary current consumption.
There is accordingly a need to solve one or more of these disadvantages.

Bit rate adaptation in a data processing flow


An image analysis and enhancement system is provided with an image processor, imaging metrics, an image storage depository, and a reconfigurable sensor device that can be present at the same location. A remote reconfigurable sensor device is connected to the image processor via a communication link. Both the reconfigurable sensor device and the remote reconfigurable sensor device are equipped with selectable optical elements and imaging elements that are selected in a desired combination and orientation to capture desired image frames from a target scene or object. The selectable optical and imaging elements are provided with actuating devices to move and translate the selected optical and imaging elements into a desired orientation with one another, so that a desired imaging technique can be employed to obtain an enhanced image. The system is applicable to industrial, medical and military use.

1. Field of the Invention
The present invention pertains to the field of imaging. More particularly, the present invention relates to a system of imaging that utilizes a plurality of image collection hardware elements that can be selectively employed to give a desired image configuration for a desired imaging technique.
2. Discussion of the Background
The prior art demonstrates a number of techniques used for image processing. These techniques involve configuring and then reconfiguring an image to achieve an improved image, i.e., an image reconfiguration.
For example, it is well established that contrast is reduced when a scene is viewed through a medium with suspended particles in it, but contrast can be enhanced by viewing the scene through two orthogonal polarizations, then taking the difference between the two polarized scenes. Taking the difference between the two polarizations has the effect of reducing the scattering, thus enhancing the contrast. The medium could be the earth's atmosphere filled with dust, or aerosols or a piece of biological tissue viewed through a microscope. U.S. Pat. No. 5,975,702 to Pugh, Jr. et al. that issued Nov. 2, 1999 and which is herein incorporated by reference demonstrates this method of polarization differencing.
The ability to collect a large number of narrow hyperspectral images of the same scenes allows one to then select the best set of a smaller number of bands that give the best signal to noise ratio, and the bands need not may be contiguous.
A well established art in the field of hyperspectral imaging has been made possible by the voltage controlled acousto-optical tunable filter. The imagery that can be collected through such tunable filters can be quite varied—from topographical scenes to the imaging of biological specimens.
Acousto-optic tunable filters (AOTF's) are taught in U.S. Pat. No. 4,720,177, U.S. Pat. No. 4,685,772 and U.S. Pat. No. 5,329,397 to Chang which issued on Jan. 19, 1988, Aug. 11, 1987, and Jul. 12, 1994, respectively, the teachings of which are herein incorporated by reference. In U.S. Pat. No. 5,576,880 that issued Nov. 19, 1996, and which is herein incorporated by reference as well, Chang teaches an acoustic-optic modulator. AOTF's are used in a variety of imaging and display systems. An example of a display system utilizing an AOTF is U.S. Pat. No. 5,410,371 to Lambert which issued on Apr. 25, 1995, the teachings of which are herein incorporated by reference.
Another imaging technique has been to obtain an in-focus image and an out-of-focus image and then subtract the out-of-focus image from the in-focus image to obtain an enhanced image by removing the lower frequency components. This concept is disclosed in U.S. Pat. No. 6,433,325 to Trigg which issued on Aug. 13, 2002 the teachings of which are herein incorporated by reference. FIG. 1 demonstrates an embodiment from the Trigg patent in which a microscope body 18 having an optically aligned lens 14 and focal array 16 is operably connected to a ball screw assembly 20 that is driven by a motor 22 and controlled by a computer 24. A sample 12 resting on a sample stage 10 can be brought in and out of focus by the operation of the ball screw assembly.
The highest frequency component that can be captured in a focal plane array is limited by the detector pitch, or the spacing between the centers of the pixel elements. Under the Nyquist criteria, the highest frequency that a band-limited spectra can contain to be fully recoverable is one half the sampling rate, which in the case of the staring focal plane array is one half of the detector pitch. Since infrared scenes typically contain frequencies higher than one half the sampling rate of the focal plane array, the result is aliasing, or the overlap of adjacent spectra leading to distortion of the sampled signals and the loss of information in the reconstruction process.
The reduction in distortion from aliasing can be achieved by a process of microscanning that shifts the image plane a fraction of the detector pitch in two coordinates over the focal plane array. This technique allows the capture of higher frequency components in an image that would otherwise be lost in distortion. The technique is presented in U.S. Pat. No. 5,774,179 to Chevrette et al. that issued on Jun. 30, 1998, the teachings of which are hereby incorporated by reference.
To establish some measure of quality of an image, a conceptual ruler or metric is needed. One commonly used metric in image analysis that has been used is the peak signal to noise ratio (PSNR).
If one image is defined as the reference image, then the degree of dissimilarity with a comparison image is given in terms of a distance measure or error. The most obvious measure of distance between two images is obtained by comparing them on a pixel-by-pixel basis and taking the difference between the pixel values (pixel difference metrics). For example, if a sensor device collects an image and it is compressed for transmission, and then decompressed, the decompressed image will differ from the original image by the errors or artifacts introduced by the compression-decompression process.
The variety of image similarity metrics previously used in imaging technology, has included spectral angle mapping, Euclidian distance and others. These metrics have ambiguities, and efforts have been made to improve them with something called a "spectral similarity scale". A method for determining spectral similarity is disclosed in U.S. Pat. No. 6,763,136 that issued to Sweet on Jul. 13, 2004 which is hereby incorporated by reference.
In that the type of image that is desired and the circumstances and conditions under which an image is obtained can vary greatly, a need is seen for an image analysis and enhancement system that has the ability to utilize a multiplicity of imaging techniques positioned at local and/or remote locations.

The United States of America as represented by the Secretary of the Army


The device for holding a film roll in a laminator. The film roll holding device of the present invention helps a user correctly install the film roll in the laminator without confusing a film roll installation orientation. Furthermore, the film roll holding device can appropriately tension the film during a film-coating process despite having a simple structure.

As well known to those skilled in the art, in laminators, films wound around upper and lower film rollers pass between a pair of heating rollers and a pair of feed rollers. Thereafter, an object material passes between both the heating rollers and the feed rollers after being guided by a guide plate. Thus, the films are attached to upper and lower surfaces of the object material.
The laminators are classified into a laminator using a film roll formed by rolling a film around a paper tube, and a laminator using sheet films which are marketed after being cut into various sizes.
The present invention relates to a device to solve problems occurring in conventional laminators using the film rolls.
Such a film-roll type laminator has two film rolls to supply upper and lower films to heating rollers. The upper and lower films are respectively coated on upper and lower surfaces of an object material.
Each of the film rolls must be installed in the laminator such that an adhesive surface of the film faces towards a surface of the object material. Therefore, when the film roll is installed in the laminator, the user must always confirm a correct film roll installation orientation. However, it is difficult to distinguish the film roll installation orientation. Thus, in the film-roll type laminator, a problem of installing the film roll to the laminator in a backwards orientation frequently occurs.
Furthermore, both ends of the upper and lower film rolls must be aligned with both sides of the object material. However, it is very difficult for general users. If the upper and lower film rolls are not precisely aligned with the object material, both sides of the object material may not be coated with the films.
As well, the film extracted from the film roll must be tensioned to a predetermined tension to prevent the film from being undesirably folded. To achieve this purpose, conventional laminators have a separate unit to tension a film. Therefore, the conventional laminators are problematic in that the costs of the laminator are excessively increased.

Device for holding a film roll in a laminator