Disclosed are methods of treating subjects having conditions related to angiogenesis including administering an effective amount of a polymeric form of thyroid hormone, or an antagonist thereof, to promote or inhibit angiogenesis in the subject. Compositions of the polymeric forms of thyroid hormone, or thyroid hormone analogs, are also disclosed.

Thyroid hormones, L-thyroxine (T4) and L-triiodothyronine (T3), regulate many different physiological processes in different tissues in vertebrates. Most of the actions of thyroid hormones are mediated by the thyroid hormone receptor ("TR"), which is a member of the nuclear receptor superfamily of ligand-activated transcription regulators. This superfamily also includes receptors for steroid hormones, retinoids, and 1,25-dihydroxy vitamin D3. These receptors are transcription factors that can regulate expression of specific genes in various tissues and are targets for widely used drugs, such as tamoxifen, an estrogen receptor partial antagonist. There are two different genes that encode two different TRs, TRα and TRβ. These two TRs are often co-expressed at different levels in different tissues. Most thyroid hormones do not discriminate between the two TRs and bind both with similar affinities.
Gene knockout studies in mice indicate that TRβ plays a role in the development of the auditory system and in the negative feedback of thyroid stimulating hormone by T3 in the pituitary, whereas TRα, modulates the effect of thyroid hormone on calorigenesis and on the cardiovascular system. The identification of TR antagonists could play an important role in the future treatment of hypothyroidism. Such molecules would act rapidly by directly antagonizing the effect of thyroid hormone at the receptor level, a significant improvement for individuals with hypothyroidism who require surgery, have cardiac disease, or are at risk for life-threatening thyrotoxic storm.
Thus, there remains a need for the development of compounds that selectively modulate thyroid hormone action by functioning as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) would prove useful for medical therapy. Recent efforts have focused on the design and synthesis of thyroid hormone (T3/T4) antagonists as potential therapeutic agents and chemical probes. There is also a need for the development of thyromimetic compounds that are more accessible than the natural hormone and have potentially useful receptor binding and activation properties.
Thyroid hormone receptor preferentially binds 3,5,3′-triiodo-L-thyronine (T3), a hormone analogue derived by tissue deiodination of circulating L-thyroxine (T4). However, the ability of T4 and T3 to activate intracellular signal transduction cascades, independently of TR, has recently been described by several laboratories. Acting independently of TR, thyroid hormone also modulates activity of the plasma membrane Na+/H+ exchanger, Ca2+-stimulable ATPase, several other ion pumps or channels, and GTPase activity of synaptosomes. Studies from several laboratories have demonstrated the ability of thyroid hormone to activate the MAPK signal transduction cascade. These pathways typically are activated by physical and chemical signals at the cell surface. Although the kinetics and analog specificity for binding of thyroid hormone to the plasma membrane have been repeatedly reported, a cell surface receptor that accounts for these TR-dependent actions for thyroid hormone has not been previously identified.
Our laboratory has shown in the CV-1 monkey fibroblast cell line, which lacks functional TR, and in other cells that T4 activates the mitogen-activated protein kinase (MAPK; ERK112) signaling cascade and promotes the phosphorylation and nuclear translocation of MAPK as early as 10 min following application of a physiological concentration of T4. In nuclear fractions of thyroid hormone-treated cells, we have described complexes of activated MAPK and transactivator nucleoproteins that are substrates for the serine kinase activity of MAPK. These proteins include signal transducer and activator of transcription (STAT)-1α, STAT3, p53, estrogen receptor (ER)-α and, in cells containing TR, the nuclear thyroid hormone receptor for T3 (TRβ1). Thyroid hormone-directed MAPK-dependent phosphorylation of these proteins enhances their transcriptional capabilities. The effects of T4-induced MAPK activation are blocked by inhibitors of the MAPK signal transduction pathway and by tetraiodothyroacetic acid (tetrac), a thyroid hormone analog which inhibits Tq binding to the cell surface. Thyroid hormone-activated MAPK may also act locally at the plasma membrane, e.g., on the N+/H+ antiporter, rather than when translocated to the cell nucleus. A cell surface receptor for T4, that is linked to activation of the MAPK cascade has not previously been identified.
Integrins are a family of transmembrane glycoproteins that form noncovalent heterodimers. Extracellular domains of the integrins interact with a variety of ligands, including extracellular matrix glycoproteins, and the intracellular domain is linked to the cytoskeleton. Thyroid hormone was shown a decade ago to influence the interaction of integrin with the extracellular matrix protein, laminin, but the mechanism was not known. Integrin αVβ3 has a large number of extracellular protein ligands, including growth factors, and upon ligand-binding can activate the MAPK cascade. Several of the integrins contain an Arg-Gly-Asp ("RGD") recognition site that is important to the liganding of matrix and other extracellular proteins that contain an Arg-Gly-Asp sequence.
Thus, it would be desirable to identify and provide an initiation site for the induction of MAPK signaling cascades in cells treated with thyroid hormones, or analogs and polymers thereof, thereby providing for methods of modulating growth factors and other polypeptides whose cell surface receptors clustered around this initiation site.
It is estimated that five million people are afflicted with chronic stable angina in the United States. Each year 200,000 people under the age of 65 die with what is termed "premature ischemic heart disease." Despite medical therapy, many go on to suffer myocardial infarction and debilitating symptoms prompting the need for revascularization with either percutaneous transluminal coronary angioplasty or coronary artery bypass surgery. It has been postulated that one way of relieving myocardial ischemia would be to enhance coronary collateral circulation.
Correlations have now been made between the anatomic appearance of coronary collateral vessels ("collaterals") visualized at the time of intracoronary thrombolitic therapy during the acute phase of myocardial infarction and the creatine kinase time-activity curve, infarct size, and aneurysm formation. These studies demonstrate a protective role of collaterals in hearts with coronary obstructive disease, showing smaller infarcts, less aneurysm formation, and improved ventricular function compared with patients in whom collaterals were not visualized. When the cardiac myocyte is rendered ischemic, collaterals develop actively by growth with DNA replication and mitosis of endothelial and smooth muscle cells. Once ischemia develops, these factors are activated and become available for receptor occupation, which may initiate angiogenesis after exposure to exogenous heparin. Unfortunately, the "natural" process by which angiogenesis occurs is inadequate to reverse the ischemia in almost all patients with coronary artery disease.
During ischemia, adenosine is released through the breakdown of ATP. Adenosine participates in many cardio-protective biological events. Adenosine has a role in hemodynamic changes such as bradycardia and vasodilation, and adenosine has been suggested to have a role in such unrelated phenomena as preconditioning and possibly the reduction in reperfusion injury (Ely and Beme, Circulation, 85: 893 (1992).
Angiogenesis is the development of new blood vessels from preexisting blood vessels (Mousa, S. A., In Angiogenesis Inhibitors and Stimulators: Potential Therapeutic Implications, Landes Bioscience, Georgetown, Tex.; Chapter 1, (2000)). Physiologically, angiogenesis ensures proper development of mature organisms, prepares the womb for egg implantation, and plays a key role in wound healing. The development of vascular networks during embryogenesis or normal and pathological angiogenesis depends on growth factors and cellular interactions with the extracellular matrix (Breier et al., Trends in Cell Biology 6:454-456 (1996); Folkman, Nature Medicine 1:27-31 (1995); Risau, Nature 386:671-674 (1997). Blood vessels arise during embryogenesis by two processes: vasculogenesis and angiogenesis (Blood et al., Bioch. Biophys. Acta 1032:89-118 (1990). Angiogenesis is a multi-step process controlled by the balance of pro- and anti-angiogenic factors. The latter stages of this process involve proliferation and the organization of endothelial cells (EC) into tube-like structures. Growth factors such as FGF2 and VEGF are thought to be key players in promoting endothelial cell growth and differentiation.
Control of angiogenesis is a complex process involving local release of vascular growth factors (P Carmeliet, Ann NY Acad Sci 902:249-260, 2000), extracellular matrix, adhesion molecules and metabolic factors (R J Tomanek, G C Schatteman, Anat Rec 261:126-135, 2000). Mechanical forces within blood vessels may also play a role (O Hudlicka, Molec Cell Biochem 147:57-68, 1995). The principal classes of endogenous growth factors implicated in new blood vessel growth are the fibroblast growth factor (FGF) family and vascular endothelial growth factor (VEGF) (G Pages, Ann NY Acad Sci 902:187-200, 2000). The mitogen-activated protein kinase (MAPK; ERK1/2) signal transduction cascade is involved both in VEGF gene expression and in control of proliferation of vascular endothelial cells.
Intrinsic adenosine may facilitate the coronary flow response to increased myocardial oxygen demands and so modulate the coronary flow reserve (Ethier et al., Am. J. Physiol., H131 (1993) demonstrated that the addition of physiological concentrations of adenosine to human umbilical vein endothelial cell cultures stimulates proliferation, possibly via a surface receptor. Adenosine may be a factor for human endothelial cell growth and possibly angiogenesis. Angiogenesis appears to be protective for patients with obstructive blood flow such as coronary artery disease ("CAD"), but the rate at which blood vessels grow naturally is inadequate to reverse the disease. Thus, strategies to enhance and accelerate the body's natural angiogenesis potential should be beneficial in patients with CAD.
Similarly, wound healing is a major problem in many developing countries and diabetics have impaired wound healing and chronic inflammatory disorders, with increased use of various cyclooxygenase-2 (CoX2) inhibitors. Angiogenesis is necessary for wound repair since the new vessels provide nutrients to support the active cells, promote granulation tissue formation and facilitate the clearance of debris. Approximately 60% of the granulation tissue mass is composed of blood vessels which also supply the necessary oxygen to stimulate repair and vessel growth. It is well documented that angiogenic factors are present in wound fluid and promote repair while antiangiogenic factors inhibit repair. Wound angiogenesis is a complex multi-step process. Despite a detailed knowledge about many angiogenic factors, little progress has been made in defining the source of these factors, the regulatory events involved in wound angiogenesis and in the clinical use of angiogenic stimulants to promote repair. Further complicating the understanding of wound angiogenesis and repair is the fact that the mechanisms and mediators involved in repair likely vary depending on the depth of the wound, type of wound (burn, trauma, etc.), and the location (muscle, skin, bone, etc.). The condition and age of the patient (diabetic, paraplegic, on steroid therapy, elderly vs infant, etc) can also determine the rate of repair and response to angiogenic factors. The sex of the patient and hormonal status (premenopausal, post menopausal, etc.) may also influence the repair mechanisms and responses. Impaired wound healing particularly affects the elderly and many of the 14 million diabetics in the United States. Because reduced angiogenesis is often a causative agent for wound healing problems in these patient populations, it is important to define the angiogenic factors important in wound repair and to develop clinical uses to prevent and/or correct impaired wound healing.
Thus, there remains a need for an effective therapy in the way of angiogenic agents as either primary or adjunctive therapy for promotion of wound healing, coronary angiogenesis, or other angiogenic-related disorders, with minimum side effects. Such a therapy would be particularly useful for patients who have vascular disorders such as myocardial infarctions, stroke or peripheral artery diseases and could be used prophylactically in patients who have poor coronary circulation, which places them at high risk of ischemia and myocardial infarctions.
Thyroid hormones, analogs, and polymeric conjugations play important roles in the development of the brain. Increasing evidence suggests that the deprivation of polymeric thyroid hormones in the early developmental stage causes structural and functional deficits in the CNS, but the precise mechanism underlying this remains elusive.
The mammalian nervous system comprises a peripheral nervous system (PNS) and a central nervous system (CNS, comprising the brain and spinal cord), and is composed of two principal classes of cells: neurons and glial cells. The glial cells fill the spaces between neurons, nourishing them and modulating their function. Certain glial cells, such as Schwann cells in the PNS and oligodendrocytes in the CNS, also provide a myelin sheath that surrounds neural processes. The myelin sheath enables rapid conduction along the neuron. In the peripheral nervous system, axons of multiple neurons may bundle together in order to form a nerve fiber. These, in turn, may be combined into fascicles or bundles.
During development, differentiating neurons from the central and peripheral nervous systems send out axons that grow and make contact with specific target cells. In some cases, axons must cover enormous distances; some grow into the periphery, whereas others are confined within the central nervous system. In mammals, this stage of neurogenesis is complete during the embryonic phase of life and neuronal cells do not multiply once they have fully differentiated.
A host of neuropathies have been identified that affect the nervous system. The neuropathies, which may affect neurons themselves or associated glial cells, may result from cellular metabolic dysfunction, infection, exposure to toxic agents, autoimmunity, malnutrition, or ischemia. In some cases, the cellular neuropathy is thought to induce cell death directly. In other cases, the neuropathy may induce sufficient tissue necrosis to stimulate the body's immune/inflammatory system and the immune response to the initial injury then destroys neural pathways.
Where the damaged neural pathway results from CNS axonal damage, autologous peripheral nerve grafts have been used to bridge lesions in the central nervous system and to allow axons to make it back to their normal target area. In contrast to CNS neurons, neurons of the peripheral nervous system can extend new peripheral processes in response to axonal damage. This regenerative property of peripheral nervous system axons is thought to be sufficient to allow grafting of these segments to CNS axons. Successful grafting appears to be limited, however, by a number of factors, including the length of the CNS axonal lesion to be bypassed, and the distance of the graft sites from the CNS neuronal cell bodies, with successful grafts occurring near the cell body.
Within the peripheral nervous system, this cellular regenerative property of neurons has limited ability to repair function to a damaged neural pathway. Specifically, the new axons extend randomly, and are often misdirected, making contact with inappropriate targets that can cause abnormal function. For example, if a motor nerve is damaged, regrowing axons may contact the wrong muscles, resulting in paralysis. In addition, where severed nerve processes result in a gap of longer than a few millimeters, e.g., greater than 10 millimeters (mm), appropriate nerve regeneration does not occur, either because the processes fail to grow the necessary distance, or because of misdirected axonal growth. Efforts to repair peripheral nerve damage by surgical means has met with mixed results, particularly where damage extends over a significant distance. In some cases, the suturing steps used to obtain proper alignment of severed nerve ends stimulates the formulation of scar tissue which is thought to inhibit axon regeneration. Even where scar tissue formation has been reduced, as with the use of nerve guidance channels or other tubular prostheses, successful regeneration generally still is limited to nerve damage of less than 10 millimeters in distance. In addition, the reparative ability of peripheral neurons is significantly inhibited where an injury or neuropathy affects the cell body itself or results in extensive degeneration of a distal axon.
Mammalian neural pathways also are at risk due to damage caused by neoplastic lesions. Neoplasias of both the neurons and glial cells have been identified. Transformed cells of neural origin generally lose their ability to behave as normal differentiated cells and can destroy neural pathways by loss of function. In addition, the proliferating tumors may induce lesions by distorting normal nerve tissue structure, inhibiting pathways by compressing nerves, inhibiting cerbrospinal fluid or blood supply flow, and/or by stimulating the body's immune response. Metastatic tumors, which are a significant cause of neoplastic lesions in the brain and spinal cord, also similarly may damage neural pathways and induce neuronal cell death.
One type of morphoregulatory molecule associated with neuronal cell growth, differentiation and development is the cell adhesion molecule ("CAM"), most notably the nerve cell adhesion molecule (N-CAM). The CAMs are members the immunoglobulin super-family. They mediate cell-cell interactions in developing and adult tissues through homophilic binding, i.e., CAM-CAM binding on apposing cells. A number of different CAMs have been identified. Of these, the most thoroughly studied are N-CAM and L-CAM (liver cell adhesion molecules), both of which have been identified on all cells at early stages of development, as well as in different adult tissues. In neural tissue development, N-CAM expression is believed to be important in tissue organization, neuronal migration, nerve-muscle tissue adhesion, retinal formation, synaptogenesis, and neural degeneration. Reduced N-CAM expression also is thought to be associated with nerve dysfunction. For example, expression of at least one form of N-CAM, N-CAM-180, is reduced in a mouse demyelinating mutant. Bhat, Brain Res. 452: 373-377 (1988). Reduced levels of N-CAM also have been associated with normal pressure hydrocephalus, Werdelin, Acta Neurol. Scand. 79: 177-181 (1989), and with type II schizophrenia. Lyons, et al., Biol. Psychiatry 23: 769-775 (1988). In addition, antibodies against N-CAM have been shown to disrupt functional recovery in injured nerves. Remsen, Exp. Neurobiol. 110: 268-273 (1990).
Currently no satisfactory method exists to repair the damage caused by traumatic injuries of motor neurons and diseases of motor neurons. There are 15,000 to 18,000 new cases of spinal cord injury each year in the United States. In addition, there are approximately 200,000 survivors of spinal cord injury. The annual cost of care for these patients exceeds $7 billion. The pathophysiology following acute spinal cord trauma is a complex and not fully understood mechanism. The primary tissue damage caused by mechanical trauma occurs immediately and is irreversible. Allen, J. Am. Med. Assoc. 57: 878-880 (1911). Experimental evidence indicates that much of the post-traumatic tissue damage is the result of a reactive process that begins within minutes after the injury and continues for days or weeks. Janssen, et al., Spine 14: 23-32 (1989) and Panter, et al., (1992). This progressive, self-destructive process includes pathophysiological mechanisms such as hemorrhage, post-traumatic ischemia, edema, axonal and neuronal necrosis, and demyelinization followed by cyst formation and infarction. For review, see Tator, et al., J. Neurosurg, 75: 15-26 (1991) and Faden, Crit. Rev. Neurobiol. 7: 175-186 (1993). Proposed injurious factors include electrolyte changes whereby increased intracellular calcium initiates a cascade of events (Young, J. Neurotrauma 9, Suppl. 1: S9-S25 (1992) and Young, J. Emerg. Med. 11: 13-22 (1993)), biochemical changes with uncontrolled transmitter release (Liu, et al., Cell 66: 807-815 (1991) and Yanase, et al., J. Neurosurg 83: 884-888 (1995), arachidonic acid release, free-radical production, lipid peroxidation (Braughler, et al., J. Neurotrauma 9, Suppl. 1: S1-S7 (1992), eicosanoid production (Demediuk, et al., J. Neurosci. Res. 20: 115-121 (1988), endogenous opioids (Faden, et al., Ann Neurol. 17: 386-390 (1985), metabolic changes including alterations in oxygen and glucose (Faden, Crit. Rev. Neurobiol. 7: 175-186 (1993)), inflammatory changes (Blight, J. Neurotrauma 9, Suppl. 1: S83-S91 (1992), and astrocytic edema (Kimelberg, J. Neurotrauma 9, Suppl. 1: S71-S81 (1992). For the past 400 years surgical approaches including laminectomy and decompression, accompanied by fusion, have been the most commonly practiced treatment strategies. Hansebout, "Early Management of Acute Spinal Cord Injury", pp. 181-196 (1982) and Janssen, et al., Spine 14: 23-32 (1989). However, these procedures have not involved the application of techniques to augment the regenerative properties of spinal cord tissue.
A host of diseases of motor neurons have been identified, including demyelinating diseases, myelopathies, and diseases of motor neurons such as amyotrophic lateral sclerosis ("ALS"). INTERNAL MEDICINE, ch. 121-123 (4th ed., J. H. Stein, ed., Mosby, 1994). Multiple sclerosis ("MS") is the most common demyelinating disorder of the central nervous system, causing patches of sclerosis (i.e., plaques) in the brain and spinal cord. MS has protean clinical manifestations, depending upon the location and size of the plaque. Typical symptoms include visual loss, diplopia, nystagmus, dysarthria, weakness, paresthesias, bladder abnormalities, and mood alterations. Myriad treatments have been proposed for this long-term variable illness. The list of proposed treatments encompasses everything from diet to electrical stimulation to acupuncture, emotional support, and various forms of immunosupressive therapy. None have proved to be satisfactory.
Progressive loss of lower and upper motor neurons occurs in several diseases (e.g., primary lateral sclerosis, spinal muscular atrophy, benign focal amyotrophy). However, ALS is the most common form of motor neuron disease. Loss of both lower and upper motor neurons occur in ALS. Symptoms include progressive skeletal muscle wasting, weakness, gasciculations, and cramping. Some cases have predominant involvement of brainstem motoneurons (progressive bulbar palsy). Unfortunately, treatment of motor neuron and related disease is largely supportive at this time. INTERNAL MEDICINE, ch. 123 (4th ed., J. H. Stein, ed., Mosby, 1994).
Accordingly, there is a need in the art for treatments of motor neurons disorders and injuries, and related deficits in neural functions. It is, therefore, an object of the present invention to provide compositions and methods for stimulating angiogenesis, for inducing neuronal differentiation, and for preventing the death or degeneration of neuronal cells.
The tyrosines are iodinated at one (monoiodotyrosine) or two (diiodotyrosine) sites and then coupled to form the active hormones (diiodotyrosine+diiodotyrosine→tetraiodothyronine [thyroxine, T4]; diiodotyrosine+monoiodotyrosine→triiodothyronine [T3]. Another source of T3 within the thyroid gland is the result of the outer ring deiodination of T4 by a selenoenzyme: type I 5′-deiodinase (5′D-I). Thyroglobulin, a glycoprotein containing T3 and T4 within its matrix, is taken up from the follicle as colloid droplets by the thyroid cells.
Lysosomes containing proteases cleave T3 and T4 from thyroglobulin, resulting in release of free T3 and T4. The iodotyrosines (monoiodotyrosine and diiodotyrosine) are also released from thyroglobulin, but only very small amounts reach the bloodstream. Iodine is removed from them by intracellular deiodinases, and this iodine is used by the thyroid gland.
The T4 and T3 released from the thyroid by proteolysis reach the bloodstream, where they are bound to thyroid hormone-binding serum proteins for transport. The major thyroid hormone-binding protein is thyroxine-binding globulin ("TBG"), which has high affinity but low capacity for T4 and T3. TBG normally accounts for about 75% of the bound hormones. Other thyroid hormone-binding proteins—primarily thyroxine-binding prealbumin, also called transthyretin ("TTR"), which has high affinity but low capacity for T4, and albumin, which has low affinity but high capacity for T4 and T3-account for the remainder of the bound serum thyroid hormones. About 0.03% of the total serum T4 and 0.3% of the total serum T3 are free and in equilibrium with the bound hormones. Only free T4 and T3 are available to the peripheral tissues for thyroid hormone action.
Thyroid hormones have two major physiologic effects: (1) They increase protein synthesis in virtually every body tissue. (T3 and T4 enter cells, where T3, which is derived from the circulation and from conversion of T4 to T3 within the cell, binds to discrete nuclear receptors and influences the formation of mRNA.) (2) T3 increases O2 consumption by increasing the activity of the Na+, K+-ATPase (Na pump), primarily in tissues responsible for basal O2 consumption (ie, liver, kidney, heart, and skeletal muscle). The increased activity of Na+, K+-ATPase is secondary to increased synthesis of this enzyme; therefore, the increased O2 consumption is also probably related to the nuclear binding of thyroid hormones. However, a direct effect of T3 on the mitochondrion has not been ruled out. T3 is believed to be the active thyroid hormone, although T4 itself may be biologically active.
The pool of thyroid hormones critical for the biological actions of the hormones is the pool of free thyroid hormone. The size of this pool is determined for short time periods by uptake/release of thyroid hormones into/from cell and binding/release of thyroid hormones by thyroid hormone-binding proteins. Both proportions and absolute concentrations of these proteins differ in blood plasma and cerebrospinal fluid ("CSF"). The most pronounced difference is found for transthyretin ("TTR"), which is the only thyroid hormone-binding plasma protein synthesized in the brain (Schreiber G, Southwell B R, Richardson S J. Hormone delivery systems to the brain-transthyretin. Exp Clin Endocrinol Diabetes. 1995; 103(2):75-80). TTR is also distinct from the other two thyroid hormone-binding plasma proteins in humans by the absence of genetic deficiencies. TTR gene expression was initiated during evolution much earlier in the brain than in the liver. The structure of the domains of TTR involved in thyroxine (TR) T4 binding has been completely conserved for 350 million years. These observations point to a special functional significance of TTR in the brain. It is proposed that this is the determination of the level of free T4 in the extracellular compartment of the brain. T4 can then be converted in the brain to triiodothyronine T3 by specific deiodinases. This T3 can interact with receptors in the cell nuclei, regulating gene transcription.
Alzheimer's disease is a severe neurodegenerative disorder, and currently about 4 million Americans suffer from this disease. As the aging population continues to grow, this number could reach 14 million by the middle of next century unless a cure or prevention is found. At present, there is no sensitive and specific premortem test for early diagnosis of this disease. Alzheimer's disease is currently diagnosed based on the clinical observation of cognitive decline, coupled with the systematic elimination of other possible causes of those symptoms. The confirmation of the clinical diagnosis of "probable Alzheimer's disease" can only be made by examination of the postmortem brain. The Alzheimer's disease brain is characterized by the appearance of two distinct abnormal proteinaceous deposits in regions of the brain responsible for learning and memory (e.g., cerebral cortex and hippocampus). These deposits are extracellular amyloid plaques, which are characteristic of Alzheimer's disease, and intracellular neurofibillary tangles ("NFTs"), which can be found in other neurodegenerative disorders as well. Amyloid peptides are typically either 40 or 42 amino acids in length ("A1-40" or "A1-42", respectively) and are formed from abnormal processing of a larger membrane-associated protein of unknown function, the amyloid precurser protein ("APP"). Oligomeric aggregates of these peptides are thought to be neurotoxic, eventually resulting in synaptic degeneration and neuronal loss. The amount of amyloid deposition roughly correlates with the severity of symptoms at the time of death.
In the past, there have been several attempts for the design of radiopharmaceuticals that could be used as diagnostic agents for a premortem diagnosis of Alzheimer's disease. Bomebroek et al. showed that the amyloid-associated protein serum amyloid P component (SAP), labeled with 123I, accumulates at low levels in the cerebral cortex, possibly in vessel walls, of patients with cerebral amyloidosis (Bomebroek, M., et al., Nucl. Med. Commun. (1996), Vol. 17, pp. 929-933).
Saito et al. proposed a vector-mediated delivery of 123I-labeled A1-40 through the blood-brain barrier. It is reported that the iodinated A1-40 binds A amyloid plaque in tissue sections (Saito, Y., et al., Proc. Natl. Acad. Sci. USA 1995, Vol. 92, pp. 10227-10231). U.S. Pat. No. 5,231,000 discloses antibodies with specificity to A4 amyloid polypeptide found in the brain of Alzheimer's disease patients. However, a method to deliver these antibodies across the blood-brain barrier has not been described. Zhen et al. described modifications of the amyloid-binding dye known as "Congo Red™", and complexes of these modified molecules with technetium and rhenium. The complexes with radioactive ions are purported to be potential imaging agents for Alzheimer's disease (Zhen et al., J. Med. Chem. (1999), Vol. 42, pp. 2805-2815). However, the potential of the complexes to cross the blood-brain barrier is limited.
A group at the University of Pennsylvania in the U.S.A. (Skovronsky, M., et al., Proc. Natl. Acad. Sci. 2000, Vol. 97, pp. 7609-7614) has developed a fluorescently labeled derivative of Congo Red that is brain permeable and that non-specifically binds to amyloid materials (that is, peptides in-pleated sheet conformation). This compound would need to be radiolabeled and then run through pre-clinical screens for pharmacokinetics and toxicity before clinical testing. In contrast, our invention utilizes derivatives of naturally occurring substances alone or in combinations for the diagnosis, prevention, and treatment of Alzheimer's disease. Klunk et al. reported experiments with a derivative of Congo Red™, Chrysamine G ("CG"). It is reported that CG binds synthetic-amyloid well in vitro, and crosses the blood-brain barrier in normal mice (Klunk et al., Neurobiol. Aging (1994), Vol. 15, No. 6, pp. 691-698). Bergstrom et al. presented a compound labeled with 123I as a potential radioligand for visualization of M1 and M2 muscarinic acetylcholine receptors in Alzheimer's disease (Bergstrom et al., Eur. J. Nucl. Med. (1999), Vol. 26, pp. 1482-1485).
Recently, it has been discovered that certain specific chemokine receptors are upregulated in the brains of patients with Alzheimer's disease (Horuk, R. et al., J. Immunol. (1997), Vol. 158, pp. 2882-2890); Xia et al., J. Neuro Virol (1999), Vol. 5, pp. 32-41). In addition, it has been recently shown that the chemokine receptor CCR1 is upregulated in the brains of patients with advanced Alzheimer's disease and absent in normal-aged brains (Halks-Miller et al, CCR1 Immunoreactivity in Alzheimer's Disease Brains, Society for Neuroscience Meeting Abstract, #787.6, Volume 24, 1998). Antagonists to the CCR1 receptor and their use as anti-inflammatory agents are described in the PCT Published Patent Application, WO 98/56771.
None of the above described proposals have resulted in a clinical development of an imaging agent for the early diagnosis of Alzheimer's disease. Accordingly, there is still a clinical need for a diagnostic agent that could be used for a reliable and early diagnosis of Alzheimer's disease. Additionally, the proposed strategies would also be useful for the inhibition of amyloid plaque formation or buildup in Alzheimer patients. Accordingly, it is an object of the present invention to provide compositions and methods for the early diagnosis, prevention, and treatment of neurodegenerative diseases, such as, for example Alzheimer's disease.
It is interesting to note that angiogenesis also occurs in other situations, but which are undesirable, including solid tumour growth and metastasis; rheumatoid arthritis; psoriasis; scleroderma; and three common causes of blindness—diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma (in fact, diseases of the eye are almost always accompanied by vascularization. The process of wound angiogenesis actually has many features in common with tumour angiogenesis. Thus, there are some conditions, such as diabetic retinopathy or the occurrence of primary or metastatic tumors, where angiogenesis is undesirable. Thus, there remains a need for methods by which to inhibit the effect of angiogenic agents for the treatment of cancers.

Thyroid hormone analogs and methods of use


An implantable medical device having a concave ceramic housing component; a concave metal housing component attached to the ceramic housing component to form a hermetically sealed enclosure; and an electronic trans-housing magnetic flux component disposed within the enclosure. Another aspect of the invention provides an implantable medical device having a ceramic housing component; a metal housing component; a circumferential sealing member attached to a periphery of the ceramic housing component and to a periphery of the metal housing component to form a hermetically sealed enclosure; and an electronic trans-housing magnetic flux component disposed within the enclosure. Still another aspect of the invention provides an implantable medical device with a first metal housing component; a second metal housing component, the second metal housing component forming an opening; a ceramic housing component disposed in the opening, the first metal housing component, the second metal housing component and the ceramic housing component cooperating to form a hermetically sealed enclosure; and an electronic trans-housing magnetic flux component disposed within the enclosure.

Many implantable medical electronic devices utilize an internal source of electrical energy to power the device electronics for the purposes of, for example, diagnostics and/or therapy. Additionally, many implantable devices require such a significant amount of power that it is necessary to utilize transcutaneous energy transmission (TET) from an extracorporeal source to an implanted receiver which is connected to a rechargeable battery. To date, one of the more efficient recharging means employs an external transmission coil and an internal receiver coil which are inductively coupled. In this TET approach, the external primary transmission coil is energized with alternating current (AC), producing a time varying magnetic field that passes through the patient's skin and induces a corresponding electromotive force in the internal secondary receiving coil. The voltage induced across the receiving coil may then be rectified and used to power the implanted device and/or charge a battery or other charge storage device. Additionally, many medical electronic devices rely on noninvasive telemetry in order to allow data and control signals to be bi-directionally communicated between the implanted medical device and an external device or system. Such telemetry can be accomplished via a radio frequency (RF) coupled system using a transmitting antenna to a receiving antenna by way of a radiated carrier signal, or by using the power transfer coils for data transmission.
Electronic circuits and systems that are to be implanted in living organisms are hermetically packaged in a biocompatible material for the purposes of protecting the electronic circuitry from body fluids and protecting the organism from infection or other injury caused by the implanted materials. The most commonly used materials for implantable electronic devices are biocompatible metals, glass, and ceramics. Biocompatible metals include, for example without limitation, titanium, a titanium alloy, stainless steel, cobalt-chromium, platinum, niobium, tantalum, and various other possible alloys. Normally, metal enclosures consist of separate metal parts welded together to insure hermeticity. However, implant enclosures made of conductive metal present difficulties with respect to both transcutaneous energy transmission and telemetry. Specifically, the time varying magnetic charging field induces eddy currents within the metal housing and inhibits the magnetic flux as it passes through the case. With respect to RF telemetry from the implanted device to a receiver external to the patient, the metal case acts as a Faraday cage and tends to limit the rate of information transfer between the implanted device and the external system due to circulating eddy currents that absorb energy from the magnetic field and produce a magnetic field that opposes the incident magnetic field. The magnitude of the eddy currents is approximately proportional to the frequency of the AC magnetic field because the magnitude of the voltage induced within the conductive material is proportional to the time rate of change of magnetic flux as described in Faraday's Law, E=−dΦ/dt, where E is the induced voltage and Φ is the magnetic flux impinging on the material. The carrier frequency for telemetry is limited by the amount of eddy current attenuation that the system can tolerate.
It is necessary to transmit significant amounts of power through the device case in order to recharge the device battery in a reasonable period of time. The implanted induction charging system typically uses a two-winding transformer with a non-ferrous (air) core. The energy transfer efficiency is approximately proportional to the number of turns in the transformer windings and the rate of change (frequency) of the alternating current, as follows:e2=M di1/dt+L2 di2/dt
Where e2 is the voltage induced across the secondary winding, M is the mutual inductance of the primary and secondary windings, L2 is the inductance of the secondary winding and di1/dt and di2/dt are the time rate of change (frequency) of the primary and secondary currents.
Because the physical size of the implanted device limits the size and, hence, the inductance (L2) of the receiving coil within the device, it is desirable to operate the inductive coupling system at the highest possible frequency in order to obtain the maximum coupling efficiency and energy transfer. Raising the operating frequency, however, increases the eddy current losses, so that the overall induction system efficiency is severely reduced. Additionally, such induced eddy currents create unwanted heat within the implantable enclosure.
A number of approaches have been proposed to address the limitations of induced eddy currents upon a metallic medical device enclosure with respect to TET and telemetry systems:
Ceramic Sleeve with a Metal Header. One approach is to utilize a deep drawn ceramic sleeve forming the majority of the enclosure body. The sleeve has a closed end, an open end for receiving electronic components and a metallic header for closing the open end (see U.S. Pat. No. 4,991,582.) Such a device, when implanted, has ceramic distal, proximal and side walls (relative to the skin) and an extracorporeal charging and/or telemetry device. This approach has, however, primarily been limited to small medical device enclosures (e.g., cochlear implants) due to the weight of the ceramic material. For larger devices such as an implantable pulse generator, the weight of the ceramic sleeve becomes a significant limitation due to the overall weight of the enclosure given the amount of ceramic used, the relatively large density of the ceramic, and the required large wall thickness (see also U.S. Pat. No. 6,411,854).
Polymer Casing. Another approach is to avoid using both metal (problematic due to eddy currents) and ceramic (problematic due to weight) in favor of a biocompatible polymer material for the outer enclosure. This approach attempts to use epoxy to encapsulate the receiving coil, antenna, and a secondary enclosure and provide a hermetically sealed sub-housing for the system electronics. The polymer and/or epoxy material does not, however, provide for a true hermetic seal, as eventually body fluids migrate through the material and degrade the receiving coil and antenna.
External Coil. In order to circumvent the problem of the metal housing material reducing the efficiency of the TET induction system efficiency, some devices have opted to place the receiving induction coil on the outside of the metal housing. This approach, however, increases both the size of the implant, the complexity of the surgical implant process, and the complexity of the device given the necessity for additional hermetic electrical feed-through connections between the secondary coil and the internal electronic circuitry. Additionally, the external coil would still have to be a biocompatible material as with the polymer casing approach above.
Thin Metal Window. U.S. Pat. No. 7,174,212 presents an approach for increasing the efficiency of high speed/high carrier frequency telemetry via the use of (1) a metallic housing having a thin metal telemetry window having a thickness on the order of 0.005 inches and/or (2) a metal alloy (e.g., titanium alloy) window having reduced electrical conductivity parameters. However, as the window material still is made of an electrically conductive material (although reduced in thickness), this solution is non-ideal as an RF telemetry signal and/or a magnetic field will still induce eddy currents thereby reducing the efficiency of the telemetry link.
Machined Grooves in Metal Casing. U.S. Pat. No. 5,913,881 presents an approach for increasing the efficiency of high speed/high carrier frequency telemetry by creating grooved recesses arranged on either or both sides of the implanted housing wall to reduce the overall thickness of the wall and to create discontinuities along the wall surface in order to reduce the conductivity of the metal housing wall, thereby decreasing the induced eddy currents and providing increased telemetry efficiency.
Other hermetic housings for implantable medical devices are described in U.S. Pat. No. 4,785,827 and U.S. Pat. No. 5,876,424.
Improved medical device structures and methods of manufacture are needed to overcome at least the shortcomings stated above.

Housing for an implantable medical device


This invention concerns an animal cover 1 comprising a piece of fabric 2 with an extended surface area and at least one spike mat 3-5. Each spike mat 3-5 is arranged and fixed in place on the side 2a of the piece of fabric 2 that is in contact with the animal, with the spikes 3a-5a of the spike mat facing in towards the animal.

The use of various types of animal cover to keep an animal warm and dry is previously known. Such covers are normally manufactured from fabric or a material similar to fabric with an extended surface area and with various properties. They are either placed onto the animal or wrapped around the animal, or both, in order to offer warm protection that also protects from water during transport, while the animal is outdoors, and on other occasions.


The present invention provides a sheet conveying apparatus for conveying a sheet comprising a convey member for applying a conveying force to a sheet, a drive source for driving the convey member, and a drive transmitting means for transmitting a drive force from a first drive transmitting member attached to the drive source to a second drive transmitting member attached to the convey member through one or more speed reduction members stepwisely. Among the first drive transmitting member, second drive transmitting member and speed reduction members, manufacturing accuracy of the speed reduction member disposed at a front stage of the second drive transmitting member is greater than manufacturing accuracies of the other members.

1. Field of the Invention
The present invention relates to a sheet conveying apparatus for conveying a sheet member such as a recording sheet and an image forming apparatus using such a sheet conveying apparatus.
2. Related Background Art
Image forming apparatuses having a pin-feed tractor have been used as output equipments for personal computers, word processors, facsimiles and the like.
In a conventional example shown in FIG. 14, a convey roller 50 and driven pinch rollers 51a, 51b for urging a sheet against the convey roller are used as sheet convey means. A so-called U-turn path is provided for conveying the sheet around the convey roller 50.
When a cut sheet is used as a recording medium, the cut sheet is pinched between the convey roller 50 and the pinch rollers 51a, 51b, thereby conveying the sheet by friction forces generated between these rollers. On the other hand, when a continuous sheet (also referred to as "fan-fold sheet" hereinafter) is used, pin holes formed in the fan-fold sheet are engaged by pins 52a of a pin-feed tractor 52, and the sheet is pinched between the convey roller 50 and the pinch rollers 51a, 51b, thereby conveying the sheet to a recording portion by friction forces generated between these rollers.
In any case, the recording is effected by a recording head 53 regarding the conveyed sheet, and thereafter, the sheet is shifted upwardly and discharged out of the apparatus by a discharge roller 54a and a pinch roller 54b for urging the sheet against the discharge roller. In the image forming apparatus having the U-turn path, an inlet opening and a discharge opening for the fan-fold sheet can be arranged at a rear portion of the apparatus, and the selection of and the switching between the fan-fold sheet and the cut sheet can be performed by manipulating a lever, in a condition that the sheets were set.
However, in order to convey several kinds of sheets (particularly, sheets having great resiliency such as post cards, envelopes and the like), it is necessary that a diameter of the convey roller 50 is increased to reduce load resistance. Further, in the image forming apparatus, when the sheet is intermittently conveyed by a predetermined amount, the smaller the diameter of the convey roller 50 the greater the rotational angle of the convey roller 50. To the contrary, although the greater the diameter of the convey roller 50 the smaller the rotational angle, it is hard to be influenced upon eccentricity of the convey roller 50.
Accordingly, the large diameter of the convey roller not only reduces the load resistance in the U-turn path, but also eliminates one of factors for worsening conveyance accuracy of the convey roller 50.
On the other hand, in view of serial-recording, the intermittent conveyance of sheet requires high accuracy; if the accuracy is poor, one-line recording area obtained by one scan of the recording head will be overlapped with the previous one-line recording area or be excessively spaced apart from the previous one-line recording area, thereby worsening the recording quality greatly. In many cases, in drive force transmission in a sheet conveying apparatus, a rotational force of a motor is transmitted to the convey roller through gears and/or belt; in order to provide predetermined torque of the convey roller, the drive force is transmitted with speed reduction. The most preferential factor for giving the influence upon the sheet conveyance accuracy is eccentricity of drive force transmitting members (such as gears, belt and the like) and eccentricity of the convey roller. In order to minimize the influence of such eccentricity, various efforts for improving the accuracy of such elements have been tried.
On the other hand, when the diameter of the convey roller 50 is increased, the speed reduction ratio of the rotational force of the motor and the number of speed reduction steps or stages are increased, the conveyance accuracy of the convey roller 50 is worsened.
As mentioned above, although it is desirable to improve the manufacturing accuracy of the drive force transmitting members and speed reduction members (such as gears) in order to enhance the conveyance accuracy, there are technical limitations and increase in cost. If the diameter of the convey roller 50 is decreased, certain kinds of sheets including the fan-fold sheet cannot be handled and the advantage of the U-turn path cannot be utilized.

Sheet conveying apparatus and image forming apparatus


A method of adjusting a response of an energy measuring filter, such as an FIR filter, of a pulse processor based on a slope of a preamplifier signal having a plurality of step edges each corresponding to a respective photon is provided that includes receiving a digital version of the preamplifier signal comprising a plurality of successive digital samples each having a digital value, the preamplifier signal having a portion defined by a first one of the step edges and a second one of the step edges immediately following the first one of the step edges, using the digital values of each of the digital samples associated with the portion to determine an average slope of the portion normalized by a length of the portion, and using the average slope of the portion normalized by a length of the portion to correct the response of the energy measuring filter.

Energy-dispersive radiation spectrometry systems, such as, without limitation, X-ray spectrometry systems or gamma-ray spectrometry systems, are used for detecting, measuring and analyzing radiation emissions, such as X-ray emissions or gamma-ray emissions, from, for example, a scanning electron microscope (SEM). A typical energy-dispersive radiation spectrometry system includes the following four main components: (1) a detector, (2) a pre-amplifier, (3) a pulse processor, and (4) a computer-based analyzer. For convenience only, and not for purposes of limitation, the following description will relate to X-ray spectrometry systems and photons in the form of X-rays (as compared to, for example, photons in the form of gamma-rays that are detected in a gamma-ray spectrometry system).
The detector, which usually takes the form of a semiconductor sensor of some type, converts an incoming X-ray into a very small current pulse, typically on the order of tens of thousands of electrons, with a duration of about tens to a few hundreds of nanoseconds. The magnitude of each of the current pulses is proportional to the energy of the X-ray.
The pre-amplifier amplifies the current pulse output by the detector and typically converts it into a voltage signal in the range of tenths of millivolts up to a few hundreds of millivolts. There are two main types of preamplifiers: "tail pulse" or RC-coupled preamplifiers, and pulsed-reset preamplifiers. In a pulsed-reset type of preamplifier, the charge generated in the sensor is integrated in a feedback capacitor such that the resulting voltage increases in steps of varying heights and intervals, until it reaches an upper limit. When that limit is reached, a "reset" pulse is applied which drains the accumulated charge from the feedback capacitor, restoring the preamplifier to near its minimum output voltage in a short time, typically a few microseconds. Then, charge due to the interaction of X-rays with the detector accumulates on the feedback capacitor again, and the cycle repeats. In contrast, tail-pulse preamplifiers act as high-pass filters on the voltage step signal output by the detector, with an exponential return to baseline whose time constant is long compared to the charge integration time in a feedback capacitor of the preamplifier. The subject matter described elsewhere herein applies to pulsed-reset preamplifiers.
The pulse processor receives the pre-amplifier signal and generates a numeric representation of the X-ray's energy through an integration process. In older energy-dispersive radiation spectrometry systems, the pulse processor included two separate components, namely a "shaping amplifier" and an analog to digital converter. Modern energy-dispersive radiation spectrometry systems, on the other hand, typically combine these functions, with the newest designs digitizing the preamplifier signal directly and carrying out all pulse detection and filtering functions using digital signal processing. The subject matter described elsewhere herein applies to all-digital pulse processing.
The computer-based analyzer accumulates the X-ray energies output by the pulse processor into a spectrum or plot of the number of X-rays detected against their energies. The spectrum is divided into a somewhat arbitrary number of small ranges called "channels" or "bins." In older systems, a hardware component called a multi-channel analyzer (MCA) did the accumulation of X-rays into spectrum channels and a computer read out the summed result. In modern systems, the MCA function is handled in software, either by the computer or even within the pulse processor.
The job of the pulse processor is made more complex by several factors. For example, electronic noise is superimposed on the underlying signal received from the preamplifier. For X-rays that are near the lowest detectable energy level, the preamplifier output step height may be significantly smaller than the peak-to-peak excursions of the electronic noise. In such as case, the X-ray can only be detected by filtering the signal for a relatively long period of time before and after the step, to average away the contribution of the noise.
Second, the steps in the preamplifier output are not instantaneous. In the absence of noise, the signal would be a sigmoidal (S-shaped) curve. This is due to bandwidth limitations, device capacitance, and the time required for all the electrons generated by an X-ray to reach the anode of the sensor. These electrons can be visualized as a small cluster or cloud, which moves through the sensor material toward the anode under the influence of the bias voltage field within the semiconductor sensor.
In addition to the electrons generated by X-rays, there is also a slow continuous flow of electrons to the feedback capacitor of the preamplifier due to leakage. This leakage current appears as a slight positive slope in the preamplifier output even in the absence of X-rays. The amount of leakage current is a strong function of temperature in semiconductor detectors; in silicon devices, leakage approximately doubles for each 7 degree C. increase in temperature. The newest generation of commercial silicon sensors, referred to as "Silicon Drift Detectors" (SDDs), operate at much higher temperatures than traditional so called Lithium-Drifted Silicon (Si(Li)) which must be cooled to liquid nitrogen temperature for proper operation. Thus, leakage currents are much higher when SDDs are employed and the background slope in the preamplifier output is correspondingly higher as well.
The most common type of digital filter used in digital pulse processing is the so-called triangle or trapezoidal filter, which is illustrated in FIGS. 2A-2C. A triangle or trapezoidal filter simply takes an average of the preamplifier signal during a short period of time before a step edge and afterwards, possibly separated by a small gap of zero weight, and subtracts them as shown in FIG. 2A. This type of filtering is well-known in the art, and is popular because it is very easy to compute. Only four arithmetic operations are required per sample of the digitized preamplifier waveform for a continuous convolution of the filter with the digitized waveform. The response of such a convolution, as shown in the middle portion of FIG. 2C, is a triangle (possibly with a flat top if there is a gap in the filter), hence the common name for this type of filtering.
If the background slope of the signal is not zero, as shown by the dotted line in FIG. 2B, a triangular or trapezoidal filter convolved with it will have a constant response equal to the shaded area of FIG. 2B. When a step edge is superimposed, the resulting maximum response of the filter is increased by a constant amount as shown in the bottom portion of FIG. 2C. This has been known in the art for more than 30 years, and was described in 1975 by U.S. Pat. No. 3,872,287 to Koeman. If the background slope is known, the measured energy of the X-ray can be corrected for the effects of the background slope by subtracting the known response of a digital filter to the slope.
The classical method of determining the slope, as described by the '287 patent and also used in some commercial analog pulse processors, is to trigger an energy measurement artificially in the absence of an X-ray. The average response of a large number of such artificial triggerings will be the offset required to correct the energy of a response to a real X-ray. But as the '287 patent notes, this makes the assumption that the background slope is constant.
Leakage current is indeed expected to be constant if (as noted above) the sensor's temperature is held constant, but there are other potential sources of background slope in the signal which may not be constant over time. The aftereffects of a reset may induce a slow exponential change in the background slope, depending on the design of the preamplifier. Various kinds of low-frequency noise coupled into the preamplifier output, most commonly at power-line frequencies, can also cause the local slope to vary with time. The phenomenon known in the art as "microphonics" describes the coupling of acoustic signals from the environment into the preamplifier signal, as physical components of the detector assembly act as capacitive microphones. The effect of a time-varying background slope is to cause the entire spectrum, including the artificially-triggered peak, to both move up and down in energy. As a result, averaged over time, the center of the artificially-triggered peak may still represent the average offset, but the peaks will be significantly broadened by the instability of the peak positions.
U.S. Pat. No. 5,349,193 to Mott discloses a method for estimating the local slope in the neighborhood of a step edge. The '193 patent also shows the effects of slope in FIG. 6g thereof, and of time-varying slope in FIG. 6h thereof. Looking at FIG. 4 of the '193 patent, block 48 and the accompanying text describe a triangle filter used to detect edges of all energies. Block 48 is detailed in FIG. 6a, where the three arithmetic logic units (ALUs) 202, 204, and 206 make up the triangle filter, and FIFO 210 with accumulator 208 accumulate a running sum of 2SC successive outputs of the peak-detecting filter. The filter output is also tested against an energy threshold in comparator 214, and the accumulation in FIFO 210 is blocked if the output is above threshold. In this way, only samples from the background slope are accumulated in the FIFO. The average of the slope (simply computed by bit-shifting the sum down SC bits in block 220) is used to correct the data stream before energy-measurement filters in block 52 are applied. This eliminates the need for a separate correction factor for each of the many measurement filters stored in the coefficient tables in blocks 58 and 60.
While the method described in the '193 patent is effective, there is room for improvement in the area of slope correction in digital pulse processing.

Digital pulse processor slope correction


A method determines an amino acid sequence that binds to a target molecule or a base sequence encoding the same. The method pans for bringing a library constructed by a display method, followed by incubation. The method sequences for analyzing a base sequence before panning step and the polypeptide group of the library after panning by a next-generation sequencer, or determining an amino acid sequence based on a base sequence obtained by analyzing the base sequence of a nucleic acid encoding all the polypeptides by a next-generation sequencer. The method scores for evaluating and scoring, based on the results of the sequencing step, an amplification ratio. The method determines a sequence for selecting a polypeptide with a high score and determines an amino acid sequence of the polypeptide or a base sequence as an amino acid sequence that binds to the target molecule or as a base sequence of a nucleic acid encoding the polypeptide.

Recently, relationships between various diseases and biomolecules have been reported and molecular targeted drugs or molecular targeted therapies that target such disease-related molecules have been developed. Under such situations, a technology of designing an antibody, peptide, aptamer, or the like having high specificity and affinity to a predetermined target molecule and capable of interacting with the target molecule has been developed.
For example, a method of constructing a library including a variety of polypeptides and screening a polypeptide that binds to a target molecule from such a library has been used widely. For construction of a polypeptide library, a display method capable of associating a genotype with a phenotype has drawn attention and a phage display method, a ribosome display method, an mRNA display method, a cDNA display method, and the like have been developed.
Of these, the phage display method is most popular. In 1985, Smith G. P. reported the possibility of a protein being displayed on the surface of a filamentous phage (Non-Patent Document 1); in 1990, McCafferty J., et al. applied the method to preparation of a monoclonal antibody (Non-Patent Document 2); and in 1991, Smith G. P., et al. reported the possibility of scFv or Fab being also displayed on a phage (Non-Patent Document 3).
The phage display method includes a step called "panning" in which after construction, based on a gene sequence or the like of an antibody in the blood of an animal immunized with a target molecule as an antigen, of a phage library displaying the antibody or a fragment thereof, the phage on which the antibody or fragment that binds to the target molecule has been displayed is enriched. Panning is performed by preparing a solid-phase carrier having a target molecule immobilized thereon or a cell for expressing the target molecule therein, bringing that into contact with a phage library, and collecting the phage that has bound to the target molecule. Panning is typically repeated at least three to five times or so and the phage that binds to the target molecule is enriched gradually.
Then, Escherichia coli or the like is infected with a phage group obtained by panning, and a phage is rescued from about 40 to 100 Escherichia coli clones obtained on the plate. The phage thus obtained not only displays a polypeptide having binding ability to the target molecule but also stores therein genetic information of the antibody in the phage DNA so that this genetic information can also be used for the production of the antibody or fragment thereof.
As described above, the phage display method is highly useful as a method of isolating a polypeptide that binds to a target molecule. On the other hand, a step of infecting Escherichia coli clones with a phage and thereby selecting clones requires labor and time and only a limited number of Escherichia coli clones can be selected so that only phages greatly amplified by panning can be selected. For example, even when 100 clones are selected, it is difficult to obtain a molecule that is displayed on a phage that has a content of less than 1% in a library after panning. Polypeptides that bind to a target molecule available by this method are known to have a sequence very similar to each other, but it is desired to obtain, as a drug candidate, a plurality of polypeptides that binds to different sites of the target molecule.

Method for determining and system for determining polypeptide bonding to target molecule


A technique for reconstructing phase currents based on measurements of a DC bus current. Non-observable regions of DC bus current samples to reconstruct phase currents are reduced in size by using two phase space vector modulation. The non-observable regions can be further reduced by omitting deadtime insertions for switch actuations when output current is higher than a given threshold. Voltage command vectors in non-observable areas can be constructed by two time averaged vectors one of which is constructed to obtain an observable DC bus current reflecting motor phase current. The additive vectors have the same combined time average value as that of the voltage command vector in order to preserve volt-seconds. Current samples may also be averaged to provide a more accurate reconstruction of phase current. Current samples are time delayed to avoid transients for more accurate readings. When three phase PWM inverter modulation results in inability to determine the motor phase current from the DC bus measurement, the technique includes dynamically switching to two phase PWM modulation to reduce the time interval when the motor phase current is not determinable through the DC bus current measurement.

1. Field of the Invention
The present invention relates generally to motor current feedback measurements, and relates more specifically to a computational reconstruction of motor current obtained through measurement of a DC bus current feeding the motor driver inverter.
2. Description of Related Art
Inverters for three phase motor drives are well known in the industry. Typically, a DC bus supplies switched power to different phases of an AC motor through an inverter. A design approach used to supply switching commands and sequences to the inverter involves the use of space vector modulation using pulse width modulation (PWM) arrangement. For example, a switch vector plane is illustrated in FIGS. 1A and 2A with specific switch states for controlling the switches of the inverter as noted at the vertices of the hexagon. As known to those of skill in the art, the switch state generally refers to the states of the high side switches in the three inverter half bridges. For example, state V2 (110) means that the high side switches connected to phases U, V and W are controlled so that the high side switches connected to phases U and V are on and the high side switch connected to phase W is off. Correspondingly, the low side switches for phases U, V and W would be, at the same time, respectively, off, off and on.
With this type of motor control, it is desirable to accurately measure motor phase current to provide a high performance control. However, it is often difficult to accurately measure motor phase current over wide current and temperature ranges. For example, current sensing resistors may be used in the motor phase lines. However they do not provide the accuracy and precision needed in a high performance motor drive, especially at high currents, and also waste power. Current sensing transformers may also be used, but these are also subject to non-linearities and can be large and expensive to implement.
In a pulse width modulated (PWM) inverter drive system, motor phase current can be determined from measurement of the DC bus current when non-zero basic vectors are used. Each basic vector is assigned a specific time in a PWM cycle to generate the command voltage vector. However, if a basic vector is used only for a very short period of time, motor phase current cannot be directly determined from the DC bus current. This lack of observability of motor phase current is due to practical considerations in the implementation of the PWM inverter drive system. For example, time delays caused by A/D converter sample and hold times, slewing of voltage during switch turn on, and other delay factors and other parasitic effects that distort the DC link current from an ideal step waveform to an overshoot with ringing type waveform prevent the effects of basic vectors used for a very short time from being observed on the DC bus.
In the space vector plane shown in FIG. 1A, the non-observable regions are illustrated as being located along the borders of the sections of the space vector plane, i.e., around the basic vectors in the shaded regions. Without being able to observe motor phase currents during these control periods, it is difficult to achieve a robust and high performance motor drive. FIG. 1B illustrates the case where one phase can be accurately sampled during vector (100) duration), but neither of the other phase currents can be directly sampled because the duration of the active vector is too short in the interval T2/2, i.e., the reference voltage vector (110) is in the non-observable area of FIG. 1A.
With respect to observability of motor phase current through measurement of the DC bus current, various attempts have been made to overcome the drawbacks described above. In one approach, the switching frequency of the inverter is varied to avoid the problem with unobservability. However, this approach includes a change in the controller gains, and a coordination with the switching frequency, adding to the complexity of the control. Also, when the voltage vector is in the non-observable region, double references in an opposite phase are used to compensate for the non-observable current, increasing the number of switching events.
Another difficulty in observing motor currents by measuring DC bus current is illustrated in FIG. 2A, where a low modulation index is used. During low modulation index cycles, the PWM signals for the three phases have nearly equal durations. As a result, the particular active voltage vector is not used long enough to ensure proper sampling of the DC link (or bus) current. This problem is illustrated in FIG. 2B, where switching intervals occur so closely together that reconstruction of the motor current by measurement of the DC bus current is problematic at best. In addition, a minimum time delay is often used to secure a good current sample of the DC bus current after a particular switching sequence occurs to avoid switching transient signals. The minimum time delay adds to the difficulty of measuring the DC bus current, since there is not enough time between the differing switching states to obtain a current sample for at least one of the phases of the two that are measured, as illustrated in FIG. 2B. Accordingly, accurate motor phase current reconstruction cannot be properly achieved.
When the modulation index is low, resulting in short active voltage vectors that prevent proper sampling of the DC link current, one solution is to replace all active vectors less than a certain time period, 30 microseconds for example, with a zero vector, and then adding the missing time in the next switching period. This technique, however, results in poor performance at low speed due to high harmonic distortion.
Another technique reduces or eliminates zero vectors when the active vectors are too short, and introduces two complementary voltage vectors closest to those already used in the switching cycle. This technique introduces additional switching, and therefore generates more EMI noise. In addition, a very low modulation index still creates problems in performance.
Another technique for overcoming the above drawbacks is to adjust the duty cycle so that switching states are offset to permit an elimination of voltage error within a single switching period. Another technique uses two switching periods in the PWM control to adjust the duty cycles and remove voltage error between the switching events. While these techniques permit the PWM drive to operate at low speed, a higher sample rate is needed to avoid phase errors between the samplings of the motor current.
In a PWM inverter drive system, switching sequences cause current values delivered to the motor phases to ramp up or down over a given switching interval. In practice, it is not feasible to obtain a complete measurement of the current delivered in the motor drive system, due to the high speed processing that would be required. Accordingly, current values are sampled over a given switching interval, potentially resulting in large variations between estimated current values based on samples, and actual current values experienced by the motor. If a current sample taken during a ramp interval is used to estimate the changing current for the entire interval, inaccuracies will occur. It would be desirable to obtain a more accurate technique for sampling motor current based on switching sequences.
Another issue that arises in motor current sampling is transients or "ringing" in the DC bus current when switch transitions occur. An example of problems with ringing is illustrated in FIG. 3. If a sample of DC bus current is taken near a switching event where ringing occurs in a phase current, the sample may not accurately reflect motor phase current. In addition, the DC bus current is typically observed in the shape of a ramp when a switch transition occurs to energize a given phase. If a current sample is taken in an arbitrary part of the switching sequence where the motor phase current is ramping up, the sample DC bus current will not accurately reflect the average motor phase current value over the entire switching interval.

Motor current reconstruction via DC bus current measurement


Systems and methods that facilitate the setup and visualization of a configurable process, for example a chromatography experiment to be conducted using a configurable chromatography system. A user interface displays category regions representing sections of a process, and displays a plurality of selectable items representing components appropriate for placement in the category regions. A user interface control causes selection of one of the selectable items and placement of the selected item into one of the category regions, to define a selected process configuration. The user interface control may be a scrolling control that causes a set of selectable items appropriate for placement in the respective category region to scroll through the category region. When the computer displaying the user interface is also connected to the system being configured, the user interface may also facilitate setup, monitoring, and control of the resulting process.

Chromatography is an analytical technique for separating components of a chemical mixture. Chromatography may be used for the identification, extraction, and purification of species of interest, for example proteins, peptides, nucleic acids, monoclonal antibodies, or other species of interest in biological research and analysis, or drug manufacturing. Chromatography may be used in many other applications as well. These techniques have reached such a high level of sophistication that virtually any biological species can be obtained in a highly purified form.
However, different species may require different processes for isolation, for example different sample preparation methods, different separation media, and different conditions under which separation is performed. Accordingly, configurable chromatography systems have been developed, in which varying components may be selected and interconnected in varying ways for the performance of different separations.


The present invention relates to a separator for a lithium secondary battery, a method for manufacturing the separator, and a lithium secondary battery including the separator. The separator includes a porous substrate and a heat resistance porous layer positioned on at least one surface of the porous substrate, wherein the heat resistance porous layer includes a sulfonic acid group-containing polysulfone.

A separator for an electrochemical battery separates a positive electrode from a negative electrode and continuously maintains ion conductivity in a battery and thus makes the battery charged and discharged but mechanically shrinks or is damaged due to melting characteristics at a low temperature. Herein, the positive and negative electrodes contact each other and may cause an explosion of the battery. In order to overcome this problem, technology of suppressing a shrinkage of the separator at a high temperature is required. The technology of suppressing a shrinkage of the separator may be representatively a method of mixing an inorganic particle having high thermal resistance with an organic binder having adherence and then, coating the mixture on the separator to increase thermal resistance of the separator.
In this way, research on improving safety of the battery and simultaneously, adherence, workability, and the like of the separator has been actively made by suppressing a direct contact of the positive and negative electrodes to prevent the shrinkage of the separator despite excessive increase of an internal temperature of the battery in an unexpected environment.
On the other hand, requirement of developing a large capacity battery has increased a role of the separator. The separator in the large capacity battery needs to be designed to improve electrochemical safety and performance as well as to have high thermal stability.

Separator for lithium secondary battery, method for manufacturing same, and lithium secondary battery including same

Dankook University Cheonan Campus Industry Academic Cooperation Foundation


A variable resistance memory device may include a first electrode and a second electrode. The device may further include a chalcogenide glass layer between the first electrode and the second electrode. The chalcogenide glass layer may include a chalcogenide glass material co-deposited with a metal material. The device may also include a metal ion source structure between the chalcogenide glass layer and the second electrode. The device may include a buffer layer between the first electrode and the chalcogenide glass layer.

A typical variable resistance memory device, or memristor, may be "programmed" to have two logic states, such as a low resistance state (on-state) and a high resistance state (off-state). In order to program the memristor into a low resistance state, a potential difference may be applied across a memory stack of the memristor. The potential difference may form one or more conductive pathways through the memory device, thereby decreasing the resistance of the memristor. In order to program the memristor into a high resistance state, a reverse potential difference may be applied across the memory stack. The reverse potential difference may alter, eliminate, or reduce the one or more conductive pathways, increasing the resistance of the memristor. The programmed resistance may be permanent, or semi-permanent, until changed by another applied potential. To read the resistance state of the memristor, a smaller potential difference (e.g., a voltage that is insufficient to change the resistance state) may be applied to the memory stack and a resultant current may be measured to determine the resistance state.
U.S. Pat. No. 7,087,919, filed on Apr. 7, 2004 and entitled, "Layered Resistance Variable Memory Device and Method of Fabrication," describes an example of a variable resistance memory device that relies on ion conduction to alter a resistance of the device. The device has at least one layer of silver-selenide between a first chalcogenide glass layer and a conductive adhesion layer, which may also be a chalcogenide glass layer. When a potential difference is placed across the device, the silver may form one or more conductive channels through the chalcogenide glass layer, thereby altering a resistance of the device. U.S. Pat. No. 7,087,919 is hereby incorporated by reference in its entirety.
U.S. Pat. No. 7,190,048, filed on Jul. 19, 2004 and entitled "Resistance Variable Memory Device and Method of Fabrication," describes another example of a variable resistance memory device that includes a stack with at least one layer of tin-chalcogenide proximate a first chalcogenide glass layer. During a conditioning step, tin-selenide from the tin-chalcogenide layer is incorporated into the chalcogenide glass layer to form conducting channels. Movement of silver ions into or out of that conducting channel during subsequent programming forms a conductive pathway, which causes a detectable resistance change across the memory device. U.S. Pat. No. 7,190,048 is hereby incorporated by reference in its entirety.
One potential challenge associated with typical memristor devices is that when the memristor is in a low resistance state, a high current may be drawn through the memristor in response to an applied voltage potential. The high current may result in high power consumption, which may decrease the economic value, or feasibility, of using typical memristor devices for some applications such as high density arrays. The high current may also produce heat that may alter the chemical structure of the device stack. Another potential problem associated with typical memristors is that the dynamic range of programmable resistance may be limited. For example, the dynamic range of programmable resistance of a typical memristor may only enable binary resistance states (e.g., an on-state or an off-state). As such, typical memristors may not be suitable for applications that depend on multiple discrete states or a continuous range of states.

Tunable variable resistance memory device


The present invention provides a processor synthesis system and a processor synthesis method which enable a designer to synthesize a CPU that does not depend on a specific process technology and has the bit width customized to the requirements of the specific application. The processor synthesis method according to the present invention comprises steps of generating and outputting processor definition information to define a CPU based on primary parameters entered by the designer; generating a compiler and an assembler for generating an instruction code for the CPU defined by the processor definition information; and executing simulation using the instruction code output by the generated compiler and the assembler so as to facilitate optimization of the designed CPU and reduce development costs.

1. Field of the Invention
The present invention relates to a processor synthesis system and a processor synthesis method for implementing an ASIC (Application Specific Integrated Circuit), an LSI circuit designed for a specific application in digital information processing control. The implemented ASICs are used in the controllers of control apparatuses, sequence controllers of multi-media apparatuses, and controllers of household appliances,
2. Discussion of the Related Art
In the conventional ASIC, a general purpose microprocessor is built in a chip as the Central Processing Unit (CPU).
When using general purpose microprocessors, users can easily select and use microprocessors which are commercially available. In this case, however, the architectures of the microprocessors have already been fixed. The CPU bitwidths of the existing microprocessors, for example, are designed to be 2.sup.n bits including 8 bits, 16 bits, 32 bits, and the like. Accordingly, several functions of the microprocessors remain unused when the size of the control unit of the microprocessor is comparatively small and the control logic is simple and mainly focuses on the operation of addition, subtraction, and bit control. When the control logic can be implemented using the 10-bit CPU bitwidth, a 16-bit microprocessor must be used instead of a 10-bit microprocessor. It is because the bitwidths of the general purpose microprocessors have already been fixed and a 10-bit general purpose microprocessor is not available now. Thus, 6 bits of the CPU bitwidth remain unused.
The CPU bitwidth has a direct effect on the size of a chip. Consequently, the problem arises that a chip itself becomes highly redundant, because the CPU on that chip has the unused 6-bit data. In view of the aforementioned problems, a system has been desired which can synthesize the CPU having the optimal bitwidth specifically customized to perform desired functions.
The present structure for placing a CPU on an ASIC is known as a mega cell. It is called mega, because it is large. This mega cell is a microprocessor, custom designed at the transistor level in a specific ASIC technology. Present mega cell CPUs are actually microprocessors which have been designed with fixed architectures and the CPU bitwidths of 16 bits or 32 bits. Consequently, when the application requires the microprocessors other than 16-bit or 32-bit microprocessors and is moved to a new technology (or even next generation of the current technology), the mega cell must be redesigned. Since the mega cell has been designed at the transistor level, this redesign process is considerably expensive and creates schedule delay.
In view of the aforementioned problems, a system has been desired which is capable of designing the CPU at the level higher than the transistor level.
The special mega cell technology for placing a CPU on an ASIC also creates problems for system simulation and emulation, since the mega cell technology is different from the technology for fabricating the rest of the ASIC.
A module compiler is a tool for automatically creating the layout patterns of modules when the information on the functions of the modules, bit widths, and the like required for creating the layout patterns is supplied as parameters.
FIG. 35 is a block diagram showing the function of a conventional module compiler for creating the layout patterns of modules automatically. It is described on page 60-61, in the book entitled "Basic Concepts and Applications of the ASIC technology" by Masaharu Imai and the Institute of Electronics, Information and Communication Engineers of Japan, the first edition of which was published on Feb. 20, 1994.
As shown in FIG. 35, automatic module generation involves using programmed circuit netlists and programmed layout patterns of RAMs (Random Access Memory), ROM(s) (Read Only Memory), the ALU (Arithmetic Logic Unit), etc., and a technology file storing design rules. In the automatic module generation process which does not depend on a specific design technology, by altering the design technology, various layout patterns of modules can be generated, using the lines of 1.3 .mu.m, 1.0 .mu.m, or 0.8 .mu.m in width. The user should only specifies such parameters as the number of words, the bitwidth, and the like.
Next, a conventional logic synthesis system is described.
FIGS. 36 and 37 are block diagrams showing how the conventional "Tsutsuji" logic synthesis system marketed by Zuken Incorporated is used for generating a netlist.
In FIG. 36, a "Tsutsuji" 850 receives a block diagram 810 prepared by a designer using computer-aided design (CAD) systems, implements logic synthesis, and generates a netlist 860. Based on the generated netlist 860, a semiconductor chip is fabricated.
FIG. 37 shows a case where a hardware description language (HDL) is used instead of a block diagram. The hardware description language (HDL) for the "Tsutsuji" logic synthesis system is written in a logic description format (LDF). The "Tsutsuji" 850 receives an LDF 820, implements logic synthesis, and generates the netlist 860.
In the "Tsutsuji" logic synthesis system, functional components to be designed and used as input data are not necessarily restricted to those of specific manufacturers. The generated netlist can be generated in a format of a specific silicon manufacturer. Consequently, a chip which does not depend on a specific semiconductor technology can be designed.
FIGS. 38 and 39 are block diagrams of the "Retargettable Compiler System" disclosed in Japanese Unexamined Patent Application HEI3-144829.
FIG. 38 is a block diagram showing the overall configuration of the "Retargettable Compiler System".
A compiler 911 comprises syntax analysis means 912, code generation means 913, target specification and recognition means 914, target-dependent information holding means 915, and instructions expressed in an intermediate language 916. The syntax analysis means 912 receives a source program 917 and translates the source program 917 into the instructions expressed in the intermediate language 916 which is independent of a specific computer architecture. The code generation means 913 receives the instructions expressed in the intermediate language 916 and translates the instructions expressed in the intermediate language 916 into an object program 918, targeting the computer architecture recognized by the target specification and recognition means 914 and by referring to the detailed information held in the target-dependent information holding means 915. The detailed information held in the target-dependent information holding means 915 includes data on the hardware configuration and execution characteristics such as the set of machine instructions, types and numbers of registers, the data format, and the addressing system.
FIG. 39 is a block diagram showing an example of how the conventional "Retargettable Compiler System" is used.
As shown in FIG. 39, using a single compiler, the conventional "Retargettable Compiler System" can compile one source program 917 into three object programs 918a, 918b, and 918c for computer architectures 920a, 920b, and 920c respectively.
As a retargettable compiler similar to that described above, the General Purpose C Compiler (GCC) may be pointed out. The General Purpose C Compiler is a C compiler for the GNU (GNU is not UNIX) operating system. GNU refers to the computer software distributed for free by Free Software Foundation, Inc. of the U.S.A. (Refer to page 397 of the "Dictionary of New Information and Communications Terms 1996" by the Nikkei BP Publication Center, the first edition of which was published on Oct. 9, 1995.)
As public-domain software, the lcc compiler prepared by C. W. Fraser of the AT&T Bell Laboratory and D. R. Hanson of the Princeton University may be pointed out. This program is the public-domain software which is available via the Internet. The lcc compiler is a retargettable compiler whereby the instruction code of the existing processor such as SPARC, MIPS, R300, or INTEL 386 can be generated.
The compiler of the above-mentioned type, when supplied with parameters for a target computer, compiles the source program into the object program specifically matched to the architecture of the target computer. The architecture of a computer, for example, may include 8086 manufactured by Intel Corporation, MC68000 manufactured by Motorola, Incorporated, and the like. These compilers target the hardware architecture which has already been fixed. By prestoring detailed information on the fixed hardware architecture into the compiler, retargettable compilation becomes possible. Thus, when a new hardware architecture is to be determined, or a new CPU is to be designed, the compiler for the newly-designed CPU is not readily available.

Processor synthesis system and processor synthesis method


A method of dynamically controlling open hole pressure within a wellbore having a drill string positioned therein. The method comprising the steps of pumping a fluid down the drill string, into an annulus formed by the drill string and the interior of the wellbore, and then subsequently up the annulus to the surface of the ground; selectively applying wellhead pressure to the annulus through selectively pumping an additional quantity of the fluid or a quantity of a secondary fluid across the annulus; and, controlling the application of wellhead pressure applied to the annulus by controlling one, or both, of (a) the operation of a wellhead pressure control choke, and (b) the flow rate of the additional quantity of fluid or the secondary fluid pumped across the annulus, to thereby maintain open hole pressure within a desired range.

Common methods of drilling wells from the surface down through underground formations employ the use of a drill bit that is rotated by either a downhole motor (sometimes referred to as a mud motor), through rotation of a drill string extending from the surface, or through a combination of both surface and downhole drive mechanisms. Where a downhole motor is utilized, energy is typically transferred from the surface to the downhole motor by pumping a drilling fluid or "mud" down through a drill string and channeling the fluid through the motor causing the rotor of the downhole motor to rotate and drive the rotary drill bit. The drilling fluid or mud serves the further function of entraining rock cuttings and circulating them to the surface for removal from the well. In some instances the drilling fluid may also help to lubricate and cool the drill bit and other downhole components.
When drilling for oil and gas there are many instances where the underground formations that are encountered contain fluid (generally water, oil or gas) at very high pressures. Traditionally, when drilling into such formations a high density drilling fluid or mud is utilized in order to provide a high hydrostatic pressure within the wellbore to counteract the high fluid pressure. In such cases the hydrostatic pressure of the mud meets or exceeds the underground fluid pressure thereby ensuring well control and preventing a potential blowout. Where the hydrostatic pressure of the drilling mud is approximately the same as the underground fluid pressure, a state of balanced drilling is achieved. Due to the potential danger of a blowout in high pressure wells, in most instances an overbalanced situation is desired with the hydrostatic head of the drilling mud exceeding the underground formation pressure by a predetermined safety factor. The high density mud and the high hydrostatic head that it creates also helps to prevent a blowout in the event that a sudden fluid influx or "kick" is experienced when drilling through a particular underground formation that is under very high pressure, or when first entering a high pressure zone.
Unfortunately, such prior systems that employ high density drilling muds to counterbalance the effects of high formation pressures have met with only limited success. In order to create a sufficient hydrostatic head, the density of the drilling mud often has to be relatively high (for example from 15 to 25 pounds per gallon), necessitating the use of costly density enhancing additives. Such additives not only significantly increase the cost of the drilling operations, but can also present environmental difficulties in terms of their handling and disposal. High density muds may also not be compatible with many standard surface separation systems that are commonly in use. In typical surface separation systems the high density solids are removed preferentially to the drilled solids and the mud must be re-weighted to ensure that the desired density is maintained before it can be pumped back into the well.
High density drilling muds also present an increased potential for plugging downhole components, particularly where the drilling operation is unintentionally suspended due to mechanical, electrical, hydraulic or other failure. In addition, the high hydrostatic pressure created by the column of drilling mud in the string often results in a portion of the mud being driven into the formation, requiring additional fresh mud to be continually added at the surface and thereby further increasing costs. Invasion of the drilling mud into the subsurface formation may also cause irreparable damage to the formation.
Another limitation of such prior well pressure systems concerns the degree and level of control that may be exercised over the well. The hydrostatic pressure applied to the wellbore is primarily a function of the density of the mud and its depth or column height. For that reason there is only a limited ability to alter the hydrostatic pressure applied to the formation. Generally, varying the hole pressure requires an alteration of either the density of the drilling mud or the drilling fluid injection rate. The former can be an expensive and time consuming process, and the latter is limited and not always practical since it may have an adverse affect on the ability to clean the hole.
As a means to address some of the above deficiencies, others have suggested pumping fluids into the annulus of the well to thereby control bottom hole circulating pressure through controlling friction pressure. Such a method is described in U.S. Pat. No. 6,607,042, dated Aug. 19, 2003. While friction pressure methods of this sort may be effective in controlling bottom hole pressure, they can also increase the level of complexity of the overall drilling process, and necessitate the use of additional equipment that can have the result of increasing both capital and operating costs.
Still others have suggested controlling bottom hole pressure through the use of a surface back pressure system. Typically, such systems involve continuously monitoring borehole pressure to create a pressure model that is then used to predict fluctuations in downhole pressure. The model is continuously updated through the use of a computer or microprocessor that receives signals from downhole pressure sensors, flow meters and other such devices. The pressure model is then in turn used to control wellhead back pressure. Such a method is described in United States patent application publication number U.S. 2003/0196804, dated Oct. 23, 2003. As in the case of friction pressure systems, current surface back pressure systems add a significant level of complexity to the drilling operations, necessitate the use of additional equipment, and to a large extent are dependent upon the accuracy and predictability of a constantly changing downhole pressure model. Neither friction pressure nor currently available surface back pressure systems are designed to specifically counteract the effects of surge and swab pressures caused by the movement of the drill string.

Method of dynamically controlling open hole pressure in a wellbore using wellhead pressure control