The present application relates to conjugates of STING agonists and small molecule modulators of the PD-1/PD-L1 protein/protein interaction, as well as methods of treating cancer using the conjugates.

The innate immune system is the first line of defense against infection from foreign microorganisms including bacteria, viruses, parasites and other infectious threats by responding to certain danger signals associated with cellular or tissue damage. This response is initiated by activation of so-called pattern recognition receptors that can detect different forms of foreign antigens, i.e., nucleic acids, peptides, carbohydrates, and more, which then lead to production of interferons (IFNs), proinflammatory chemokines and cytokines, and anti-microbial peptides to fight infection (Palm N W and Medzhitov R., "Pattern recognition receptors and control of adaptive immunity," Immunol Rev (2009) 227:221-233; Takeuchi O and Akira S. "Innate immunity to virus infection," Immunol Rev (2009) 227:75-86; Beutler B A. TLRs and innate immunity. Blood (2009) 113:1399-1407). STING (stimulator of interferon genes), also known as MITA, MPYS, ERIS, and TMEM173, is one such pattern recognition receptor in the innate immune response that detects cytosolic nucleic acids (Ishikawa H and Barber G N., "STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling," Nature (2008) 455:674-678). Direct binding of STING to its ligands induces a conformational change of the complex resulting in a downstream signaling cascade involving TBK1 activation, IRF-3 phosphorylation, and production of type I IFNs and other proinflammatory cytokines, such as TNF, IL-6 and IFNγ (Ishikawa and Barber, supra).
Type I IFNs play a central role in orchestrating host anti-viral response through inhibiting viral replication in infected cells, activating and enhancing antigen presentation and triggering the adaptive immune response through direct and indirect action on T and B cells (McNab F, et al., "Type I interferons in infectious disease," Nat Rev Immunol (2015) 15:87-103; Crosse K M, et al., "Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling," J Innate Immun (2018) 10:85-93). Therefore, this cytokine acts as a master regulator whose induction in the early stages of viral infection modulates downstream signaling cascades that promote both pro-inflammatory and anti-inflammatory responses. Thus type I IFNs have been evaluated as a therapeutic agent for chronic viral infection such as HCV and HIV (Enomoto H, et al., "Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C," World J Hepatol (2015) 7:2681-2687; Azzoni L, et al., "Pegylated interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration," J Infect Dis (2013) 207:213-222; Lane H C, et al. "Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection: A randomized, placebo-controlled trial," Ann Intern Med (1990) 112:805-11).
The use of type I interferons (the IFNα family and IFNβ) as potential antitumor agents has also been investigated (Kirkwood J., "Cancer immunotherapy: the interferon-alpha experience," Semin Oncol (2002) 29:18-26; Tarhini A A, et al., "IFN-alpha in the treatment of melanoma," J Immunol (2012) 189:3789-3793). IFNs have multiple anticancer mechanisms that include: direct inhibition on tumor cell proliferation and angiogenesis; induction of tumor-specific cytotoxic T-cells; plus other immunoregulatory effects on antibody production, natural killer (NK) cell activation, macrophage function, delayed-type hypersensitivity, and major histocompatibility complex antigen expression (Hervas-Stubbs S, et al., "Direct effects of type I interferons on cells of the immune system," Clin Cancer Res (2011) 17:2619-2627; Vannucchi S, et al. "Perspectives in biomolecular therapeutic intervention in cancer: from the early to the new strategies with type I interferons," Curr Med Chem (2007) 14:667-679).
Anticancer activity of type I IFNs has been demonstrated in patients with hematological malignancies (e.g., hairy cell leukemia) and solid tumors (e.g., renal cell carcinoma and malignant melanoma) (Quesada J R, et al., "Alpha interferon for induction of remission in hairy-cell leukemia," N Engl J Med (1984) 310:15-18; Pizzocaro G, et al., "Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study," J Clin Oncol (2001) 19:425-431; Garbe C, et al., "Diagnosis and treatment of cutaneous melanoma: state of the art," Melanoma Res (2007) 17:117-127). However, the results and overall efficacy have been modest. This may be due to intrinsic resistance to IFN-induced cell death, to the short half-life (˜30 minutes) of intravenously or subcutaneously dosed IFN, to dose-limiting systemic toxicities, and/or to the development of neutralizing antibodies against recombinant IFN protein. Thus, the development of an agent like a STING agonist to induce production of type I interferons will be of interest to the field. Currently, there are two different classes of STING agonists: cyclic dinucleotides and small molecule structures.
Cyclic dinucleotides (CDNs) can directly bind and activate STING, and the complex of bacterial CDN and STING has been confirmed by X-ray crystallography recently (Burdette D L, et al., "STING and the innate immune response to nucleic acids in the cytosol," Nat Immunol (2013) 14:19-26). In mammalian cells, the primary sensor of cyclic double stranded DNA (dsDNA), namely cyclic GMP-AMP synthetase (cGAS), can convert those cyclic dsDNA into a mammalian CDN cGAMP (cyclic guanosine monophosphate-adenosine monophosphate) (Gao P, et al., "Structure-function analysis of STING activation by c[G(2′,5′)pA(3′5′)] and targeting by antiviral DMXAA," Cell (2013) 154:748-762). The interaction of cGAMP and STING has also been confirmed by X-ray crystallography (Cai X, et al., "The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling," Mol Cell (2014) 54:289-296). Synthetic derivatives of cGAMP have been synthesized and showed excellent cellular potency to activate both mouse and human STING in vitro, as well as demonstrated good anti-tumor efficacy in preclinical mouse models (Corrales L, et al, "Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity," Cell Rep (2015) 11:1018-1030).
Small molecules that can activate STING have also been identified, DMXAA (5,6-dimethylxanthenone-4-acetic acid) and CMA (10-carboxymethyl-9-acridanone) (Perera P Y, et al., "Activation of LPS-inducible genes by the antitumor agent 5, 6-dimethylxanthenone-4-acetic acid in primary murine macrophages. Dissection of signaling pathways leading to gene induction and tyrosine phosphorylation," J Immunol (1994) 153:4684-4697; Kramer M J, et al., "Antiviral activity of 10-carboxymethyl-9-acridanone," Antimicrob Agents Chemother (1976) 9:233-238). These two chemically-unrelated compounds can activate the STING pathway, and block multiple viruses from replication (Guo F, et al., "STING agonists induce an innate antiviral immune response against hepatitis B virus," Agents Chemother (2015) 59:1273-1281; Cheng G, et al., "Pharmacologic activation of the innate immune system to prevent respiratory viral infections," Am J Respir Cell Mol Biol (2011) 45:480-488). Intriguingly, DMXAA demonstrates excellent anti-tumor activity in preclinical mouse models by priming CD8+ T cells responses to promote rejection of established tumors in a STING-dependent manner, inducing tumor necrosis through disruption of tumor vasculature, as well as augmenting cancer vaccine effect (Corrales, supra; Wallace A, et al., "The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes," Cancer Res (2007) 67:7011-7019; Tang C K, et al., "The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant," Plos One (2013) 8:1-6).
A major concern for systemic delivery of a STING agonist is the potential for the induction of a cytokine storm. One approach to restrict STING agonism to the tumor microenvironment while avoiding systemic toxicity is to co-target PD-L1, which is highly expressed in tumors and many tumor infiltrating antigen presenting cells. PD-L1 interacts with PD-1 receptor (also known as CD279) or CD80 (also known as B7.1) which are expressed on activated T cells, NK T cells, B cells, and macrophages (Greenwald R J, et al., "The B7 family revisited," Annu. Rev. Immunol 2005;23:515-548; Okazaki T, et al., "The PD-1-PD-L pathway in immunological tolerance," Trends Immunol 2006; 4:195-201).
Blockade of PD-L1/PD-1 signaling improves T cell responses in a range of preclinical cancer models. Antibodies against PD-L1 can enhance or restore T cell effector function, including cytokine production and cytolytic activity against tumor cells, as well as increased proliferation and/or infiltration of tumor-reactive CD8+ T cells into established tumors (Iwai Y, et al., "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade," PNAS 2002; 99(19):12293-12297; Okudaira K, et al., "Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model," Int J Oncol 2009; 35:741-749; Zhou Q, et al., "Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization," J Immunol 2010; 185:5082-5092; Blank C, et al., "Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro," Int J Cancer 2006; 119:317-327). Therapeutic use of blocking antibodies to PD-L1 has produced durable clinical responses in a wide variety of solid and hematologic malignancies (Topalian S L, et al., "Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer," N Engl J Med 2012; 366:2443-2454; Herbst R S, et al., "Predictive correlates of response to the anti-PD-L1 antibody in Cancer," Nature 2014; 515:563-567; Powles T, et al., "MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer," Nature 2014; 515:558-562; Garon E B, et al., "Pembrolizumab for the treatment of non-small-cell lung cancer," N Engl J Med 2015; 372:2018-2028; Ansell S M, et al., "PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma," N Engl J Med 2015; 372:311-319).
Hence, there is a need for small molecule entities that can activate human STING and induce upregulation of IRF3 and NFκB pathway, which can later lead to production of IFNs and other proinflammatory cytokines and chemokines in a PD-L1-dependent manner. This type of immunomodulatory agent may be useful not only in infectious disease to activate innate immunity, but also in cancer, and as vaccine adjuvants. There is a further need for to limit STING agonism to the tumor microenvironment. This application addresses these needs and others.

PD-L1/STING conjugates and methods of use


Systems and methods to provide low carbon intensity (CI) transportation fuels through one or more targeted reductions of carbon emissions based upon an analysis of carbon emissions associated with a combination of various options for feedstock procurement, feedstock refining, processing, or transformation, and fuel product distribution pathways to end users. Such options are selected to maintain the total CI (carbon emissions per unit energy) of the transportation fuel below a pre-selected threshold that defines an upper limit of CI for the transportation fuel.

Certain gases, such as carbon dioxide, methane, nitrous oxide, hydrofluorocarbons, perfluorinated chemicals, sulfur hexafluoride, etc., when released to the atmosphere are purported to adversely contribute to climate change and have been labeled as greenhouse gases. To mitigate perceived climate change, much worldwide attention and focus has been placed on reducing the release of these greenhouse gases to atmosphere. Greenhouse gases, such as carbon dioxide, are directly released to atmosphere through the combustion of fossil fuels, biomass and other carbon-containing materials. However, providing services as well as the manufacturing and processing of goods contributes indirectly to the atmospheric release of carbon dioxide and other greenhouse gases. To quantify the direct and indirect release of greenhouse gases attributable to consumer and/or industrial activity, the carbon intensity or emission intensity was developed as a measure of the greenhouse gases emitted per unit of activity/production. With respect to transportation fuel and hydrogen production and use, the carbon intensity may be defined as the lifecycle greenhouse gases emitted per unit of energy. By assessing the lifecycle greenhouse gas emissions, all greenhouse gas emissions attributable to the fuel or hydrogen are accounted for during the entire lifecycle of the fuel or hydrogen from acquisition to processing to combustion. The carbon intensity for transportation fuels and hydrogen is often reported in units of grams of carbon dioxide equivalent per mega joule of energy. Because some greenhouse gases, such as methane, are considered to have a greater climatic effect than carbon dioxide, greenhouse gas emissions are reported in carbon dioxide equivalents.
Typical implementations of a low carbon intensity energy strategy may focus on the direct use by an end user or consumer of alternative, renewable sources of low carbon energy, such as power generated by wind, solar, or geothermal. For example, low carbon intensity renewable power may be generated at wind farms, solar farms, geothermal power plants/facilities, and/or hydroelectric facilities. Often, however, such farms and facilities are located at long distances from the end user or consumer. Thus, the alternative energy must be transferred from these remote locations to the end user over long distances, e.g., via high voltage transmission lines.
Inherent in such transmission is a loss of energy and an inefficient use of resources. Further, the transferred renewable power often is in a form that requires adaptation in order to be usable, which thereby increases its carbon intensity further. For example, to avoid conventional higher carbon intensity fuels in gasoline fueled vehicles, an end user or consumer may purchase an electric vehicle and install a home charging station to take advantage of renewable power. However, such choices may come at a considerable expense to the end user, who must purchase the electric vehicle and charging station. Moreover, the indirect use of higher carbon intensity fuels may also be overlooked. The construction of the electrical vehicles and their required accessories may contribute to significant carbon emissions if conducted using higher carbon intensity fuels. The production of electric vehicles may also create environmentally hazardous events and/or byproduct materials (e.g., mined nickel for use in batteries). Thus, this interplay may negate the overall environmental impact of the electric vehicle, even if energy is provided at a lower carbon intensity.
Similarly, renewable natural gas may often be produced at facilities located at long distances from the end user. Such long distances will necessitate transportation of the renewable natural gas via pipeline or truck to the end user or consumer. The use of conventional higher carbon intensity fuels or energy sources in such transportation will increase the carbon intensity of the renewable natural gas significantly.
Furthermore, a consumer that chooses the direct use of alternative, renewable energy source may continue to purchase higher carbon intensity liquid fuels from convenience stores or other retail outlets for occasions when electric vehicles are insufficient (e.g., long distance driving or lack of charging facilities). These higher carbon intensity liquid fuels originate in traditional refineries and similar facilities and are transported to such convenience stores with such transport further increasing the carbon intensity of the transportation fuel.
FIG. 1 illustrates a typical implementation 100 of a low carbon intensity energy strategy, which is largely focused on the use by the end user or consumer 102 of alternative, renewable sources of low carbon energy 108, 111, such as renewable natural gas produced from biomass wastes, electric power generated by wind, solar, geothermal, and/or hydroelectric sources, etc. As illustrated in FIG. 1, low carbon intensity renewable electric power 108 is generated at wind farms, solar arrays, geothermal power plants/facilities, and/or hydroelectric facilities. The electric power generated at these sources must often be transmitted long distances via high voltage transmission lines 109 to the renewable energy infrastructure 110 accessible by the consumer 102. This renewable energy infrastructure may include electric vehicles, charging stations, renewable natural gas pipelines and fueling stations, etc. However, when the renewable electric power reaches the consumer 102 via the renewable energy infrastructure 110, the consumer 102 may have to take further action, e.g., purchase an electric vehicle, in order to be able to properly make use of the renewable energy.
Renewable natural gas (RNG) is produced from biomass wastes at facilities 111, such as landfills, wastewater treatment plants, dairies, slaughterhouses and agricultural waste facilities, which are also oftentimes far from the consumer 102. The decomposition and/or biodegradation of biomass wastes produces methane and other gases. RNG is the methane that is separated via conventional separation techniques from other gases evolved during the decomposition of these biomass wastes. As a greenhouse gas, methane is considered to have a much greater impact than carbon dioxide, i.e., about 26 times the effect of carbon dioxide. Thus, reclaiming methane that would otherwise be released to atmosphere may significantly reduce greenhouse gas emissions. RNG is interchangeable with natural gas for pipeline and distribution purposes; therefore, the RNG may be marketed as a renewable energy and offered via typical distribution channels 107, e.g., truck or pipeline, to the end user or consumer 102. The renewable energy infrastructure 110, as shown in FIG. 1, encompasses the equipment and facilities necessary to permit such distribution channels for RNG, which allow the fuel to be accessible to the end user consumer 102. Again, however, the end user or consumer 102 may be forced to purchase vehicles powered by natural gas in order to be able to properly make use of the renewable energy.
As further illustrated in FIG. 1, the consumer 102, in many cases, will continue to purchase higher carbon intensity liquid fuels from convenience stores 104 or other retail outlets for occasions when electric vehicles are insufficient, e.g., long distance driving. Higher carbon intensity fuels 106 may also be transported 105 and employed indirectly by the consumer. Such indirect uses may include, but are not limited to, constructing and providing the renewable energy infrastructure 110 to permit the customer or consumer 102 to take advantage of the renewable energy. Further, higher CI liquid fuels may be necessary to produce the renewable energy and transport the renewable energy.
FIG. 17 illustrates a typical implementation 1700 of a hydrogen production strategy, which may largely focus on the use, by refinery processes, of high carbon intensity hydrogen 1711, such as hydrogen produced in a typical steam reforming process 1706 utilizing a typical natural gas feedstock 1704. As illustrated in FIG. 17, natural gas feedstock 1702 may be generated at wellheads or refineries. The natural gas feedstock 1702 generated at these sources may be transmitted long distances via pipeline, vehicle, marine vessel, or rail 1704 or may be transmitted via pipeline from a co-located refinery for use in a steam reforming process 1706. This steam reforming process 1706 may include a typical methane steam reformer located in a typical refinery. A typical steam reforming process 1706 may produce a high carbon intensity hydrogen 1711 and carbon dioxide 1708, the high carbon intensity due in part to carbon dioxide 1708 produced via the steam reforming process 1706. The carbon dioxide 1708 may be released into the atmosphere 1710. Further, the high carbon intensity hydrogen 1711 may be transported via pipeline/piping 1712 for refinery processing 1714 at a co-located or remote refinery. Such high carbon intensity hydrogen 1711 may further increase the carbon intensity of an output of the refinery processing 1714. The refinery processing 1714 (e.g., at a co-located refinery) may produce a high carbon intensity transportation fuel 1718 for use by an end user. The high carbon intensity transportation fuel 1718 may include a carbon intensity which is increased further, due to the use of the high carbon intensity hydrogen 1711.
Accordingly, Applicants have recognized a need for systems and methods to provide an energy consumer with low carbon intensity transportation fuels and low carbon intensity hydrogen through conventional pathways in which the low carbon intensity transportation fuels and low carbon intensity hydrogen are achieved through targeted reductions of carbon emissions associated with the various stages of fuel and hydrogen selection, production, and transport. The present disclosure is directed to embodiments of such systems and methods.

This patent is subject to a terminal disclaimer.

Systems and methods for holistic low carbon intensity fuel production


Methods of treating an affective disorder in an individual are disclosed. Affective disorders include major depression, melancholic and atypical subtypes, and dysthymia.

Affective and mood disorders are included in a group of mental disorders characterized by neuroendocrine dysregulation and are characterized by a disturbance in the regulation of mood, behavior, and affect. Affective and mood disorders can have serious impact on an individual's functional ability, interpersonal relationships and behavior. Major depression and dysthymia are examples such disorders.
Major depression is a syndromal, episodic and recurrent illness with both psychological and biological components. A diagnosis of bipolar disorder is given to those patients with recurring depression and mania. Those patients with recurrent depression alone have a unipolar pattern. Within the spectrum of depressive illness, there are two distinct subtypes: melancholic depression and atypical depression (Gold et al., N. Engl. J. Med., 319:348-353 (1988); and Gold et al., N. Engl. J. Med., 319:413-420 (1988)).
Melancholic depression is equally common among those with a pattern of unipolar and bipolar depression. Melancholic depression is characterized by hyposomnia (early morning awakening), anorexia and diurnal variation in mood, and is associated with a state of hyperarousal in which patients are painfully preoccupied with personal inadequacy, loss, feelings of worthlessness, guilt and suicidal ideation (Licinio et al., Bailliere's Clin. Endocrin. Met., 5(1):51-58 (1991)).
Atypical depression is more common in bipolar patients than in unipolar depressed patients. Atypical depression is characterized by a state which seems to be opposite to that of melancholic depression. Patients with atypical depression have a syndrome of hypoarousal with hypersomnia, hyperphagia, weight gain and mood liability (Licinio et al., Bailliere's Clin. Endocrin. Met., 5 (1):51-58 (1991)).
Neuroendocrine dysregulation, specifically changes in the hypothalamic-pituitary-adrenal (HPA) axis, has been investigated as a biological correlate of depression. Overall, the HPA axis regulates physiologic responses to stress. The hypothalamus controls endocrine functions and the autonomic nervous system. It is involved in behaviors related to fight, flight, feeding and mating, many of which are altered during episodes of depression. The hypothalamus releases corticotrophic-releasing hormone (CRH) in response to stress, which then stimulates the anterior pituitary to secrete adrenocorticotrophic-releasing hormone (ACTH). ACTH prompts the adrenal cortex to release cortisol which, through elaborate feedback mechanisms signals the hypothalamus to increase or decrease CRH production.
Under ordinary circumstances, activation of hypothalamic CRH is terminated rapidly by the negative feedback of rising glucocorticoid levels. However, in melancholic depression, hypercortisolism does not adequately restrain the production of CRH in the hypothalamus. Thus, in melancholic depression, CRH levels are chronically elevated causing hyperactivity of the HPA axis, hypercortisolism and ACTH levels that are numerically normal, but excessive in the context of high levels of circulating cortisol (Gold et al., N. Engl. J. Med., 314:1329-1335 (1986)). Antidepressant treatments consistently lower HPA axis activity in individuals with melancholic depression. In contrast, atypical depression is associated with hyposecretion of hypothalamic CRH. Thus, in atypical depression, hypothalamic CRH levels are lower than normal causing hypoactivity of the HPA axis. For a review, see Gold et al., Mol. Psychiatry, 1:257-264 (1996).
Dysthymia is a chronic disorder characterized by symptoms that include poor appetite or overeating, low energy (decreased arousal), insomnia or hypersomnia, and poor concentration. These functions are modulated by neuropeptides in the brain, such as CRH (Vale, W. et al., Science, 213:1394-1397 (1981)). Generally, dysthymia is characterized by hypothalamic CRH levels that are higher than normal, thereby causing hyperactivity of the HPA axis. However, in dysthymia, hypothalamic CRH levels can be lower than normal, causing hypoactivity of the HPA axis, in individuals with a higher than normal body mass index (BMI). Thus, in dysthymia, hypothalamic CRH levels are inversely related to the BMI of the individual.
Effective disorders are extremely common in general medical practice, as well as in psychiatry. The severity of these conditions covers an extraordinarily broad range, from normal grief reactions to severe, incapacitating, and sometimes fatal psychosis. The lifetime risk of suicide in major affective disorders is about 10 to 15%, but this statistic does not begin to represent the morbidity and cost of this group of under-diagnosed illnesses. Typically these disorders are treated with antidepressant agents or lithium salts (GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Eight Ed., 1990; Pergramon Press, New York, N.Y.). Nevertheless, many shortcomings and problems continue to be associated with all drugs used to treat affective disorders. In addition to less than-dramatic efficacy in some cases, virtually all the drugs used to treat disorders of mood are potentially lethal when acute over dosage occurs and can cause appreciable morbidity even with careful clinical use.

Methods of neuroendocrine regulation of affective disorders


A wirelessly powered inflatable medical implant system includes a medical provider software application, a patient external controller and a MR-Conditional, nonferrous pump in reservoir implant. The medical provider software application programs the patient external controller for the patient to transmit wireless power and control signals to circuitry in a pump in reservoir implant. In response, the pump in reservoir implant, containing a fluid reservoir and pump package submerged therein, transfers fluid from the reservoir through tubing, and into one or more inflatable medical implants. Submerging the pump package within the reservoir simplifies surgery in males and pump placement in females and provides pump package heatsinking to limit implant overheating.

Inflatable medical implants with manually operated pumps and reversing switches placed in the male scrotum or female labia, which transfer fluid back and forth between an abdominal reservoir and inflatable penile cylinders, urethra cuffs and anal cuffs, are known for treatment of erectile dysfunction, urinary incontinence and fecal incontinence. Some patients, particularly older people with arthritis, find it difficult to operate the implanted manual pump and reversing switch, and there is not a comfortable place to implant the pump in females. Therefore, many patients elect not to have treatment.
More recent concepts replace the implanted manual pump and reversing switch with an electrically driven pump which may be controlled and powered from an external source. In operation, an external unit sends energy and control signals wirelessly to an internal unit, which then activates a separately placed pump unit. Signals may also be fed back from the internal unit to the external unit to control energy flow.
In certain systems, external alternating current power is transmitted transdermally by close-coupled magnetic induction typically operating in the band from 100 KHz to 200 KHz and forming an air core electrical transformer with its primary winding external to the patient and its secondary winding internal to the patient. Due to the low permeability of air and body tissue, few magnetic flux linkages connect between these primary and secondary windings; not like in an iron core transformer where most of the magnetic flux is coupled between primary and secondary windings. Therefore the primary and secondary windings must be placed within a few millimeters of each other to safely transmit any appreciable power, which means the implanted transformer secondary may be implanted in the dermis, a physically and cosmetically uncomfortable situation.
In some systems, this placement problem is alleviated with an internal rechargeable battery or capacitor to accumulate enough energy over time from a magnetic induction source so that when needed, the pump gets enough power to transfer the required fluid. Other systems use high voltages to increase power transmission over longer distances, however increasing the transmitted voltage increases the risk of electric shock. In all these systems, the voltage induced in the internal secondary winding can vary widely due to the patient's placement of the external primary windings with respect to the implanted secondary winding.
Full-wave Schottky diode bridge rectifiers with electromagnetic interference filters are known to convert the secondary winding's varying alternating current voltage into varying direct current voltage. However these full-wave bridge rectifiers have two diode voltage drops in their current delivery path, which set a limit on their efficiency.
In many of these systems, one or more linear voltage regulators are used to convert the varying direct current voltage to stable direct current voltage to power the electronics and the motor. These linear voltage regulators waste transmitted energy and can generate significant heat in the implant.
Technology to limit linear voltage regulator inefficiency is known in the form of a transdermal voltage feedback loop which limits how much voltage is applied to the external primary winding and reaches the internal regulator through the secondary winding, and therefore limits how much power is transmitted and must be dissipated in the linear regulator. Other systems use switch mode power supplies, which can achieve 70-90% efficiency.
In some systems, brushed direct current and brushless direct current motors are known to drive the pump. Both brushed and brushless direct current motors have rotors and stators containing ferrous material and are MR-Unsafe. Brushed direct current motors may be connected to switch mode power supply's output though a solid state forward-off-reversing switch.
Brushless direct current motors are comprised of a direct current to 3-phase inverter and a 3-phase induction motor. Such inverters generate 3-phase pulse width modulated signals to drive a metal-oxide-semiconductor field-effect transistor 3-phase half control bridge circuit, which then feeds the motor.
Positive displacement rotating internal gear fluid pumps, which can be built in millimeter diameters, are also known. For submerged operation, such pumps use a hermetically sealed motor magnetically coupled to the pump to prevent fluid from entering the motor. This magnetic coupling is MR-Unsafe.
What is needed is a MR-Safe or MR-Conditional apparatus without reduction gears and with efficient power transmission and conversion, which will transmit enough power transdermally to inflate and deflate medical implants in less time and with greater efficiency, higher reliability, lower implant voltage, in a small implant volume and with minimal surgical impact for men by not involving the scrotum, and, especially for incontinent women, where there is not a comfortable place to implant a separate pump unit.

Transdermally powered MR-conditional medical implant inflator system


A programmable interrupt controller for use in a multiprocessing environment that can support a serial bus to send interrupt information to the processors. The interrupt serial bus has a data line to drive all the interrupt information to all the processors and a clock line to synchronize edges for the data stream. A third line, normally tri-stated, may be used to provide a parity error indication for the serial bus. The serial data includes a processor identification, a pin identification and state information. As the programmable interrupt controller sends the interrupt data on the serial bus, all the processors clock the data and check parity. If a processor finds a parity error, it drives the parity error indication low so that the information may be transmitted again. No processor will execute the command contained in the serial message before the time has elapsed for any of the processors to report a parity error. If there is no parity error, the processor accepts and decodes the message and asserts or deasserts the appropriate signal.

1. Field of the Invention
The present invention relates to interrupts within a computer system, and more specifically to an interrupt controller for more efficient handling of interrupts in a computer system.
2. Description of the Related Art
A typical computer system contains at least one interrupt service provider, usually a central processing unit (CPU), and a number of input/output (I/O) devices peripheral to the CPU(s). These I/O devices commonly include hard disk drives, floppy disk drives, video adapters, parallel ports, serial ports, and other similar I/O type devices. An I/O device may need to alert the CPU(s) or request service when it completes a task or has a status change, such as finishing a data transfer, completing an operation, receiving data, or the occurrence of an error condition.
The typical mechanism for an I/O device to request service from the CPU(s) involves an interrupt request. An interrupt request is generally a hardware signal sent from the requesting device to a CPU notifying the CPU that the I/O device requires service. Other system devices such as timers, direct memory access (DMA) controllers, and other processors may generate interrupt request signals.
One advantage of using interrupts over other techniques, such as polling, is that the CPU is free to perform other operations between interrupts. When a CPU receives an interrupt request, it stops executing the current instruction routine, saves its state, and jumps to an interrupt service routine. The interrupt service routine includes instructions specific to the device requesting the interrupt so that the CPU can respond to the device condition or status change that instigated the interrupt request. When the interrupt service routine is completed, the CPU restores its state and returns to its location prior to the interrupt.
Referring to FIG. 1, a computer system 100 using interrupts is shown according to the prior art. The computer system 100 includes a CPU 110, and a main memory system 120 coupled to a host bus 180. The main memory system 120 typically includes a memory controller and system memory (not shown). A bus bridge 140 is coupled to the host bus 180 and an expansion bus 190 and typically includes a DMA controller (not shown). The expansion bus 190 typically conforms to a popular bus standard such as the Industry Standard Architecture (ISA), Extended Industry Standard Architecture (EISA), Microchannel Architecture (MCA), or Peripheral Component Interconnect (PCI). Alternatively, multiple expansion busses are included, such as a PCI bus further coupled to an ISA bus. Several I/O devices 150, 160, 170 are coupled to the expansion bus 190. The I/O devices 150, 160, 170 are typically devices such as a floppy disk drive, video adapter, parallel port, or other devices as are well known in the art.
The bus bridge 140 and the I/O devices 150, 160, 170 generate interrupt requests along interrupt request lines 142, 152, 162, 172, respectively, to notify the CPU 110 that service is needed. The interrupt, requests along lines 142, 152, 162, 172 are collected by a programmable interrupt controller (PIC) 130. The programmable interrupt controller 130 is coupled to the host bus 180 and the expansion bus 190. Generally, when the programmable interrupt controller 130 receives one of the interrupt requests along lines 142, 152, 162, 172 it sends an interrupt signal on line 132 to the CPU 110. When the CPU 110 receives the interrupt signal on line 132, it finishes its current operation and sends an interrupt acknowledge along line 112 to the programmable interrupt controller 130. When the programmable interrupt controller 130 receives the interrupt acknowledge it sends an interrupt vector to the CPU 110 over the host bus 180. The interrupt vector indicates the location of the appropriate interrupt service routine to the CPU 110.
Generally speaking, in a typical system, a programmable interrupt controller receives the interrupt request signals from the various system devices and organizes the requests to be sent to the CPU(s). Normally, the programmable interrupt controller includes a mask register associated with each interrupt. The mask register is programmed to block a certain interrupt so that the CPU will not be interrupted by that particular interrupt. The programmable interrupt controller contains other registers associated with each interrupt for indicating information such as the interrupt status and interrupt vector for each interrupt.
The programmable interrupt controller also functions as an overall manager for interrupt requests. It receives the interrupt requests from each device, determines which requests are sent to the CPU(s) first, and handles new incoming interrupt requests. Some devices have more immediate need for service than other devices. Therefore, the programmable interrupt controller provides a priority system to be assigned to the interrupt requests. Generally, the programmable interrupt controller determines which one of the current interrupt requests has the highest priority and forwards that request to a CPU first. Occasionally, an interrupt request will be received by the programmable interrupt controller that has a higher priority than the interrupt request currently being serviced. One technique commonly employed to deal with this situation is interrupt nesting. In interrupt nesting, the programmable interrupt controller allows the incoming interrupt request to interrupt the servicing of an earlier interrupt request currently being serviced if the incoming interrupt request is of higher priority than the earlier interrupt request currently being serviced. If the incoming interrupt request is not of higher priority, it is put in order with other pending interrupt requests, usually according to the source of the interrupt. However, this requires that the queue in each nesting buffer be of sufficient size to accommodate all of the potential interrupt sources. Accordingly, there is a need for an interrupt controller that will optimize the storage of pending interrupts.
In addition to resolving priority among devices needing to be serviced, the controller will also need to resolve a task priority to determine to which CPU in a multiple CPU system the interrupt should be sent. Typically, the CPU or device servicing an interrupt is assigned a task priority according to the level of importance of the task being performed. When a new task is to be performed, it is customary to search for a device that has the lowest task priority, and assign the new task to that device (for an interrupt that does not have a destination previously specified). However, if more than one device shares the same task priority, there is a chance that one device will always end up performing the new task, while other devices at the same task priority level may never be assigned the task. Therefore, it would be desirable to introduce a scheme to ensure that no such uneven distribution of system load occurs.
It can easily be understood that a relatively large amount of time may pass before an interrupt request is serviced, especially if the interrupt request has a low priority. The amount of time between the assertion of an interrupt request and the actual servicing of the interrupt request is called the interrupt latency. A problem associated with large interrupt latencies is that the status of the requesting device may change during the latency period so that servicing is no longer required, and thus the CPU will unnecessarily execute the interrupt service routine. This unnecessary execution of interrupt service routines results in extra overhead because the CPU spends time trying to service a condition which no longer exists, and thus overall system throughput is degraded. Therefore, a technique is desired for preventing invalid interrupt requests from being sent to the CPU.
A typical programmable interrupt controller implementation includes storage registers associated with each interrupt which store the current state of the interrupt, such as pending or in-service. Also, storage registers are required to store information for each interrupt request, such as the vector information and the priority level. Interrupt request receiving circuitry in the programmable interrupt controller coordinates the interrupt request state and other information with processor interface circuitry in the programmable interrupt controller. For systems with a large number of interrupt request sources, the amount of circuitry required to implement the above storage registers is very large. If the system supports multiple CPUs, then the above storage registers may need to be repeated in the programmable interrupt controller for each CPU, further increasing the size of the circuitry. Also, a large amount of circuitry is required to coordinate, manage, and access the storage registers. For an integrated programmable interrupt controller, a large portion of the chip area is require to implement the storage registers and associated circuitry. Therefore, it is desirable to have a more efficient way of referencing and implementing the required storage information for each interrupt.
Additionally, a typical programmable interrupt controller includes control circuitry associated with each interrupt request input to track the changes in the state of the interrupt request. This control circuitry includes some storage elements that are used to store the current state, and some combinatorial logic to determine the outputs and the next state based on the current state and other inputs. Similar control circuitry is required for each interrupt request input. If the number of interrupt request inputs is large, the amount of circuitry required to implement all the control circuitry can become prohibitively large. Therefore, a more efficient way of implementing the interrupt request control circuitry is desired.
In addition, a centralized programmable interrupt controller in a multiprocessing environment must be able to transmit a variety of interrupts, typically sending each to a different pin on a processor. For example, a 486-type processor has pins for system management interrupts (SMI), non-maskable interrupts (NMI), RESET interrupts, and maskable interrupts. In addition, there may be other functions, such as processor initialization and interrupt acknowledge that must be performed on a per processor basis and thus require their own pin. One way for a programmable interrupt controller to support multiple processors is for the programmable interrupt controller to have a pin for every interrupt in every processor. In a large multiprocessing system, the number of pins required can become prohibitive. As such, there is a need for a way to reduce the number of pins required on a programmable interrupt controller to support a large number of interrupts in a multi-processing environment.

Serial bus for transmitting interrupt information in a multiprocessing system


A carrier support arrangement that attaches to a vehicle between a rear bumper crash bar and mounting pads that are provided at the rear of the body of the vehicle. The carrier support is formed of a transverse support bar that has a modified hollow tubular beam construction, with attachment lands its ends. Tubular socket members receive attachment rods of the associated carrier. The tubular beam construction if formed of an upper member and lower member welded together. The web portions of the beam have a series of triangular cutouts, leaving a series of diagonal struts. This construction achieves a weight savings without sacrifice of strength or torsion resistance.

This invention relates to mounts for attaching a trailer hitch, bike rack, ski rack, or other carrier system for a motor vehicle. The invention is more particularly concerned with a support arrangement that attaches to a vehicle between a rear bumper crash bar and mounts therefor that are provided at the rear of the body of the vehicle.
The device of this invention may be employed on an automobile of the type in which the rear bumper is mounted onto the body of the vehicle, which may be a sedan, station wagon, hatchback or other light vehicle. The vehicle design allows for a structural bumper support, e.g., a crash bar, to be mounted on spaced apart attachment pads on the vehicle body. Then the decorative cover of the bumper is mounted over the crash bar. There may be conventional bumper components provided, e.g., foam shock absorber. A transverse support beam for the carrier device has left and right plates, or lands, which are apertured so they may be bolted in place, and these are sandwiched between the vehicle attachment pads and the bumper crash bar. The support beam has welded to it a pair of laterally-spaced tubular receptacles or ports that project to rearward. The ports serve as sockets into which the trailer hitch, bike rack, ski rack, or other carrier device is mounted.
A prior model load carrier of this type is described in U.S. Pat. No. 6,827,377 to Ferrigan. In that model, the transverse support beam is made of a heavy-grade steel, which adds considerably to the vehicle weight. The transverse beam is formed of a heavy-gauge steel, and has full flanges at the upper and lower edges of a beam web.
The applicant of this invention has recently designed an improved carrier support that is adapted to a match the rear bumper design for the recent model years for one vehicle on which this arrangement can be installed, namely the Mini™, of which several models (e.g., COOPER, COOPER D, COOPER S, CLUBMAN) are available. That design is described in the U.S. Pat. Appln. Pub. No. 2009/0115209 A1. The contents of that published patent application are incorporated by reference herein. That carrier support employs a carrier support beam of a modified C-channel design, and has a pair of cantilevered mounting bars that project forward to mate with square tubular members that are present at the rear of the vehicle. However, not all vehicles have such square tubular members available, and it has been desired to create a support beam of sufficient strength that it can be supported on the bumper mounting pads, but also can be constructed so it does not add significantly to the overall weight of the vehicle.

Carrier support for attaching to a motor vehicle


A threaded joint for a steel pipe includes a pin and a box each of which is provided with a contact surface that includes an unthreaded metal contact portion having a seal portion and a threaded portion. This threaded joint includes an ultraviolet ray-curable resin coating film that is formed on the contact surface of at least one of the pin and the box; and an acrylic silicone resin coating film that is formed on at least a portion of a surface of the ultraviolet ray-curable resin coating film.

Oil country tubular goods (for example, a tubing through which a fluid such as crude oil flows; and a casing which surrounds a tubing), which are used in oil drilling for mining crude oil or gas oil, are generally several tens of meters long and are connected using threaded joints until they have a length to reach an oil well. In the past, the depth of an oil well was 2,000 m to 3,000 m (2,187 yards to 3,280 yards). However, in recent deep oil wells such as undersea oil wells, there are cases where the depth of an oil well reaches a range of 8,000 m to 10,000 m (8,748 yards to 10,936 yards) or deeper.
Depending on the usage environment thereof, a threaded joint for a steel pipe used for connecting oil country tubular goods is affected by a load such as an axial tension force caused by the weight of oil country tubular goods and a threaded joint; a complex pressure such as an internal or external surface pressure; and heat in the ground. Therefore, the threaded joint is required to maintain the airtightness of oil country tubular goods without being damaged even in such a tough environment.
FIG. 1 is a diagram schematically illustrating an assembly state of oil country tubular goods A and a coupling B which is a threaded joint component. In the oil country tubular goods A, a pin 1 having male threads 11 (refer to FIG. 2) is formed on external surfaces of both ends thereof. In the coupling B, a box 2 having female threads 21 (refer to FIG. 2) is formed on internal surfaces of both ends thereof. An end of the oil country tubular goods A is connected to an end of the coupling B in advance.
FIG. 2 is a diagram schematically illustrating the details of a pin-box structure of a typical threaded joint (also referred to as a special threaded joint) used for connecting the oil country tubular goods A. The pin 1 is a joint component having the male threads 11 and is typically formed on an end portion of the oil country tubular goods A. The box 2 is a joint component having the female threads 21 and is typically formed on an internal surface of the threaded joint component (coupling B). The pin 1 further includes, in addition to the male threads 11, a seal portion 13 and a shoulder portion 14 which are positioned closer to a tip end side of a steel pipe than the threaded portion. Correspondingly, the box 2 further includes, in addition to the female threads 21, a seal portion 23 which is positioned inside of the joint portion; and a shoulder portion 24 which comes into contact with the shoulder portion 14 of the pin 1. The seal portions 13 and 23 and the shoulder portions 14 and 24 of the pin 1 and the box 2 are an unthreaded metal contact portion of the threaded joint for a steel pipe. Reference numeral 12 represents a lip portion at a tip end of the pin 1 and reference numeral 31 represents a portion where the pin 1 is not in contact with the box 2 (a portion in which bleeding oil remains during connecting).
An end of the oil country tubular goods A is inserted into the coupling B, and the male threads 11 and the female threads 21 are connected to each other. As a result, the seal portion 13 of the pin 1 and the seal portion 23 of the box 2 come into contact with each other at an appropriate interference amount to form a metal seal. This metal seal secures the airtightness of the oil country tubular goods A connected to the coupling B. In this kind of threaded joint, in particular, in the seal portions 13 and 23, non-repairable seizure called galling may occur.
When the tubing and casing are lowered to an oil well, there are cases where a threaded joint connected thereto is disconnected due to various kinds of problems; they are pulled up from the oil well; and then they are connected and lowered again. American Petroleum Institute (API) requires galling resistance and airtightness in the sense that galling does not occur and the airtightness of oil country tubular goods is secured even when makeup (connecting) and breakout (disconnecting) are performed 10 times in the case of a tubing joint or 3 times in the case of a casing joint.
In order to improve airtightness and galling resistance during connecting, in the related art, a viscous liquid lubricant (referred to as "compound grease") containing heavy metal powder is coated onto a contact surface (the threaded portion and unthreaded metal contact portion) of the threaded joint. In API standard BUL5A2, such a compound grease is specified. The compound grease also exhibits rust prevention performance of preventing rust on the coated contact surface.
However, since the compound grease contains a large amount of powder of heavy metals such as zinc, lead, and copper, the coated grease may be washed and overflow on an external surface during the connecting of the threaded joint. As a result, there is a possibility that, in particular, harmful heavy metals such as lead may have an adverse effect on the environment (in particular, marine organisms). In addition, since the work environment deteriorates due to the coating operation of the compound grease, there is a concern of an adverse effect on a human body by the coating operation. Therefore, a threaded joint for a steel pipe capable of exhibiting superior galling resistance without using the compound grease is required.
As a threaded joint which can be used for connecting oil country tubular goods without coating the compound grease, many threaded joints for a steel pipe have been proposed until now in which a contact surface thereof is coated with a solid lubricant coating film composed of an organic or inorganic resin containing lubricating powder such as molybdenum disulfide or graphite.
As described above, in a threaded joint for a steel pipe having a seal portion, since galling is likely to occur particularly in the seal portion, it is necessary that rusting of the seal portion be prevented. This is because galling is likely to occur when the rust occurs. In addition, changes in the shape of the seal portion by corrosion causes deterioration in airtightness. In a threaded joint for a steel pipe which is not coated with the compound grease, since the rust prevention performance by the compound grease is not exhibited, the rust prevention of the seal portion is further important. However, the above-described solid lubricating coating film does not have sufficient rust prevention performance for preventing a cut portion of a joint including a seal portion from being rusted when being stored in a highly corrosive environment for a long period of time.
Patent Document 1 discloses a threaded joint for a steel pipe having superior rust prevention performance that includes an ultraviolet ray-curable resin coating film formed of a photocurable composition, which is curable by the irradiation of ultraviolet rays, on a contact surface of the threaded joint.

NIPPON STEEL & SUMITOMO METAL CORPORATION


In a ring-shaped optical distributive network, provided with a central node and a number (N) of network nodes, distribution signals DS are transmitted in two signal transport directions (F, B) by the central node. For the execution of a drop-and-continue function (DC function), each network node comprises a coupling arrangement (21) provided with an optical 2.times.2 switch (28) and a tapping device (33). The switch and the tapping device are mutually coupled in such a way that the DC function can be carried out in a switchable manner in only one of both signal transport directions simultaneously. The switch (28) is turned over when distribution signals from a signal transport direction in a related network node are no longer received. Such a network is self-healing for a single network failure.

The invention relates to a coupling arrangement for coupling a first and a second optical connection, said coupling arrangement comprising
a first optical point of connection for coupling the first optical connection, PA1 a second optical point of connection for coupling the second optical connection, and PA1 a third point of connection, the coupling arrangement further comprising PA1 a first device which is situated between the first and the second point of connection, provided with PA1 a first sub-point of connection which can be coupled to the first point of connection, PA1 a second sub-point of connection which can be coupled to the second point of connection, and PA1 a third and a fourth sub-point of connection for coupling to a second device, and PA1 the second device, which is coupled to the third and fourth sub-point of connection, said second device being provided with an output which is coupled to the third point of connection. PA1 an input which is coupled to the third sub-point of connection of the optical switch, and PA1 a further output which is coupled to the fourth sub-point of connection of the optical switch. PA1 an optical amplifier provided with an input and an output, and PA1 an optical power splitter provided with an input and a first and a second output, PA1 an optical receiver provided with a signal input and an electrical signal output, for receiving an optical signal at the signal input and delivering a corresponding electrical signal at the signal output, PA1 an optical transmitter provided with a signal input and a signal output, for receiving an electrical signal at the signal input and transmitting a corresponding optical signal at the signal output, PA1 in which the signal input of the optical receiver is coupled to the third sub-point of connection of the optical switch, the signal output of the receiver is coupled to the signal input of the optical receiver and to the third point of connection of the coupling arrangement, and the signal output of the optical transmitter is coupled to the fourth sub-point of connection of the optical switch. In an optical network, such a coupling arrangement can also function as an optical network terminating unit.
Such a coupling arrangement is employed in a node of an optical video transport and distribution system as described in M. Yamashita and T. Tsuchiya, "Optical video transport/distribution system with video on demand service", SPIE Vol. 1817 Optical Communications (1992), pp. 12-22 (referred to hereinafter as "Yamashita and Tsuchiya"). This system comprises a distributive network in which a number of network nodes are included in a single optical fibre connection, while a main node is connected to the ends of the optical fibre connection via an optical power splitter, so that a ring-shaped network is formed. The fibre connection is used bi-directionally. In the main node the signals to be distributed, hereinafter referred to as distribution signals, are transmitted as optical signals in both signal transport directions over the optical fibre connection via the optical power splitter. In each network node the distribution signals from both transport directions are amplified, and partly passed on in each of the two transport directions to a subsequent network node, and partly dropped and, via a uni-directional optical connection, further conducted to an optical network terminating unit (ONU) to which a number of subscriber lines are connected. For this drop-and-continue function, each network node is provided with a coupling arrangement of the above-mentioned kind. The coupling arrangement comprises a bi-directional optical amplifier (the first device), implemented as a quadruple port, with which the distribution signals from both signal transport directions are first amplified and are subsequently split into two signal parts in a power coupler. For each signal transport direction one signal part is subsequently transmitted further over the fibre connection in that signal transport direction, and the other (dropped) signal part is conducted to a separate input of two inputs of an optical switch (the second device). The switch, under the control of a control signal, passes the signal part which is presented to one of the two inputs of the switch on to downstream circuits via an output of the switch. The control signal is derived from distribution signals in both transport directions via an optical tapping point placed in the fibre connection at one side adjacent to the bi-directional amplifier in the network node. If the signal in a network node from one of both signal transport directions drops out, as is the case, for example, for a rupture in the fibre connection or on failure of a bi-directional amplifier in a network node elsewhere in the ring-shaped network, then the optical signal over the fibre connection from the other signal transport direction will still be received. This prior art distributive network is therefore self-healing, and the optical switch in the coupling arrangement in each network node has the function of a protective switch. However, this prior art technique has a major disadvantage. Bi-directional amplifiers are very sensitive for reflections and Rayleigh backscattering, so that only a small number of such amplifiers can be applied in a bi-directional fibre connection. This restricts the number of network nodes which can be included in the ring-shaped network and thus the total dimensioning of distributive networks considerably.

Coupling arrangement for coupling optical connections


An system for minimizing the output torque ripple effect in a switched reluctance electric motor operating in phase overlap mode positions at least one compensating coil such that, when energized, the magnetic flux of the field created by current flowing through the compensation coil couples and opposes the magnetic flux created in the main winding of compensation coil.

The torque spikes created during the switching intervals of phase overlap operation in a SRM are generally referred to as "torque ripples." Torque ripples arise as a result of the increase in magnetic flux field that occurs when two of the sequential phases of the SRM are energized at the same time. Currently, torque ripple effect is minimized using expensive current shaping circuits. A low cost technique is needed for passively minimizing torque ripple effect in SRMs.

Low torque ripple switched reluctance motor regulation system


A humanized monoclonal antibody that binds to an advanced glycation end-product-modified protein or peptide on a cell comprises a heavy chain and a light chain. The antibody binds a carboxymethyllysine-modified protein or peptide. A composition comprises a humanized monoclonal antibody that binds to an advanced glycation end-product-modified protein or peptide on a cell and a pharmaceutically acceptable carrier.

Advanced glycation end-products (AGEs; also referred to as AGE-modified proteins, or glycation end-products) arise from a non-enzymatic reaction of sugars with protein side-chains (Ando, K. et al., Membrane Proteins of Human Erythrocytes Are Modified by Advanced Glycation End Products during Aging in the Circulation, Biochem Biophys Res Commun., Vol. 258, 123, 125 (1999)). This process begins with a reversible reaction between a reducing sugar and an amino group to form a Schiff base, which proceeds to form a covalently-bonded Amadori rearrangement product. Once formed, the Amadori product undergoes further rearrangement to produce AGEs.
Antibodies that bind to an AGE-modified protein on a cell are known in the art. Examples include those described in U.S. Pat. No. 5,702,704 to Bucala and U.S. Pat. No. 6,380,165 to Al-Abed et al. Non-human anti-AGE antibodies are also commercially available. For example, R&D Systems, Inc. (Minneapolis, Minn.) sells a murine anti-AGE antibody raised against carboxymethyl lysine conjugated with keyhole limpet hemocyanin. Commercially-available antibodies are designed for laboratory or diagnostic purposes and may contain material that is not suited for in vivo use in animals or humans. These antibodies are not therapeutic antibodies and are not intended for administration to a human subject.
AGEs and AGE-modified cells have been associated with several pathological conditions including diabetic complications, inflammation, retinopathy, nephropathy, stroke, endothelial cell dysfunction, and neurodegenerative disorders (Bierhaus A, "AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept," Cardiovasc Res, Vol. 37(3), 586-600 (1998)). The association between AGEs and various pathological conditions, diseases and disorders has led to the identification of AGEs as a therapeutic target. Therapies for targeting and removing AGE-modified cells include the application of ultrasound and the administration of antibodies, including humanized antibodies, that bind to AGEs (see, for example, WO 2009/143411, US 2013/0243785 and US 2016/0215043). Antibody-based immunotherapies are particularly desirable because of their ability to specifically target and kill cells that express the antigen to which the antibody binds while sparing cells that do not express the antigen.
Antibodies are Y-shaped proteins composed of two heavy chains and two light chains. The two arms of the Y shape form the fragment antigen-binding (Fab) region while the base or tail of the Y shape forms the fragment crystallizable (Fc) region of the antibody. Antigen binding occurs at the terminal portion of the fragment antigen-binding region (the tips of the arms of the Y shape) at a location referred to as the paratope, which is a set of complementarity determining regions (also known as CDRs or the hypervariable region). The complementarity determining regions vary among different antibodies and gives a given antibody its specificity for binding to a given antigen. The fragment crystallizable region of the antibody determines the result of antigen binding and may interact with the immune system, such as by triggering the complement cascade or initiating antibody-dependent cell-mediated cytotoxicity (ADCC).
Therapeutic monoclonal antibodies were initially produced in mice using the hybridoma technique. A significant problem with administering murine and other unmodified non-human antibodies to human subjects is the risk of the human immune system attacking the non-human antibodies. Many human patients that receive murine antibodies develop an allergic reaction termed the human anti-mouse antibody response (HAMA response). The HAMA response could be mild, such as a rash, or life-threatening, such as renal failure. In addition, the human immune system will often neutralize the murine antibodies, reducing their half-life and impairing their ability to target the intended antigen.
Non-human antibodies may be made less immunogenic to humans by engineering the antibodies to contain a combination of non-human and human antibody components. The non-human antibody is chosen for its specificity for a desired target antigen. A chimeric antibody may be produced by combining the variable region of a non-human antibody with a human constant region. Chimeric antibodies are approximately 70% human and are less immunogenic than unmodified non-human antibodies. A humanized antibody may be produced by replacing the complementarity determining regions (CDRs) of a human antibody with those of a non-human antibody. Humanized antibodies are approximately 95% human and are less immunogenic than chimeric antibodies due to the inclusion of a greater amount of human antibody components. Humanization is a well-known scientific technique (see, for example, U.S. Pat. No. 5,693,762) and has progressed to the point that custom antibody humanization services are commercially available.

Humanized monoclonal advanced glycation end-product antibody


An MRI contrast medium of improved safety and efficacy is disclosed. The composition includes a source of calcium ions and a source of manganese ions in a ratio of from 2:1 to 40:1 in a vehicle suitable for parenteral administration. A method of enhancing an MRI signal in a mammalian tissue with the foregoing composition is also provided.

Magnetic resonance imaging enables noninvasive visualization of tissues and organs of the human body. Contrast in the images generated may be enhanced through the use of an agent that alters the relaxation of water in the tissues of interest relative to bulk water. Species with unpaired electrons, such as the paramagnetic transition and lanthanide metal ions, may be used for this purpose. Manganese chloride was investigated as a contrast agent by Lauterbur and by Wolf in animal models. Both investigators demonstrated significant image enhancement of the liver and other organs (but not blood) through the use of manganese chloride, but determined that the potential clinical utility of the agent was limited by acute cardiac toxicity. Development of contrast agents based on other paramagnetic metal ions is similarly constrained by toxicity and solubility. For instance, gadolinium chloride, acetate and sulfate demonstrate poor tolerability, including symptoms of heavy metal poisoning and accumulation of gadolinium in the liver, spleen and bone.
Chelates of paramagnetic transition and lanthanide metals have been used with some success in diagnostic imaging to overcome both the toxicity and solubility problems. (See U.S. Pat. No. 4,647,447.) Application of this technology has enabled the development of several gadolinium based MR contrast agents including Gd-DTPA (Magnevist.TM., Schering), Gd-DTPA-BMA (Omniscan.TM., Nycomed Amersham PL), Gd-HP-DO3A (Prohance.TM., Bracco Diagnostics) and Gd-DOTA (Dotarem.TM., Guerbet), as well as the manganese-based contrast agent MnDPDP (Teslascan.TM., Nycomed Amersham PL). There are, however, drawbacks associated with the use of chelation to solve problems of toxicity. Metals ions are not irreversibly held in chelate complexes, but are subject to equilibrium between bound and free states. In vivo, this equilibrium is further complicated by equilibria between the chelator and endogenous metal ions as well as between the paramagnetic metal ion and endogenous ligands. Greis, in U.S. Pat. No. 5,098,692 and Bosworth, in U.S. Pat. No. 5,078,986 disclose the use of excess chelator to minimize the amount of free metal ion in chelate-based diagnostic compositions. Nonetheless, the potential for the dissociation of metal ion from the complex remains. The free chelator, either excess or released, may introduce additional toxicity on its own or through chelation of those endogenous metal ions that are required as cofactors for essential enzymes or for other biological functions. Unfortunately, chelates also demonstrate reduced solution relaxivity relative to the free metal ions. The interaction of paramagnetic metal ions with water molecules, which shortens proton relaxation time relative to bulk water and gives rise to signal enhancement, is obtunded by chelation, since the same sites of metal-water interaction are used to form the non-covalent associations between metal and chelate. Thus chelation provides safety at the price of reduced imaging efficacy (compared to the free metal ion). In practice this loss of efficacy may be as high as 60-80%.
Manganese chelate image enhancement agents are known: e.g MnDPDP, MnDTPA, MnEDTA and derivatives, Mn porphyrins such as MnTPPS.sub.4, and fatty acyl DTPA derivatives. These manganese chelates are not known to bind to endogenous macromolecules, as is the case for manganese ion. As a consequence, the enhanced efficacy seen for Mn ion following macromolecular association is seen for Mn chelates only as a function of the rate at which and the extent to which the manganese ion dissociates from the complex. This results in the need for increased dosing of Mn chelates relative to free Mn ion. The dose must be additionally increased to make up for losses due to renal excretion of the chelate during the time course of the diagnostic examination. In a variation on chelation, Quay (European patent application 308983) has described the use of manganese amino acid coordination complex solutions. This application also discusses the addition of calcium ions to the manganese amino acid solutions at levels up to 0.75 mole equivalents relative to manganese.
About ten years ago, Schaefer et al investigated a mixture of Mn++ and Ca++ salts in the form of manganese gluconate and calcium gluconate in a one to one mole ratio, administered intravenously to dogs, for cardiac perfusion imaging. Although the agent discriminated normally perfused from ischemic tissue, Schaefer et al also noted acute cardiotoxicity similar to that seen with manganese chloride alone. The authors suggested that a possible way around the observed adverse cardiac effects might be to employ a chelate rather than a salt of manganese. No further studies employing manganese gluconate and calcium gluconate or other salts or complexes providing Mn++ and Ca++ in a higher ratio than one- to-one have subsequently appeared.
U.S. Pat. Nos. 5,525,326 and 5,716,598 describe oral manganese formulations for imaging of the gastrointestinal tract and for liver imaging; the latter takes advantage of the fact that the blood supply from the GI tract passes through the liver, which removes the manganese from the blood stream prior to return of the blood to the heart. Additional oral agents have been investigated, including manganese polymers, manganese impregnated molecular sieves, manganese clays and foodstuffs with high manganese content, such as blueberry juice. In general, cardiovascular safety is achieved for these agents at the expense of limiting the diagnostic utility of the agents to MR examination of the GI tract and in some cases, the liver. The administration of manganese in nanoparticulate form has been described in U.S. Pat. No. 5,401,492. Other particulate approaches include sequestration of Mn compounds in liposomes and metal clusters, such as manganese oxalate and manganese hydroxyapatite. Particulate agents are useful for a limited number of diagnostic applications, namely, the gastrointestinal tract and organs, such as the liver and the spleen, that are involved in the uptake and sequestration of blood borne particles.
Thus it would be useful to have an agent for diagnostic imaging of tissues, systems and organs, particularly in humans, that would increase the contrast in an MR image without giving rise to problems of toxicity. It would also be useful to have an agent that could be employed for a wide variety of tissues, systems and organs that are physiologically remote from the gastrointestinal tract.

Manganese compositions and methods for MRI


The invention provides vascular access methods, systems and devices facilitating long-term, repeated, percutaneous access to a patient's blood stream. This is provided by an access tube apparatus adapted for anastomosis to the sidewall of a target anatomical vessel. The access tube has a replaceable occluder that fits within the conduit of the access tube in between blood treatments or when vascular access is otherwise not needed. When such access is desired, the percutaneously accessible occluder is simply removed from the access tube.

Examples of procedures that require repeated access to anatomical vessels include dialysis and the delivery of medicines for an extended period of time. The multiple punctures that such repeated access necessitates eventually render the accessed vessels unsuitable for further effective injections. Accordingly, there is a need for apparatus, methods, and systems for facilitating long-term, repeated vascular access.
Dialysis procedures, for example, typically employ catheters, which are inserted into a patient's bloodstream to withdraw blood for treatment and then return treated blood back into the bloodstream. However, there are a number of drawbacks to such catheter systems. For example, because the catheters of such systems are inserted directly into the lumen of a patient's blood vessel, they obstruct blood flow in the vessels. Therefore, the diameter of catheters available for dialysis is quite limited. A dialysis catheter must be sufficiently small to allow for a relatively smooth path for blood flow around the catheter. Because high flow rates through catheters are desirable to maximize the efficiency of dialysis procedures, this limitation is disadvantageous.
Dialysis procedures and systems utilizing catheters have a number of other disadvantages. For example, because the catheters of such systems are inserted directly into a patient's bloodstream, they are susceptible to developing thrombi, infection, and/or other complications. In addition, prior to each treatment with a conventional catheter dialysis system, the patient's skin and blood vessel must be punctured in one or more locations. These repeated punctures can damage a patient's blood vessels to the extent that they can no longer withstand further punctures. Also, repeated punctures of a patient's skin can be painful and can likewise damage the skin. Moreover, because the repeated use of larger needles and catheters causes greater damage to a patient's blood vessels and skin, this further limits the effectiveness of conventional dialysis procedures.
One solution to the need for repeated access which does not employ intraluminal catheters is disclosed in U.S. Pat. No. 3,826,257 issued to Buselmeier. Buselmeier discloses a percutaneous vascular access device utilizing a U-shaped shunt tube, the ends of which are anastomosed in an end-to-end manner to the severed ends of an artery and adjacent vein. The other ends of the artery and vein are tied off and allowed to become non-functional.
There are numerous drawbacks and disadvantages to the Buselmeier device, some of which will now be discussed. First, in Buselmeier, blood flow in the shunt tube is constantly exposed to foreign or non-native surfaces which are not easily replaceable—i.e., not without further recurring surgical procedures. Because there is such a large non-native surface area exposed to blood flow in the vessel, and because those surfaces that are exposed are not easily replaceable, the Buselmeier device is prone to complications such as thrombosis, blood stagnation, and infection. The only way to prevent or control such complications would be to replace the device, which requires an invasive surgical procedure. A replacement surgery would be needed on a more frequent periodic basis than would be practical. Moreover, the surgeries themselves tend to cause trauma to the vessels being accessed, which may ultimately leave them unsuitable for further access. For at least these reasons, the Buselmeier configuration is not suitable for effective long-term vascular access.
In addition, the Buselmeier device has blood from an artery re-routed directly into a vein. The characteristics of the fluid flow in an artery are significantly different from the characteristics of the fluid flow in a vein. These fluid flow dissimilarities may lead to additional adverse effects that detrimentally affect the long term accessibility of the blood vessels that must be accessed for the external blood treatment to be effectively performed. For example, in an arterio-venous (AV) graft constructed as a vascular access for dialysis, the blood flow and blood pressure characteristic of the arterial circulation are so different from the blood flow and blood pressure in the vein into which the blood of the AV graft flows that the vein usually develops hyperplasia and stenoses. Because of these fluid flow dissimilarities, it is preferable to avoid the detrimental impact on the vessels and their long-term accessibility caused by the Buselmeier configuration, even apart from the persistent surgical procedures needed to avoid the blood-flow complications discussed above.
It is therefore desirable to provide devices, systems, and methods that permit repeated access to a blood vessel or other anatomical vessel for external treatment, such as hemodialysis, in such a way that the vessel being accessed is available for successive dialysis operations. Moreover, it is desirable, particularly from a patient's perspective, to provide such devices, systems, and methods wherein access to a blood vessel is obtained without the need for puncturing the patient's skin and blood vessels each time access is needed.
It is also desirable to provide devices, systems and methods that permit repeated access to a blood vessel for the purpose of delivering medicines into the patient's blood stream in such a way that the receiving blood vessel is not so severely damaged that it cannot be used after a few administrations of medicine.
Furthermore, it would be desirable to provide a device that is suitable for repeated vascular access for the purpose of long term medicine delivery into the patient's blood flow and also for the purpose of effectively practicing hemodialysis for a long period of time. It would also be advantageous to provide such a device that can be connected to any of several veins and/or arteries or a combination thereof as desired. In addition, it would be desirable to provide such a device or system wherein the hemodialysis procedure could be completed without obstructing the flow of blood in the patient's bloodstream and thereby limiting the diameter of available tubes for blood transport.
The practical advantages of such devices and systems would be considerably enhanced if the device or system is reliably attachable to a blood vessel. These goals should be accomplished while minimizing, or avoiding to the maximum extent possible, undesirable adverse effects such as vessel thrombosis, blood stagnation, the formation of undesirable blood disturbances, and infection. Such complications are minimized by providing a configuration designed to minimize the exposure of the blood stream to non-native materials between accesses and can be further minimized by providing a configuration wherein the only non-native surface area exposed to blood flow is replaceable.
The prior art has yet to provide an apparatus or system having the desirable characteristics discussed above. Accordingly, there is a need for methods and apparatus that provide for repeated vascular access while minimizing the problems which are associated with those of the prior art.

Apparatus and methods for occluding an access tube anastomosed to sidewall of an anatomical vessel

Integrated Vascular Interventional Technologies, L.C., (“IVIT LC”)


An electron gun for a color cathode ray tube is formed such that parallel vertical blades are extending toward cathodes formed at both edges of each electron beam passing hole in the outgoing plate of a focus electrode. Horizontal blades extending toward the cathodes at a predetermined length are formed at the edges of the top and bottom portions of electron beam passing holes in the incoming plate of a dynamic focus electrode. Thus, the horizontal blades are inserted into the electron beam passing holes of the focus electrode, which reduces astigmatism due to deflection aberration and improves the focusing characteristics.

The present invention relates to an electron gun for a color cathode ray tube, and, more particularly, to an electron gun for a color cathode ray tube, wherein the focusing characteristic of electron beams is improved by reducing astigmatism caused by an uneven magnetic field of a deflection yoke.
The resolution of a color cathode ray tube depends on the size of an electron beam which lands on a phosphor screen. Accordingly, in order to obtain a high resolution picture, it is important that the electron beam spot projected onto the phosphor screen is as small as possible without distortion or a halo. However, in conventional color cathode ray tubes, since the RGB electron guns are arranged in-line, and a deflection yoke is adopted which deflects magnetic field as a pincushion in the horizontal direction and as a barrel in the vertical direction, astigmatism of the electron beams emitted from the electron gun and landing on the phosphor screen, occur due to the uneven magnetic field of the deflection yoke.
When the electron beams produced from such an electron gun land on the center of the phosphor screen, the deflection magnetic field does not affect them, so astigmatism of the electron beams does not occur, thus enabling the formation of a circular electron beam spot without halo. However, when deflected toward the periphery of the phosphor screen, the electron beams diverge in the horizontal direction and are excessively focused in the vertical direction due to the deflection magnetic field. Therefore, the beam spot formed on the screen has a halo in the vertical direction around its bright core which is distorted in the horizontal direction, so that picture resolution is degraded.
One example of an electron gun for a conventional color cathode ray tube is illustrated in FIG. 1, which is devised to solve the above-described problem.
The conventional electron gun has a sequentially arranged triode consisting of cathodes 2, a control electrode 3, and a screen electrode 4, and a main lens system composed of a focus electrode 5, a dynamic focus electrode 6, and a final accelerating electrode 7. Vertically-elongated electron beam passing holes 5H are formed in focus electrode 5 to correspond to horizontally-elongated electron beam passing holes 6H in dynamic focus electrode 6. A predetermined static focus voltage Vf is supplied to focus electrode 5. An anode voltage Ve higher than focus voltage Vf is supplied to final accelerating electrode 7. A parabolic dynamic focus voltage Vfd is supplied to dynamic focus electrode 6, which is synchronized with the vertical/horizontal synchronizing signals of the deflection yoke and its negative peak is the same as focus voltage Vf.
In electron gun 1 of the conventional color cathode ray tube formed as described above, when the electron beams do not deflect, in other words, when the electron beams emitted from electron gun 1 land on the center of the phosphor screen, dynamic focus voltage Vfd whose negative peak voltage is the same as focus voltage Vf is supplied to dynamic focus electrode 6. Thus the potential of focus electrode 5 and dynamic focus electrode 6 is the same, so that a quadrupole lens is not formed between them. Therefore, the electron beams simply pass through a major lens formed between dynamic focus electrode 6 and final accelerating electrode 7, and then land on the center of the phosphor screen.
In contrast, when the electron beams emitted from cathodes 2 deflect toward the periphery of the phosphor screen due to the uneven deflection magnetic field, dynamic focus voltage Vfd synchronized with a deflection signal is applied to dynamic focus electrode 6, so that a quadrupole lens having a focusing lens in a focusing section and a diverging lens in a diverging section is formed between focus electrode 5 and dynamic focus electrode 6. Due to the vertically-elongated electron beam passing holes 5H formed in the outgoing plane of focus electrode 5 and the horizontally-elongated electron beam passing holes 6H formed in the incoming plane of dynamic focus electrode 6, the lens has a weaker focusing force and a stronger diverging force in the vertical direction relative to the horizontal direction. Therefore, the electron beams passing through the quadrupole lens having the two lenses are under the influence of a force which focuses in the horizontal direction and diverges in the vertical direction, so that the cross-sectional shape of the beams becomes vertically-elongated. When the vertically-elongated electron beam deflects toward the periphery of the phosphor screen after having passed through the major lens formed between dynamic focus electrode 6 and final accelerating electrode 7, the deflecting magnetic field of the deflection yoke compensates the distortion of the electron beam caused by the uneven deflecting magnetic field. That is, the electron beam diverges in the horizontal direction, and is focused in the vertical direction. As a result, a circular beam spot can be obtained at the periphery of the phosphor screen.
However, in electron gun 1 of the conventional color cathode ray tube, since vertically-elongated electron beam passing holes 5H are formed in the outgoing plane of focus electrode 5, and horizontally-elongated electron beam passing holes 6H are formed in the incoming plane of dynamic focus electrode 6, during assembly, it is difficult to make the vertically-elongated electron beam passing holes 5H accurately correspond to the horizontally-elongated electron beam passing holes 6H. Moreover, if vertically-elongated electron beam passing holes 5H do not exactly correspond to horizontally-elongated electron beam passing holes 6H, the quadrupole lens formed between beam passing holes 5H and 6H becomes asymmetric which abnormally distorts the electron beams passing through the lens so that a desirable electron beam spot cannot be obtained To be specific, focus electrode 5 and dynamic focus electrode 6 which form the quadrupole lens are spaced apart from each other by a predetermined interval. For this reason, since an external electric field, i.e., an electric field flowing inside the neck, possibly encroaches between focus electrode 5 and dynamic focus electrode 6, the static lens may be distorted by leakage of the electric field.

Electron gun for a color cathode ray tube


A high speed IO buffer is disclosed. The high speed IO buffer includes a first P-type metal oxide semiconductor (PMOS) transistor coupled to an IO voltage source. The high speed IO buffer also includes a first N-type metal oxide semiconductor (NMOS) transistor coupled to a ground source, a second PMOS transistor coupled to the first PMOS transistor and a pad and a second NMOS transistor coupled to the first NMOS transistor and the pad. The first PMOS transistor, the first NMOS transistor, the second PMOS transistor and the second NMOS transistor are arranged in a cascoded arrangement.

An input output (TO) circuit enables transmission of signals in/out of an integrated circuit (IC). A programmable IO supports multiple standards, e.g., high voltage standards, low voltage standards, high speed standards, low speed standards and etc. The programmable IO is commonly available in Programmable Logic Device (PLD).
The programmable IO is typically built with 2.5V Complementary Metal Oxide Semiconductor (CMOS) transistors. The 2.5V CMOS transistor has an acceptable reliability profile to support high voltage standards, but at the same time, has a performance bottleneck when supporting low voltage standards. The electrical current propagating through the drain of a 2.5V transistor is significantly insufficient for the purpose of IO functions for the low voltage standards. There are techniques for overcoming low drain current in 2.5V transistors, by way of increasing planar width on the 2.5V transistors, but such techniques may increases the total capacitance within the transistor.
The programmable IO supports high speed memory interface standards, which require relatively fast transistors in terms of switching on and off within the programmable IO. However, one of the drawbacks of relatively fast transistors is having a low overdrive voltage limit. Hence, when utilizing fast transistors, the programmable IO may not support high voltage standards, e.g., standards that utilize voltages of 2.5V or 3.3V.
It is within this context that the embodiments described herein arise.


A method for estimating an emergency level of a vehicular accident includes detecting an event associated with the vehicular accident, initiating a video recording of an interior and/or exterior of the vehicle in response to the detecting of the event, uploading the video recording on a remotely accessible page, and reviewing the uploaded video recording to estimate the emergency level of the vehicular accident. Also disclosed herein is a system for accomplishing the same.

Vehicular accidents are a common occurrence in modern day travel, and some may be more serious than others. In response to more serious accidents, emergency personnel are often dispatched to the accident scene to provide medical attention or other assistance to injured occupant(s) of the vehicle(s) involved. In many instances, the emergency personnel have limited knowledge, if any at all, of the severity of the accident, including the extent of injury to the vehicle occupants and/or the extent of injury to the vehicle, prior to arriving at the accident scene.

System and method for estimating an emergency level of a vehicular accident


An appliance, such as a flashlight, accepts first and second batteries. The appliance also includes an electrical load, such as a light source. A first circuit, such as a DC to DC converter, receives power from the first battery and supplies power to the load. A second circuit, such as a DC to DC converter, receives power from the second battery and supplies electrical power to the load. In one embodiment, the appliance accepts batteries having multiple physical sizes.

Primary or non-rechargeable batteries are available in a variety of physical sizes, chemistries, and voltages. For example, alkaline and carbon-zinc primary batteries are commonly available in AAA, AA, C, and D size cells which provide a nominal output voltage 1.5 volts direct current (VDC). Secondary or rechargeable batteries are likewise available in a variety of physical sizes, chemistries, and voltages. Examples include lithium ion, nickel metal hydride (NiMH), and nickel cadmium (NiCd) batteries which are available in a range of sizes and voltages. NiMH and NiCd batteries, for example, are commonly available in AAA, AA, C, and D size cells which provide a nominal output voltage of 1.2 VDC. Of course, still other battery sizes, chemistries, and voltages are also available.
Electrical appliances which rely on batteries as a source of electrical energy are ubiquitous. These appliances perform a variety of functions and are used in numerous situations, including for example consumer, commercial, industrial, and medical applications. Consequently, portable electric appliances present a wide variety of electrical loads, such as a light source in the case of a flashlight, sophisticated electronic circuitry and displays in the case of computing and medical devices, electric motors in the case of devices which produce motion, heating and cooling devices, and the like. Moreover, these devices are packaged in any number of sizes and shapes, depending on the characteristics of the particular appliance and its application. Generally, however, it is desirable that these portable devices be readily transportable by a human.
The batteries received by these devices are often connected electrically in series so as to provide the voltage needed to power the load. Where relatively larger currents are required, two or more batteries (or groups of batteries connected in series) are sometimes connected electrically in parallel.
While such configurations have proven to be extremely useful, they can present operational issues. Thus, for example, the mixing of primary and secondary batteries, partially discharged batteries, batteries having differing charge states, or batteries having different chemistries can deleteriously affect the performance of the batteries and the operation of the appliance. It can also be difficult or impossible to hot swap batteries during the operation of the appliance.
Another recurring issue is the availability of batteries to power these appliances. A particularly vexing situation arises when batteries of the size or type required by a particular appliance are not readily at hand. While an appliance which accepts batteries of more than one size or type provides additional flexibility, the mixing of different size batteries can likewise deleteriously affect the performance of the batteries and the operation of the appliance.

Enhanced portable battery powered electrical appliance