The described invention provides methods and regimens for treating adverse consequences of a persistent and progressive myocardial injury-due to a vascular insufficiency that occurs early or late in a subject in need thereof, and progressive myocardial injury-preventing compositions that contain a chemotactic hematopoietic stem cell product, and, optionally, an additional active agent. The method treats ongoing vascular insufficiency affecting coronary circulation by (i) stimulating neoangiogenesis in a peri-infarct border zone, thereby improving myocardial perfusion; and, (ii) through a paracrine effect, preventing apoptosis of cardiomyocytes in the peri-infarct border zone. The neoangiogenesis and paracrine-mediated reduction of apoptosis reduces progressive myocardial cell loss, which leads to improvement in cardiac function and a reduction of risk of major adverse cardiovascular events.

The Cardiac Cycle
The term "cardiac cycle" is used to refer to all or any of the mechanical events related to the coronary blood flow or blood pressure that occurs from the beginning of one heartbeat to the beginning of the next. Blood pressure increases and decreases throughout the cardiac cycle. The frequency of the cardiac cycle is the heart rate. Every single 'beat' of the heart involves five major stages: (1)"late diastole," which is when the semilunar valves close, the atrioventricular (Av) valves open and the whole heart is relaxed; (2) "atrial systole," which is when the myocardium of the left and right atria are contracting, AV valves open and blood flows from atrium to ventricle; (3) "isovolumic ventricular contraction," which is when the ventricles begin to contract, AV and semilunar valves close, and there is no change in volume; (4) "ventricular ejection," which is when the ventricles are empty but still contracting and the semilunar valves are open; and (5) "isovolumic ventricular relaxation," when pressure decreases, no blood is entering the ventricles, the ventricles stop contracting and begin to relax, and the semilunar valves are shut because blood in the aorta is pushing them shut. The cardiac cycle is coordinated by a series of electrical impulses that are produced by specialized heart cells found within the sino-atrial node and the atrioventricular node.
Coronary Blood Flow
The flow of blood through the coronary arteries is pulsatile, with characteristic phasic systolic and diastolic flow components. Systolic flow, which relates to the contraction or pumping phase of the heart cycle, has rapid, brief, retrograde responses. Diastolic flow, which relates to the relaxation or filling phase of the heart cycle, occurs during the relaxation phase after myocardial contraction, with an abrupt increase above systolic levels and a gradual decline parallel with that of aortic diastolic pressures. Intramural coronary blood volume changes during each heartbeat, with the myocardium accommodating the volume change brought about by muscular contraction. Coronary venous flow is out of phase with coronary arterial flow, occurring predominantly in systole and nearly absent during diastole.
For each heartbeat, blood pressure varies between systolic and diastolic pressures. The term "systolic pressure" refers to the peak pressure in the arteries, which occurs near the end of the cardiac cycle when the ventricles are contracting. The term "diastolic pressure" refers to the minimum pressure in the arteries, which occurs near the beginning of the cardiac cycle when the ventricles are filled with blood.
Coronary blood flow not only is phasic but also varies with the type of vessel and location in the myocardium. Coronary arterioles appear to have specialized regulatory elements along their length that operate "in series" in an integrated manner. A system of multiple functional "valves" permits fine control of the coronary circulation. The smallest arterioles dilate during metabolic stress, resulting in reduced microvascular resistance and increased myocardial perfusion. Stenosis or narrowing of a blood vessel produces resistance to blood flow related directly to the morphologic features of the stenosis. As the upstream arteriolar pressure decreases due to a fall in distending pressure across the stenosis, myogenic dilation of slightly larger arterioles upstream occurs and causes an additional decrease in resistance. Increased flow in the largest arterioles augments shear stress and triggers flow-mediated dilation, further reducing the resistance of this network.
The arterial and venous pulsatile flow characteristics of the heart are dependent on intramyocardial compliance. The term "compliance" refers to a measure of the tendency of a hollow organ to resist recoil toward its original dimensions upon removal of a distending or compressing force. The higher the compliance the more elastic the material. Compliance is calculated using the following equation, where ΔV is the change in volume, and ΔP is the change in pressure:C=ΔV/ΔP
The capacity of the heart as a reservoir is controlled by resistance arterioles to coronary vascular inflow. Outlet resistance is related to intramural cardiac veins. The intramyocardial capillary resistance influences both arterial and venous responses but predominantly acts in concert with outlet resistance.
Approximately 75% of total coronary resistance occurs in the arterial system, which comprises conductance (R1), prearteriolar (R2) and arteriolar and intramyocardial capillary vessels (R3). Normal epicardial coronary arteries in humans typically are 0.3 to 5 mm in diameter, and do not offer appreciable resistance to blood flow. Normally, large epicardial vessel resistance (R1) is trivial until atherosclerotic obstructions compromise the lumen. Precapillary arterioles (R2), 100 to 500 μm in size) are resistive vessels connecting epicardial to myocardial capillaries and are the principal controllers of coronary blood flow. They contribute approximately 25% to 35% of total coronary resistance. Distal precapillary arteriolar vessels (<100 μm in diameter), the main site of metabolic regulation of coronary blood flow, are responsible for 40-50% of coronary flow resistance. The dense network of about 4000 capillaries per square millimeter ensures that each myocyte is adjacent to a capillary. Capillaries are not uniformly patent (meaning open; affording free passage), because precapillary sphincters regulate flow according to the needs of the myocardium.
Several conditions, such as left ventricular hypertrophy, myocardial ischemia, or diabetes, can impair the microcirculatory resistance (R3), blunting the maximal absolute increase in coronary flow in times of increased oxygen demand.
Ischemia
The myocardium depends almost entirely on aerobic metabolism, since oxygen stores in the heart are meager. Myocardial oxygen supply rises and falls in response to the oxygen (energy) demands of the myocardium. The term "autoregulation" refers to the ability to maintain myocardial perfusion at constant levels in the face of changing driving forces. Autoregulation maintains coronary perfusion at relatively constant levels over a wide range of mean aortic pressure. When aortic pressure exceeds its upper or lower limits, coronary blood flow precipitously declines or increases proportionately.
The heart needs to be supplied with a sufficient quantity of oxygen to prevent underperfusion. When reduced perfusion pressure distal to stenoses is not compensated by autoregulatory dilation of the resistance vessels, ischemia, meaning a lack of blood supply and oxygen, occurs. Because the zone least supplied generally is the farthest out, ischemia generally appears in areas farthest away from the blood supply.
After total or near-total occlusion of a coronary artery, myocardial perfusion occurs by way of collaterals, meaning vascular channels that interconnect epicardial arteries. Collateral channels may form acutely or may preexist in an under-developed state before the appearance of coronary artery disease. Preexisting collaterals are thin-walled structures ranging in diameter from 20 μm to 200 μm, with a variable density among different species. Preexisting collaterals normally are closed and nonfunctional, because no pressure gradient exists to drive flow between the arteries they connect. After coronary occlusion, the distal pressure drops precipitously and preexisting collaterals open virtually instantly.
The term "myocardial ischemia" refers to a decrease in blood supply and oxygen to the cells of the myocardium. The development of myocardial ischemia has been attributed to two mechanisms: (1) increased myocardial oxygen demand, and (2) decreased myocardial perfusion and oxygen delivery. (Willerson, J. T. et al., J. Am. Coll. Cardiol. 8(1): 245-50 (1986)). Myocardial ischemia generally appears first and is more extensive in the subendocardial region, since these deeper myocardial layers are farthest from the blood supply, with greater need for oxygen.
Transient ischemia, hibernating myocardium, and myocardial infarction are clinically different conditions.
Transient Ischemia.
The term "transient ischemia" as used herein refers to a reversible (meaning that the myocytes survive the insult) narrowing of a coronary artery at rest or with exercise where there is no thrombus or plaque rupture but where blood supply cannot be met. Every time the heart's oxygen demand increases, an imbalance between oxygen demand and supply is created. Transient ischemia produces a cascade of events beginning with metabolic and biochemical alterations leading to impaired ventricular relaxation and diastolic dysfunction, impaired systolic function, and electrocardiographic abnormalities with ST segment alterations, followed by increased end-diastolic pressure with left ventricular dyssynchrony, hypokineses, akinesis, and dyskinesis, and lastly painful symptoms of angina. Even though ischemic myocytes experience physiological and metabolic changes within seconds of the cessation of coronary flow, resulting in T wave and sometimes ST segment abnormalities (but without serum enzyme elevation), no cell death results from the ischemia. Kloner, R. A. and Jennings, R B, Circulation 104: 2981-89 (2001). Once blood flow is re-established, a complete recovery of myocyte contractile function takes place.
Although angina pectoris (chest pain) may be a symptom of transient ischemia, by and large transient ischemia is silent (meaning ST-segment depression of at least 1 mm is present without associated symptoms, e.g., chest pain) in 79% of subjects. In most patients with stable angina, for example, physical effort or emotion, with a resultant increase in heart rate, blood pressure, or contractile state, or any combination thereof, increases myocardial oxygen demand without an adequate delivery in oxygen delivery through tightly narrowed (stenosed) coronary arteries. More than 40% of patients with stable angina treated with one or more antianginal drugs have frequent episodes of silent ischemia, which has been shown to predict a higher risk of coronary events and cardiac death. Deedwania, P C, Carbajal, E V, Arch. Intern. Med. 150: 2373-2382 (1991).
Chronic Myocardial Ischemia.
The term "chronic myocardial ischemia (CMI)" as used herein refers to a prolonged subacute or chronic state of myocardial ischemia due to narrowing of a coronary blood vessel in which the myocardium "hibernates", meaning that the myocardium downregulates or reduces its contractility, and hence its myocardial oxygen demand, to match reduced perfusion, thereby preserving cellular viability and preventing myocardial necrosis. This hibernating myocardium is capable of returning to normal or near-normal function on restoration of an adequate blood supply. Once coronary blood flow has been restored to normal or near normal and ischemia is resolved, however, the hibernating myocardium still does not contract. This flow-function mismatch resulting in a slow return of cardiac function after resolution of ischemia has been called stunning. The length of time for function to return is quite variable, ranging from days to months, and is dependent on a number of parameters, including the duration of the original ischemic insult, the severity of ischemia during the original insult, and the adequacy of the return of the arterial flow. A number of studies have provided evidence for inflammation in hibernating myocardium. Heusch, G. et al., Am. J. Physiol. Heart Circ. Physiol. 288: 984-99 (2005). A study conducted in a porcine model of myocardial hibernation in which the mean rest (left anterior descending coronary artery (LAD) coronary blood flow was reduced to about 60% of baseline for a period of 24 hours to four weeks, detected apoptotic myocytes in all experimental pigs in the hibernating regions supplied by the stenotic LAD, suggesting that functional downregulation may not be adequate to prevent gradual, ongoing myocyte death through apoptosis in hibernating myocardium. Chen, C, et al., J. Am. Coll. Cardiol. 30: 1407-12 (1997).
Acute Myocardial Infarction (AMI).
Another type of insult occurs during AML AMI is an abrupt change in the lumen of a coronary blood vessel which results in ischemic infarction, meaning that it continues until heart muscle dies. On gross inspection, myocardial infarction can be divided into two major types: transmural infarcts, in which the myocardial necrosis involves the full or nearly full thickness of the ventricular wall, and subendocardial (nontransmural) infarcts, in which the myocardial necrosis involves the subendocardium, the intramural myocardium, or both, without extending all the way through the ventricular wall to the epicardium. There often is total occlusion of the vessel with ST segment elevation because of thrombus formation within the lumen as a result of plaque rupture. The prolonged ischemic insult results in apoptotic and necrotic cardiomyocyte cell death. See Kajstura, J., et al., Lab Invest. 74: 86-107 (1996). Necrosis compromises the integrity of the sarcolemmal membrane and intracellular macromolecules such that serum cardiac markers, such as cardiac-specific troponins and enzymes, such as serum creatine kinase (CK), are released. In addition, the patient may have electrocardiogram (ECG) changes because of full thickness damage to the muscle. An ST-Elevation Myocardial Infarction (STEMI) is a larger injury than a non-ST-elevation myocardial infarction. ST-segment elevation and Q waves on the ECG, two features highly indicative of myocardial infarction, are seen in only about half of myocardial infarction cases on presentation.
AMI remains common with a reported annual incidence of 1.1 million cases in the United States alone (Antman, E. M., Braunwald, E., Acute Myocardial Infarction, in Principles of Internal Medicine, 15th Ed., Braunwald, E. et al., Eds., New York: McGraw-Hill (2001)). Preclinical and clinical data demonstrate that following a myocardial infarction, the acute loss of myocardial muscle cells and the accompanying peri-infarct border zone hypo-perfusion result in a cascade of events causing an immediate diminution of cardiac function, with the potential for long term persistence. The extent of myocardial cell loss is dependent on the duration of coronary artery occlusion, existing collateral coronary circulation and the condition of the cardiac microvasculature. Paul et al., Am. Heart J. 131: 710-15 (1996); Pfeffer, M. A., Braunwald, E., Circulation 81: 1161-72 (1990); Sheilban, I. e. al., J. Am. Coll. Cardiol. 38: 464-71 (2001); Braunwald E., Bristow, M. R., Circulation 102: IV-14-23 (2000); Rich et al., Am. J. Med. 92:7-13 (1992); Ren et al., J. Histochem. Cytochem. 49: 71-79 (2002); Hirai, T. et al., Circulation 79: 791-96 (1989); Ejiri, M. et al., J. Cardiology 20: 31-37 (1990). Because myocardial cells have virtually no ability to regenerate, myocardial infarction leads to permanent cardiac dysfunction due to contractile-muscle cell loss and replacement with nonfunctioning fibrotic scarring. Frangogiannis, N. G., et al., Cardiovascular Res. 53(1): 31-47 (2002). Moreover, compensatory hypertrophy of viable cardiac muscle leads to microvascular insufficiency that results in further demise in cardiac function by causing myocardial muscle hibernation and apoptosis of hypertrophied myocytes in the peri-infarct border zone.
Among survivors of myocardial infarction, residual cardiac function is influenced by the extent of ventricular remodeling (meaning changes in size, shape, and function, typically a progressive decline in function, of the heart after injury). Alterations in ventricular topography (meaning the shape, configuration, or morphology of a ventricle) occur in both infarcted and healthy cardiac tissue after myocardial infarction. Pfeffer, M. A., Braunwald, E., Circulation 81: 1161-72 (1990). Ventricular dilatation (meaning a stretching, enlarging or spreading out of the ventricle) causes a decrease in global cardiac function and is affected by the infarct size, infarct healing and ventricular wall stresses. Recent efforts to minimize remodeling have been successful by limiting infarct size through rapid reperfusion (meaning restoration of blood flow) using thromobolytic agents, and mechanical interventions, including, but not limited to, placement of a stent, along with reducing ventricular wall stresses by judicious use of pre-load therapies and proper after-load management. Id. Regardless of these interventions, a substantial percentage of patients experience clinically relevant and long-term cardiac dysfunction after myocardial infarction. Sheiban, I. et al., J. Am. Coll. Cardiol. 38: 464-71 (2001). Despite revascularization of the infarct related artery circulation and appropriate medical management to minimize ventricular wall stresses, a significant percentage of these patients experience ventricular remodeling, permanent cardiac dysfunction, and consequently remain at an increased lifetime risk of experiencing adverse cardiac events, including death. Paul et al., Am. Heart J. 131: 710-15 (1996); Pfeffer, M. A., Braunwald, E., Circulation 81: 1161-72 (1990).
At the cellular level, immediately following a myocardial infarction, transient generalized cardiac dysfunction uniformly occurs. In the setting of a brief (i.e., lasting three minutes to five minutes) coronary artery occlusion, energy metabolism is impaired, leading to demonstrable cardiac muscle dysfunction that can persist for up to 48 hours despite immediate reperfusion. This so-called "stunned myocardium phenomenon" occurs subsequent to or after reperfusion and is thought to be a result of reactive oxygen species. The process is transient and is not associated with an inflammatory response. Frangogiannis, N. G., et al., Cardiovascular Res. 53(1): 31-47 (2002). After successful revascularization, significant recovery from stunning occurs within three to four days, although complete recovery may take much longer. Soli, R., Prog. Cardiovascular Disease 40(6): 477-515 (1998); Sakata, K. et al., Ann. Nucleic Med. 8: 153-57 (1994); Wollert, K. C. et al., Lancet 364: 141-48 (2004).
Coronary artery occlusion of more significant duration, i.e., lasting more than five minutes, leads to myocardial ischemia (i.e. an insufficient blood flow to the heart's muscle mass) and is associated with a significant inflammatory response that begins immediately after reperfusion and can last for up to several weeks. Frangogiannis, N. G., et al., Cardiovascular Res. 53(1): 31-47 (2002); Frangogiannis, N. G. et al., Circulation 98: 687-798 (1998).
The inflammatory process following reperfusion is complex. Initially it contributes to myocardial damage but later leads to healing and scar formation. This complex process appears to occur in two phases. In the first so-called "hot" phase (within the first five days), reactive oxygen species (in the ischemic myocardial tissue) and complement activation generate a signal chemotactic for leukocytes (chemotaxis is the directed motion of a motile cell, organism or part towards environmental conditions it deems attractive and/or away from surroundings it finds repellent) and initiate a cytokine cascade. Lefer, D. J., Granger, D. N., Am. J. Med. 4:315-23 (2000); Frangogiannis, N. G., et al., Circulation 7:699-710 (1998). Mast cell degranulation, tumor necrosis factor alpha (TNF.alpha.) release, and increased interleukin-6 (IL-6), intercellular adhesion molecule 1 ("ICAM-1" or CD-54, a receptor typically expressed on endothelial cells and cells of the immune system), selectin (L, E and P) and integrin (CD11a, CD11b and CD18) expression all appear to contribute to neutrophil accumulation and degranulation in ischemic myocardium. Frangogiannis, N. G. et al., Circulation 7: 699-710 (1998), Kurrelmeyer, K. M, et al., Proc. Natl. Acad. Sci. USA. 10: 5456-61 (2000); Lasky, L. A., Science 258: 964-69 (1992); Ma, X. L., et al., Circulation 88(2): 649-58 (1993); Simpson, P. J. et al., J. Clin. Invest. 2: 624-29 (1998). Neutrophils contribute significantly to myocardial cell damage and death through microvascular obstruction and activation of neutrophil respiratory burst pathways after ligand-specific adhesion to cardiac myocytes. Entman, M. L., et al., J. Clin. Invest. 4: 1335-45 (1992). During the "hot" phase, angiogenesis is inhibited due to the release of angiostatic substances, including interferon gamma-inducible protein (IP 10). Frangogiannis, N. G., et al., FASEB J. 15: 1428-30 (2001).
In the second phase, the cardiac repair process begins (about day 6 to about day 14), which eventually leads to scar formation (about day 14 to about day 21) and subsequent ventricular remodeling (about day 21 to about day 90). Soon after reperfusion, monocytes infiltrate the infarcted myocardium. Attracted by complement (C5a), transforming growth factor B1 ("TGF-B1") and monocyte chemotactic protein 1 ("MCP-1"), monocytes differentiate into macrophages that initiate the healing process by scavenging dead tissue, regulating extracellular matrix metabolism, and inducing fibroblast proliferation. Birdshall, H. H., et al., Circulation 3: 684-92 (1997). Secretion of interleukin 10 (IL-10) by infiltrating lymphocytes also promotes healing by down-regulating inflammatory cytokines and influencing tissue remodeling. Frangogiannis, N. G. et al., J. Immunol. 5:2798-2808 (2000). Mast cells also appear to be involved in the later stages of myocardial repair by participating in the formation of fibrotic scar tissue. Stem Cell Factor (SCF) is a potent attractor of mast cells. SCF mRNA has been shown to be up-regulated in ischemic myocardial segments in a canine model of myocardial infarction and thus may contribute to mast cell accumulation at ischemic myocardial sites. Franigogiannis, N. G. et al., Circulation 98: 687-798 (1998). Mast cell products (including TGF-B, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and gelatinases A and B) induce fibroblast proliferation, influence extracellular matrix metabolism, and induce angiogenesis. Fang, K. C., et al., J. Immunol. 162: 5528-35 (1999); Takeshi, S., et al., Cardiology 93: 168-74 (2000).
Following a myocardial infarction, neoangiogenesis occurs after the "hot" phase of the inflammatory process subsides (about day 5) coincident with rising levels of VEGF (VEGF peaks at about day 7 and gradually subsides to baseline at about day 14 to about day 21). During this phase of the healing process, endothelial precursor cells (EPCs) are mobilized and recruited to the infarct site. Shinitani, S., et al., Circulation 103: 2776-79 (2001). Without being limited by theory, it has been suggested that the chemokine stromal cell derived factor-1 (SDF-1), which is the ligand for the CXCR-4 chemokine receptor expressed by CD34+ cells, also plays a role in homing of cells to areas of ischemic damage. Ceredini, D. J., et al., Nature Medicine 10: 858-63 (2004); Askari, A., et al., Lancet 362: 697-703 (2003); Yamaguchi, J. et al., Circulation 107: 1322-34 (2003). While it is known that SDF-1 plays a role in hematopoiesis and is involved in migration, homing and survival of hematopoietic progenitors, and while SDF-1 has been implicated in ischemic neovascularization in vivo by augmenting EPC recruitment to ischemic sites (Yamaguchi et al. Circulation 107:1322-1328 (2003), SDF-1's role in neoangiogenesis is not certain. There is suggestive evidence implicating SDF-1. For example, SDF-1 gene expression is upregulated during hypoxia, a deficiency of oxygen in the tissues, by hypoxia inducible factor-1. Furthermore, CD34+ cells are capable of homing to areas of ischemia, rich in SDF-1, including infarcted myocardium. Askari et al., Lancet 362: 697-703 (2003). Moreover, virtually all CD34+ CXCR-4+ cells co-express VEGF-2 and therefore migrate in response to VEGF as well as SDF-1. Peichev M., et al., Blood 95: 952-58 (2000). CD34+CXCR-4+VEGF-1 cells, once recruited, are capable of contributing to neoangiogenesis. Yamaguchi, J. et al., Circulation 107: 1322-34 (2003).
The Peri-Infarct Border Zone
The zone of dysfunctional myocardium produced by coronary artery occlusion extends beyond the infarct region to include a variable boundary of adjacent normal appearing tissue. (Hu, Q., et al., Am. J. Physiol. Heart Circ. Physiol. 291: H648-657 (2006)). This ischemic, but viable, perinfarct zone of tissue separates the central zone of progressive necrosis from surrounding normal myocardium. The peri-infarct zone does not correlate with enzymatic parameters of infarct size and is substantially larger in small infarcts. Stork, A., et al., European Radiol. 16(10): 2350-57 (2006).
Ischemia due to edema and compression of the blood vessels in the border zone may be very important to outcome after an AMI. It is known, for example, that after an AMI, transient ischemia occurs in the border zones, and that percutaneous coronary interventions, which open up the infarct-related artery, can adversely affect the health of the peri-infarct border zones. It has been suggested that intermediate levels of mean blood flow can exist as the result of admixture of peninsulas of ischemic tissue intermingled with regions of normally perfused myocardium at the border of an infarct. (Hu, Q., et al., Am. J. Physiol. Heart Circ Physiol. 291: H648-657 (2006)). However, the boundary of the intermingled coronary microvessels, which in dogs is no more than 3 mm in width, cannot explain the relatively broad region of dysfunctional myocardium surrounding an infarct. Murdock, R H, Jr., et al., Cir. Res. 52: 451-59 (1983); Buda, A J, et al., J. Am. Coll. Cardiol. 8: 150-58 (1986). Progressive dysfunction of this peri-infarct myocardium over time may contribute to the transition from compensated remodeling to progressive heart failure after an AMI.
Heart Failure
Heart failure is a complex clinical syndrome that arises secondary to abnormalities of cardiac structure and/or function that impair the ability of the left ventricle to fill or eject blood. See Hunt, S. J. Am. Coll. Cardiol. 46: e1-e82 (2005). It is a progressive condition where the heart muscle weakens and cannot pump blood efficiently. Patients may be categorized as having heart failure with depressed ejection fraction ("EF") (referred to as "systolic failure"), or having heart failure with a normal EF or heart failure with a preserved EF (referred to as "diastolic failure"). Patients may have significant abnormalities of left ventricle (LV) contraction and relaxation and yet have no symptoms, in which case they are referred to as having "asymptomatic heart failure". When a patient with chronic heart failure deteriorates, the patient is referred to as having "decompensated heart failure", or, if the symptoms arise abruptly, as having "acute decompensated heart failure".
The various diagnostic criteria used to determine the presence of heart failure are shown in the following Table (V. L. Roger, Intl. J. Environ. Res. Public Health 7(4): 1807-30 (2010)):
European SocietyGothenburg Score4Framingham1Boston2of Cardiology3 nCriteria/method of assessmentMAJORCATEGORY I:1. Symptoms ofCARDIAC SCORECRITERIA:Historyheart failure (at restHistory of heartSelf-ParoxysmalRest dyspneaor during exercise)disease (1-2 pts)reportnocturnal dyspnea(4 pts)andAngina (1-2 pts)Self-or orthopneaOrthopnea (4 pts)2. ObjectivereportNeck veinParoxysmalevidence of cardiacEdema (1 pt)Self-distensionnocturnaldysfunction (at rest)reportRalesdyspnea (3 pts)andNocturnal DyspneaSelf-CardiomegalyDyspnea on3. Response to(1pt)reportAcute pulmonarywalking on leveltreatment directedRales (1 pt)Physicaledema S3 gallop(2 pts)towards heart failureexamIncreased venousDyspnea on(in cases whereAtrial fibrillationECGpressure ≧16 cmclimbing (1 pt)diagnosis is in(1 pt)waterCATEGORYdoubt).PULMONARY SCORECirc.time ≧25 secII: PhysicalCriteria 1 and 2History of ChronicSelf-Hepatojugularexaminationshould be fulfilled inbronchitis/asthmareportrefluxHeart rateall cases(1-2 pts)MINORabnormality (1-2Cough, phlegm, orSelf-CRITERIA:pts)wheezing (1 pt)reportAnkle edemaJugular venousRhonchi (2 pts)PhysicalNight coughpressureexamDyspnea onelevation (1-2Cardiac and pulmonary score areexertionpts)calculated and used toHepatomegalyLung cracklesdifferentiate Cardiac formPleural effusion(1-2 pts)pulmonary dyspneaVital capacityWheezing (3 pts)decreased 1/3Third heartfrom maximumsound (3 pts)Tachycardia rateCATEGORYof ≧120/min)III: ChestMAJOR ORradiographyMINORAlveolarCRITERION:pulmonaryWeight loss ≧4.5 kgedema (4 pts)in 5 days inInterstitialresponse topulmonarytreatmentedema (3 pts)HEARTBilateral pleuralFAILURE:effusions (3 pts)present with 2Cardiothoracicmajor or 1 majorratio ≧0.50 (3and 2 minorpts)criteriaUpper-zone flowredistribution (2pts)HEARTFAILURE:Definite 8-12pts, possible 5-7pts, unlikely 4pts or less1McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N. Engl. J. Med. 285: 1441-1446 (1971)2Carlson K J, Lee DC Goroll AH, Lehy M, Johnson RA, an analysis of physicians' reasons for prescribing long-term digitalis therapy in outpatients. J. Chronic Dis. 38: 733-39 (1985)3Guidelines for the diagnosis of heart failure The Task Force on Heart Failure of the European Society of Cardiology. Eur. Heart J. 16: 741-751 (1995)4Eriksson H, Caidahl K, Larsson B, Ohlson LO, Welin L, Wilhelmsen L, Svardsudd K. Cardiac and pulmonary causes of dyspnoea-validation of a scoring test for clinical-epidemiological use: the Study of Men Born in 1913. Eur. Heart J. 8: 1007-1014 (1987)
The prognosis of heart failure is poor with reported survival estimates of 50% at 5 years and 10% at 10 years; left ventricular dysfunction is associated with an increase in the risk of sudden death. Id.
To date, no ideal therapy exists for preventing the long term adverse consequences of vascular insufficiency, particularly vascular insufficiency after myocardial infarction. Large vessel revascularization (meaning the successful placement of a stent) is insufficient in addressing increased demands posed by compensatory myocardial hypertrophy. As a result, infarct extension and fibrous replacement commonly occur, regardless of large vessel revascularization, appropriate medical management of ventricular wall stresses, and potential natural, albeit suboptimal, CD34+ cell-mediated neoangiogenesis (one of theories relating to the underlying cause of myocardial infarction is that the ability to mobilize these cells may be biologically limited).
Intense interest has developed in evaluating the ability of endothelial and myocardial precursor cells to limit damage to the myocardium after infarction and to limit or prevent ventricular remodeling. Significant preclinical data and some clinical data demonstrate the safety and potential of cell therapy using a variety of cell precursors (particularly hematopoietic cells) to contribute to neoangiogenesis, limited cardiac myogenesis (principally by fusion), and muscle preservation in the myocardial infarct zone. See, e.g., Jackson, et al., J. Clin. Invest. 107: 1395-1402 (2001); Edelberg, J. M., et al., Cir. Res. 90: e89-e93 (2002); Schichinger, V. et al., New Engl. J. Med. 355 (12): 1210-21 (2006) (using bone marrow-derived progenitor cells); Assmus, B. et al., New Engl. J. Med. 355 (12) 1222-32 (2006) (using bone marrow-derived progenitor cells), but see Lunde, K. et al., New Eng. J. Med. 355 (12): 1199-209 (2006) (using hone marrow-derived progenitor cells).
Bone marrow consists of a variety of precursor and mature cell types, including hematopoietic cells (the precursors of mature blood cells) and stromal cells (the precursors of a broad spectrum of connective tissue cells), both of which appear to be capable of differentiating into other cell types. Wang, J. S. et al., J. Thorn. Cardiovasc. Surg. 122: 699-705 (2001); Tomita, S. et al., Circulation 100 (Suppl. II): 247-256 (1999); Saito, T. et al., Tissue Eng. 1: 327-43 (1995). Unmodified (i.e., not fractionated) marrow or blood-derived cells have been used in several clinical studies, for example, Hamann, K. et al., Japan Cir. J. 65: 845-47 (2001); Strauer, B. E., et al., Circulation 106: 1913-18 (2002); Assmus, et al., Circulation 106: 3009-3017 (2002); Dobert, N. et al., Eur. J. Nuel. Med. Mal. Imaging, 8: 1146-51 (2004); Wollert, K. C. et al., Lancet 364: 141-48 (2004). Since the mononuclear fraction of bone marrow contains stromal cells, hematopoietic precursors, and endothelial precursors, the relative contribution of each of these populations to the observed effects, if any, remains unknown.
CD34 is a hematopoietic stem cell antigen selectively expressed on hematopoietic stem and progenitor cells derived from human bone marrow, blood and fetal liver. Yin et al., Blood 90: 5002-5012 (1997); Miaglia, S. et al., Blood 90: 5013-21 (1997). Cells that express CD34 are termed CD34+. Stromal cells do not express CD34 and are therefore termed CD34−. CD34+ cells isolated from human blood may be capable of differentiating into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. See Yeh, et al., Circulation 108: 2070-73 (2003). CD34+ cells represent approximately 1% of bone marrow derived nucleated cells; CD34 antigen also is expressed by immature endothelial cell precursors (mature endothelial cells do not express CD34). Peichev, M. et al., Blood 95: 952-58 (2000). In vitro, CD34+ cells derived from adult bone marrow give rise to a majority of the granulocyte/macrophage progenitor cells (CFU-GM), some colony-forming units-mixed (CFU-Mix) and a minor population of primitive erythroid progenitor cells (burst forming units, erythrocytes or BFU-E). Yeh, et al., Circulation 108: 2070-73 (2003). CD34+ cells also may have the potential to differentiate into, or to contribute to, the development of new myocardial muscle, albeit at low frequency.
Techniques have been developed using immunomagnetic bead separation to isolate a highly purified and viable population of CD34+ cells from bone narrow mononuclear cells. See U.S. Pat. Nos. 5,536,475, 5,035,994, 5,130,144, 4,965,205, the contents of each of which is incorporated herein by reference. Two clinical studies support the clinical application of bone marrow derived CD34+ cells after myocardial infarction. See C. Stamm, et al., Lancet 361: 45-46 (2003); Herenstein, B. et al., Blood Supplement, Abs. 2696 (2004).
Neoangiogenesis
Neovascularization, the formation of new blood vessels, is inherent in vascular tissue, and it can be induced by trauma, ischemia, inflammation, or tumor growth. The creation of new blood vessels is dependent on a complicated interaction between locally produced cytokines and cells derived from the tissue area, and blood circulation. Neovascularization can be divided into three processes: angiogenesis, vasculogenesis, and arteriogenesis.
Angiogenesis is the formation of new capillaries by sprouting from the existing capillary net, probably from the postcapillary venules; arteriogenesis is the transformation of preexisting aterioles/collaterales into small muscular arteries and/or de novo formation of new vessels with a tunica media; and vasculogenesis is the formation of new vessels from multipotent endothelial stem cells.
In vasculogenesis, circulating endothelial progenitor cells (EPC) contribute to new blood vessel growth (capillaries) by secreting the necessary growth factors and chemokines for endothelial cells to migrate or by incorporating into the newly formed vessels. During angiogenesis, endothelial cells are activated by ischemia and grow in the direction of angiogenic signals. The endothelial cells fuse and develop a lumen, thereby forming a new, small capillary vessel.
In arteriogenesis, circulating leukocytes are attracted to the activated endothelium. They assist in enlarging collateral anastomosis (connection of two blood vessels).
Angiogenic Growth Factors
Neoangiogenesis (meaning formation of new or recent blood vessels), is dependent on a complex interaction between extracellular matrix, endothelial cells and pericytes in response to an imbalance in the presence of angiogenic, as compared to angiostatic factors in the local environment (Fangogiannis, N G, The FASEB Journal, Vol. 15, June 2001, pp. 1428-1430).
A large number of angiogenic factors and their receptors have been identified including basic fibroblast growth factor, platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor, fibroblast growth factor, angiopoietin-1, transforming growth factor beta-1 (TGF-β1), transforming growth factor alpha (TGF-α), and epidermal growth factor (EGF) (Rifkin D B, Moscatelli D., J Cell Biol 1989; 109:1-6; Nicosia R F, Nicosia S V, Smith M., Am J Pathol 1994; 145:1023-1029; Takahashi Y, Bucana C D, Liu W et al. J Natl Cancer Inst 1996; 88:1146-1151; Jouanneau J, Moens G, Montesano R et al., Growth Factors 1995; 12:37-47; Suri C, McClain J, Thurston G et al. Science 1998; 282:468-471; Pepper M S, Vassalli J D, Orci L et al., Exp Cell Res 1993; 204:356-363; Gleave M E, Hsieh J T, Wu H C et al., Cancer Res 1993; 53:5300-5307).
Angiogenesis in the tissue can be initiated by local production and liberation of vascular growth factors. Many different vascular growth factors have now been discovered, which can induce angiogenesis by stimulation of growth and migration of endothelial cells. Angiogenic potentials of growth factors depend on their ability to induce a proliferation of endothelial cells, a modification in cell adhesion (i.e., cell to cell and cell to extracellular matrix peptides interactions) and/or a remodeling process of the extracellular matrix and the basement membrane. Main growth factors are direct-acting endothelial cell mitogens (e.g., FGF, VEGF, HGF). Other factors (PDGF, TGF-beta, and TNF-alpha) can be indirectly mitogenic, by promoting an overexpression of a direct-acting mitogen. Members of the CXC chemokine family also have been reported to play a role in the regulation of angiogenesis. CXC chemokines behave as either angiogenic or angiostatic, depending on the presence of an ELR protein motif (ELR positive chemokines such as IL-8 are angiogenic, ELR negative chemokines such as IP-10 are angiostatic).
During recent years, a number of experimental studies have shown that treatment with angiogenic growth factors can promote the development of collaterals to ischemic tissue in models of progressive coronary occlusion, and acute myocardial infarction.
Direct-Acting Endothelial Cell Mitogens
Vascular Endothelial Growth Factor (VEGF)
VEGF is a diffusible endothelial cell-specific mitogen and angiogenic factor that also increases vascular permeability (Ferrara N, Davis-Smyth T., Endocr Rev 1997; 18:4-25; Torimura T, Sata M, Ueno T et al. Hum Pathol 1998; 29:986-991). It elicits a pronounced angiogenic response in a variety of in vivo models (Connolly D T, Heuvelman D M, Nelson R et al., J Clin Invest 1989; 84:1470-1478; Plate K H, Breier G, Weich H A et al. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992; 359:845-848; Phillips G D, Stone A M, Jones B D et al., In Vivo 1994; 8:961-965; Tolentino M J, Miller J W, Gragoudas E S et al. Arch Ophthalmol 1996; 114:964-970; Cao Y, Linden P, Farnebo J et al. Proc Natl Acad Sci USA 1998; 95:14389-14394). Endothelial cell survival in newly formed vessels is VEGF-dependent (Alon T, Hemo I, Itin A et al. Nat Med 1995; 1:1024-1028). Three high-affinity cognate endothelial receptors for VEGF have been identified: VEGFR-1/Flt-1, VEGFR-2/Flk-1/KDR, and VEGFR-3/Flt-4. These receptors function as signaling molecules during vascular development (Mustonen T, Alitalo K., J Cell Biol 1995; 129:895-898). VEGFR-1 and VEGFR-2 are cell surface receptor tyrosine kinases (RTKs), which are localized on endothelial cells during embryogenic development. VEGF RTKs, members of a large family of RTKs, are essential components of signal transduction pathways that affect cell proliferation, differentiation, migration, and metabolism. VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation and vasculogenesis (Millauer B, Wizigmann-Voos S, Schnurch H et al., Cell 1993; 72:835-846; Quinn T P, Peters K G, De Vries C et al., Proc Natl Acad Sci USA 1993; 90:7533-7537).
Hypoxia can directly increase the synthesis of VEGF receptors, permitting a tissue-targeting of VEGF during ischemia induced angiogenesis. Beyond angiogenesis, the permanent expression of VEGF receptors by quiescent endothelium suggests a role of VEGF in the maintenance of endothelial integrity. Recently, among CD34+ mononuclear blood cells, some putative circulating endothelial cell progenitors have been isolated, which are incorporated in post-natal angiogenic sites. Flk-1 is expressed by those monocytes, assimilated to angioblasts, and by early hematopoietic stem cells, but ceases to be expressed as soon as hematopoietic differentiation is initiated towards non-endothelial specificities. Flt-1, also present on monocytes seems to be involved in monocyte chemotaxis. Bautch, V L, Blood 2006 107: 3-4, DOI: 10.1182/blood-2005-10-4061; Feistritzer, C et al., Am. J. Respir. Cell Mol. Biol., Vol. 30, pp. 729-735, 2004; Itokawa, T et al., Mol Cancer Ther 2002; 1: 295-302; Patschan, D et al., Am J Physiol Renal Physiol 291: F176-F185, 2006.
In vitro, VEGF stimulates the proliferation and migration of endothelial cells and forms tube-like structures, but it can also inhibit endothelial cell apoptosis. Upregulation of plasminogen activators and collagenases by VEGF induces extracellular matrix proteolysis. This allows the migration of endothelial cells and release of growth factors responsible for an auto-amplification. In addition, VEGF augments vessels permeability and may cause extravasation of plasma proteins necessary for the formation of a new extracellular matrix. It can also accelerate reendothelialization, attenuate intimal hyperplasia in balloon-injured carotid artery. Wang, S et al., PNAS, Vol. 105, No. 22, pp. 7738-7743; Bernatchez, P N et al., The Journal of Biological Chemistry, Vol. 274, No. 43, Oct. 22, 1999, pp. 31047-31054; Asahara, T et al., Circulation, 1995; 91: 2793-2801.
Fibroblast Growth Factor (FGF)
FGF comprises sixteen members (FGF-1 to FGF-16) with a wide range of targets and potentials. Two of them have been studied concerning their angiogenic power: acidic FGF (or FGF-1) and basic-FGF (or FGF-2). Four isoforms of FGF-2 (18 to 24 kD) have been described, and have widespread expression. Binding of FGF-1 or FGF-2 to heparan sulphates enhances their autocrine or paracrine bioactivity.
FGF-receptors originate from the super-family of immunoglobulins, with 4 types identified: FGF-R1, R2, R3, and R. With variable affinity, those tyrosine kinase-type receptors have been isolated on cardiomyocytes, endothelial and smooth muscle cells. In vitro, stimulation of endothelial cells by FGF-2 leads to the formation of capillary-like tubular structures, subsequent to proliferation and migration of endothelial cells.
The physiological involvement of FGF during ischemia-induced angiogenesis is not entirely understood.
Scatter Factor/Hepatocyte Growth Factor (SH/HGF)
HGF, a 80 kDa heterodimeric cytokine, binds heparan sulfate as soon as it is secreted by mesenchymal cells. Ischemia was found to be a positive stimulus of expression of both HGF and its tyrosine kinase receptor. In vitro, the formation of tube-like structures, subsequent to HGF's direct activation of endothelial cell proliferation and migration, is highly enhanced by upregulation of VEGF-A in smooth muscle cells.
Other Mitogens
Angiopoietin-1 (Ang-1)
Angiopoietin-1, expressed by mesenchymal cells, is considered to be the principal ligand of TIE-2, a tyrosine kinase receptor, which is expressed on vascular endothelial cells and early hematopoietic cells. Angiopoietin-2 (ang-2) is a second ligand that inhibits TIE-2 phosphorylation, and acts like a competitive inhibitor of Ang-1.
Platelet Derived Growth Factor (PDGF)
Platelets, macrophages, endothelial cells and vascular smooth muscle cells provide three kinds of PDGF: AA, BB, or AB. Shear-stress and hypoxia have been reported to upregulate PDGF-BB expression in endothelial cells and in macrophages. Shear-stress activates PDGF-β receptors expressed by endothelial cells, smooth muscle cells and pericytes.
PDGF is considered to be a proangiogenic factor. It is not a direct mitogen for endothelial cells, but is able to enhance production of both FGF-2 and VEGF by smooth muscle cells. Recruitment of smooth muscle cells and pericytes represents probably the principal contribution of PDGF during angiogenesis,
Transforming Growth Factor (TGF)
TGF-β is a 25 kDa homodimeric polypeptide; its distribution includes kidneys, liver, heart, platelets, and endothelial cells. TGF-β production is sensitive to the variation of shear stress exerted on endothelial cells. TGF-β is considered to be a positive regulator of angiogenesis in vivo.
Apoptotic Pathways
Apoptotic cell death is induced by many different factors and involves numerous signaling pathways, some dependent on caspase proteases (a class of cysteine proteases) and others that are caspase independent. It can be triggered by many different cellular stimuli, including cell surface receptors, mitochondrial response to stress, and cytotoxic T cells, resulting in activation of apoptotic signaling pathways.
The caspases involved in apoptosis convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death. The caspases at the upper end of the cascade include caspase-8 and caspase-9. Caspase-8 is the initial caspase involved in response to receptors with a death domain (DD) like Fas.
Receptors in the TNF receptor family are associated with the induction of apoptosis, as well as inflammatory signaling. The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. The Fas-FasL interaction plays an important role in the immune system and lack of this system leads to autoimmunity, indicating that Fas-mediated apoptosis removes self-reactive lymphocytes. Fas signaling also is involved in immune surveillance to remove transformed cells and virus infected cells. Binding of Fas to oligimerized FasL on another cell activates apoptotic signaling through a cytoplasmic domain termed the death domain (DD) that interacts with signaling adaptors including FAF, FADD and DAX to activate the caspase proteolytic cascade. Caspase-8 and caspase-10 first are activated to then cleave and activate downstream caspases and a variety of cellular substrates that lead to cell death.
Mitochondria participate in apoptotic signaling pathways through the release of mitochondrial proteins into the cytoplasm. Cytochrome c, a key protein in electron transport, is released from mitochondria in response to apoptotic signals, and activates Apaf-1, a protease released from mitochondria. Activated Apaf-1 activates caspase-9 and the rest of the caspase pathway. Smac/DIABLO is released from mitochondria and inhibits IAP proteins that normally interact with caspase-9 to inhibit apoptosis. Apoptosis regulation by Bcl-2 family proteins occurs as family members form complexes that enter the mitochondrial membrane, regulating the release of cytochrome c and other proteins. TNF family receptors that cause apoptosis directly activate the caspase cascade, but can also activate Bid, a Bcl-2 family member, which activates mitochondria-mediated apoptosis. Bax, another Bcl-2 family member, is activated by this pathway to localize to the mitochondrial membrane and increase its permeability, releasing cytochrome c and other mitochondrial proteins. Bcl-2 and Bcl-xL prevent pore formation, blocking apoptosis. Like cytochrome c, AIF (apoptosis-inducing factor) is a protein found in mitochondria that is released from mitochondria by apoptotic stimuli. While cytochrome C is linked to caspase-dependent apoptotic signaling, AIF release stimulates caspase-independent apoptosis, moving into the nucleus where it binds DNA. DNA binding by AIF stimulates chromatin condensation, and DNA fragmentation, perhaps through recruitment of nucleases.
The mitochondrial stress pathway begins with the release of cytochrome c from mitochondria, which then interacts with Apaf-1, causing self-cleavage and activation of caspase-9. Caspase-3, -6 and -7 are downstream caspases that are activated by the upstream proteases and act themselves to cleave cellular targets.
Granzyme B and perforin proteins released by cytotoxic T cells induce apoptosis in target cells, forming transmembrane pores, and triggering apoptosis, perhaps through cleavage of caspases, although caspase-independent mechanisms of Granzyme B mediated apoptosis have been suggested.
Fragmentation of the nuclear genome by multiple nucleases activated by apoptotic signaling pathways to create a nucleosomal ladder is a cellular response characteristic of apoptosis. One nuclease involved in apoptosis is DNA fragmentation factor (DFF), a caspase-activated DNAse (CAD). DFF/CAD is activated through cleavage of its associated inhibitor ICAD by caspases proteases during apoptosis. DFF/CAD interacts with chromatin components such as topoisomerase II and histone H1 to condense chromatin structure and perhaps recruit CAD to chromatin. Another apoptosis activated protease is endonuclease G (EndoG). EndoG is encoded in the nuclear genome but is localized to mitochondria in normal cells. EndoG may play a role in the replication of the mitochondrial genome, as well as in apoptosis. Apoptotic signaling causes the release of EndoG from mitochondria. The EndoG and DFF/CAD pathways are independent since the EndoG pathway still occurs in cells lacking DFF.
Hypoxia, as well as hypoxia followed by reoxygenation can trigger cytochrome c release and apoptosis. Glycogen synthase kinase (GSK-3) a serine-threonine kinase ubiquitously expressed in most cell types, appears to mediate or potentiate apoptosis due to many stimuli that activate the mitochondrial cell death pathway. Loberg, R D, et al., J. Biol. Chem. 277 (44): 41667-673 (2002). It has been demonstrated to induce caspase 3 activation and to activate the proapoptotic tumor suppressor gene p53. It also has been suggested that GSK-3 promotes activation and translocation of the proapoptotic Bcl-2 family member, Bax, which, upon aggregation and mitochondrial localization, induces cytochrome c release. Akt is a critical regulator of GSK-3, and phosphorylation and inactivation of GSK-3 may mediate some of the antiapoptotic effects of Akt.
Akt (also known as protein kinase B) is a 60 kDa serine/threonine kinase. It is activated in response to stimulation of tyrosine kinase receptors such as platelet-derived growth factor (PDGF), insulin-like growth factor, and nerve growth factor (Shimamura, H, et al., J. Am. Soc. Nephrol. 14: 1427-1434, 2003; Datta K, Franke T F, Chan T O, Makris A, Yang S I, Kaplan D R, Morrison D K, Golemis E A, Tsichlis P N, Mol Cell Biol 15: 2304-2310, 1995; Kulik G, Klippel A, Weber M J, Mol Cell Biol 17: 1595-1606, 1997; Yao R, Cooper G M, Science 267: 2003-2006, 1995). Stimulation of Akt has been shown to be dependent on phosphatidylinositol 3-kinase (PI3-kinase) activity (Fruman D A, Meyers R E, Cantley L C, Annu Rev Biochem 67: 481-507, 1998; Choudhury G G, Karamitsos C, Hernandez J, Gentilini A, Bardgette J, Abboud H E, Am J Physiol 273: F931-938, 1997, Franke T F, Yang S I, Chan T O, Datta K, Kazlauskas A, Morrison D K, Kaplan D R, Tsichlis P N, Cell 81: 727-736, 1995; Franke T F, Kaplan D R, Cantley L C, Cell 88: 435-437, 1997).
Akt has been shown to act as a mediator of survival signals that protect cells from apoptosis in multiple cell lines (Brunet A, Bonni A, Zigmond M J, Lin M Z, Juo P, Hu L S, Anderson M J, Arden K C, Blenis J, Greenberg M E, Cell 96: 857-868, 1999; Downward J, Curr Opin Cell Biol 10: 262-267, 1998). For example, phosphorylation of the pro-apoptotic Bad protein by Akt was found to decrease apoptosis by preventing Bad from binding to the anti-apoptotic protein Bcl-XL (Dudek H, Datta S R, Franke T F, Birnbaum M J, Yao R, Cooper G M, Segal R A, Kaplan D R, Greenberg M E, Science 275: 661-665, 1997; Datta S R, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg M E, Cell 91: 231-241, 1997). Akt was also shown to promote cell survival by activating nuclear factor-kB (NF-kB) (Cardone M H, Roy N, Stennicke H R, Salvesen G S, Franke T F, Stanbridge E, Frisch S, Reed J C, Science 282: 1318-1321, 1998; Khwaja A, Nature 401: 33-34, 1999) and inhibiting the activity of the cell death protease caspase-9 (Kennedy S G, Kandel E S, Cross T K, Hay N, Mol Cell Biol 19: 5800-5810, 1999).
Animal Models
Peripheral artery disease (PAD), also called peripheral vascular disease (PVD), is modeled by the hind limb model of ischemia in which the femoral artery of the mouse is tied off to simulate peripheral artery disease. PAD, which commonly affects the arteries supplying the leg and includes all diseases caused by the obstruction of large arteries in the arms and legs, can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism or thrombus formation. Restriction of blood flow due to arterial stenosis or occlusion often leads patients to complain of muscle pain on walking (intermittent claudication). Any further reduction in blood flow causes ischemic pain at rest. This condition is called chronic limb ischemia, meaning the demand for oxygen cannot be sustained when resting. Ulceration and gangrene may then supervene in the toes, which are the furthest away from the blood supply, and can result in loss of the involved limb if not treated.
Therapies for limb ischemia have the goals of collateral development and blood supply replenishment. Bone marrow derived CD34+mononuclear cells have been tested in such hindlimb ischemia models, but the hindlimb ischemia model does not model what takes place in the heart. A preferred therapy after AMI would stop cells from dying during recovery that leads to reverse remodeling and failure, or replace the dying cells with cardiomyocytes.
The closest animal model, the pig model, is not a good model of human disease because (i) all experiments generally are done in nonatherosclerotic animals, (ii) the animals are not treated with angioplasty, (iii) normal pigs do not embolize blood vessels; (iv) circulation of the pig is not exactly the same as human; and (iv) the peri-infarct border zone may not be the same.
A marginal improvement in angina symptoms recently was reported when CD34+ cells were mobilized with G-CSF, apheresed after 5 days, and then injected into an ischemic area of the heart based on Naga mapping. [Northwestern University (2009 Apr. 1). Adult Stem Cell Injections May Reduce Pain And Improve Walking In Severe Angina Patients. ScienceDaily. Retrieved Oct. 21, 2010, from http://www.sciencedaily.com-/releases/2009/03/090330091706.htm] Data from a phase I trial conducted by the present inventors has provided evidence that subjects treated with at least 10×106 isolated autologous CD34+hematopoietic stem cells containing a subpopulation of at least 0.5×106 potent CD34+ cells expressing CXCR-4 and having CXCR-4 mediated chemotactic activity (n=9) experienced significant improvement in resting perfusion rates at 6 months compared to subjects receiving 5 million cells (n=6) and control (n=15), as measured by the SPECT Total Severity Score (−256 versus +13, p=0.01). U.S. Patent Applications 61/169,850 and 61/119,552, incorporated herein by reference.
The described invention is a therapy for preventing the long-term adverse consequences of vascular insufficiency, particularly vascular insufficiency that produces expansion of the myocardial infarct area after an AMI progressing to heart failure. Administration of a potent dose of a nonexpanded, isolated population of autologous mononuclear cells enriched for CD34+ cells, which further contains a subpopulation of potent CD34+ cells expressing CXCR-4 and having CXCR-4-mediated chemotactic activity, administered early or late after occurrence of an AMI can result in a reduction in major adverse cardiac events, including, but not limited to, premature death, recurrent myocardial infarction, the development of congestive heart failure, significant arrhythmias, and acute coronary syndrome, and the worsening of congestive heart failure, significant arrhythmias, and acute coronary syndrome. Paracrine effects of the chemotactic hematopoietic stem cell product used in the claimed methods prevent the fragile cardiomyocytes in the peri-infarct border zone from dying, which prevents progressive myocardial cell loss, and which leads to improvement in function and a reduction of risk of major adverse cardiovascular events. In other words, 10×106 CD34+ potent cells administered in a clinical setting is used as a surrogate to provide enough CD34+/CXCR-4+ cells that have CXCR-4-mediated chemotactic activity and that move in response to SDF-1 to effect a biological effect (paracrine and neoangiogenic), which prevents cardiomyocyte cell death and later changes consistent with ventricular modeling.

This patent is subject to a terminal disclaimer.

Compositions and methods for treating progressive myocardial injury due to a vascular insufficiency


A multi-purpose wire stripping tool can be used to strip the insulation jacket from Romex-type electrical cable, strip the insulation from individual wires, cut the wires to a desired length, and crimp splice caps and sleeves onto joined wires. The tool includes a pair of opposed handle members joined at an axis portion and extending into a pair of opposed jaw members, the jaw members bearing a sleeve crimper portion, a wire cutter portion, and a wire stripper portion including a plurality of different wire gauge orifices. The jaw members terminate in a cable insulation jacket stripper portion perpendicularly disposed to the plane of the handle members.

1. Field of the Invention
This invention relates generally to hardware and tools, and more specifically to an improved wire stripping tool for use with Romex-type electrical cable (wire rope).
2. Description of the Prior Art
Hand tools such as those used in electrical wiring installation are well known. Typically, such tools include pliers used for bending and pulling wires, knives or wire strippers used for removing insulation from wires, and crimping tools used for clamping sleeves or caps onto joined wires. Many such tools are "multi-purpose", that is, include the ability to perform two or more of these tasks. For example, H. M. Ocko U.S. Pat. No. 1,699,805 provides an electrician's tool bearing an exposed blade to cut an insulation jacket surrounding a pair of wires, and a wire stripping orifice to remove the insulation from an individual wire. However, such tools are generally ill-designed for removing the heavy insulation jacket or sheathing from Romex-type wire cable.
Sawyer et al. U.S. Pat. No. 5,062,192 provides a cable stripping tool that is suitable for cutting the insulation jacket from Romex-type cables. That tool includes a pair of hinged handles that bear a first pair of blades to slice across the insulation jacket, and a second pair of blades to slit the length of the insulation jacket and enable its removal from the insulated wires beneath. However, this tool may be difficult to use in the cramped spaces commonly associated with Romex cable installation, such as electrical junction boxes. In addition, this tool does not provide (and because of its structure would be difficult to incorporate) additional wire stripping and/or sleeve crimping features.


For producing an abrasive tape (11) including a film substrate (2) and a polishing abrasive layer (10) laminated on one surface of the film substrate (2) and having on the outer surface thereof a plurality of recessed parts (9), the film substrate (2) is wrapped partially around the outer peripheral surface of a roll formplate (1) having on the surface thereof a plurality of concavities (5), and, as the roll formplate (1) is rotated, the film substrate (2) is fed thereto. On one hand, an ionizing radiation curing type resin (3) is supplied into the interface between the roll formplate (1) and the film substrate (2) therearound to be formed by the concavities (5), and the recessed parts (9) are formed on the resin surface. During this forming, radiation rays (R) are projected from an ionizing radiation ray source (8) toward the resin (3) thereby to cure the resin (3) and, at the same time, to render the resin (3) and the film substrate (2) into an integral structure. The abrasive tape (11) obtained in this manner is separated from the roll formplate (1). The abrasive tape (11) thus obtained is of high product quality. The production method is highly efficient and is suitable for mass production of abrasive tapes of identical concave-convex surface figuration.

As abrasive tapes of the above stated kind, in general, there are those of a structural organization wherein, on a substrate material, a coating comprising a polishing abrasive material and a binder component is applied to form a polishing film. An abrasive tape of this character has a simple structural organization and can be readily produced. During its use, however, debris formed from the workpiece being polished tends to infiltrate between the abrasive polishing film of the abrasive tape and the workpiece. If the polishing process is continued in this state, the surface of the workpiece will be damaged by this polishing debris, or the polishing debris will adhere to the film surface and cause its pores or recesses to become clogged. As a result, the polishing capacity of the abrasive tape has dropped considerably heretofore.
Furthermore, an abrasive tape provided with grooves in its polishing layer has been proposed. In the process of forming the polishing layer of this tape, a paint containing a large quantity of an inorganic ingredient in a coating compound is applied. Then the concavities and convexities of the Bernard cell due a "convection cell phenomenon" which occurs in the coating layer at the time when the solvent is dried are utilized as groove forms of the polishing layer. (Reference: Japanese Pat. Laid-Open Publn. No. 62-255069.) In the case of this abrasive tape, however, the shape as viewed in plan view of the grooved parts thus formed becomes restricted to an approximately hexagonal shape for reasons due to the production method. Moreover, it has been difficult to form recesses consistently of the same pattern, and products of stable quality could not be easily obtained. Furthermore, the control of conditions such as the composition of the solvent of the coating material for forming the polishing layer, the coating quantity, and the drying conditions in the production process for uniformity and stabilization of the pattern of the grooved parts to be thus formed has been difficult. Consequently, there has been the problem of extremely complicated production procedures. Furthermore, the concavities and convexities that can be formed on this abrasive tape is limited, in terms of the number of the polishing abrasive, to between #6,000 and #7,000 (measuring according to JIS R 6001). Polishing abrasives of numbers higher than this (i.e., concavities and convexities of dimensions less than this) could not be obtained.
Furthermore, in the method described in the above mentioned Japanese Pat. Laid-Open Publn. No. 62-255069 and other known methods (Japanese Utility Model Laid-Open Publn. Nos. 55-89564 and 59-39168), the forming of polishing layers into concave-convex pattern forms by using a printing process such as gravure printing and screen printing is disclosed. Furthermore, in Japanese Pat. Laid-Open Publn. No. 2-83172, the forming of a concave/convex pattern by applying a coating of a resin liquid in which polishing abrasive particles have been dispersed on a film substrate and laminating thereon by pressing a film for imparting concavities/convexities is disclosed. By this method, it has not been possible to prevent completely the formation of projections of independent polishing abrasive material on the surface of the polishing layer thus obtained. When such projections are present, the workpiece undergoing polishing is damaged by scratching or scoring. Thus this method becomes unsuitable especially for polishing requiring precision.
Furthermore, because of friction between the abrasive tape and the workpiece being polished, the abrasive tape and the workpiece become electrostatically charged at the time of polishing. For this reason the removal of polished debris from the polished parts becomes difficult, and residual polishing debris becomes entrapped between the abrasive tape and the workpiece, whereby scratch damage occurs, or dust in the air or polishing debris is adsorbed on the surface after polishing and must be subsequently cleaned off.
Furthermore, depending on the conditions, sparking may occur between the abrasive tape and the workpiece and damage the surface of the workpiece in some cases.
Accordingly, it is an object of the present invention to obtain an abrasive tape of high quality which is capable of solving the above described problems of the prior art.
It is another object of this invention to obtain a novel method by which the above described abrasive tape can be stably produced.

Abrasive tape and method of producing the same


A zero-delay buffer circuit includes a modified phase-locked loop (PLL) circuit configured to minimize clock skew among data output buffers of modules within a high-speed network switch system. Each module includes an application-specific integrated circuit (ASIC) chip that contains the modified PLL circuit; circuitry inserted within a feedback loop of the PLL is representative of a clock distribution tree that is common to the output buffers of the chip. The absolute delay of that tree typically differs among the ASICs because of process, voltage and temperature variations within the system. The circuitry inserted within the feedback loop effectively compensates for the absolute delay of the common distribution tree circuit components.

In a network switch system having a plurality of modules coupled to a bi-directional bus, one of the signals transmitted to bus interface circuits on each module is a clock signal used to control the timing of data transfer operations. This clock signal synchronizes the transmission and reception of data between physically separated points on the bus.
For proper operation of the system, clock signals should arrive at the bus interface circuitry at the same time; otherwise, reliable data transmission is not ensured. For example, if a bus interface circuit receiving data is "clocked" later than others, the earlier-clocked bus interface circuits may overwhelm the data before it is stored at its proper destination. This lack of simultaneity in reception of the clock signals, i.e., clock skew, directly increases the amount of time that the data must remain stable on the bus to ensure reliable data transmission; this, in turn, increases the time required for each data transfer on the bus and, thus reduces the speed of the bus.
The amount of clock skew introduced into a network switch system is a direct function of the variations and propagation delays among clock transmitter and receiver chips, and velocity factor differences in module etch of the system. A chip, i.e., a small, single piece of silicon on which integrated circuits are formed, typically comprises transistors. In digital logic applications, a transistor switches "on" when saturated and "off" when non-conducting to generate full "signal" swings between two power supply voltages. Propagation delay is affected by the switching speed of the transistor and is highly dependent upon variations in the fabrication process of the chip. In addition, the applied voltage, the operating temperature and the loading conditions of the chip effect its switching speed.
For logic switching applications, the transistors of a chip are typically configured as inverter and buffer circuits. An inverter inverts the logic sense of a binary signal; a buffer is used merely for signal amplification. That is, the buffer circuit does not produce any particular logic function since the binary value of the output is the same as the binary value of the input. However, buffering of low-level signals within semi-conductor chips to develop high-level digital pulse signals is very susceptible to propagation delay variations due to process, voltage, and temperature (PVT) variations. Differences in propagation delay between clock buffer chips in a system directly translate into skew. The magnitude of such skew is exacerbated when the clocking speed of the system (and, in particular, the switching speed of the transistors) increases.
The problem of clock skew in a high-speed clocking system is addressed partly by employing a central system clock source that generates and distributes clock signals to the respective modules over unidirectional clock lines. For example, clock generation circuits of the source preferably distribute the generated clock signals over identical trace lengths such that these signals arrive essentially simultaneously at the modules. In each module, the incoming clock signals are typically processed, e.g., shaped and amplified, before use by various components of the module. Such processing necessarily delays the signals; the delays can be expected to vary from module to module of the system because of PVT variations among the modules.
In addition, the topology of the clock distribution path located on each module can be expected to vary from module to module. These variations contribute significantly to clock skew and the present invention is directed to the reduction of that skew. More specifically, the present invention is directed to delivering low-skew, high-speed clock signals to points on the module where the clock signals are actually used, i.e., at their output buffers.

Network switching system including a zero-delay output buffer


A method and system, for component replacement, which use a combination of replaceable component life tracking and error condition occurrence history to identify the need for component replacement.

Many systems have multiple components that wear at different rates and are replaced as they wear out in order to keep the whole system operating. In such systems the replacement of some or all worn out components may require specially trained service professionals such as field service engineers. Some systems may be provided with replaceable components that are replaceable by the system operator, thereby eliminating, or at least reducing the frequency of, the need to place a service call. This not only may reduce overall maintenance costs, but also reduces system down time by eliminating response time. In either case, replacement by a service call or by the operator, it is desirable to track the usage of replaceable components so as to accurately anticipate when they will fail. U.S. Pat. No. 6,718,285, issued in the name of Schwartz, et al., issued on Apr. 6, 2004, henceforth referred to as the Schwartz patent, discloses a replaceable component life tracking system and is hereby incorporated in this application by reference.
The Schwartz patent discloses a replaceable component life tracking system in which the usage of each replaceable component is tracked using a predetermined parameter. In a preferred embodiment, the system is a printing device and the usage of each replaceable component is tracked using the parameter corresponding to the number of pages printed. The life expectancy of each replaceable component is predetermined, and as the usage of each replaceable component is tracked, it is compared to the predetermined life expectancy, and the result periodically reported to the system operator via an operator interface. If any replaceable component usage reaches the life expectancy of that replaceable component, the operator is notified immediately, and instructed that the replaceable component ought to be replaced.
For most systems, for a number of reasons, a life tracking process of the type described above only provides an approximate forecast of the end of useful life of the replaceable components. For example, the wear rate of some or all of the replaceable components may not be constant with respect to the predetermined usage parameter. In the printing device embodiment, for example, all printed pages do not necessarily result in the same wear rate for all replaceable components. Furthermore, if the system is one that stops and starts between jobs, wear of the replaceable components may be occurring, but with no incrementing of the usage parameter. It is well known that in systems of this type the components wear faster when many shorter jobs are being run versus fewer longer jobs. Also, most replaceable components do not fail instantaneously due to wear, but rather tend to degrade gradually.
As a result of these observations, the decision of when to replace a component as its usage approaches or exceeds the life expectancy is left to the system operator. Furthermore, the operator may be willing to accept some degradation of system performance and therefore replace components less frequently thereby decreasing operating costs. In the printing device embodiment, image quality on the printed pages may degrade slowly and, if the images being printed are less demanding textual images versus pictorial images for example, or if the customers are less demanding, the operator may choose to continue to use a component well past the life forecasted by the life tracking process.

Method and system for component replacement based on use and error correlation


Controlling a vehicle according to a trained neural network model capable of being used to generate an output from which one or more vehicle operating variables can be estimated. The neural network model can be used to process, as input, aggregated data corresponding to operational and/or environmental characteristics experienced by the vehicle during at least a portion of a voyage. The aggregated data can include a range of values collected over a period of time when the vehicle is traversing the portion of the voyage. The output generated by the neural network model, based on processing the input, can be further processed in order to determine, for example, an estimated state of charge and/or an estimated remaining flight time for the vehicle. Such estimated values can thereafter be used by a controller of the vehicle to maintain course or maneuver to a charging station.

Autonomous and semi-autonomous vehicles typically operate using exhaustible fuel sources that can often require the vehicles to frequently refuel over relatively brief periods of operation. As a result, delays in particular voyages can occur, thereby resulting in a recipient of a payload, carried by a particular vehicle, to not receive the payload at an expected time. This can be especially concerning when the payload is being provided to fulfill an emergency service available by an entity that has employed the vehicle to deliver the payload.
Although a respective entity can attempt to preemptively schedule refueling stops for a vehicle that is tasked with completing a voyage, oftentimes such predictions do not consider environmental conditions that can affect vehicle performance along a voyage. For instance, an internal resistance of a battery can be negatively affected by cold temperatures, resulting in the battery appearing to have a lower charge capacity. Many subsystems of a vehicle can depend on an apparent charge capacity of a battery to be above a particular threshold. Therefore, the inability to reliably predict apparent changes to such battery characteristics, and the effects they have on the subsystems of a vehicle, can result in loss of function and/or damage to the vehicle, depending on a circumstance in which a function is lost (e.g., an inability to no longer hover can cause an unmanned aerial vehicle (UAV) to crash land). Furthermore, environmental conditions, such as wind speed and direction, can cause operational characteristics of the subsystems of the vehicle to change, at least in order to compensate for such conditions (e.g., maintaining trajectory during a headwind). As a result, an amount of current and/or voltage provided by the battery may not be accurately calculable by an entity that is preemptively planning the voyage of the vehicle, thereby increasing a risk that the vehicle may lose functionality in response to a loss of available charge.

Using machine learning techniques to estimate available energy for vehicles


An information processing device includes a power control section and a function-suppressing section. The power control section switches between a predetermined mode and a low-power mode on the basis of a pre-specified setting condition relating to power consumption of the information processing device. The low-power mode is lower in electricity consumption quantities than the predetermined mode. When switching from the low-power mode to the predetermined mode in a period of operation of an external security apparatus, the function-suppressing section suppresses a part of functions of the device in the predetermined mode.

1. Technical Field
The present invention relates to an information processing device, a control method thereof, computer readable medium, and a security system.
2. Related Art
Heretofore, there have been information processing devices equipped with power-saving modes, which are capable of reducing power consumption. For example, a device is known, which can automatically alter a process of switching to a low-power mode, in which brightness of a display device is lowered and the like, or suchlike in accordance with a condition of usage by users.
Furthermore, a device is known that monitors a printing state of a printing device main body and, upon recognizing that the printing device main body is in any of at least three stable states, which differ in power consumption amounts, restricts power supplies to components of the printing device main body in accordance with the identified stable state.

Information processing device, method of controlling the device, computer readable medium, and security system


Provided are various embodiments of a positive electrode for a secondary battery, which in one embodiment includes a first positive electrode material mixture layer formed on a positive electrode collector, and a second positive electrode material mixture layer formed on the first positive electrode material mixture layer, wherein the first positive electrode material mixture layer has an operating voltage of 4.25 V to 6.0 V and includes an active material for overcharge which generates lithium and gas during charge; a method of preparing such a positive electrode for a secondary battery; and a lithium secondary battery including such a positive electrode.

Demand for secondary batteries as an energy source has been significantly increased as technology development and demand with respect to mobile devices have increased. Among these secondary batteries, lithium secondary batteries having high energy density and voltage, long cycle life, and low self-discharging rate have been commercialized and widely used.
However, with respect to the lithium secondary battery, it may be overcharged beyond a normal charge region, and this phenomenon is referred to as "overcharge phenomenon". In a case in which the lithium secondary battery is overcharged above a normal operating voltage, heat is generated due to electrical resistance in the battery to gradually increase the temperature, wherein, in this case, since an excess amount of lithium is discharged from a positive electrode in comparison to a normal charge state and an amount of lithium, which is more than an amount of lithium that may be accommodated, is introduced into a negative electrode, the excess lithium is precipitated in the form of lithium metal on the surface of the negative electrode. Also, structural collapse occurs in the positive electrode during overcharge to provide oxygen as well as thermal energy, and, when a separator is melted by heat rapidly generated from the positive electrode and the negative electrode, the positive electrode and the negative electrode may be in a state in which an internal short occurs. When this state is reached, the battery becomes extremely dangerous and may even explode.
Thus, in order to solve the above-mentioned problems, research into a method of further including an additive, such as an overcharge inhibitor, in an electrolyte solution and development of related materials have been actively studied. However, even if the electrolyte solution includes the inhibitor, there is a limitation in that it is difficult to prevent an exothermic phenomenon of the positive electrode or the negative electrode in advance.
An overshooting phenomenon occurs in which the voltage increases as the resistance increases during overcharge. However, there is a limitation in that stability of a battery, in which safety is not ensured, is reduced because the battery generates heat or explodes before the occurrence of the overshooting phenomenon.

Positive electrode for secondary battery and secondary battery including the same


An inversion apparatus includes a support frame configured to movably support an inversion table. The support frame includes a forwardly extending foot platform that helps a user mount and dismount the apparatus when the apparatus is in an operative configuration. A CPU is preferably mounted on the inversion table to collect data and transmit to an output device, such as a mobile phone.

Along with cardio exercise and strength exercise, stretching and/or body manipulation may be considered another fundamental form of exercise or physical fitness that is important for overall health and well being. One specific form of beneficial stretching and/or body manipulation may be accomplished by inverting one's body relative to an underlying floor surface. Some examples of known inversion apparatus are disclosed in U.S. Pat. Nos. 5,967,951, 7,052,448, 7,663,653, 7,118,518, 7,125,372, 7,507,192, 7,544,157, 7,585,264, 7,625,326, 7,625,327, 7,867,154, 8,051,512, 8,291,533, 8,480,543, 8,556,787, D551,725, D581,996, D617,855, D650,025, D650,026 and D664,220. An object of the present invention is to provide new and improved inversion apparatus.

Inversion methods and apparatus having electronics unit to accumulate data


An organic feed method for use as food supplements for humans or animals as well as for feeding plants. The organic feed method generally includes first mixing an organic material such as peat moss or compost with water at a ratio of approximately 1.2 pounds of organic material to 1 gallon of water. The resulting mixture is pumped through a wet mill grinder to reduce size, maintaining a temperature of below 130 degrees Fahrenheit through the mixture and grinding processes. After grinding, the resulting mush is pumped through a 400 mesh filter, cooled to room temperature, and bottled as an organic feed. The organic feed may be utilized as a health or nutritional food supplement for humans or animals. The organic feed may also be mixed with water or chemicals such as fertilizer and applied to plants as plant feed.

1. Field of the Invention
The present invention relates generally to an organic feed method and more specifically it relates to an organic feed method for use as food supplements for humans or animals as well as for feeding plants.
2. Description of the Related Art
Any discussion of the related art throughout the specification should in no way be considered as an admission that such related art is widely known or forms part of common general knowledge in the field.
Different types of organic feeds have been in use for years to aid in plant development as well as nutrition supplementation for humans and animals. While these methods have had their uses, there has still been room for improvement in terms of efficiency for organic feeds, particularly with regard to how they are manufactured.
Because of the inherent problems with the related art, there is a need for a new and improved organic feed method for use as food supplements for humans or animals as well as for feeding plants.


An electrical connector (100) includes a dielectric housing, a contact terminal (3), a compression spring (4) and a retaining terminal (5). The contact terminal has a body portion (30) and a contact portion (310) extending from an upper end of the body portion. A first wing (301) and a second wing (302) perpendicularly bend from opposite edges of the body portion. The retaining terminal includes a solder portion (510) projecting beyond the housing for electrically connecting a printed circuit board and a pair of arms (53) extending from the solder portion for directly and electrically connecting with the first wing and the second wing of the contact terminal. The spring is compressed between the retaining contact and the contact terminal. An upper end of the spring engages with the contact terminal and a lower end of the spring engages with the retaining terminal.

1. Field of the Invention
The present invention relates to an electrical connector and more particularly, to an electrical connector mounted on a printed circuit board or the like.
2. Description of the Prior Art
Electrical connectors are usually mounted on a printed circuit board as a component of a contact device, as disclosed in U.S. Pat. No. 5,727,954 issued to Kato on Mar. 17, 1998. In this patent, the Kato connector is of a two-part construction vertically defining a plurality of through holes. A plurality of terminals received in the through holes and each include an upper terminal normally upwardly projecting beyond a corresponding through hole, a lower terminal apart from the upper terminal and normally downwardly projecting beyond the through hole and a middle spring compressed between the upper terminal and the lower terminal. The upper terminal and the lower terminal have opposite wedge-shaped ends. The ends are inserted into opposite upper and lower coiled hollows of the spring respectively. The assembled terminal is held in the through hole such that the terminal as a whole can be axially movable relative to the assembled housing. In use, a mating electrical device (battery, memory card or printed circuit board etc.) depresses and electrically connects the upper terminal. The upper terminal electrically connects with the lower terminal via the spring positioned therebetween. The lower terminal is electrically contacted under pressure with a wiring substrate, thereby the mating device electrically connects with the wiring substrate via the electrical connector.
However, the spring may be invalidated such as distortion and resilient less after a period of use. Furthermore, the opposite wedge-shaped ends of the upper terminal and the lower terminal are inclined to get away from the coiled hollows of the invalid spring, resulting in an unreliable connection between the upper and the lower terminals. As a result, the electrical connector cannot reliably interconnect the mating device with the wiring substrate.
Hence, an improved electrical connector is needed to overcome the foregoing shortcomings.


In a bearing arrangement including a thrust bearing and a radial bearing, the thrust bearing includes a first thrust plate which is fixedly secured to a stator plate, and the radial bearing is integrally attached to the first thrust plate of the thrust bearing. Because the radial bearing is directly attached to the first thrust plate of the thrust bearing, the perpendicularity of the radial bearing with respect to the thrust support surface can be easily ensured. Also, the first thrust plate normally consists of a highly rigid member, and this also contributes in the favorable perpendicularity of the radial bearing with respect to the thrust support surface. This bearing arrangement is useful in a spindle motor for turning a floppy disk in a floppy disk drive.

Conventionally, a spindle motor as illustrated in FIG. 7 was typically used as an electric motor for rotating a 3.5-inch floppy disk in a floppy disk drive. In the illustrated spindle motor, a tubular radial bearing 3 made of oil-less metal is fixedly and directly secured, for instance by crimping, to a stator plate 1 made of ferromagnetic material and carrying an electric circuit thereon. A thrust ball bearing 5 is attached to the upper surface of the stator plate 1 so as to concentrically surround the radial bearing 3. The thrust ball bearing 5 comprises a retainer 5b rotatably carrying a plurality of steel balls 5a, and a pair of annular thrust plates 5c and 5d interposing the retainer assembly therebetween. The lower thrust plate 5c is secured to the stator plate 1 by a bonding agent or the like. A plurality of drive coils 7 are mounted on the upper surface of the stator plate 1 so as to concentrically surround the thrust ball bearing 5. A rotor shaft 11 fixedly attached to a rotor plate 9 is rotatably supported by the radial bearing 3, and the rotor plate 9 abuts the upper surface of the thrust plate 5d. An annular drive magnet 13 is secured to the rotor plate 9 so as to oppose the drive coils 7.
In this spindle motor, the rotor shaft 11 is supported by the radial bearing 3 with respect to the radial direction, and the rotor plate 9 is supported by the thrust ball bearing 5 with respect to the axial direction while the rotor plate 9 rotates around the pivot shaft 11. A floppy disk mounted on the back (upper) side of the rotor plate 9 by known retaining means not shown in the drawing can be rotatively driven as required.
However, according to this conventional spindle motor, because the radial bearing 3 supporting the rotor shaft 11 is directly attached to the stator plate 1 by crimping, the pressure applied to the stator plate 1 for crimping tends to produce deformation in the stator plate 1 so that the rotor shaft 11 may tilt or may be otherwise improperly installed, and this can seriously damage the commercial value of the motor. For instance, the rotor plate 9 may undergo a whirling movement, or the floppy disk may not turn in a prescribed plane.
Also, when the stator plate 1 made of ferromagnetic material is subjected to the magnetic attractive force of the drive magnet 13 attached to the rotor plate 9, the stator plate 1 may tilt around the thrust ball bearing 5, and a significant deflection may be produced in the part of the stator plate 1 adjacent to the radial bearing 3. This can lead to a significant tilting of the rotor shaft 11, and the floppy disk may not be turned in a prescribed plane as desired. In FIG. 8, the letter S indicates the displacement of the stator plate 1 that may be produced in a part near the radial bearing 3 in this manner.
Also, because the radial bearing 3 and the thrust ball bearing 5 are separately formed, and respectively attached to the stator plate 1, the dimensional and positional errors of these two parts may add up, and it is therefore highly difficult to ensure the perpendicularity of the rotor shaft 11 with respect to the thrust support surface (double dot chain line A in FIG. 9).

Motor bearing arrangement and electric motor using the same


A food product includes at least one shell that contains one or more ingredients within the at least one shell. The at least one shell can be dissolved or melted into a heated liquid to release the one or more ingredients and form a heated beverage. As a particular example, multiple shells could be formed from chocolate and can contain ingredients for hot cocoa (such as cocoa mix and marshmallows). The multiple shells could be arranged in a particular pattern and decorated to form a character, such as a snowman.

There are an overwhelming number of different types of confectionery products that are available for purchase by consumers. Confectionery products include products that are generally rich in sugars and carbohydrates, such as various forms of chocolate. The confectionery industry is constantly looking for new products that are unique or that capture consumer interest.

Food products with shells that are dissolved or melted to release ingredients and form heated beverages


IEEE 802.11 power saving mode (PSM) defines two different power modes under which stations operate: active mode and power save (PS) mode. This disclosure introduces devices, methods, and systems to implement an additional power save with ultra low power (PS-ULP) mode that further reduces power consumption. In one aspect, a method of communicating a power management mode of a station on a wireless network is disclosed. The method includes transmitting by a station a first message on the wireless network, the first message indicating one of at least three power management modes, wherein the indication is communicated in a power management portion of a frame control field of a media access control header. The power management portion comprises more than one bit; and operating the station in a power management state in accordance with the indicated power management mode.

Wireless networks enable communication with mobile devices, including those in ad-hoc networks. Wireless networks facilitate rapid field deployment, when compared to fixed wired networks. While wireless networks have their advantages, devices on wireless networks may consume a large amount of power during packet reception or while waiting to receive packets. Systems, methods, and devices that reduce power consumption may increase the time between battery charges and may reduce operational costs.
Communication standards incorporate power saving approaches to meet this need. For example, IEEE 802.11 power saving mode (PSM) defines two different power modes under which stations operate: active mode and regular power save (PS) mode. Stations in active mode may receive frames at any time. When in active mode, a station's primary receiver operates in an awake state, with sufficient power to receive frames.
Stations in regular PS mode may receive frames when their receivers are in an awake state. Stations in regular PS mode conserve power by transitioning to a lower power state (doze state) which usually consumes at least an order of magnitude less power than active state. When in doze state, the receiver does not operate with sufficient power to receive frames. In regular PS mode, all nodes in the network are synchronized to transition to wake up (transition to active state) to listen to beacon messages.
Broadcast, multicast or unicast messages to a power saving station are buffered at the transmitter and announced during the period when the nodes are in an awake state. The announcement is made using an ad hoc traffic indication message (ATIM) during a small time interval at the beginning of the beacon interval called the ATIM window. If a station receives a directed ATIM frame in the ATIM window, it sends an acknowledgement and stays awake for the entire beacon interval waiting for data packets to be transmitted. Immediately after the ATIM window, an access point can transmit buffered broadcast frames, multicast frames, data packets, and management frames addressed to stations that are known to be active based on previously received acknowledgements. Otherwise, the station may switch to the low-power doze state to conserve energy. In IEEE 802.11, a station's power management mode is indicated in the frame control field of the media access control header for each packet.
In regular PS mode, stations conserve power by transitioning to doze state most of the time, except for short intervals agreed with the transmitter when signals may be sent from the transmitter to the receiver. This is neither flexible nor efficient because in certain applications, the traffic pattern is unpredictable. The agreed awake time may not match the traffic pattern, so some awake times may not correspond to transmit times. There may also be times when transmitted signals are not received because they are transmitted outside of the agreed awake time.
Existing power save modes like 802.11 regular PS mode can be improved upon to further reduce power consumption. By further reducing power consumed by devices when waiting to receive packets or when receiving packets, power would be further conserved and operational costs further reduced.

Systems and methods for low power operations on wireless networks