The invention is directed to formulations comprised of multiple dietary and endogenously made antioxidants and B-vitamins and the use of these formulations in preventing and treating coronary artery disease.

1. Field of the Invention
The invention is directed to formulations comprised of multiple dietary and endogenously made antioxidants and B-vitamins and the use of these formulations in preventing and treating coronary artery disease.
2. Description of the Related Art
Coronary artery disease (CAD) remains the number one cause of death in the U.S.A. About 1.5 million new cases are detected annually, and approximately 1 million people die of this disease every year. The current estimate is that about 62 million Americans have one or more types of cardiovascular disease, and about 14 million per year suffer from heart attack or angina. The direct and indirect financial cost in the U.S.A. of this disease is estimated to be about 329 billion dollars annually.
Various organizations and health professionals have proposed primary prevention strategies that involve changes in the diet and lifestyle. Although these recommendations appear rational, they have not had any significant impact in reducing the risk of heart disease. This may be due to the fact that most people do not follow lifestyle changes and diet modifications, and those who do follow them do not start until atherosclerosis is well established. At present, statin with or without niacin is recommended to patients with high LDL-cholesterol and low HDL-cholesterol, and aspirin for the primary prevention as well as for the treatment of CAD. However, some patients at higher cholesterol-lowering drug doses may exhibit muscle pain and liver toxicity, and a significant number of these patients develop varying degrees of aspirin resistance. Therefore, the current strategy for the prevention and treatment of CAD needs improvement.
Since increased oxidative stress and homocysteine level are considered major risk factors in the etiology of CAD, it appears rational to suggest that daily supplementation with multiple dietary and endogenously made antioxidants together with B-vitamins may enhance the efficacy of the current strategies for the prevention and treatment of CAD. Although the U.S. Prevention Service Task Force recommends vitamin supplements to reduce the risk of cancer and CAD, the role of antioxidants alone or in combination with standard therapy in the prevention or treatment of CAD has become a controversial and confusing issue for the public as well as professionals. This is due to the fact that interventional trials with dietary antioxidants, mostly with vitamin E alone or in combination with cholesterol-lowering drugs, have produced inconsistent results, varying from a beneficial effect to no effect to a harmful effect.
A few excellent reviews have summarized the published data on these issues, but did not identify possible reasons for inconsistent results of interventional trials with antioxidants, and did not propose any specific recommendations for the prevention or as adjunct to standard therapy for the treatment of CAD. Based on the current inconsistent results of intervention studies, it is inappropriate to promote the notion that antioxidants have no value in the prevention or treatment of CAD or that they may have adverse effects in CAD patients taking statins and/or niacin.
The following is a discussion of etiologic risk factors, and epidemiologic, laboratory and intervention studies with antioxidants alone or in combination with statins and/or niacin. It identifies the possible reasons for inconsistent results. The discussion also proposes a scientific rationale for why nutritional formulations may improve the efficacy of standard therapy in the prevention or treatment of CAD.
I. Etiologic Risk Factors for CAD
Several investigations have identified risk factors for the development of CAD. These include a family history, age, High LDL-cholesterol and low HDL-cholesterol, high saturated fat intake, hypertension, physical inactivity, cigarette smoking, obesity, diabetes mellitus, inflammatory reactions and coronary calcium level. The combination of these risk factors may increase the risk or the rate of progression of CAD more then that produced by any one individual risk factor. One of the mechanisms of most of these diverse risk factors, such as inflammatory reactions, cigarette smoking and hyperglycemia, may involve the production of enhanced levels of free radicals. Increased levels of free iron, copper or manganese, impaired mitochondrial function or antioxidant deficiency can further increase the production of free radicals. Free radicals derived from oxygen and nitrogen, referred to as reactive oxygen species (ROS) and reactive nitrogen species (RNS), can damage lipids, proteins, RNA and DNA. Although certain levels of free radicals are essential for driving the biological reactions necessary for human survival, excess levels of these free radicals can increase the risk of most human chronic diseases, including CAD.
A. Oxidative Damage, C-reactive Proteins and Cholesterol
LDL-cholesterol is commonly referred to as a "bad cholesterol" because it is easily oxidizable by free radicals. Oxidized LDL-cholesterol may be one of the early events that could initiate plaque formation by increasing the formation of foam cells in the arterial wall; enhancing platelet adhesion and aggregation, triggering thrombosis and impairing elasticity of the coronary arteries. Oxidized LDL-cholesterol can also increase vascular smooth muscle cell proliferation by activating c-myc, and its binding partner MAX, and the carboxy-terminal domain-binding factors activator protein-2 (AP-2), and elongation 2 factor (E2F) in human coronary artery smooth muscle cells. The importance of c-myc in the progression of atherosclerotic lesions is demonstrated by the fact that gene therapy, by decoy/oligodeoxynucleotide which inactivates E2F, delivered to human bypass vein grafts intraoperatively, caused fewer graft occlusions and critical stenosis after 12 months.
Oxy LDL-cholesterol is also engulfed by macrophages to form foam cells, and C-reactive protein increases the uptake of oxyLDL-cholesterol by macrophages. Both foam cells and increased proliferation of vascular smooth muscle cells contribute to the formation of plaque in the coronary arteries. Thus lowering the level of LDL-cholesterol and preventing the oxidation of this form of cholesterol should reduce the initiation, as well as the progression, of CAD.
B. Endothelial Cells, Free Radicals and Homocysteine
Endothelial cells of the vascular wall are damaged by the free radicals and the secretory products of inflammatory reactions (i.e., free radicals, cytokines and prostaglandin E2), as well as by homocysteine. Endothelial cell-derived nitric oxide (NO) is a potent vasodilator that is formed during the metabolism of arginine, and it is responsible for regulating vascular tone. It is now recognized that endothelial cell dysfunction may also be one of the early events in the development of CAD.
Damage to endothelial cells may impair the nitric oxide synthase (NOS) pathway, which in turn may impair endothelium-dependent coronary artery dilation. Thus, deficiency in the production of NO may interfere with the function of the vessel wall. The level of inducible NOS (iNOS) mRNA in vascular smooth muscle cells of a healthy arterial wall is low, but the levels of iNOS mRNA and protein in macrophages and in the majority of early lesions and in all advanced atherosclerotic lesions are high. This suggests that these sources may release an excessive amount of NO that could increase the progression of coronary artery dysfunction. Thus, the role of NO in maintaining normal vascular function depends upon maintaining proper levels of NO.
Both deficiency and excess production of NO can impair vasomotion and can enhance endothelial dysfunction. In the case of deficiency, restoring the physiological level of NO can improve the endothelial dysfunction and vascular wall defect. Damaged endothelial cells reduce the release of nitric oxide (NO) which impairs the vasodilation of arteries. Therefore, protecting the endothelial cells against free radicals may be considered helpful in prevention or treatment strategy. Once the plaque is formed, it serves as a continuous stimulus for increased inflammatory reactions that in turn causes a gradual progressive increase in plaque size.
C. Development of Aspirin Resistance
Aspirin is commonly recommended for the primary prevention and treatment of CAD, because it reduces inflammatory reactions and production of prostaglandin E2 (PGE2) by inhibiting cyclooxygenase activity. PGE2 is one of the major factors responsible for platelet aggregation. About 5-12% of cardiac patients develop resistance to aspirin and about 24% of patients taking aspirin become semi-responders. The exact mechanisms of aspirin resistance remain to be elucidated. It is possible that aspirin doses commonly used fail to suppress cyclooxygenase activity, requiring physicians to increase aspirin doses. It is also possible that aspirin becomes ineffective in reducing the activity of cyclooxygenase and/or that PGE2 is produced non-enzymatically. The latter would make patients totally resistant to aspirin. It has been reported that the risk of major cardiac events may increase by about 3-fold in aspirin resistant patients. Therefore, resolving the issue of aspirin resistance has become a new challenge for researchers in cardiology.
II. Role of Antioxidants in the Prevention and Treatment of CAD
In humans, different types of inorganic and organic free radicals derived from oxygen and nitrogen are produced. Oxygen-derived free radicals include O−.(anion), OH.(hydroxyl free radicals), O.(oxy free radicals), RO.(peroxy free radical) and R.(organic free radical). Nitrogen-derived free radicals include NO.(nitric oxide) and NOOH.(peroxynitrite). Humans also produce certain antioxidants such as antioxidant enzymes, glutathione, coenzyme Q10, alpha lipoic acid and NADH(nicotinamide adenine dehydrogenase, reduced form). They also consume antioxidants through their diet, such as vitamin A, vitamin C, vitamin E, beta-carotene and other carotenoids, phenolic compounds, and the mineral selenium (which acts as a cofactor for glutathione peroxidase).
These antioxidants, at least in part, have different affinities with various types of free radicals. With these complexities of relationship between antioxidant and oxidant reactions, it is not rational to utilize one or two antioxidants for the prevention or the treatment of any diseases, including CAD. In addition, an individual antioxidant, when it becomes oxidized, acts as a free radical. Therefore, the use of a single antioxidant in, for example, heavy smokers (men or women), who have a high oxidative body environment, to reduce the risk of any chronic diseases makes no scientific sense. Unfortunately, most human trials in CAD involve one or two dietary antioxidants without consideration of internal oxidative environment and this may be one of the major reasons for the inconsistent results.
Another reason could be that all intervention trials published thus far do not give proper consideration to the form of dietary antioxidants (natural vs. synthetic vitamin E and β-carotene, with the natural form being more effective than the synthetic form), did not include both vitamin and β-carotene (β-carotene having functions other than being a precursor of vitamin A), did not include d-alpha tocopherol as well as d-α-tocopheryl succinate (α-tocopheryl succinate being the most effective form of vitamin E) and did not include endogenously made antioxidants such as co-enzyme Q10, glutathione elevating agents (n-acetylcysteine) and alpha-lipoic acid.
A. Laboratory Studies
Most laboratory studies support the hypothesis that supplementation with antioxidants may prevent and reduce the rate of progression of atherosclerosis. For example, Vitamin E supplementation has been known to reduce the development of early aortic atherosclerotic lesions in chickens and rabbits. Further, stenosis progression was decreased in male monkeys receiving vitamin E supplementation in comparison to those receiving an unsupplemented atherosclerosis-promoting diet. The above studies utilized vitamin E alone. A high oxidative internal environment may not exist in rodents; therefore, it is unlikely that adverse effects of a single antioxidant can be observed in the animal model. This may not be true in humans, especially in heavy smokers. In addition, unlike in humans, the lifestyle and diet are fairly constant in these animal models.
B. Proposed Mechanisms of Action of Antioxidants
Several mechanisms of action of antioxidants in reducing the risk of CAD have been proposed, although most studies have focused on the action of vitamin E alone. For example, vitamin E reduces oxidation of membrane and LDL cholesterol, reduces c-myc activated pathways responsible for smooth muscle cell proliferation, reduces aggregation of platelets in normal subjects, type I diabetes patients and heart transplant recipients on cyclosporine, and inhibits the protein kinase C pathway.
Vitamin C prevents lipid oxidation and oxyLDL-cholesterol mediated pathway. Vitamin C also potentiates nitric oxide activity in normalizing vascular function in patients with cardiac disease associated with hypercholesterolemia, hyperhomocysteinemia, hypertension and smoking.
The combination of vitamins C and E produces a synergistic inhibition on LDL-cholesterol oxidation.
Alpha-tocopheryl succinate inhibits the expression of c-myc in some mammalian cells, and α-tocopherol reduces the proliferation of vascular smooth muscle cell proliferation in culture by inhibiting protein kinase C activity that is independent of antioxidant properties.
Co-enzyme Q10 acts as a cofactor in the Krebs's cycle in mitochondria to generate ATP.
Alpha-lipoic acid improves glucose utilization in peripheral tissue by stimulating glucose transport and uptake. Therefore, it can improve the function of damaged muscle or endothelial cells.
SH-compounds such as glutathione are one of the most important intracellular antioxidants responsible for protecting cells against free radical damage. Oxidative damage can reduce the level of SH-compounds within the cells. Therefore, glutathione-elevating agents such as N-acetylcysteine (NAC) and α-lipoic acid may be useful in restoring intracellular levels of glutathione in endothelial cells and cardiac muscle cells, thereby improving the function of these cells and protecting them from further oxidative damage.
Thus, mechanistic data exist that support the rationale for using a mixture of dietary and endogenously made antioxidants in the prevention, and as an adjunct to standard therapy, in the treatment of CAD.
C. Epidemiological Studies
Epidemiological studies are a useful way to establish an association between dietary nutrients including antioxidants and the risk of CAD. However, some inherent complexities of the varied human diet and lifestyle, techniques of data collection that rely on memory or short-term dietary records and the multifactorial nature of CAD, make it difficult for them to yield consistent results. Nevertheless, 6 out of 8 epidemiologic studies that have been performed with vitamin E alone show an inverse relationship between vitamin E intake and the risk of CAD.
In particular, in a WHO/MONICA study there was a high inverse association between age-specific mortality from ischemic heart disease and lipid-standardized vitamin E levels. In a Polish study, plasma levels of vitamin E were significantly lower in patients with stable and unstable angina compared to healthy control persons. In a UK study, an inverse association between plasma vitamin E levels and risk of angina was reported. In a Harvard study of 39,910 male health professionals, a 36% lower relative risk of CAD was demonstrated among those consuming 60 IU vitamin E per day in comparison to those consuming less than 7.5 IU vitamin E per day. Men who took at least 100 IU vitamin E per day for at least 2 years had a 37% lower risk of CAD than those who did not take vitamin E. Another Harvard study of 87,245 healthy nurses with a follow-up period of 8 years revealed that women in the top fifth of vitamin E intake had a 34% lower relative risk of major CAD in comparison to those in the lowest fifth. The relative risk of CAD was 48% lower in women taking vitamin E supplements of more than 100 mg per day for at least 2 years. Vitamin E obtained only from the diet provided no such protection. In another US study of 11,000 people of age 67 or over, with a follow up period of 6 years, it was found that vitamin E supplementation was associated with a 47% reduction in mortality from CAD. Further reduction was observed in people who were taking vitamin E supplements together with vitamin C.
In contrast to the 6 investigations discussed above, 2 studies failed to observe any association between serum selenium, vitamin A or vitamin E and the risk of death from CAD. Because of numerous confounding factors associated with diet and lifestyle, epidemiologic studies have produced inconsistent results. It is surprising that most studies have shown inverse relationship between vitamin E intake and the risk of CAD.
D. Intervention Studies in Humans
CAD is considered a multi-factorial disease that involves multiple risk factors such as increased oxidation and inflammatory reactions, high levels of LDL-cholesterol and low levels of HDL-cholesterol, as well as high levels of homocysteine and glucose. Each of these risk factors may contribute variable degrees of risk to the initiation and progression of CAD. Therefore, the purpose of any intervention trials should be to attenuate these risk factors for CAD. This would require a multifactorial approach involving, statin with or without niacin, multiple dietary and endogenously made antioxidants, B-vitamins and mineral selenium, and aspirin. Unfortunately, to date no such studies have been performed.
The clinical studies that have been published have produced inconsistent results. This is due to the fact that form, type, number, dose and dose-schedule of antioxidants, study end points, observation period and patient population differ from one study to another. When antioxidants were used in combination with cholesterol-lowering drugs, similar inconsistent results for the same reasons were also noted.
The published intervention trials can be divided into four groups, (a) those using a single dietary antioxidant in patients with no prior cardiac events; (b) those using a single dietary antioxidant in patients with prior cardiac events; (c) those using two or more dietary antioxidants with or without prior cardiac events; and (d) those using one or more dietary antioxidants in combination with cholesterol-lowering drugs in patients with or without prior cardiac events. Each of these is discussed below.
1.) Intervention Trials with One Dietary Antioxidant in Patients with No Prior Cardiac Event
A summary of 5 intervention trials involving the use of one dietary antioxidant in patients with no prior cardiac events is presented in Table 1 below. Data showed that dose and type of antioxidants, population type, study endpoint and follow-up period differ from one study to another. Nevertheless, three studies showed the beneficial effects of dietary antioxidants, one study reported no beneficial effect and another investigation showed an adverse effect.
For example, vitamin E supplementation (544 IU) improved endothelial-dependent flow-mediated dilation (FMD) of blood vessels in smokers with hypercholesterolemia. An elevation of plasma homocysteine by methionine impaired endothelial function in healthy male subjects. Pretreatment with vitamin C (2 g/day) prevents this effect and reduced arterial stiffness. In the Cambridge Heart Antioxidant Study (CHAOS) involving 2002 patients with angiographically proven coronary atherosclerosis, it was found that patients receiving 400 or 800 I.U. of vitamin E per day for a median follow-up period of 510 days (about 18 months) had a 77% lower risk of non-fatal myocardial infarction than the placebo group. However, a small (18%) but statistically significant increase in cardiovascular death was observed in the vitamin E group. The investigators suggested that most of the deaths in the vitamin E group occurred in the early part of the follow-up period; and therefore, they were unlikely due to vitamin E.
In contrast to the above observation, vitamin E supplementation in the HOPE trial involving 9,541 patients with high risk for cardiac events (atherosclerotic disease, diabetes plus one cardiac risk factor such as hypertension, elevated total cholesterol, low HDL cholesterol, cigarette smoking or documented microalbumineria), but without any evidence of heart failure, did not reduce death, stroke or non-fatal myocardial infarction in comparison to control. The exact reasons for this discrepancy between CHAOS and HOPE trials are unknown. However, it was pointed out that the HOPE trial used vitamin E (400 IU) from natural sources that had α-tocopherol and tocotrienol, and that the α-tocopherol portion was only about 50 IU. It was suggested that larger doses of α-tocopherol may be required to reduce the inflammation and atherogenesis.
Another study showed that daily consumption of 800 I.U. of vitamin E increased the levels of oxidative stress markers in heavy smokers. This was expected because vitamin E in the presence of an elevated level of oxidative environment oxidized that is present in heavy smokers was oxidized and acted as a free radical. Among non-smokers, vitamin E may produce transient benefits on certain criteria, but it would be ineffective on a long-term basis. Therefore, both CHAOS and HOPE trials have serious limitations, since they have utilized only vitamin E. From the studies presented in this section, no conclusion regarding the value of antioxidants for the prevention or treatment of CAD can be drawn.
TABLE 1Summary of intervention trials with vitamin E or vitaminC in high risk patients with no prior cardiac eventsName ofNo. ofType ofCriteria ofFollow-upStudyPatientsAntioxidantStudyPeriodResultsHOPE9,541a  Vitamin EDeath, stroke4.5yno effect400 IUNon-fatal MICHAOS2,002b  Vitamin E (d-αT)Death, non-fatal510dreduced400 or 800 IUMI—42cVitamin E(α-TA)FMD4monthsimproved544 IU—10dVitamin EOxidative stress3weeksincreases800 IU—80eVit. C-2gPlasma homocysteine,6hoursreducedMethione-100 mg/kgarterial stiffnessHOPE (Heart Outcomes Prevention Evaluation);CHAOS (Cambridge Heart Antioxidant Study);MI (myocardial infarction);FMD (endothelial-dependent flow-mediated dilation)aHigh risk for cardiac events (known atherosclerotic disease, diabetes plus one cardiac risk factor such as hypertension, elevated total cholesterol, low HDL cholesterol, cigarette smoking or documented microalbumineria), and not have heart failure.bProven atherosclerotic diseasecHypercholesterolemia, smokers and smokers with hypercholesterolemiadHeavy smokerseHealthy male subjects receiving methionine to increase homocysteine levels2.) Intervention Trials Utilizing Only Vitamin E in Patients with Prior Cardiac Events
A summary of 4 intervention trials using only vitamin E in high-risk patients with prior cardiac events is presented in Table 2 below. Results showed that doses of vitamin E, patient population, study endpoint and follow-up periods differ from one investigation to another. Nevertheless, three of four studies showed beneficial effects of vitamin E and one study revealed that the use of a low dose of vitamin E was ineffective.
For example, in a trial involving 100 patients having coronary angioplasty, those receiving 1200 I.U. of vitamin E daily for a 4-month period showed restenosis in 34.6% of patients, whereas those receiving a placebo showed stenosis in 50% of patients. In another study involving 75 patients, those receiving α-tocopherol (1200 IU/day) for a period of 5 months had lowered C-reactive proteins and monocyte interleukin-6 in diabetes type 2 patients with or without macrovascular complications in comparison to BMI-matched healthy controls. In still another study, supplementation with α-tocopherol (800 IU) decreased LDL-C oxidation in patients with chronic renal failure, but the benefit was greater in patients with peritoneal dialysis than that in hemodialysis.
In contrast to the above three studies, results of the ATBC trial involving 1862 men for a period of 6 years showed no significant difference in the number of major coronary events or cardiovascular death between the vitamin E group (50 mg/day) and placebo group. This study has utilized a much lower dose of vitamin E than the previous four studies. This could explain the above inconsistency in results. Again, using only one dietary antioxidant in these trials may not be significant for cardiac prevention or treatment.
TABLE 2Summary of intervention trials with vitamin E alonein high risk patients with prior cardiac eventsName ofNo. ofType ofCriteriaFollow-upStudyPatientsAntioxidantof StudyPeriodResults—100a Vitamin EStenosis4monthsreduced1200 IU—75bVitamin EC- reactive5monthsreduced1200 IUprotein—33cVit. E (d-αT)LDL12weeksreduced800 IUoxidationATBC1862d Vitamin EDeath, CAD6yno effect50 mgeventsAll vitamins were given once a day until specified otherwiseaAngioplastybType II diabetes with or without macrovascular complications and BMI-matched healthy controlcPatients undergoing peritoneal dialysis (N = 17) or hemodialysis (N = 16)dMale heavy smokers who have a previous history of myocardial infarction3.) Intervention Trials Utilizing Two or More Antioxidants in Patients with or without Prior Cardiac Events
A summary of 9 interventional trials with two or more antioxidants in high risk patients with or without prior cardiac events is presented in Table 3 below. Results showed that dose, type and number of antioxidants, patient population, study endpoint and follow-up periods differ from one study to another. Nevertheless, six studies showed beneficial effects, one study revealed no beneficial effect while two revealed harmful effects.
In a double-blind randomized prospective study, supplementation with 500 mg vitamin C and 400 IU vitamin E twice daily retarded early progression of transplant associated coronary arteriosclerosis. Supplementation with vitamin E and slow release vitamin C also reduced atherosclerosis. Another study has reported that supplementation with tomato juice (500 ml/day), vitamin C (500 mg/day) and vitamin E (800 IU/day) decreased oxidation of LDL cholesterol and plasma levels of C-reactive proteins in type 2 diabetes patients. It has been suggested that vitamin C may slow atherogenesis by improving endothelial-dependent vasodilation in patients with hyperglycemia and abnormal lipids, perhaps by preventing oxidation by nitric oxide. Pretreatment with 800 I.U. of vitamin E and 1000 mg of vitamin C prevented the above action of a high fat diet on endothelium-dependent vasodilation of the brachial artery. A clinical trial involving 317 patients who received a placebo or multiple antioxidants (700 IU vitamin E, 500 mg vitamin C and 30,000 IU beta-carotene) or probucol 4 weeks before and 6 months after undergoing angioplasty procedures, showed no significant difference in the rates of restenosis between the vitamin group and placebo group; however, probucol, a powerful antioxidant, was effective in reducing restenosis. Another study has shown that supplementation with multiple vitamins reduced the homocysteine level and LDL-cholesterol oxidation. Among CARET participants, supplementation with 30 mg β-carotene and 25,000 I.U. retinyl palmitate for a 5-year period did not change lipid levels. This may be due to the fact that only vitamin A and its precursor were used in this study and this may not be sufficient to alter lipid levels. In the ATBC trial involving 1862 male heavy smokers, supplementation with 50 mg vitamin E and 20 mg β-carotene for a period of 5.3 years increased major cardiac risks. This may due to the fact that doses of these antioxidants were low and male heavy smokers had high levels of oxidative environment. This could have resulted in rapid oxidation of these antioxidants, thereby increasing the CAD risk factors. Supplementation with vitamin C (500 mg/day) and vitamin E (800 IU/day) increased the risk of atherosclerosis among postmenapausal women with a history of varying levels of stenosis. Again, no conclusion regarding the value of antioxidants in prevention or treatment of CAD can be made, because endogenously made antioxidants were missing from these trials. Even the doses and number of dietary antioxidants varied from one study to another.
TABLE 3Summary of intervention trials with two or more antioxidantsin high risk patients with or without prior cardiac eventsName ofNo. ofType ofCriteria ofFollow-upStudyPatientsAntioxidantStudyPeriodResults—19cVit. E-400 IUCoronary1yreducedVit. C-500 mgAtherosclerosis—520f  Vit. E, slowAtherosclerosis6yreducedrelease vit. C—tomato juice 15 ml/d, vit COxyLDL-C,decreased500 mg, vit E 800 IUC-reactive protein—20eVitamin E 800 IU Vitamin C-1 gFMD6hincreased—317d Probucol- 500 mg Vitamin E-700 IURestenosis5-7moprobucol reduced moreVitamin C-500 mg β-carotene-30,000 Ithan combination182f  Multivitaminshomocysteine,6moReducedLDL-C oxidationCARET52aβ-Carotene-30 mg RetinylLipid levels5yno effectpalmitate-25000 IUATBC1862b Vit E (α-T)-50 mgMajor cardiac5.3yincreasedβ-carotene-20 mgWave423g Vit E 800 IU; vitamin C 1 gStenosis2.8yincreasedCARET (Carotene Retinol Efficacy Trial);ATBC (Alpha-Tocopherol Beta-Carotene Cancer Prevention Study);WAVE (Women's Angiographic Vitamin and Estrogen);FMD (endothelial-dependent flow-mediated dilation).All vitamins were given once a day until specified otherwise.a and b= male heavy smokers;c= cardiac transplant;d= angioplasty;e= normal individuals consuming high-fat meal;f= hypercholestrolemic;g= post-menopausal women with 15-75% stenosis;h= type II diabetes patients.4.) Intervention Trials Utilizing One or More Antioxidants in Combination with Cholesterol-lowering Drugs in Patients with or without Prior Cardiac Events
A summary of 6 interventional trials with one or more antioxidants in combination with cholesterol-lowering drugs in high risk patients with or without prior cardiac events is described in Table 4 below. The number, type, dose and dose schedules of antioxidants, patient population, observation period and criteria of study were different. Three studies revealed beneficial effects, one showed no beneficial effects, whereas two investigations by the same group showed deleterious effects when combined with simvastatin-niacin.
It has been reported that vitamin E supplementation (300 IU/day) together with simvastatin for an 8 week period improved endothelial-dependent flow-mediated dilation (FMD) as well as endothelial-dependent nitroglycerine-mediated dilation (NMD) in the brachial artery of patients with hypercholesterolemia more that that produced by simvastatin alone. A short-term beneficial effect may be obtained by high doses of a single antioxidant. Indeed, it has been reported that coenzyme Q10 has been shown to be useful in improving the function of damaged cardiac muscle associated with congestive heart failure and idiopathic dilated cardiomyopathy. In these instances, coenzyme Q10 probably improves the mitochondrial function of damaged cardiac muscles and protects them from further injury.
One study using 156 men with previous coronary bypass surgery who were receiving a cholesterol-lowering drug combination (colestipol-niacin) alone or in combination with vitamin E 100 I.U. per day showed that the vitamin E treated group revealed less progression of the narrowing of their coronary arteries in comparison to cholesterol-lowering drugs alone during a 4-year trial period. In The Heart Protection Study involving 20,500 patients with high risk, supplementation with antioxidants vitamins (vitamin E 650 mg, vitamin C 250 mg and β-carotene 20 mg) together with simvastatin for a period of 5.5-years did not interfere with the beneficial effect of this statin. Doses of antioxidants were small in this study, and endogenously made antioxidants were not included in the antioxidant regimen. Opposite results were obtained by recent clinical studies in which vitamin C, 1000 mg, vitamin E as d-α-tocopherol, 800 IU, natural beta-carotene, 25 mg and selenium, 100 μg per day were given together with mevastatin-niacin in a subset of patients with low level of HDL-cholesterol. Results revealed that niacin-induced elevation of HDL cholesterol was blocked by antioxidant supplements. This has not been reproduced by another clinical study; and therefore, the value of this investigation remains uncertain. In addition, dietary antioxidants vitamin A and β-carotene, and endogenously made antioxidants, n-acetylcysteine (a glutathione-elevating agent), α-lipoic acid, and co-enzyme Q10 as well as B-vitamins were missing from their formulation.
The same group of investigators, using the same formulation, reported that a mixture of dietary antioxidants reduced the degree of proximal artery stenosis in comparison to placebo controls. However, in combination with simvastatin-niacin it was less effective than the simvastatin-niacin group. Because of the small sample size (40 patients per group) and unusually large variation in the results (200-700% variation around the mean value), no conclusion regarding the value of antioxidants in the prevention or treatment of CAD can be drawn. The same group using the same mixture of dietary antioxidants reported that treatment of patients with simvastatin plus niacin alone or with the dietary antioxidants significantly reduced total cholesterol, LDL-cholesterol and triglycerides, and increase HDL-cholesterol levels in comparison to those who were not treated. There was no significant difference between those receiving simvastatin plus niacin or those receiving simvastatin, niacin and antioxidants.
Analysis of plasma levels of noncholesterol sterols suggested that lathosterol was directly and β-sitosterol was inversely related to stenosis. It was interesting to note that treatment with simvastatin plus niacin or simvastatin, niacin and antioxidants, decreases the level of lathosterol and increases the level of β-sitolsterol to similar degrees. These data suggest that newly identified predictors of stenosis were not significantly affected by the addition of antioxidants to the group receiving simvastatin plus niacin. Nevertheless, the investigators concluded that antioxidants prevent the efficacy of simvastatin plus niacin treatment.
Most intervention studies have recommended taking supplements once a day. Based on the biological-half life of antioxidants that varies from 6-10 h, the recommendation of taking antioxidants once a day may not produce an optimal effect on the prevention or as an adjunct to standard therapy in the treatment of CAD. The two clinical studies have attracted the attention of cardiologists and primary care physicians, and have led them to believe that antioxidants have either no value or may adversely affect the strategy for cardiac prevention and treatment. However, the analysis of their data suggests that such conclusion may be premature. Based on conflicting results of intervention trials with one or more dietary antioxidants and lack of data on appropriately designed clinical trials with multiple dietary and endogenously made antioxidants, it is not appropriate to propagate an idea that antioxidants may harm patients with cardiac risks, and that they have no role in prevention or treatment of CAD.
TABLE 4Summary of intervention trials with one or more antioxidants in combination with cholesterol-loweringdrugs in high risk patients with or without prior cardiac eventsName ofNo. ofType of Antioxidant +Criteria ofFollow-upStudyPatientsCholesterol-lowering drugsStudyperiodResults— 7aSimvastatin +FMD NMD8weeksimprovedvit. E-300 IU—126bStandard therapy +Cardiac muscle6yimprovedCo-enzyme Q10function33.3 mg (thrice/day)CLAS156cColestipol + niacinProgressive2yreducedVit. E- 100 IU or moreAtherosclerosisHPS20,500d  Simvastatin + Vit. E-650 mgCardiac events5.5yno better than than drugVit. C-250 mg − carotene-20 mgaloneHATS160eSimvastatin + niacin + Vit.Stenosis3yreduced drug effectivenessE-800 IU, Vit. C-1 g −but was more effective thancarotene- 25 mg,controlselenium-100 mcg (N = 46)HATS153eSameHDL1yreduce drug effectivenessCLAS (Cholesterol-Lowering Atherosclerosis Study);HPS (Heart Protection Study);HATS (HDL-atherosclerosis Treatment Study);FMD (endothelium-dependent flow-mediated dilation);NMD (endothelium-independent nitroglycerine-mediated dilation);HDL- (high density lipoprotein cholesterol);N (sample size for the group).All vitamins were given once a day until specified otherwise;a= hypercholesterolemia;b= idiopathic dilated cardiomyopathy;c= coronary bypass surgery;d= women, elderly diabetics, people with low baseline cholesterol pre-treatment and those with prior occlusive non-coronary vascular disease;e= coronary disease with low HDL- cholesterol.III. Scientific Rationale for Using Multiple Dietary and Endogenously Made Antioxidants, and B-vitamins and Minerals in the Prevention or as an Adjunct to Standard Theraphy in the Treatment of CAD
Since increased production of free radicals may be involved in the initiation and progression of CAD, the use of antioxidants appears to be a rational choice for the prevention and treatment of this disease. The use of single antioxidants for the prevention or treatment of CAD is not recommended because antioxidants act as free radicals when oxidized. Instead, the present invention, as described below, involves the use of formulations incorporating multiple dietary and endogenously made antioxidants because many different types of free radicals are produced and each antioxidant has a different mechanism of action and has a different affinity for each of these free radicals, depending upon the cellular environment.
For example, β-carotene (BC) is more effective in quenching oxygen radicals than most other antioxidants. BC can perform certain biological functions that cannot be carried out by its metabolite, vitamin A, and vice versa. In particular, it has been reported that BC treatment enhances the expression of the connexin gene, which codes for a gap junction protein in mammalian cells in culture, whereas vitamin A treatment does not produce such an effect. Vitamin A can induce cell differentiation in certain normal and cancer cells, whereas BC does not. The gradient of oxygen pressure varies within the cells. Vitamin E is more effective as a quencher of free radicals in reduced oxygen pressure, whereas BC and vitamin A are more effective in higher atmospheric pressure. Vitamin C is necessary to protect cellular components in aqueous environments, whereas carotenoids, vitamins A and E protect cellular components in non-aqueous environments. Vitamin C also plays an important role in maintaining cellular levels of vitamin E by recycling the vitamin E radical (oxidized) to the reduced (antioxidant) form.
Also, the oxidative DNA damage produced by oxidized vitamin C could be ameliorated by vitamin E. The form and type of vitamin E used are also important in any clinical trial. It is known that various organs of rats selectively absorb the natural form of vitamin E. It has been established that alpha tocopheryl-succinate (α-TS) is the most effective form of the vitamin. The inventors have reported that oral ingestion of α-TS (800 I.U./day) in humans increased plasma levels of not only α-tocopherol, but also of α-TS, suggesting that α-TS can be absorbed from the intestinal tract before hydrolysis to α-tocopherol. Selenium is a co-factor of glutathione peroxidase, and Se-glutathione peroxidase also acts as an antioxidant. Therefore, selenium supplementation together with other antioxidants is also essential.
Glutathione, an endogenously produced compound, represents a potent intracellular protective agent against damage produced by free radicals. It catabolizes H2O2 and anions. However, oxidized glutathione may make the cell more sensitive to further oxidative injuries. Therefore, increasing the intracellular levels of glutathione in vascular endothelial cells, vascular smooth muscle cells and cardiac muscles, may be very useful in the management of CAD. Oral supplementation with glutathione failed to significantly increase plasma levels of glutathione in human subjects, suggesting that this tripeptide is completely hydrolyzed in the G.I. tract. N-acetylcysteine and α-lipoic acid increase the intracellular levels of glutathione, and therefore, they can be used in combination with dietary antioxidants.
Furthermore, damaged vascular endothelial cells and cardiac muscle cells may not produce sufficient amounts of ATP due to a reduction in the synthesis of coenzyme Q10. Therefore, supplementation with coenzyme Q10 may be necessary for prevention, and as an adjunct to standard therapy for the treatment of CAD. In addition to being a weak antioxidant, coenzyme Q10 acts as a co-factor for generating ATP in the mitochondria. It also scavenges peroxy radicals faster than α-tocopherol, and like vitamin C, can regenerate vitamin E in a redox cycle. B-6, B12 and folic acid are essential for reducing the level of homocysteine.
IV. Antioxidants and Aspirin Resistance
It has been reported that antioxidants in combination with aspirin is more effective in inhibiting cyclooxygenase activity than either agent administered by itself. Alpha tocopherol succinate has been shown to reduce the action of PGE2 on adenylate cyclase. Thus, antioxidants can prolong the efficacy of aspirin among semi-responders and may prevent platelet aggregation among those who have developed total resistance.

Formulations comprising multiple dietary and endogenously made antioxidants and B-vitamins and use of same


A transceiver includes a power amplifying circuit, a first balance-unbalance circuit, a switchable matching circuit, and a low-noise amplifying circuit. The power amplifying circuit generates differential output signals during a transmitting mode of the transceiver. The first balance-unbalance circuit converts the differential output signals into a single-ended output signal. The switchable matching circuit receives the single-ended output signal on a signal port of the transceiver during the transmitting mode, and converts a single-ended receiving signal on the signal port into a single-ended input signal during a receiving mode of the transceiver. The low-noise amplifying circuit converts the single-ended input signal into a low-noise input signal during the receiving mode.

The invention relates to a transceiver and related switching method applied therein, and more particularly to a transceiver having an on-chip Balun and an on-chip TR (Transmit/Receive) switch, and a related method.
In a conventional transceiver, a TR (Transmit/Receive) switch is a device arranged to switch between a transmitter and a receiver of the transceiver. When the transceiver operates under a transmitting mode, the TR switch is arranged to couple the pre-transmitted signal outputted from the power amplifier to the antenna. When the transceiver operates under a receiving mode, the TR switch is arranged to couple the receiving signal of the antenna to the receiver. Two problems may arise from the conventional TR switch. The TR switch has intrinsic loss to the signal as it passes through because the TR switch may not be perfectly impedance matched with the transmitter and the receiver. The TR switch may also malfunction due to the large swing of the pre-transmitted signal when the transceiver operates under the transmitting mode.
For a differential communications system, an off-chip transformer balun (balanced/unbalanced) is further used to convert the signals between single ended and differential. An off-chip transformer balun will cause the overall cost higher because of the additional work of installing the off-chip transformer balun into the transceiver. Moreover, the off-chip transformer balun may occupy a large area of the PCB (Printed Circuit Board), which also increases the total cost.
Providing a low cost and low loss transceiver for the differential communications system is therefore a significant concern in this field.

This patent is subject to a terminal disclaimer.

Transceiver and related switching method applied therein


A closure assembly for a camshaft phaser. A plug or a cap is provided with either a radially-sealing gasket seal or a face-sealing gasket seal, the seal being formed by insertion of the plug into a bore, or by installation of a cap over a neck formed in a cover plate. The closure is provided with a plurality of spaced-apart locking elements, and the plate is provided with a plurality of spaced-apart, radially extending second locking elements in the form of fingers surrounding a central opening. During assembly, the closure is mated to the plate with the first locking elements interspersed with the second locking elements. The closure is rotated to bring the locking elements into locking engagement with each other, preventing counter-rotation of the closure. No threads or torque specifications are required.

Camshaft phasers for varying the timing of valves in internal combustion engines are well known. A typical phaser comprises a stator that is connected with the cam drive system driven by the engine crankshaft and a rotor within the stator connected to the camshaft. The phaser is able to vary the rotary position of the rotor with respect to the stator and thus to vary the valve timing imposed on the camshaft with respect to the crankshaft and pistons.
A prior art camshaft phaser is closed by a threaded metallic plug and an O-ring that seals on a tapered face just inside the bore. The threaded plug is screwed into a threaded cover. The plug is torqued to a required specification, but the torque level is expected to stay above the minimum required specification during thermal cycling, otherwise the plug could loosen and disengage during the life of the engine. A loosened plug or an opened phaser could cause unacceptable leakage negatively effecting operation of the phaser, a failure of the drive belt, unacceptable loss of engine oil pressure, and external oil leaks.
What is needed in the art is an improved closure assembly for a camshaft phaser wherein a plug or cap is sealingly retained in a phaser opening without threads or torquing and no compromise in retention capability during use of the phaser.
It is a principal object of the present invention to prevent disengagement and leakage of a closing plug or cap on a camshaft phaser.


A pinpoint forecast of the possible impact of a tsunami is created by processing near real-time tsunami data, including seismic data or wave data obtained using underwater pressure sensors, bathymetry data of the body of water in which the tsunami occurs, and topographic data of specific locations. Notifications are provided to subscribers via their mobile devices. The forecast presents the notification in a form that is easily understandable and which allows the subscriber to take any appropriate action. Disaster response personnel responsible for warning the populace can be similarly notified in a further embodiment. Additional assistance can be provided by activating disaster response and notification devices in the specific locations to be impacted. By providing the location-specific notifications and other actionable data, the system and method clarifies precisely where danger due to the tsunami exists on an individual basis and simplifies the evacuation from the affected areas, aiding public safety.

A tsunami is a series of long waves in a body of water, which can flood adjacent and distant coastlines with potentially devastating consequences for the inundated communities. For instance, the 2004 Sumatra tsunami resulted in more than 235,000 deaths and displaced 1.7 million people across 16 countries. Similarly, the Tōhoku tsunami that struck Japan on Mar. 11, 2011 is reported to have caused 15,853 casualties, resulted in 3,452 people being declared missing, 6,023 people injured, and over 220 billion dollars in damage.
Tsunami warning systems are crucial to reducing human casualties caused by the tsunamis. These warning systems strive to provide a notification of tsunami danger far enough in advance to allow precautionary steps, including the evacuation of the populace from the affected areas, to be taken. Such systems are on the receiving end of a chain of tsunami reaction activities that begin with the kinds of data that are associated with an event that could trigger a tsunami, such as an underwater or coastal seismic event or other oceanographic disturbances.
In the United States, the National Oceanic and Atmospheric Administration (NOAA) has the primary responsibility over forecasting and monitoring the occurrence of tsunamis. NOAA operates a fleet of oceanographic buoys, known as Deep-ocean Assessment and Reporting of Tsunamis (DART®) stations, and receives seismic data collected by the United States Geological Survey (USGS) and other agencies. NOAA analyzes the data to forecast the occurrence of a tsunami continually updates such forecast as more data becomes available. State-level centers are notified by NOAA if a tsunami threat is deemed likely to occur. Relevant civil authorities review the tsunami notifications and decide how to best act based on the notifications, such as issuing warnings or evacuation orders.
Unfortunately, warnings and orders are not always effective. First, such warnings and evacuation orders are often issued for a large geographic locale, erring on the side of caution by being overly inclusive. If such over-inclusion happens often, residents may doubt the accuracy of such warnings and could even disobey evacuation orders in the orders in the belief that a false alarm exists. Further, such warnings may be incomplete. For example, a tsunami has multiple characteristics, such as wave height, inundation, spread, and arrival time. The degree to which the coastal region may be affected is topologically-specific and that level of specificity is normally omitted from the more populace-oriented warnings of general danger. This lack of specificity can be addressed with actionable location-centric data, yet the various agencies responsible for tsunami response remain focused on high level and conservative warning messages, in part due, to the overriding need to act promptly as well as lack of readily available reliable actionable data.
Accordingly, there is a need for an improved way to provide notifications of a tsunami danger.

System and method for providing near real-time tsunami notification with the aid of a digital computer


The vehicle battery controller includes a controller for interconnecting an auxiliary battery to a main battery for engine starting or charging. If the auxiliary battery voltage is lower than a first threshold before engine starting its subsequent use is inhibited. If the main battery voltage exceeds the auxiliary battery voltage by more than a predetermined margin, the auxiliary battery is not used for engine starting. When the engine is running and the charging system is operating, the auxiliary battery is disconnected when the common voltage is below a second threshold.

In automotive vehicles, it is known to provide the electrical system with a rechargeable battery, such as a lead-acid accumulator, which is recharged by an engine-driven battery charger, such as an alternator or dynamo. The battery is used to start or "crank" the engine, such as an internal combustion engine, and to supply electrical power to the electrical system when the engine-driven charger cannot supply sufficient power, for instance, at relatively low engine speeds. For higher engine speeds, the charger supplies power to the electrical system and recharges the battery until it is recharged to its normal maximum working capacity
It is also known to provide a rechargeable auxiliary battery, such as a lead-acid accumulator, to assist in starting the engine. The auxiliary battery is also recharged by the engine-driven battery charger and, once recharged to its maximum normal capacity, is isolated from the electrical system.
According to the invention, there is provided a vehicle battery controller for controlling the connection of a rechargeable auxiliary battery to a rechargeable main battery of a vehicle electrical system including an engine-driven battery charger, the controller comprising a first comparison means for connecting the auxiliary battery to the main battery during engine starting if the auxiliary battery voltage is greater than a first threshold, and a second comparison means for disconnecting the auxiliary battery from the main battery during engine running if a battery voltage is less than a second threshold.
The battery voltage which is measured during engine running when the auxiliary battery is connected to the main battery is effectively a common battery voltage and may be measured at any suitable point of the electrical system, such as at the auxiliary battery or at the main battery. The auxiliary battery voltage is preferably measured at the auxiliary battery so as to avoid the effects of voltage differences occurring between the auxiliary battery and other points in the electrical system, for instance caused by the flow of current through the finite resistance of conductors.
Preferably the second comparison means is arranged, after disconnection of the auxiliary battery from the main battery, to connect the auxiliary battery to the main battery if the main battery voltage is greater than a third threshold. Preferably the third threshold is substantially equal to the second threshold.
Preferably the controller is arranged, after disconnection of the auxiliary battery from the main battery, to measure a first voltage change of the auxiliary battery voltage and a second voltage change of the main battery voltage. Preferably the controller is arranged to connect the auxiliary battery to the main battery if the first voltage change is negative and the second voltage change is positive. Preferably the controller is arranged to decrement the second threshold if the first voltage change is negative and the second voltage change is positive. Preferably the controller is arranged to increment the second threshold if the first voltage change is positive and the second voltage change is negative.
According to another aspect of the invention, there is provided a vehicle electrical system including a controller according to the invention.
Preferably the controller is arranged to control a switch, such as a contactor, connected between the auxiliary battery and the main battery. This is thus possible to provide an arrangement which will reliably allow a vehicle engine to be started after lack of use for a substantial time period. During such lack of use, various loads such as clocks and alarms systems remain connected to the main battery and may, after a sufficient time period, discharge the main battery to such an extent that it is unable to start the engine. Such a situation is aggravated in cold conditions where the main battery capacity is further reduced. During lack of use, the auxiliary battery is isolated and so is not discharged by any loads within the vehicle. In normal circumstances and in cold conditions, the auxiliary battery retains sufficient charge to allow the vehicle engine to be started, irrespective of the condition of the main battery.
In accordance with another object of the invention there is provided a method of controlling the use of an auxiliary battery in a vehicle electrical system which includes a main battery, an auxiliary battery, an engine starting apparatus and an engine-driven battery charger, the method comprising the steps of:
(a) comparing the auxiliary battery voltage with a first threshold before the engine is started and preventing connection of the auxiliary battery to the main battery if the auxiliary battery voltage is less then said threshold;
(b) comparing the excess of the main voltage battery over the auxiliary voltage battery with a predetermined margin;
(c) connecting the auxiliary battery to the main battery after an engine starting operation if the excess exceeds the margin, but before the engine starting operation otherwise;
(d) comparing the common battery voltage when the engine is running and the batteries are interconnected with a second threshold; and
(e) disconnecting the auxiliary battery from the main battery if the common battery voltage is less then said second threshold.


A light-emitting diode chip (1), in which over a substrate (2), a series of epitaxial layers (3) with a radiation-emitting active structure (4) based on InGaN is disposed. Between the substrate (2) and the active structure (4), a buffer layer (20) is provided. The material or materials of the buffer layer (20) are selected such that their epitaxial surface (6) for the epitaxy of the active structure (4) is unstressed or slightly stressed at their epitaxial temperature. The active structure (4) has In-rich zones (5), disposed laterally side by side relative to the epitaxial plane, in which zones the In content is higher than in other regions of the active structure (4). A preferred method for producing the chip is disclosed.

The term InGaN-based light-emitting diode chips in conjunction with the present invention is understood fundamentally to mean all light-emitting diode chips whose radiation-emitting zone has InGaN or related nitrides as well as mixed crystals based thereon, such as Ga(Al,In)N.
InGaN-based light-emitting diode chips are known for instance from The Blue Laser Diode by Shuji Nakamura and Gerhard Fasol, Springer Verlag Berlin Heidelberg 1997, page 209 ff.

Ingan-based light-emitting diode chip and a method for the production thereof


Systems and methods enabling uplink power sharing for dual connectivity are disclosed. Embodiments are described herein in which a maximum Uplink (UL) power on each link is configured statically, semi-statically, or dynamically. In general, regardless of the embodiment, uplink power for uplink transmissions from a wireless device on two simultaneous links is controlled such that the total uplink power does not exceeds a maximum UL transmission power level while, in some embodiments, taking into account priorities of the two links and/or priorities of various uplink channels transmitted by the wireless device on the two links. Notably, while the embodiments described herein focus on dual connectivity, the embodiments described herein can easily be extended to any number of two or more simultaneous links.

Long Term Evolution (LTE) uses Orthogonal Frequency Division Multiplexing (OFDM) in the downlink and Discrete Fourier Transform (DFT)-spread OFDM in the uplink. The basic LTE downlink physical resource can thus be seen as a time-frequency grid as illustrated in FIG. 1 where each resource element corresponds to one OFDM subcarrier during one OFDM symbol interval. In the time domain, LTE downlink transmissions are organized into radio frames of 10 milliseconds (ms), where each radio frame includes ten equally-sized subframes of length Tsubframe=1 ms. FIG. 2 is a schematic diagram of an LTE time-domain structure.
Resource allocation in LTE is typically described in terms of resource blocks, where a resource block corresponds to one slot (0.5 ms) in the time domain and 12 contiguous subcarriers in the frequency domain. A pair of two adjacent resource blocks in time (1.0 ms) is known as a resource block pair. Resource blocks are numbered in the frequency domain, starting with 0 from one end of the system bandwidth.
The notion of Virtual Resource Blocks (VRBs) and Physical Resource Blocks (PRBs) has been introduced in LTE. The actual resource allocation to a User Equipment device (UE) is made in terms of VRB pairs. There are two types of resource allocations, localized and distributed. In the localized resource allocation, a VRB pair is directly mapped to a PRB pair, hence two consecutive and localized VRBs are also placed as consecutive PRBs in the frequency domain. On the other hand, distributed VRBs are not mapped to consecutive PRBs in the frequency domain, thereby providing frequency diversity for the data channel transmitted using these distributed VRBs.
Downlink transmissions are dynamically scheduled in LTE. In particular, in each subframe, the base station transmits control information pertaining to which terminals, or UEs, data is transmitted and upon which resource blocks the data is transmitted in a downlink subframe. This control signaling is typically transmitted in the first 1, 2, 3, or 4 OFDM symbols in each subframe, and the number n=1, 2, 3, or 4 is known as the Control Format Indicator (CFI). The downlink subframe also contains Common Reference Symbols (CRS), which are known to the receiver and used for coherent demodulation of, for example, the control information. A downlink system with CFI=3 OFDM symbols as control is illustrated in FIG. 3.
From LTE Release 11 onwards, the above described resource assignments can also be scheduled on the enhanced Physical Downlink Control Channel (ePDCCH). For Release 8 to Release 10, only the Physical Downlink Control Channel (PDCCH) is available. The PDCCH is used to carry Downlink Control Information (DCI) such as scheduling decisions and power-control commands. More specifically, the DCI includes downlink scheduling assignments, uplink scheduling grants, and power control commands. In particular, downlink scheduling assignments include Physical Downlink Shared Channel (PDSCH) resource indication, transport format, Hybrid Automatic Repeat Request (HARQ) information, and control information related to spatial multiplexing (if applicable). A downlink scheduling assignment also includes a command for power control of the Physical Uplink Control Channel (PUCCH) used for transmission of HARQ acknowledgements in response to downlink scheduling assignments. Uplink scheduling grants include Physical Uplink Shared Channel (PUSCH) resource indication, transport format, and HARQ-related information. An uplink scheduling grant also includes a command for power control of the PUSCH. Power control commands included in the DCI include power control commands for a set of terminals, or UEs, as a complement to the commands included in the scheduling assignments/grants.
One PDCCH carries one DCI message with one of the formats above. As multiple terminals can be scheduled simultaneously, on both downlink and uplink, there must be a possibility to transmit multiple scheduling messages within each subframe. Each scheduling message is transmitted on a separate PDCCH, and consequently there are typically multiple simultaneous PDCCH transmissions within each cell. Furthermore, to support different radio channel conditions, link adaptation can be used, where the code rate of the PDCCH is selected to match the radio channel conditions.
To allow for simple yet efficient processing of the control channels in the terminal, the mapping of PDCCHs to resource elements is subject to a certain structure. This structure is based on Control Channel Elements (CCEs), which consists of nine Resource Element Groups (REGs). The number of CCEs, one, two, four, or eight, required for a certain PDCCH depends on the payload size of the control information (DCI payload) and the channel coding rate. This is used to realize link adaptation for the PDCCH; if the channel conditions for the terminal to which the PDCCH is intended are disadvantageous, a larger number of CCEs needs to be used compared to the case of advantageous channel conditions. The number of CCEs used for a PDCCH is also referred to as the Aggregation Level (AL).
The network can then select different aggregation levels and PDCCH positions for different UEs from the available PDCCH resources. For each PDCCH, as illustrated in FIG. 4, a Cyclic Redundancy Check (CRC) is attached to each DCI message payload. The identity of the terminal (or terminals) addressed—that is, the Radio Network Temporary Identifier (RNTI)—is included in the CRC calculation and not explicitly transmitted. Depending on the purpose of the DCI message (unicast data transmission, power control command, random access response, etc.), different RNTIs are used; for normal unicast data transmission, the terminal-specific Cell RNTI (C-RNTI) is used. After CRC attachment, the bits are coded with a rate −1/3 tail-biting convolutional code and ratematched to fit the amount of resources used for PDCCH transmission. After the PDCCHs to be transmitted in a given subframe have been allocated to the desired resource elements (the details of which are given below), the sequence of bits corresponding to all the PDCCH resource elements to be transmitted in the subframe, including the unused resource elements, is scrambled by a cell- and subframe-specific scrambling sequence to randomize inter-cell interference, followed by Quadrature Phase Shift Keying (QPSK) modulation and mapping to resource elements. The entire collection of the REGs (including those unused by any PDCCH) is then interleaved across the entire control region to randomize inter-cell interference as well as capturing frequency diversity for the PDCCHs.
LTE defines so-called PDCCH search spaces, which describe the set of CCEs the terminal is supposed to monitor for scheduling assignments/grants relating to a certain component carrier. A search space is a set of candidate control channels formed by CCEs on a given aggregation level, which the terminal is supposed to attempt to decode. As there are multiple aggregation levels, corresponding to one, two, four, and eight CCEs, a terminal has multiple search spaces. In each subframe, the terminals will attempt to decode all the PDCCHs that can be formed from the CCEs in each of its search spaces. If the CRC checks, the content of the control channel is declared as valid for this terminal and the terminal processes the information (scheduling assignment, scheduling grants, etc.). Each terminal in the system therefore has a terminal-specific search space at each aggregation level.
In several situations, there is a need to address a group of, or all, terminals in the system. To allow all terminals to be addressed at the same time, LTE has defined common search spaces in addition to the terminal-specific search spaces. A common search space is, as the name implies, common, and all terminals in the cell monitor the CCEs in the common search spaces for control information. Although the motivation for the common search space is primarily transmission of various system messages, it can be used to schedule individual terminals as well. Thus, it can be used to resolve situations where scheduling of one terminal is blocked due to lack of available resources in the terminal-specific search space. More important, the common search space is not dependent of UE configuration status. Therefore, the common search space can be used when the network needs to communicate with the UE during UE reconfiguration periods. FIG. 5 is a schematic diagram illustrating common and UE-specific search spaces for two UEs.
With regard to PUCCH, if a terminal has not been assigned an uplink resource for data transmission, the L1/L2 control information (channel status reports, HARQ acknowledgments, and scheduling requests) is transmitted in uplink resources (resource blocks) specifically assigned for uplink L1/L2 control on LTE Release 8 PUCCH. As illustrated in FIG. 6, these resources are located at the edges of the total available cell bandwidth. Each such resource consists of 12 "subcarriers" (one resource block) within each of the two slots of an uplink subframe. In order to provide frequency diversity, these frequency resources are frequency hopping on the slot boundary, i.e., one "resource" consists of 12 subcarriers at the upper part of the spectrum within the first slot of a subframe and an equally sized resource at the lower part of the spectrum during the second slot of the subframe or vice versa. If more resources are needed for the uplink L1/L2 control signaling, e.g. in case of very large overall transmission bandwidth supporting a large number of users, additional resource blocks can be assigned next to the previously assigned resource blocks.
LTE Release 10 (and subsequent releases of the LTE standard) supports bandwidths larger than 20 megahertz (MHz). One important requirement in LTE Release 10 is to assure backward compatibility with LTE Release 8. This should also include spectrum compatibility. That would imply that an LTE Release 10 carrier, wider than 20 MHz, should appear as a number of LTE carriers to an LTE Release 8 terminal. Each such carrier can be referred to as a Component Carrier (CC). In particular, for early LTE Release 10 deployments, it can be expected that there will be a smaller number of LTE Release 10-capable terminals compared to many LTE legacy terminals. Therefore, it is necessary to assure an efficient use of a wide carrier also for legacy terminals, i.e., that it is possible to implement carriers where legacy terminals can be scheduled in all parts of the wideband LTE Release 10 carrier. The straightforward way to obtain this would be by means of Carrier Aggregation (CA). CA implies that an LTE Release 10 terminal can receive multiple CCs, where the CCs have, or at least the possibility to have, the same structure as a LTE Release 8 carrier. CA is illustrated in FIG. 7.
The number of aggregated CCs as well as the bandwidth of the individual CCs may be different for uplink and downlink. A symmetric configuration refers to the case where the number of CCs in downlink and uplink is the same whereas an asymmetric configuration refers to the case that the number of CCs is different. It is important to note that the number of CCs configured in a cell may be different from the number of CCs seen by a terminal. A terminal may, for example, support more downlink CCs than uplink CCs, even though the cell is configured with the same number of uplink and downlink CCs.
During initial access, an LTE Release 10 terminal behaves similar to a LTE Release 8 terminal. Upon successful connection to the network, a terminal may—depending on its own capabilities and the network—be configured with additional CCs in the uplink and the downlink. Configuration is based on Radio Resource Control (RRC). Due to the heavy signaling and rather slow speed of RRC signaling, it is envisioned that a terminal may be configured with multiple CCs even though not all of them are currently used. If a terminal is configured on multiple CCs, this would imply that the terminal has to monitor all downlink CCs for PDCCH and PDSCH. This implies a wider receiver bandwidth, higher sampling rates, etc. resulting in high power consumption.
To mitigate above problems, LTE Release 10 supports activation of CCs on top of configuration. The terminal monitors only configured and activated CCs for PDCCH and PDSCH. Because activation is based on Medium Access Control (MAC) control elements—which are faster than RRC signaling—activation/de-activation can follow the number of CCs that are required to fulfill the current data rate needs. Upon arrival of large data amounts, multiple CCs are activated, used for data transmission, and de-activated if not needed anymore. All but one CC—the Downlink Primary CC (DL PCC)—can be de-activated. Therefore, activation provides the possibility to configure multiple CCs but only activate them as needed. Most of the time, a terminal would have one or very few CCs activated, resulting in a lower reception bandwidth and thus battery consumption.
Scheduling of a CC is done on the PDCCH via downlink assignments. Control information on the PDCCH is formatted as a DCI message. In LTE Release 8, a terminal only operates with one downlink and one uplink CC and, as such, the association between downlink assignment, uplink grants, and the corresponding downlink and uplink CCs is clear. In LTE Release 10, two modes of CA need to be distinguished. The first mode is very similar to the operation of multiple LTE Release 8 terminals where a downlink assignment or an uplink grant contained in a DCI message transmitted on a CC is either valid for the downlink CC itself or for an associated (either via cell-specific or UE specific linking) uplink CC. The second mode augments a DCI message with the Carrier Indicator Field (CIF). A DCI containing a downlink assignment with CIF is valid for that downlink CC indicted with CIF, and a DCI containing an uplink grant with CIF is valid for the indicated uplink CC.
DCI messages for downlink assignments contain, among other things, resource block assignment, modulation and coding scheme related parameters, HARQ redundancy version, etc. In addition to those parameters that relate to the actual downlink transmission, most DCI formats for downlink assignments also contain a bit field for Transmit Power Control (TPC) commands. These TPC commands are used to control the uplink power control behavior of the corresponding PUCCH that is used to transmit the HARQ feedback.
In LTE Release 10, the transmission of PUCCH is mapped onto one specific uplink CC, the Uplink Primary CC (UL PCC). Terminals only configured with a single downlink CC (which is then the DL PCC) and uplink CC (which is then the UL PCC) are operating dynamic Acknowledgement/Non-Acknowledgement (ACK/NACK) on PUCCH according to LTE Release 8. The first CCE used to transmit PDCCH for the downlink assignment determines the dynamic ACK/NACK resource on LTE Release 8 PUCCH. Since only one downlink CC is cell-specifically linked with the UL PCC, no PUCCH collisions can occur since all PDCCHs are transmitted using different first CCE.
Upon reception of downlink assignments on a single Secondary CC (SCC) or reception of multiple downlink assignments, CA PUCCH should be used. A downlink SCC assignment alone is untypical. The enhanced or evolved Node B (eNB) scheduler should strive to schedule a single downlink CC assignment on the DL PCC and try to de-activate SCCs if not needed. A possible scenario that may occur is that an eNB schedules a terminal on multiple downlink CCs including the PCC. If the terminal misses all but the DL PCC assignment, the terminal will use LTE Release 8 PUCCH instead of CA PUCCH. To detect this error case, the eNB has to monitor both the LTE Release 8 PUCCH and the CA PUCCH.
In LTE Release 10, the CA PUCCH format is based on the number of configured CCs. Configuration of CCs is based on RRC signaling. After successful reception/application of the new configuration, a confirmation message is sent back making RRC signaling very safe.
Transmission and reception from a node, e.g. a terminal in a cellular system such as LTE, can be multiplexed in the frequency domain or in the time domain (or combinations thereof). Frequency Division Duplex (FDD), as illustrated on the left in FIG. 8, implies that downlink and uplink transmission take place in different, sufficiently separated, frequency bands. Time Division Duplex (TDD), as illustrated on the right in FIG. 8, implies that downlink and uplink transmission take place in different, non-overlapping time slots. Thus, TDD can operate in unpaired spectrum, whereas FDD requires paired spectrum. Typically, the structure of the transmitted signal in a communication system is organized in the form of a frame structure. For example, LTE uses ten equally-sized subframes of length 1 ms per radio frame as illustrated in FIG. 9.
In case of FDD operation (upper part of FIG. 9), there are two carrier frequencies, one for uplink transmission (fUL) and one for downlink transmission (fDL). At least with respect to the terminal in a cellular communications system, FDD can be either full duplex or half duplex. In the full duplex case, a terminal can transmit and receive simultaneously, while in half duplex operation, the terminal cannot transmit and receive simultaneously (the base station is capable of simultaneous reception/transmission though, e.g. receiving from one terminal while simultaneously transmitting to another terminal). In LTE, a half duplex terminal is monitoring/receiving in the downlink except when explicitly being instructed to transmit in a certain subframe.
In case of TDD operation (lower part of FIG. 9), there is only a single carrier frequency, and uplink and downlink transmissions are always separated in time also on a cell basis. As the same carrier frequency is used for uplink and downlink transmission, both the base station and the mobile terminals need to switch from transmission to reception and vice versa. An essential aspect of any TDD system is to provide the possibility for a sufficiently large guard time where neither downlink nor uplink transmissions occur. This is required to avoid interference between uplink and downlink transmissions. For LTE, this guard time is provided by special subframes (subframe 1 and, in some cases, subframe 6), which are split into three parts: a downlink part (DwPTS), a guard period (GP), and an uplink part (UpPTS). The remaining subframes are either allocated to uplink or downlink transmission.
TDD allows for different asymmetries in terms of the amount of resources allocated for uplink and downlink transmission, respectively, by means of different downlink/uplink configurations. In LTE, there are seven different configurations as shown in FIG. 10. Note that in the description below, downlink subframe can mean either downlink or the special subframe.
To avoid severe interference between downlink and uplink transmissions between different cells, neighbor cells should have the same downlink/uplink configuration. If this is not done, uplink transmission in one cell may interfere with downlink transmission in the neighboring cell (and vice versa) as illustrated in FIG. 11. Hence, the downlink/uplink asymmetry can typically not vary between cells, but is signaled as part of the system information and remains fixed for a long period of time.
A dual connectivity framework is currently being considered for LTE Release 12. Dual connectivity refers to the operation where a given UE consumes radio resources provided by at least two different network points (master and secondary eNBs) connected with non-ideal backhaul while in RRC_CONNECTED. A UE in dual connectivity maintains simultaneous connections, or links, to anchor and booster nodes, where the anchor node is also called the Master eNB (MeNB) and the booster node is also called the Secondary eNB (SeNB). As the name implies, the anchor node terminates the control plane connection towards the UE and is thus the controlling node of the UE. The UE also reads system information from the anchor. In addition to the anchor, the UE may be connected to one or several booster nodes for added user plane support. The MeNB and the SeNB are connected via the Xn interface, which is currently selected to be the same as the X2 interface between two eNBs.
The anchor and booster roles are defined from a UE point of view. This means that a node that acts as an anchor to one UE may act as booster to another UE. Similarly, though the UE reads the system information from the anchor node, a node acting as a booster to one UE may or may not distribute system information to another UE. A MeNB operates to provide system information and terminate the control plane. In addition, the MeNB may terminate the user plane. Conversely, a SeNB operates to terminate only the user plane.
In one application, dual connectivity allows a UE to connect to two nodes in order to receive data from both of these nodes to increase the UE's data rate. This user plane aggregation achieves similar benefits as CA using network nodes that are not connected by low-latency backhaul/network connection. Due to this lack of low-latency backhaul, the scheduling and HARQ-ACK feedback from the UE to each of the nodes will be performed separately. That is, it is expected that the UE shall have two uplink transmitters to transmit uplink control and data to the connected nodes.
Uplink power control controls the transmit power of the different uplink physical channels. As an example, if the UE transmits PUSCH without a simultaneous PUCCH for the serving cell c, then the UE transmit power for PUSCH transmission in subframe i for the serving cell c is given (in milli-decibels (dBm)) by
                    P                  PUSCH          ,          c                                  (        i        )              =          min                    {                                                                                P                                          CMAX                      ,                      c                                                                                (                    i                    )                                                  ,                                                                                10                                                                                log                      10                                                                                (                                                                        M                                                      PUSCH                            ,                            c                                                                                (                          i                          )                                                                    )                                                                      +                                                      P                                          O_PUSCH                      ,                      c                                                                                (                    j                    )                                                  +                                                                            α                      c                                                                                (                      j                      )                                                        ·                                      PL                    c                                                  +                                                      Δ                                          TF                      ,                      c                                                                                (                    i                    )                                                  +                                                      f                    c                                                                          (                    i                    )                                                                                }              ,where:                PCMAX,c(i) is the configured UE transmit power defined in 3GPP Technical Specification (TS) 36.101 V12.2.0 in subframe i for serving cell c and {circumflex over (P)}CMAX,c(i) is the linear value of PCMAX,c(i),        MPUSCH,c(i) is the bandwidth of the PUSCH resource assignment expressed in number of resource blocks valid for subframe i and serving cell c,        PO_PUSCH,c(j) is a desired received power level per resource block for the serving cell c,        αc(j) is a parameter that can take a value smaller than or equal to 1, which allows for partial path-loss compensation.        PLc is the downlink pathloss estimate calculated in the UE for serving cell c in decibels (dB), where PLc=referenceSignalPower−higher layer filtered Reference Signal Received Power (RSRP), where referenceSignalPower is provided by higher layers and RSRP is defined in 3GPP TS 36.214 V12.0.0 for the reference serving cell and the higher layer filter configuration is defined in 3GPP TS 36.331 V12.0.0 for the reference serving cell.        ΔTF,c(i) is a power offset for the specific modulation and coding scheme of the PUSCH, and        fc(i) is the adjustment by power control commands.
If the total transmit power of the UE would exceed {circumflex over (P)}CMAX(i), the UE scales {circumflex over (P)}PUSCH,c(i) for the serving cell c in subframe i such that the condition
            ∑      c                                            w                          (          i          )                    ·                                    P            ^                                PUSCH            ,            c                                            (          i          )                      ≤      (                                        P            ^                    CMAX                                  (          i          )                    -                                    P            ^                    PUCCH                                  (          i          )                      )  is satisfied where {circumflex over (P)}PUCCH(i) is the linear value of PPUCCH(i), {circumflex over (P)}PUSCH,c(i) is the linear value of PPUSCH,c(i), {circumflex over (P)}CMAX(i) is the linear value of the UE total configured maximum output power PCMAX defined in 3GPP TS 36.101 V12.2.0 in subframe i, and w(i) is a scaling factor of {circumflex over (P)}PUSCH,c(i) for serving cell c where 0≤w(i)≤1. In case there is no PUCCH transmission in subframe i, {circumflex over (P)}PUCCH(i)=0.
Currently, there is no systematic solution for addressing the uplink power control problem when a UE is configured with dual connectivity. In particular, without full knowledge of uplink transmission of the other link, the MeNB and the SeNB may each expect the UE to use a high uplink power level, which in aggregate exceeds the maximum power the UE can use. There is no existing solution that enables the UE to allocate uplink power intelligently across two links when operating under power constraints. FIG. 12 is a schematic diagram illustrating uplink power for a MeNB and a SeNB exceeding a maximum allowed amount.
Further, differences between the characteristics of dual connectivity and those of CA pose challenges to uplink power control for both the eNBs and the UE when configured with dual connectivity. In particular, dual connectivity is similar to CA with multiple Timing Advance Groups (TAGs) in that the UE is simultaneously connected to two (or more) Transmission Points (TPs) that can be geographically separated. There are potentially two (or more) simultaneous downlink transmissions and two (or more) uplink transmissions for a given UE. However, the dual connectivity scenario is different from CA in several aspects.
First, in dual connectivity, the MeNB and the SeNB are allowed to be connected via a variety of backhaul links, including non-ideal backhaul links with up to 60 ms delay. In contrast, in CA, the TPs are assumed to be connected via ideal backhaul links, where delay is negligible over the X2 interface. In CA, it is assumed that the TPs have a central processing unit, which is not the case in dual connectivity. Second, in dual connectivity, the network node's MeNB and SeNB may or may not be synchronized (synchronized network or unsynchronized network). Synchronization by Global Navigation Satellite System (GNSS) or synchronization over backhaul network is not always available for small cell deployments, e.g., indoor deployment or hotspots with high buildings around. In certain deployment scenarios, it may not be feasible to synchronize the MeNB and the SeNB because the carrier frequencies that they deploy require different synchronization sources. For example, this is the case if both the MeNB and the SeNB use TDD, and the neighboring systems have different synchronization. Thus the downlink subframe boundary of the MeNB and the SeNB may or may not be aligned in time. In contrast, in CA, the network nodes are assumed to be synchronized.
Third, combining the effect of unsynchronized network and timing advance, the uplink subframe boundary misalignment, from a UE's perspective, can be up to the maximum of 7 OFDM symbols (0.5 ms). In contrast, in a CA scenario, the uplink subframe misalignment is only due to the effect of timing advance, and is considered to be limited to a maximum of ˜30 microseconds (μs) plus the additional synchronization error of the two TPs. This corresponds to about a half OFDM symbol. Fourth, in dual connectivity, each eNB (MeNB and SeNB) operates its own Radio Link Control (RLC), MAC (including scheduler), and physical layer. The MeNB and the SeNB independently schedule their own uplink and downlink transmissions. Thus, for example, the UE may have two simultaneous uplink transmissions scheduled, one by the MeNB, the other by the SeNB, without one eNB being aware of the scheduling information of the other eNB. Scheduling of PUCCH/PUCCH/Physical Random Access Channel (PRACH)/Sounding Reference Signal (SRS) of one link is not known to eNB of the other link. In contrast, in CA, a single MAC (including a scheduler) controls the multiple transmission points and has full knowledge of the scheduled transmission of a given UE.
Fifth, in dual connectivity, at least one cell in the SeNB has a configured uplink and one of them is configured with PUCCH resources. Thus, a UE may be required to transmit two PUCCHs simultaneously, one towards the MeNB, the other towards the SeNB. Two sets of Uplink Control Information (UCI) may be simultaneously transmitted via PUCCH (or PUSCH) on the MeNB link and the SeNB link. In contrast, in CA, UCI is only transmitted on one serving cell (the Primary Cell (PCell)). Sixth, in dual connectivity, PRACH may be transmitted on both links simultaneously. In contrast, in CA a PRACH is only transmitted on one component carrier at a time.
These differences pose challenges to the uplink power control mechanism for both the eNBs and the UE when configured with dual connectivity. As such, there is a need for uplink power control schemes for dual connectivity.

Uplink power sharing in dual connectivity