text:
A composition for the treatment and prevention of endothelial dysfunction comprising a therapeutically effective amount of anti-inflammatory agents comprising; acetylsalicylic acid, an amino sugar and a zinc compound.
1. A composition for the treatment and prevention of endothelial dysfunction in mammals comprising a therapeutically effective amount of anti-inflammatory agents comprising; acetylsalicylic acid, an amino sugar and a zinc compound.
2. The acetylsalicylic acid of
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7. A composition for the treatment and prevention of endothelial dysfunction in mammals comprising a therapeutically effective amount of anti-inflammatory agents comprising; acetylsalicylic acid, a second NSAID, an amino sugar, and a zinc compound.
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14. A method for the treatment and prevention of endothelial dysfunction in mammals by administering a therapeutically effective amount of anti-inflammatory agents comprising; acetylsalicylic acid, an amino sugar and a zinc compound.
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This invention involves compositions of anti-inflammatory agents for the treatment and prevention of disorders associated with endothelial dysfunction.
Endothelial cells are mesodermally derived, simple squamous epithelial cells that line the heart, blood and lymph vessels, line any closed cavity (peritoneal, pleural, pericardial, synovial) and line the intestinal tract. Endothelial cells of blood vessels have both mechanical and functional properties. They provide a barrier effect to the penetration of blood components into the vessel wall and have endocrine functions.
Vascular endothelium is a multi-functional barrier separating blood from interstitium. It plays a role in coagulation, inflammation, angiogenesis and has vasomotor functions. Endothelial dysfunction can be considered as an initial stage of atherosclerosis. Malik J, Melenovsky V, Wichterle D, Function and dysfunction of the endothelium, Cas Lek Cesk 2000 Apr. 12;139(7):197-202. Endothelium dysfunction is recognized as an early event in the pathogenesis of cardiovascular disease, and linked to hypertension, diabetes mellitus and oxidative stress. Pepine C J, Clinical implications of endothelial dysfunction, Clin Cardiol 1998 November; 21(11):795-9.
Endothelial dysfunction is characterized by a loss of barrier function and an infiltration of cellular material into the vascular wall and loss of physiological vascular tone. There is a loss of nitric oxide mediated physiological vasodilation, increased endothelial adhesion and migration of leucocytes and macrophages into the subendothelial vascular wall. Hypoxia, shear forces and oxidative stress trigger events for endothelial dysfunction. Disorders associated with endothelial dysfunction include; atherosclerosis, diabetes, infections, inflammations, cardiovascular disease and stroke.
This invention relates to a composition for the treatment and prevention of endothelial dysfunction consisting of a therapeutically effective amount of anti-inflammatory agents comprising; acetylsalicylic acid, an amino sugar and a zinc compound.
Each year 1.5 million Americans suffer heart attacks (myocardial infarction) and 500,000 die of that first attack, with 48% being females. Most of the 500,000 deaths occur within 2 hours after chest pain or other symptoms. In Britain half of all heart attack patients die within two hours of symptom onset and two-thirds of the deaths occur before admission to the hospital. Rawles J, Pre-Hospital Immediate Care 1997;1:12-18. During this critical 120 minute period, coronary thrombosis could be eliminated and the heart attack prevented if the thrombus could be averted. While the nation's death rate from heart attacks peaked in the 1960s, when the death rate from heart disease was 307.4 per 100,000 people, the rate has plummeted to 134.6 in 1996, but myocardial infarction still ranks as the nation's leading killer. Coronary artery disease (CAD) affects 13.5 million Americans, a million have survived heart attacks, 7 million have angina (myocardial ischemia), 600,000 have undergone coronary bypass surgery and 2,000 have had heart transplants. The economic burden is estimated at $150 billion annually. Tindall W N, Business & Health February 1998.
The vascular endothelium modulates blood vessel tone by secreting a variety of dilating and constricting substances. Dilating agents include nitric oxide (NO), prostacyclin, bradykinin, and endothelium-derived relaxing factor (EDRF) and heparinoids; constricting agents include endothelin, superoxide anion, endothelium-derived constricting factor, locally produced antiotensin II, and thromboxane. These agents not only control and alter vascular tone, but also can affect platelet adhesion and aggregation, influence thrombogenicity of the blood, and participate in cell proliferation and the development and progression of atherosclerosis.
Injury to endothelial cell function, primarily resulting from increased oxidant stress within the endothelium, leads to a cascade of events beginning with activation of vascular cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF α) and proceeding to expression of adhesion molecules on the cell surface that include vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial-leucocyte adhesion molecule (ELAM), which attracts monocytes and other leucocytes to adhere to the endothelial surface. Adherence is followed by infiltration of mononuclear cells into the vascular wall, together with activation of monocyte chemoattractant protein-1 (MCP-1), leads to scavenging of oxidized low-density lipoproteins (LDL), formation of lipid-laden foam cells, and development or progression of atherosclerotic plaque. Activation of prothrombogenic stimuli and inactivation of fibrinolytic factors with endothelial dysfunction predisposes these blood vessels to thrombosis. Quyyumi A A, Am J of Med 1998;105(1A):32S-39S.
Vascular injury triggers thrombosis and a proliferative response. By the release of tissue factor and exposure of subendothelial matrix, the coagulation and platelet pathways are activated and a thrombus is formed, either on a micro or macroendoluminal level. Additionally, platelet activation leads to a variety of mitogens, growth-promoting factors, and cytokines. Potent mitogens, such as platelet-derived growth factor and fibroblast growth factor, cause smooth muscle cells, fibroblasts, inflammatory cells, and endothelial cells to participate in reendothelialization. Smooth muscle cell and fibroblast proliferation and migration result from signal transduction pathways initiated by factors biding to their specific cell-surface receptor. Smooth muscle cells and fibroblasts migrate from the media to the intimal surface. Smooth muscle cells are phenotypically transformed to the synthetic subtype and secrete an extracellular matrix consisting of proteoglycans. Ward S R, Topol E J, Resident & Staff Physician 1995;41(3):11-18.
British scientists have reported a well-established link between inflammation and cardiovascular events mediated by inflammation-induced dysfunction of the arterial endothelium. Even mild systemic inflammatory responses are associated with significant alteration in endothelial function which lead to increased cardiovascular risk. Hingorani A D, et al., Circulation 2000;102:994-999.
Thrombus formation is the proximate cause of myocardial infarction, but atherosclerosis, the chief underlying cause, is a chronic disease that progresses over decades of life. Inflammation has a role in both the initiation and the progression of atherosclerosis, and anti-inflammatory agents have a role in the prevention of cardiovascular disease.
Atherosclerosis may be considered as an aberrant form of would-healing in arteries. Repeated minor trauma, leading to subendothelial hemorrhage, may well account for the tendency of atherosclerosis to occur mostly at major blood vessel flexion sites and at sites of mechanical stress, such as the carotid sinus or the bifurcation of the carotid artery. The positive injury potential resulting from petechial hemorrhages in the vascular intima will attract negatively charged platelets an leucocytes and will lead to a layered thrombus formation. Gaps between the endothelial cells of the intima will allow the insinuation of monocytes beneath the endothelium, where it seems they can become transformed into macrophages and engulf oxidized LDL to become foam cells and lead to the formation of the atherosclerotic plaque.
C-reactive protein (CRP) is a natural substance that results from an inflammatory response to injury of infection by mobilizing white blood cells. CRP is an acute-phase reactant that is a marker for underlying systemic inflammation, reported in patients with acute ischemia or myocardial ischemia and found to predict recurrent ischemia in those with unstable angina. Base-line levels of CRP in apparently healthy men can predict the risk of the first myocardial infarction and ischemic stroke. Previous infection with Chiamydia pneumonia, Heliobacter pylori, herpes simplex virus, or cytomegalovirus may be the source of the chronic inflammation detected by CRP. The rates of myocardial infarction were lower for those on acetylsalicylic acid (ASA) for all levels of CRP. Ridker P M, et al, NEJM 336(14):973-979. An elevated CRP level is related to inflammation, and increased inflammation is noted for many diseases, such as cancer, cardiovascular disease, infection, connective tissue diseases and injuries. Elevated CRP reflects an increased production of proinflammatory cytokines such as interleukin-6, which may be contributing to the pathophysiology of disease either directly or indirectly through their relationship to other important components of inflammation, thrombosis, or fibrinolysis. Kuller L H, Tracy R P, Arteriosclerosis, Thrombosis, and Vascular Biology 2000;20(4):901
The Physicians Health Study (PHS) indicates that healthy men with baseline levels of CRP in the highest quartile had a threefold increase in risk of developing future myocardial infarction and twice the risk of developing stroke. These risk estimates were stable over an 8-10 year follow-up period, were not modified by smoking status, and were independent of other cardiovascular risk factors, including total and HDL cholesterol, triglycerides, lipoproteins and fibrinogen. Elevated baseline levels of CRP are also associated with a fourfold increase in the risk of developing clinically severe peripheral arterial disease, again independent of usual risk factors. Plasma levels of ICAM-1 are elevated many years in advance of a first-ever myocardial infarction and that levels of ICAM-1 correlate with CRP. Cellular adhesion molecules, such as ICAM-1, are critical in the adhesion of circulating leucocytes to the endothelial cell and subsequent endothelial transmigration, and provide evidence that cellular mediators of inflammation have a critical role in atherogenesis. CRP levels increase with increasing prevalence of exposure to Heliobactor pylori, the bacteria responsible for gastric ulcers. Ridker P M, Circulation 1998;97:1671-1674.
Chronic subclinical infection with Chlamydia pneumoniae, Helicbacter pylori, chronic bronchitis, and chronic dental sepsis have been associated with raised values of CRP and have been implicated as risk factors for coronary heart disease. Mendall M A, BMJ 1998;316:953-954. During acute unstable angina, which if believed to be an immune system-mediated inflammatory disorder, patients had significantly greater levels of CRP and helper T-cells and significantly reduced levels of suppressor T-cells. Caligiuri G, J Am Coll Cardiol 1998;32:1295-1304.
H pylori is a spiral gram-negative rod that resides beneath the gastric mucus layer adjacent to epithelial cells. It causes a chronic mucosal inflammation and associated with peptic ulcer disease. H pylori is treated with antibiotics and bismuth or bismuth containing compounds such as bismuth subsalicylate. Tierney Jr. L M, McPhee S J, Papadakis M A, Current Medical Diagnosis and Treatment, Appelton & Lange, 3rd ed 1994 p.490.
CRP concentrations were increased in about 75% of patients within 24 hours after ischemic stroke, and higher values were significantly associated with large infarct size. Di Napoli M, BMJ 2001;322:1605. In 1950, the stroke death rate per 100,000 was 88.8. In 1996, it was 26.5. Stroke is the third leading cause of death (after heart disease and cancer). Americans suffer about 500,000 strokes each year and 150,000 stroke deaths. Cerebral thrombosis and cerebral embolism, known as ischemic stroke, account for about 80% of strokes. Cerebral thrombosis often occurs at night or first thing in the morning when blood pressure is normally low. About one-third of those who experience a transient ischemic attack (TIA) have a stroke within five years. Half of the post-TIA strokes occur within a year, 20% within one month. TIAs double the risk of heart attack. Those on ASA had 42% fewer strokes. It has been reported that immediate use of ASA be considered in all patients with acute ischemic stroke. Sandercock PAG, Lancet 1997;349:1563-1565, 1569-1581.
Many of the current studies point to an inflammatory etiology for cardiovascular and cerebrovascular disorders. Anti-inflammatory agents have shown benefits for the treatment and prevention of these endothelial dysfunction diseases. This invention provides a composition to overcome the obstacles inherent in the prior approaches.
Acetylsalicylic acid (ASA) has been known to treat and prevent cardiovascular disease by reducing thrombosis, but the real effect is as an anti-inflammatory agent. ASA inhibits cyclo-oxygenase in both platelets and endothelial cells. At low doses ASA inhibits the formation of thromboxane A2 (TXA2), a potent vasoconstrictor and platelet agonist formed via cyclo-oxygenase-dependent pathwasy in platelets. At higher doses, ASA has been shown to block the formation of prostacyclin (PGI2), a vasodilator and inhibitor of platelet aggregation, in endothelial cells.
The use of ASA for the primary prevention of CAD was examined in the PHS in which 22,000 U.S. male physicians were observed for about 5 years. Those who took 325 mg of ASA every other day had a 44% reduction in the incidence of first myocardial infarction, and a 25% reduction in the incidence of subsequent myocardial infarction, stroke, and death from cardiovascular causes. Milani R V, Lavie C J, Postgraduate Medicine 1996;99(2):109-120.
NSAIDs fall into seven major classes: proprionic acid derivatives, indole derivatives, fenamates, pyrrolealkanoic acids, pyrazolone derivatives, oxicams and salicylic acids. NSAIDs for purposes of this invention are selected from, but not limited to acetylsalicylic acid, ibuprofen, naproxen and ketoprofen. Most develop some erosions in the stomach after each dose. The number of NSAID users presenting with serious GI complications is low (1-2%), but the high usage of NSAIDs means the number affected is large. The annual death rate amongst patients with rheumatoid and osteoarthritis due to serious adverse consequences of GI ulceration (perforation and hemorrhage) has been estimated at 16,500 in the U.S. alone.
High gastric acidity contributes to NSAID injury to the stomach and duodenal bulb. Most NSAIDs are weak acids (pKa values 3.5 to 6) existing in a non-ionized form at low pH, and are lipid soluble. They readily diffuse into surface cells and become trapped at the higher intracellular pH. This accumulation causes local toxicity. Gastric acid and possibly pepsin, appears to deepen some of the superficial lesions that occur with NSAIDs. Most superficial lesions repair within 1-2 hours, but some patches of damaged tissues do not repair in time to prevent deeper tissue destruction.
The critical factor is how fast ASA is absorbed to reduce thrombosis within the 2 hour time frame. Enteric-coated ASA takes about 60 minutes to reach peak blood levels; regular ASA reaches peak blood levels in 30 minutes; but chewing an ASA tablet reaches blood levels and inhibits platelet activity in 5 minutes. Undissolved tablets and large particles that adhere to the gastric mucosa result in lesions. Micropulverized ASA particles, 100-600 μm, cause fewer lesions because they diffuse readily reducing contact with the gastric mucosa.
The dosage of ASA for the present invention consists of 325 mg per day which may be in divided dose when mixed with the amino sugar and zinc compound.
A number of patents disclose the use of ASA, primarily as analgesics both systemically and topically. Cotty et al, U.S. Pat. No. 4,049,803, discloses a composition of acetaminophen, ASA and caffeine. Patel, U.S. Pat. No. 4,867,984, discloses beads of ASA or acetaminophen coated with PVP. Frisbee, U.S. Pat. No. 4,970,081, discloses a formulation for a controlled release aspirin tablet. Bru et al, U.S. Pat. No. 5,437,874, discloses a composition of ASA or carbasalate calcium, metoclopramide, a hydrophilic polymer, anhydrous magnesium citrate and lactose. Eickhoff et al, U.S. Pat. No. 5,518,738, discloses NSAID particles coated with PVP. Liversidge et al, U.S. Pat. No. 5,552,160, discloses surface modified NSAID nanoparticles. Moshyedi, U.S. Pat. No. 5,770,215, discloses a vitamin supplement with ASA. Medford et al, U.S. Pat. No. 5,846,959, discloses a method for treating CVD with PUFA and CV drugs. Riley et al, U.S. Pat. No. 5,948,443, discloses a method for treating nutritional losses and heart disease with ASA, multivitamins and minerals. Noack et al, U.S. Pat. No. 5,973,011, discloses a method of treating endothelial dysfunction with PETN and active compounds to treat CVD. Weissman et al, U.S. Pat. No. 6,121,249, discloses a method for treating CVD with ASA, antioxidants and vitamins. Calanchi et al, U.S. Pat. No. 6,261,602 B1, discloses a microencapsulated mixture of thickening agents, disintegrating agents and pharmaceutically active substances.
NSAIDs inhibit prostaglandin (PG) synthesis by blocking the action of cyclooxygenase (COX), which exists in two forms. COX-1 is present in virtually all tissues and synthesizes PG which provides GI mucosal protection. COX-2 is activated in response to cytokines and other inflammatory factors. NSAIDs currently available inhibit both COX-1 and COX-2 to varying degrees. Selective COX-2 inhibitors, Vioxx (rofecoxib) and Celebrex (celecoxib) were promoted to provide pain relief and avoid GI complications. However, all NSAIDs, including COX-2 inhibitors, can cause GI adverse events, including life-threatening perforations, ulcers or bleeds. One study comparing Vioxx to naproxen detected a four fold risk of myocardial infarction. Nissen S E, et al, JAMA 2001;286:954-959. COX-2 isoenzymes are necessary for maintaining renal blood flow. COX-2 inhibitors have been reported too cause acute renal failure.
Platelets play an important role in the development of atherosclerosis. COX-2 inhibitors reduce the levels of prostacyclin (PGI2), a cyclooxygenase product that inhibits platelet activation and may accelerate atherosclerosis. Nonselective NSAIDs suppress both thromboxane and prostacyclin and retard atherogenesis. Pratico D, Proc Natl Acad Sci U.S.A. 2001;98:3358-3363. The cardioprotective effects of ASA are not seen with COX-2 inhibitors, which do not inhibit TXA2 production by platelets. Hart C, Modern Drug Discovery May/June 1999.
ASA has also been reported to be effective in reducing the risk of gastric cancer. Zaridze D, Int J Cancer 1999;82:473-476. ASA has also been reported to be effective against diabetic retinopathy, Alzheimers Disease, colon and rectal cancer, deep vein thrombosis, kidney failure, migraine headaches, cataracts, gallstones, and insect bites.
It is the object of this invention to incorporate an NSAID, such as ASA, to provide anti-inflammatory and anti-thrombotic benefits to prevent and treat endothelial dysfunction.
One of the gastrointestinal (GI) side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs), is aggravating or initiating colitis type disorders, and explained by the hypothesis that NSAIDs inhibit glucosamine synthetase resulting in a reduction of the glucoaminoglycan (GAG) layer of the GI tract. The GAG layer is mechanical, located in the pre-endothelial and sub-endothelial area in the arterial network, and an electrostatic barrier, due to the negative charges from the highly anionic GAGs. The neutralization of the electrostatic barrier, results in a breakdown of the GAG defense, resulting in an increase in extravasation of body fluids into the intestinal lumen and also the passage of toxins and large foreign molecular weight antigens into the circulation. Russell A L, Medical Hypothesis 1999;52(4):297-301. There is a close histological and pathophysiological association with endothelial membrane changes in GI disorders and the endothelium of the vasculature. An atheroma occurs due to a defect in GAG function at the inflammation site of the endothelium allowing the defect to be saturated with cholesterol. Aminosugars such as glucosamine, chondroitin and synthetic mucopolysaccharide pentosam sulfate have been shown to replace the GAG layer and improve GI and vascular inflammatory disorders. Rheumatoid arthritis is believed due to increased permeability of the GI tract. Glucosamine, for purposes of this invention, may be regarded as a preventative of endothelium dysfunction.
Amino sugars, for purposes of this invention, consist of but are not limited to; glucosamine, glucosamine sulphate, glucosamine hydrochloride, N-acetylglucosamine and Poly-Nag. Glucosamine, which is formed in the body as glucosamine-6-phosphate (G6-P), is a building block for glycolipids, glycoproteins, glycosaminoglycans, hyaluronate and proteoglycans. It is an essential component of cell membranes and cell surface proteins as well as interstitial structural molecules that hold cells together.
Glucosamine is a small molecule, very soluble in water, and 90% absorbed in the GI tract. Glucosamine sulfate (GS) appears to be linked to its ability to stimulate the synthesis of proteoglycans needed to stabilize cell membranes and increase intracellular ground substance. Since the anti-inflammatory ability of GS is different than that of NSAIDs, it is possible the two might have a synergistic effect in alleviating some types of inflammation. Evidence indicates a combined treatment utilizing glucosamine with an NSAID can decrease the amount of NSAID required to produce an antiexudative result by a factor of 2-2.7 times with preservation of activity. Kelly G S, Alt Med Rev 1998;3(1):27-39.
The dosage range for glucosamine can vary from 200 mg to 3000 mg per day, in divided doses, for the treatment and prevention of endothelial dysfunction, osteoarthritis and inflammation, depending on body weight and severity of symptoms. The usual dosage is 500 to 1000 mg per day based on the amount of ASA used in each dosage.
The use of amino sugars, such as glucosamine, is well known in the art. Jacobi, U.S. Pat. No. 3,859,436, discloses a topical composition of glucose, fructose, glucosamine and desoxyribose and ribose. Prudden, U.S. Pat. No. 4,006,224, discloses a method for treating ulcerative colitis with d-glucosamine. Henderson, U.S. Pat. No. 5,364,845, discloses a composition for the repair of connective tissue with glucosamine, chrondroitin sulfate and manganese. Sherman et al, U.S. Pat. No. 6,117,851, discloses a method for treating osteoarthritis.
It is a further object of this invention to incorporate an amino sugar, such as glucosamine, to enhance the GAG defense, anti-inflammatory properties, and synergistic effect with NSAIDs to treat and prevent endothelial dysfunction.
Zinc is known to have gastroprotective effects in both humans and experimental animals. Gastric lesions were induced in rats by the intragastric administration of indomethacin. Mucosal ulcerations were completely prevented by pre-treatment with zinc sulphate. These protective effects result from the inhibition of lipid peroxidation and the preservation of mucosal nitric oxide synthase. Joseph R M, Varela V, Kanji V K, Subramony C, Mihas A A, Aliment Pharmacol Ther 1999 February;13(2):203-8. Zinc sulphate taken orally was shown to heal gastric ulcers at three times the rate of a placebo. Zinc sulphate taken orally appears to act by the local action of zinc ions on the gastric mucosa. Frommer D J, Med J of Australia 1975;2:793-796.
Zinc compounds have anti-inflammatory and anti-infective properties. Zinc has an inhibitory effect on the release of histamine from mast cells due to its stabilizing effect of the mast cell membrane. Mast cells isolated from specimens of atherosclerotic plaques contained matrix metalloproteinase type 9, one of the enzymes that can produce collagen degradation. Kovanen P t, et al. J. Am College of Cardiology 1998;32:606-612. Zinc can inhibit the growth of Streptococci and Actinomyces bacteria when used as a dentifrice. Zinc compounds have antiseptic, antifungal and astringent properties. As an astringent, zinc can be used therapeutically to arrest hemorrhage by coagulating blood, check diarrhea, reduce inflammation of mucus membranes, promote healing, toughen skin and decrease sweating. Zinc's dominant biological action is membrane stabilization. The inhibitory effect of zinc on allergy and immunology make it an excellent enhancement to glucosamine and chondroitin therapy.
One of the side effects of ASA is salicylate inducted hearing loss and tinnitus. The inner ear has the highest concentration of zinc in the body. Studies have suggested that a zinc deficiency can cause a hearing-nerve impairment and tinnitus. Shambaugh G E Jr., Am J Otol 1989 March;10(2):156-60. Salicylate-induced hearing loss was completely prevented by the simultaneous administration of zinc. Gunther T, Rebentisch E, Vormnann J, J Trace Elem Electrolytes Health Dis 1989 March;3(1):51-3. Zinc was also found to be useful in treating tinnitus. Ochi K, Ohashi T, et al Nippon Jibiinkoka Gakkai Kaiho 1997 September:100(9):915-9.
In a preferred form of the invention, the composition uses a zinc salt such as zinc gluconate or sulphate, with the dosage range of 10 to 60 mg per day in divided doses. Zinc salts are selected from a group consisting of, but not limited to: zinc sulfate, zinc chloride, zinc acetate, zinc phenol sulfonate, zinc borate, zinc bromide, zinc nitrate, zinc glycerophosphate, zinc benzoate, zinc carbonate, zinc citrate, zinc hexafluorosilicate, zinc diacetate trihydrate, zinc oxide, zinc peroxide, zinc salicylate, zinc silicate, zinc stannate, zinc tannate, zinc titanate, zinc tetrafluoroborate, zinc gluconate, and zinc glycinate.
It is a further object of this invention to incorporate a zinc compound, such as zinc gluconate or sulphate, to reduce inflammation, prevent gastric ulceration, prevent toxic side effects of NSAIDs, and treat and prevent endothelial dysfunction.
To the mixture may also be added; dyes, flavorings, sweeteners, pigments, antioxidants, antibacterial agents, anti-inflammatory agents, bismuth compounds, such as those known to persons skilled in the art may be added in amounts sufficient to impart their particular characteristic.
The above-mentioned patents are hereby incorporated by reference.
Many variations of the present invention will suggest themselves to those skilled in the art in light of the above-detailed description. All such obvious modifications are ithin the full intended scope of the appended claims.
Caligiuri G, Immune system activated in patients with unstable angina J Am Coll Cardiol 1998;32:1295-1304.
Di Napoli M, C reactive protein and acute phase of ischemic stroke BMJ 2001;322:1605. Hingorani A D, et al., New explanation proposed for link between inflammation and cardiac events Circulation 2000;102:994-999.
Feldman M, Cryer B, Chewing aspirin hastens its anti-platelet effect Am J Cardiol 1999;84:404-409.
Frommer D J, The Healing of Gastric Ulcers-by Zinc Sulphate Med J of Australia 1975;2:793-796.
Gunther T, Rcbentisch E, Vormnann J, Protection against salycilate ototoxicity by zinc J Trace Elem Electrolytes Health Dis 1989 March;3(1):51-3.
Hart C, Will Super Aspirin Supersede Aspirin Modern Drug Discovery May/June 1999.
Joseph R M, Varela V, Kanji V K, Subramony C, Mihas A A, Protective effects of zinc in indomethacin-induced gastric mucosal injury: evidence for a dual mechanism involving lipid peroxidation and nitric oxide Aliment Pharmacol Ther 1999 February;13(2):203-8.
Kelly G S, The Role of Glucosamine Sulfate and Chondroitin Sulfates in the Treatment of Degenerative Joint Diesease Alt Med Rev 1998;3(1):27-39. Kuller L H, Tracy R P, The Role of Inflammation in Cardiovascular Disease Arteriosclerosis, Thrombosis, and Vascular Biology 2000;20(4):901
Malik J, Melenovsky V, Wichterle D, Function and dysfunction of the endothelium, Cas Lek Cesk 2000 April 12;139(7):197-202.
Milani R V, Lavie C J, Pharnacologic prevention of coronary artery disease Postgraduate Medicine 1996;99(2):109-120.
Nissen S E, et al,COX-2 inhibitors linked to increased cardiovascular event rate JAMA 2001;286:954-959.
Ochi K, Ohashi T, Kinoshita H, Akagi M, Kikuchi H, Mitsui M, Kaneko T, Kato I, Serum zinc level in patients with tinnitus and the effect of zinc treatment Nippon Jibiinkoka Gakkai Kaiho 1997 September:100(9):915-9.
Pepine C J, Clinical implications of endothelial dysfunction, Clin Cardiol 1998 November;21(11):795-9.
Pratico D, Aspirin and other nonspecific COX inhibitors may slow atherosclerosis Proc Natl Acad Sci U.S.A. 2001;98:3358-3363.
Rawles J, Importance of Thrombolytic Therapy Pre-Hospital Immediate Care 1997;1:12-18.
Ridker P M, Inflammation, Infection, and Cardiovascular Risk Circulation 1998;97:1671-1674.
Ridker P M, Cushman M, Stampfer M J,et al, Inflammation, Aspirin, and the Risk of Cardiovascular Disease in Apparently Healthy Men NEJM 1997;336(14):973-979.
Russell A L, Glycoaminoglycan (GAG) deficiency in protective barrier as an underlying, primary cause of ulcerative colitis, Crohn's disease, interstitial cystitis and possibly Reiter's syndrome Medical Hypothesis 1999;52(4):297-301.
Sandercock PAG, Aspirin administration recommended after Ischemic Stroke Onset Lancet 1997;349:1563-1565, 1569-1581.
Shambaugh G E Jr., Zinc: the neglected nutrient Am J Otol 1989 March;10(2):156-60.
Tierney Jr. L M, McPhee S J, Papadakis M A, Current Medical Diagnosis and Treatment, Appelton & Lange, Norwalk, Conn., 3rd ed 1994 p.490.
Tindall W N, Cardiac rehab: Movement and medication Business & Health February 1998.
Quyyumi A A, Endothelial Function in Health and Disease: New Insights into the Genesis of Cardiovascular Disease Am J of Medicine 1998;105(1A):32S-39S.
Ward S R, Topol E J, New Strategies for the Prevention of Restenosis after Coronary Angioplasty Resident & Staff Physician 1995;41(3):11-8.
Zaridze D, Aspirin, other NSAIDs help prevent gastric cancer Int J Cancer 1999;82:473-476.
U.S. Pat. No. 3,859,436 Jan. 7, 1975 Jacobi
U.S. Pat. No. 4,006,224 Feb. 1, 1977 Prudden
U.S. Pat. No. 4,049,803 Sep. 20, 1977 Cotty et al
U.S. Pat. No. 4,867,984 Sep. 19, 1989 Patel
U.S. Pat. No. 4,970,081 Nov. 13, 1990 Frisbee
U.S. Pat. No. 5,364,845 Nov. 15, 1994 Henderson
U.S. Pat. No. 5,437,874 Aug. 1, 1995 Bru et al
U.S. Pat. No. 5,518,738 May 5, 1996 Eickhoff et al
U.S. Pat. No. 5,552,160 Sep. 3, 1996 Liversidge et al
U.S. Pat. No. 5,770,215 Jan. 23, 1998 Moshyedi
U.S. Pat. No. 5,846,959 Dec. 8, 1998 Medford et al
U.S. Pat. No. 5,948,443 Sep. 9, 1999 Riley et al
U.S. Pat. No. 5,973,011 Oct. 26, 1999 Noack et al
U.S. Pat. No. 6,117,851 Sep. 12, 2000 Sherman et al
U.S. Pat. No. 6,121,249 Sep. 19, 2000 Weissman et al
U.S. Pat. No. 6,261,602B1 Jul. 17, 2001 Calanchi et al
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NYC Parks Events Calendar
Get up, get out, and do something! Just about any day of the year, you can find something fun, informative, and healthy to enjoy at an area park. Feel free to browse the listings below, or use the search tools to find an event that matches your interests and location.
Viewing 41–50 out of 14,985 events
from February 27, 2013 (x) to April 25, 2026
Saturday, November 23, 2013
Close: A Journey in Scotland at The New York Botanical Garden
at The New York Botanical Garden, Bronx
10:00 a.m.
A look at Scottish landscape design and land art.
Category: Arts & Crafts, Nature, Art
Holiday Train Show at The New York Botanical Garden
at The New York Botanical Garden, Bronx
10:00 a.m.–6:00 p.m.
Within the enchanting setting of the Enid A. Haupt Conservatory, large-scale model travel over bridges and past replicas of New York landmarks made of plant parts.
Category: Nature, Art, Kids, Winter Holidays
Nature Walk at The Ridgewood Reservoir
at Highland Park Entrance, Queens
10:00 a.m.
Enjoy the beautiful plants and wildlife of this hidden area that has been reclaimed by nature over decades of being closed to the public.
Category: Nature, Tours
Crochet Two-Color Easy Open Mesh Beach/Market Bag
at Poe Park Visitor Center (in Poe Park), Bronx
10:00 a.m.–11:00 a.m.
Category: Arts & Crafts
Weekend Volunteer Corps
at Picnic House (in Prospect Park), Brooklyn
10:00 a.m.–2:00 p.m.
Help restore our woodlands with other dedicated volunteers!
Category: Nature, Volunteer
Evergreen Lots Community Garden Clean Up Day and Bake Sale
at Evergreen Lots Community Garden, Brooklyn
11:00 a.m.–2:00 p.m.
Help clean up the lot, and start planning the new community garden. Feel free to contribute baked goods to the bake-sale fundraiser!
Category: Nature, Volunteer, Food
Reopening of Williamsbridge Oval Recreation Center/Kids and Adult Fitness Festival
at Williamsbridge Oval Recreation Center (in Williamsbridge Oval), Bronx
11:00 a.m.–4:00 p.m.
Williamsbridge Oval Recreation Center is reopening on Saturday. See the center, and celebrate with us at the Kids and Adult Fitness Festival!
Category: Arts & Crafts, Festivals, Fitness, Games, Kids, Seniors
Union Square Holiday Market
at Union Square (in Union Square Park), Manhattan
11:00 a.m.–8:00 p.m.
Shop for chic bags, luxurious salts, local, handmade belts and jewelry, men's fashion, children's wear, books, pet accessories, holiday-themed decorations & more from 100+ vendors.
Category: Arts & Crafts, Kids, Markets, Food, Winter Holidays
Imagining East River Park
at East River Tennis Courts (in John V. Lindsay East River Park ), Manhattan
11:00 a.m.–2:00 p.m.
How do you imagine East River Park? We invite the community to envision the future of the waterfront at East River Park.
Category: Accessible, Education, Volunteer, Waterfront
Central Park Tour: Seneca Village
at 85th Street and Central Park West (in Central Park), Manhattan
12:00 p.m.–1:00 p.m.
Established on land that would become part of Central Park, Seneca Village was Manhattan's first known community of African-American property owners.
Category: Education, History, Tours
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Related Information
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subset: commoncrawl


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13 Stars Who Can Look Insanely Attractive Or Totally Ugly
Kim Kardashian Sparks a Cosmetic Surgery Trend
12 Celebrities Who Are Kind of Gross
Watch Miley Cyrus Fall Down on Stage While Wearing a Fake Butt
Mismatched Celebrity Couples That Weirded Us Out
Kris Jenner's New Boyfriend Claims Kanye and Kim Don't Spend Much Time Together
Selena's Scandalous Selfie Sparks Drama
71-Year-Old Outsmarts Botox Surgeon, Looks 47
Kim Kardashian Talks Waist Training and Kylie's Lips
The Embarrassing Reason Khloe Kardashian Knew She Needed to Lose Weigh
Guess What Kylie Jenner is Hiding Behind Those Famous Lips
Kanye West Just Killed a Kardashian Family Tradition
20 Super Awkward Celebrities
Watch Ariana Grande Get Whacked on The Victoria's Secret Runway
Kim Kardashian Insists North West Will Need to Get a Job
Tori Spelling Cries Over The Thought Of Living Modestly
Kim K and The Jenners Act Totally Shameless
Emma Watson's Intentional "Side Boob"
54 Yoga Pants Pictures That Will Blow You Away
20 Celebs You Didn't Realize Have a Twin Sibling
Home / Photos Beyonce: Her Face Says It All
Shiloh Jolie-Pitt's Mini Suit May Change Fashion Forever
10 Pairs Of Stars Often Confused For Each Other
Halle Berry Can't Keep it Together: The Latest Drama Unveiled
5 Celeb Co-Stars Who Became Couples
Why We Want The Lesbian Taylor Swift Rumors To Be True
30 Child Stars Who Died Young
What the Devil? Drake Flashes Rihanna's Picture Along With Satan?
Sarah Hyland Looks Completely Different Now
Demi Lovato Shares Her Love for Curvy Women


text:
Earlier this morning Nielsen released its latest smartphone data for the US market:
By comparison comScore says that 36% of mobile phone owners have smartphones. However the most recent comScore data show a comparable share distribution for Android and the iPhone (43.7% vs. 27.3%).
Nielsen also reported that smartphone ownership for those under 45 is much greater than the overall population: 54%. It goes even higher (62%) for those 25 to 34 years old.
The Pew Internet Project said in May of this year that 42% of US mobile users own smartphones. And in a release of new survey data yesterday, Pew found that 50% of all mobile phone users have downloaded apps (vs. 43% in May 2010). However, as we know, downloads and usage are not synonymous.
As the chart above indicates, 51% of mobile phone app downloaders use between 1 and 5 apps weekly. A substantial minority (31%) use 6 or more apps per week. Average weekly app usage is higher among tablet owners.
The following chart shows the general categories downloads by populatirty/penetration according to Pew. Curiously the most popular app download category, games, doesn't appear on this list. This is probably a flaw in Pew's survey question design.
Finally, Pew says that just under half (46%) of all app downloaders have paid for apps at some point, with most spending less than $5.


text:
1577 48th St
Brooklyn, NY 11219
(718) 438-2018
Brooklyn, NY 11219
(718) 438-2018
Calendar: Semester
Get a snapshot of Rabbinical College Bobover Yeshiva Bnei Zion with this general overview, including student enrollment and graduation rates, average test scores, student demographics, and more.
Mission StatementThe Rabbinical College Bobover Yeshiva aims to carry forward the chain of Jewish learning and career training in an environment where education is personal, but rigorous and challenging. The Yeshiva defines its purpose as teaching students Torah learning skills in order to foster creative scholarship and provide the community with Talmudists, scholars, and well-educated laymen. We identify the following specific mission elements: 1. Train students in the study and analytical interpretation of the classic texts of Judaism. Foster reasoning skills, proficiency in textual analysis, the capacity for legal analysis, and a deftness in the application of advanced logic to methods of argumentation. 2. Prepare students for service careers as Yeshiva teachers, melamdim, mechanchim and maggidei shiur in a wide range of formats. 3. Provide students with the education for pursuing advanced rabbinic degrees that lead to college level teaching or practical rabbinics. 4. Develop in the student a strong moral dimension by fostering an ethical sensibility through the study of Mussar, devotional texts and Talmudic Aggadata. 5. Foster in the student a contemplative spirit, an awareness of the life of the mind and its encouragement. 6. Train those with exceptional gifts for higher research in Talmud.
School Characteristics
Private not-for-profit
$4,650 per year
Length of Study: Four or more years
Religious Affiliation: Jewish
Test Scores & GPAAverage GPA: GPA Unavailable
Average ACT: Not Available
Average SAT: Not Available
School ProfileTotal Enrollment: 235
Retention Rate: 100%
Graduation Rate: Not Available
School AccreditationNational: No
Regional: Not Available
Federal: No
Male / Female Enrollment
Total Enrollment
School data was obtained from the US Dept. of Education's Integrated Postsecondary Education Data System (IPEDS). Data may vary depending on school and academic year.


text:
What is MUNmobile?
MUNmobile is a smartphone application designed with you in mind. Featuring campus maps, news and event feeds, a university directory and much more, MUNmobile is just the beginning of a future you can hold in your hand. MUNmobile is available for use on Apple (iPad, iPhone, iPod touch) and Android devices.
What is Ellucian Go?
For the initial launch, we are utilizing an app called Ellucian Go to distribute MUNmobile. Ellucian is a major higher education software vendor and the folks behind MUN's registration and HR systems as well as Memorial Self Service. As you'll see, many schools use the Ellucian Go app as a launch pad for their mobile apps.
What if I have a problem installing MUNmobile?
While we don't anticipate any installation issues, MUNmobile is fully supported by MUN's Department of Computing and Communications (C&C). If you have a problem, please don't hesitate to contact the C&C Service Desk at 864-4595 or e-mail email@example.com.
Can I check my grades or register for classes using MUNmobile?
Not yet, but these features will be part of planned future upgrades for MUNmobile.
What do I use to log in?
In its first release, login services for MUNmobile are not needed. Simply sweep aside the login screen to access the main menu. Future enhancements will require a login and will be announced.
What if I have questions about MUNmobile?
If you have questions about MUNmobile please contact the C&C Service Desk at 864-4595 or e-mail email@example.com.


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text:
Definitions for oakvilleˈoʊk vɪl
This page provides all possible meanings and translations of the word oakville
Random House Webster's College Dictionary
Oak•villeˈoʊk vɪl(n.)
a town in SE Ontario, in S Canada, SW of Toronto, on Lake Ontario. 87,107.
Category: Geography (places)
Oakville is a federal electoral district in Ontario, Canada, that has been represented in the Canadian House of Commons since 1997.
Find a translation for the oakville definition in other languages:
Select another language:
Discuss these oakville definitions with the community:
Use the citation below to add this definition to your bibliography:
"oakville." Definitions.net. STANDS4 LLC, 2014. Web. 22 Dec. 2014. <http://www.definitions.net/definition/oakville>.


text:
Entries with no category
The search facility on my Espresso server isn't working anymore. I have changed its ip address but nothing else. Anyone any ideas? I've looked at the search code and it seems to be Perl but I've no idea where the code is directing the search to - it doesn't seem to be ip referenced. Help please.


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Yesterday, I joked about trying to make Selena Gomez have a wardrobe malfunction, and apparently she actually had one. Granted, it's slightly lower than where I was aiming, my magic is as imperfect as it is beautiful. More importantly, if you look hard enough, you can still see Justin Bieber's tear stains from the day she found out Selena has the same parts as her. (Those pronouns check out.)
Photos: Bauer-Griffin, Fame/Flynet


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Malloy to process late gun registration forms
Postmark deadline moved to Jan. 4
|Timothy Coley, left, of Bristol, and Josephy Boniface of East Granby talk during a gun rights rally at the Connecticut State Capitol in Hartford last year. The Malloy administration is granting a reprieve to gun owners who missed a deadline for registering military-style firearms and ammunition magazines that otherwise became illegal to possess on Jan. 1. (AP Photo/Journal Inquirer, Jared Ramsdell)
HARTFORD — The Malloy administration is granting a reprieve to gun owners who missed a deadline for registering military-style firearms and ammunition magazines that otherwise became illegal to possess on Jan. 1.
State police will now process the 558 applications that gun owners had mailed before the Dec. 31 cutoff date and were postmarked no later than Jan. 4.
Read more of this story and more!
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Roger Mitchell wrote on Feb 15, 2014 12:56 AM:
Mat wrote on Feb 15, 2014 1:43 AM:
FREEPRESS wrote on Feb 15, 2014 5:21 AM:
conservative1 wrote on Feb 15, 2014 7:20 AM:
Americans won't lay down like the Jews in Germany did.
BTW I love how "lawmakers" ask other lawmakers if it's ok for them to break the laws they just made. ala..Obama/obamacare. "
JOE wrote on Feb 15, 2014 7:51 AM:
Lock and Load wrote on Feb 15, 2014 8:28 AM:
Where have we heard words like that before?
My advice to Mikee is to ratchet down the inflammatory rhetoric because you're in uncharted waters. "
mr.happy wrote on Feb 15, 2014 9:11 AM:
Below me wrote on Feb 15, 2014 11:05 AM:
al.cap wrote on Feb 15, 2014 11:10 AM:
roy wrote on Feb 15, 2014 2:43 PM:
I'm hoping the number of "Patriots" goes to a half a million.
AND, remain silent forever.
When the U.S. Army, BATF, CIA, FBI, etc. come knocking at gun owner's doors, there's going to be a heluva blood bath!!! "
al.cap wrote on Feb 15, 2014 6:04 PM:
a felony, no matter how stupid, will haunt you for the rest of your life. it will forever bar you from obtaining a carry permit....anywhere. that's why they made it a felony. also, by sending in my papers, i have effectively told the state, "here i am, come get some." is that more cowardly than the guy who hides his guns in a pvc tube, buried in the woods? "
genious wrote on Feb 15, 2014 6:24 PM:
Here's a word of advice! You register those guns,and you're signing yourselves up for gun confiscation! That's this Tyrant's plan. You people would fall right into it it lock stock and barrel!
This clown isn't playing games.Give it a year or two and they'll be at your door. This one is onde of the worst governors ever elected,that is if he was elected in this state,and all the gullible geniuses bite,right on his line when it comes to guns.
This so called governor is an Obongo/Obama Minion.He's doing what he's being told to do,right from the heart of Washington.
Doesn't anyone see this? You're being used as ?Scape Goats. So what's it going to be? Compliance like a gullible idiot,or stand up for yourselves,as Citizens of Conn. and the United States of America,and defy these people.
By the way that, you'll be breaking the law? It's all Bull! You can't break a law that is ILLEGAL,and goes against the Constitution of the United States. Despite what any court has said. These Fed. Judges like Malloy,work for the Federal Government!
Wake Up! "
Below me wrote on Feb 15, 2014 6:46 PM:
GAS wrote on Feb 15, 2014 7:26 PM:
genious wrote on Feb 15, 2014 7:28 PM:
Then you're a fool!
I'll say it again by registering guns you're setting yourself up for confiscation.
This is exactly how it started in Russia Germany,and of late Australia. They murdered over a thousand people in Australia because of registering guns.
Don't think it can't happen here.
It isn't so much being a coward,it's more like being a Fool and a Patsy!
Malloy is not your friend,he's a power hungery tyrant,who kisses Obama's back end,and will do anything he's told!
Wake Up! "
Lock and Load wrote on Feb 15, 2014 9:10 PM:
My objections to this new gun law, which I've stated time and time again, are grounded in the 2nd Amendment. I remain strongly opposed to governmental intrusion, by threats and intimidation, into the lives of law-abiding citizens of this state who've done absolutely nothing wrong other than to have purchased a gun(s) and magazines that are now deemed banned with the stroke of a politician's pen, and with no quantifiable benefit to public safety.
While I do not have a crystal ball, I can reasonably surmise from the political chest pounding at the State Capitol, that they will be looking to make examples of individuals who did not comply. How, when and where those efforts begin and lead to is anybody's guess. After all, this is an election year and the last thing Dannel & company, Obama and the Democrat Party need is something akin to Kent State or military/LE assault style confiscation incident with casualties to make the national news.
That being said, I would urge all to remain vigilant because these are uncertain times. Much is being written about large ammunition purchases by federal governmental agencies, military training by the National Guard and a mock city built in Virginia to train at in preparation for civil disturbances. True or not, there should be some level of scrutiny by Congress and concern by Americans as to the spirit and intent of this administration with regard to personal freedoms and liberty. "
roy wrote on Feb 16, 2014 5:01 PM:
But somehow the government will conspire to sweep all 50 states into a trap and start confiscation in one massive swoop. "
Below me wrote on Feb 17, 2014 7:27 PM:
Post a reader commentWe encourage your feedback and dialog.
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If you're witty, to the point and quotable, your reader comments may also be included on the Around the Towns page of The Sunday Republican.
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- Lanza talked of 'teenage mall shooter' on radio show
- Judge in Sherman case won't face discipline for revealing grand jury
- Child care will pay more
- Benefits planned for girl who needs new kidney
- Panel to study dog pound
- Schools tweak exam plan
- Neighbors oppose plan for constructing 9 homes
- You go to Hugo's for tacos
- Economic development commissioners sought
- Man facing theft charges plans to open pizza shop in Wolcott


text:
When it comes to the health impacts of global warming, Americans are woefully uninformed.
In fact, according to a survey conducted by the Yale Project on Climate Change Communication and the George Mason University Center for Climate Change Communication, only about one in four can even name a health problem associated with global warming that their fellow Americans might be suffering from.
Only 14% of Americans...
DeSmog TV interviews George W Bush on global warming
DeSmog TV interviews George W Bush on global warming
It seems we have enough fans in the White House to land an exclusive DeSmog TV interview with the US Commander-in-Chief George W. himself!
Check it out. And while you're at, take a look at past DeSmog TV episodes on our YouTube Channel.
Previous Comments
I am so loving Emily Murgatroyd and DeSmog Blog TV. This wry and clever component of the DeSmog Blog site perfectly balances the enormity of global warming. This site and Emily are uniquely Canadian and demonstrates the resilience of Canadian culture. Keep it up!
Hi, you're doing great work here at DeSmogBlog. Only, as a European I find it strange that there is still a need for a 'debate' in the U.S. (we thought America was the place of the bright and the Enligthened people). In Europe, the 'debate' on global warming ended in 1990.
So keep up the good work to make it end in the U.S. too. We need you guys on board to tackle climate change.
Cheers from Belgium, Jonas
The reason the the global warming debate goes on in the US is partly explained in the July 20, 2007 article in the Miami Herald, link below. Although the article content itself deals with a problem with satellites used for hurricane monitoring the strategy that NOAA NWS management has used to downplay problems with QuikScat and global warming is being exposed in the "Recent comments" to the article.
Hurricane center report likely dooms Proenza
Posted on Fri, Jul. 20, 2007 http://www.miamiherald.com/460/story/176380.html
Don't get me wrong, I've always thought that Will Ferrel is a top-notch comedian. But I've always felt there was something missing – something to give his material a just a little nudge, to push it right over the top into pure comedy gold.
I could never figure out what was lacking. Sure, Will Ferrel makes people laugh. In fact, he's hilarious. But, somehow, he just didn't quite have what it takes to distinguish himself. What is it that the best writers of Saturday Night Live and Hollywood couldn't provide to give him that little extra pizzaz.
Now we know. It all seems so obvious. This video is just the right medicine. As this brilliant video proves, all that was needed was to have some smirking fake questions clumsily edited-in, written by what seems to be borderline retarded 8-year-olds, and shot with a cheap camera-phone. Simple, yet INGENIOUS! Take that, you professional comedy writers.
"This site and Emily are uniquely Canadian and demonstrates the resilience of Canadian culture. Keep it up!"
Indeed. If, by "uniquely Canadian", you mean "derivative, pedantic, smug, way-behind the curve, and completely un-funny." Another glass of Chardonnay for you, Jeffery?
So are you a Canadian self-hater, EH? Not surprising, really, given your chosen handle.


text: Yesterday President Obama announced his plan to combat gun violence, saying, "This is our first task as a society: keeping our children safe. This is how we will be judged. We can't put this off any longer." Two of our iVoices moms -- one liberal and one conservative -- respond to the President's recommendations.


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text:
Frontline Technologies Inc. Provides Second Bi-Weekly Status Report Regarding Management Cease Trade Order
TORONTO, April 27, 2012 /PRNewswire/ - Frontline Technologies Inc. (" Frontline" or the " Company") ( TSX-V: FLC) is providing this bi-weekly Default Status Report in accordance with National Policy 12-203 - Cease Trade Orders for Continuous Disclosure Defaults (" NP 12-203"). On March 30, 2012, the Company announced (the " Default Notice") that, for the reasons disclosed in the Default Notice, there would be a delay in the filing of its audited financial statements for the year ended December 31, 2011 and its related Management's Discussion and Analysis and Chief Executive Officer and Chief Financial Officer certifications, and its Annual Information Form for the year ended December 31, 2011 (collectively, the " Required Filings") beyond the 90 day period prescribed for the filing of such documents.
As a result of this delay in filing, on April 13, 2012, the Ontario Securities Commission (the " OSC"), the principal regulator of the Company, issued a temporary management cease trade order (the " Temporary MCTO"), which imposed restrictions on all trading in and all acquisitions of securities of the Company, whether direct or indirect, by the Chief Executive Officer and the Chief Financial Officer of the Company for a period of 15 days. All other parties are permitted to freely trade the Company's securities. On April 25, 2012, the Temporary MCTO was replaced by a permanent management cease trade order.
Frontline's auditors are completing the audit of the Company's financial statements for the year ended December 31, 2011 and the Company continues to expect to file the Required Disclosure on or before April 30, 2012. Until the Required Filings are filed, Frontline intends to continue to satisfy the provisions of the Alternative Information Guidelines (the " AIG") specified in Section 4.4 of NP 12-203 by issuing bi-weekly Default Status Reports, each of which will be issued in the form of a news release. Frontline intends to file, if required, its next Default Status Report by May 11, 2012.
Pursuant to the requirements of the AIG, the Company reports that since the issuance of the Default Notice, there has not been any material change to the information provided therein, nor has there been any failure by the Company in fulfilling its stated intentions with respect to satisfying the AIG. In addition, there has not been any specified default by the Company under NP 12-203 other than the delay in filing the Required Filings, and there is no other material information concerning the affairs of the Company that has not been generally disclosed.
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text:
Yusop, Zulkarnain and Abdul Ghaffar, Roslan (1994) Determinants of Foreign Direct Investment in the Malaysian Manufacturing Sector. Pertanika Journal of Social Sciences & Humanities, 2 (1). pp. 53-61. ISSN 0128-7702
Foreign direct investment (FDI) has played a significant role in the development of the Malaysian manufacturing sector. Unfortunately, the pattern of FDI is unevenly concentrated in a few industries such as electrical and textile which involve less skilled labour, less intensive technology and are highly dependent on imported inputs. This has led to the problems associated with a narrow manufacturing base, vulnerability to external fluctuations as well as low value added. It is therefore necessary to promote a broader manufacturing base and to further encourage FDl in resource-based industries. This study attempts to look at several quantitative factors that influence FDI in the Malaysian manufacturing sector. The results of the study indicate that a nation's economic health, currency stability, access to local financing, availability of adequate human and physical infrastructures as well as investment incentives are among the important factors influencing FDI in the manufacturing sector of Malaysia
|Item Type:
|Foreign Direct Investment (FDI), manufacturing, determinants
|Faculty or Institute:
|Faculty of Economics and Management
|Universiti Putra Malaysia Press
|ID Code:
|Deposited By:
|Nur Izyan Mohd Zaki
|Deposited On:
|20 Nov 2009 03:22
|Last Modified:
|27 May 2013 07:04
Repository Staff Only: Edit item detail
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text:
Miriam's casebook - The vegetarian mother
Anne became a vegetarian two years ago, a year after the birth of her second child, Katie, now three years old. Anne's diet includes dairy produce and eggs and she's very healthy, but she's concerned about the extra nutrients her body will need during her pregnancy. We looked at her various worries and, once we'd identified possible protein and calcium deficiencies, I suggested some ways of boosting her diet.
Being vegetarian during pregnancy
Having already had two babies, Anne knew that she might need to make some changes to her diet during her pregnancy, and now she was a vegetarian, she wanted to check a few things.
For example, she'd heard that a vegetarian diet might be short of vitamin B12; if so, would that harm her baby? She'd also read something about folic acid and spina bifida. Was her diet lacking in folic acid, and should she take supplements? She knew that some pregnant women take iron supplements; would she need to?
Anne knew that the main change she had to make to her diet would be to make sure she ate more protein, but she wanted to check what kind of protein would be best and which foods provide it. During pregnancy, the body demands increased calcium intake. Would it be best to take calcium tablets or would she be able to get enough by eating plenty of calcium-rich and calcium-fortified foods?
Differing opinions
Opinions on a vegetarian diet during pregnancy differ widely. They range from those of vegans who believe that women can carry a healthy baby to term without eating any animal protein or even taking vitamin B12 supplements, to doctors and healthcare professionals who insist that meat and fish are essential foods for a pregnant woman. In fact, both views are wrong and I'll explain why.
In the case of vegans, if no animal products, including dairy products, are eaten, vitamin B12 supplements are absolutely essential. B12 is vital to the healthy growth and development of the fetus, as well as that of a breastfed baby. Vegetarian diets often lack B12 as it only exists naturally in animal products. A vegetarian woman may need to take supplements to ensure the healthy growth of her baby.
Vegan mothers can opt either to add milk and eggs to their diet, or to take synthetic B12, during pregnancy and while they're breastfeeding.
A vegetarian diet that includes dairy products can support a pregnancy, and later breastfeeding, perfectly well, as long as you have more protein and calcium. All pregnant women should increase their milk intake to 500ml (1pt) a day (skimmed and semi-skimmed milk contain as much calcium as whole milk). Anne can also boost her protein and vitamin intake by drinking vitamin-fortified soya milk and eating lots of other soya and dairy products.
How to meet increasing needs
The simplest way for Anne to increase the protein and vitamin content of her diet would be for her to eat at least four eggs a week. Eggs will provide iron too, although not as much iron as is provided by red meat. While some vegetarians claim that they can get the same amount of iron that red meat provides by eating more green leafy vegetables, they'd have to eat almost 2kg (5lb) of these vegetables per day to do so!
I advised Anne to accept her obstetrician's advice if she is prescribed vitamin, iron, and calcium supplements, but reassured her that if her obstetrician presses her on eating meat, she should contact the Vegetarian Society (see Useful addresses) for support and further information. The following menu should take care of Anne's needs.
Suggested daily vegetarian menu
- Breakfast: Two slices of wholemeal toast with yeast extract. Cup of decaffeinated tea with skimmed milk. One banana.
- Mid-morning snack: Selection of raw vegetables with hummus (chickpea dip) and wholemeal pitta bread.
- Lunch: Baked potato, topped with cottage cheese, red pepper, tomatoes, and watercress. Glass of tomato juice. Chopped nuts and dried fruit.
- Afternoon snack: Broccoli and cheese soup (preferably fresh) with chopped walnuts and low-fat fromage frais. Two slices of rye bread.
- Dinner: Mushroom and tofu lasagna, spinach, steamed mangetout, and wholemeal garlic bread. Fresh fruit with low-fat yogurt. Grapefruit juice.
- Bedtime snack: Boiled egg and wholemeal toast "soldiers" with yeast extract. Glass of skimmed milk.
Good nutrition for a pregnant mother
Nature makes sure that a baby's nutritional needs are supplied by the body before the mother's. Anne's baby, therefore, could be better nourished than she is herself. The umbilical cord links Anne's baby with her placenta. All the nutrients necessary for healthy growth and development pass to Anne's baby through the cord. A baby needs plenty of iron for blood formation and organ growth. This can be supplied by eating iron-rich foods such as egg yolks, cereals, and molasses. Calcium is very important as it builds healthy bones and teeth. Anne needs a diet that is rich in calcium to maintain her own needs as well that of her baby. Her diet should also be packed with protein-rich foods that will nourish her baby's fast-growing muscles, bones, skin, and vital organs.
The healthy development of her baby's brain and nervous system depends on sufficient supplies of Vitamin B12 as well as on Anne having sufficient levels of folic acid in her blood. The blood sugar of the baby is always lower than that of his mother because it's used so quickly, so a constant supply of calories is needed for healthy growth.
Miriam's top tips
- Make sure you are getting the recommended daily dose of 400mcg of folic acid, either through foods rich in folic acid or by taking a folic acid supplement.
- If you don't eat any animal or dairy products, vitamin B12 supplements, available from your local pharmacy, are absolutely essential.
- A vegetarian diet that includes dairy products can support a pregnancy, and later breastfeeding, perfectly well, as long as you have more protein and calcium in your diet.
Conception Pregnancy and Birth Copyright © 2008 Dorling Kindersley Text copyright © 2008 Miriam Stoppard
Posted 16.11.2010
- Food in pregnancy
- Food-related risks in pregnancy
- Miriam's casebook - The diabetic mother
- Average weight gain during pregnancy
- The best food to eat during pregnancy
- Eating well in pregnancy
- The foods you need in pregnancy
- Eating for two at Christmas
- Vitamins for a healthy pregnancy
- A vegetarian pregnancy?
Get more on this subject…


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KOLKATA, Tuesday, December 16, 2014
'Corporate frauds set to rise in India over next two years'
A study by Deloitte India found that among key reasons for continued dominance of well known corporate frauds is reliance on inadequate or dated mechanisms to manage fraud risks. »
HYDERABAD, Sunday, December 14, 2014
CB-CID to probe fraudulent crop loan accounts of PACS
A.P. Government requests Telangana to share database of Aadhaar card holders. If the verification is done before January 9, such accounts will also be included in the first phase of debt redemption. »More on fraud AND: crime, law and justice, economic offence/ tax evasion, economy, business and finance, government aid, government debt
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Madan Mitra remanded to four-day CBI custody
There was no concrete evidence of his direct or indirect involvement in the Saradha scam, Mr. Mitra told the court. »More on fraud AND: arrest, corruption & bribery, court administration, economic offence/ tax evasion, inquiry, Kolkata, state politics
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Kailash Satyarthi of India and Malala Yousafzai from Pakistan received the Nobel Peace Prize for 2014 for their pioneering work on promoting child rights in the subcontinent, as they made an impassioned plea to globalise compassion. here»


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Photo #: NH 70598
USS Nipsic (1879-1913)
The ship's badly bent propeller on display at the Mare Island Navy Yard, California, some time prior to 1915.
This propeller was damaged during the 15-16 March 1889 hurricane at Apia, Samoa.
Courtesy of the Mare Island Naval Shipyard, 1970.
U.S. Naval Historical Center Photograph.
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19 March 2001


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Shnay: Red is no favorite, but two inspiring women are
BY JERRY SHNAY Citizen firstname.lastname@example.com February 6, 2014 3:36PM
Karen DeWitt displays her creations — a quilt, and her book, "The Bunco Club" — in her sewing room at her home in Park Forest. | Jaime Angio~For Sun-Times Media
Updated: March 10, 2014 6:11AM
Red is not our favorite color.
The single worst purchase we ever made was a 1973 red sedan that was not very well put together by a German carmaker. Something was always going wrong with it, and it was gone in less than two years.
It was the first and last red car we ever owned, but not the only time we bought something red that had wheels on it.
For 10 months out of the year, this scarlet-colored contraption that cost more than we are willing to admit sits in the corner of the cluttered garage, not used and certainly not needed. But when the snow comes, it springs into action.
A gurgle of gas, a twist of a key, a few pumps on a primer, a push on a button and it starts, doing an adequate job of moving much of the snow away from our shack. One can ask little more from such a machine than that it does its job.
Red is still not a preferred color, but I am willing to make an exception in this case. There is, however, a question to be answered. What if we move all the snow away from the driveway, and we still have no place to go?
Karen DeWitt
In the middle of this woeful winter, our spirits picked up when we read Jaime Angio's excellent story in this paper about Karen DeWitt, a Park Forest resident whose book, "The Bunco Club," has been nominated for a writing award by the Chicago Writers Association.
Karen, an artist and an ardent quilter, turned to writing after multiple sclerosis began to rob her right hand of most of its motor skills, which she needed for her artwork. It took her eight years to complete her book, writing in bits and pieces.
Her inspiration for the book was the seven women with whom she plays bunco, a dice game in which the object is to get 21 points. One book is not enough for DeWitt, who plans an entire series of books revolving around her bunco club and its players.
At times it was a struggle to string words together, and there were moments of disconnect between DeWitt's fingers and the keys of her computer.
We who glibly construct pages filled with sentences and paragraphs should pay homage to one who can do the same, line by difficult line.
Sue Kramer
When Sue Kramer would deliver this newspaper to our house, she always made sure to place it inside our front storm door.
It was not that we were special. She did it for everyone on her route. She did it because it was the right thing to do.
Doing things right was the essence of Sue's being, whether it was her involvement in one of her many projects at Faith United Protestant Church or sharing her wonderful fudge with friends and neighbors at Christmas.
Sue's husband, Ken, was the longest-serving member of Park Forest's village board, having served for 26 years. Six years ago, when asked if he wanted to run again for village trustee, Ken smiled and said he would because Sue was "forcing me out of the house." Ken retired two years ago to care for his beloved wife, who was in declining health.
Sue died last week.
I am of the opinion that during its formative years, Park Forest was molded as much by the women of the community who saw what needed to be done and made sure that their husbands got it done. Sue Kramer was one of those who did her work quietly and efficiently and always in the right way. She will be missed.


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This summary of benefits briefly highlights the benefits available to employees of Ephrata Community Hospital and its affiliates. It is not intended to be a complete description of each benefit. Specific details of an employee's benefits are provided in the Human Resources Policy Manual and in legal plan documents. If any information presented below is inconsistent with the information contained in the Human Resources Policy Manual or legal plan documents, the policy manual and/or plan documents will govern in all cases.
Employees can accrue and use vacation and sick time as well as personal and legal holidays subject to employment status, length of service, and benefits associated with each position.
Full-time and part-time employees are eligible for immediate coverage. Basic hospital care, medical care, eye care, and prescription drugs are covered within three PPO options. Employee contributions are required.
Full-time and part-time employees are eligible for immediate coverage. Diagnostic, preventative, and basic restorative services are covered. Employee contributions are required.
Full-time and part-time employees may participate in these pre-tax reimbursement accounts for health care and/or child/dependent care.
Full-time employees are covered after six months of continuous employment. Coverage is employer paid.
Supplemental employee life, spouse life, and dependent life insurance coverage is available to full-time employees covered under life insurance during the Open Enrollment period. Coverage is employee paid.
Full-time Hospital employees receive partial income replacement for illness or injury that is not work related. Eligibility begins after six months of continuous employment.
Upon meeting eligibility requirements, full-time and part-time employees may elect to contribute up to 100 percent of gross earnings into the 403(b) plan up to limits established by the IRS. Ephrata Community Hospital provides non-elective and matching plan contributions for employees who meet eligibility requirements.
Ephrata Community Hospital offers several educational assistance programs including tuition reimbursement, professional certification fee reimbursement, and educational scholarships. Employees may be eligible for 75 to 100 percent reimbursement.
Employees are eligible after completing one year of service and working the required minimum hours in the twelve months immediately preceding the leave.
Full-time and part-time employees may receive one to three days off with pay in the event of a death of a family member. Eligibility is immediate.
Eligibility is immediate for members of the Uniform Services in accordance with federal and state law.
Full-time and part-time employees are paid the difference between juror fees and regular salary. Employees are eligible after six months of continuous employment.
Professional and confidential services are available to all employees upon hire date to help employees and their immediate family members identify and resolve personal problems that may affect their personal or work lives. Initial evaluation sessions are free.
Direct deposit of an employee's pay can be made into a maximum of four accounts at financial institution(s) of the employee's choice.
Reduced-cost health, wellness, and educational programs are available to all employees through the Ephrata Community Hospital Wellness Center and the Center for Women's Health, including CPR training, diabetes programs, Freedom from Smoking, Lean Lifestyle, nutrition consults, yoga, pilates, self-defense, and massage therapy. Employees also have free use of exercise equipment at any Ephrata Community Hospital Rehab Center location across Lancaster County.
Sick child care is provided for employees through the Pediatrics Department for a nominal fee.
Employees and their relatives are eligible to receive blood replacement at no cost.
Ephrata Community Hospital will absorb 70 percent of inpatient and outpatient hospital charges not covered by insurance up to a $300 discount per bill. Employees and their spouses and tax dependents are eligible upon employee's hire date. Services must be performed at Ephrata Community Hospital.
All employees are eligible for discounts on cellular phone service and equipment, car rentals, relocation services, and computer equipment and software.
Ephrata Community Hospital reserves the right to alter, amend, or abolish benefit programs and any other terms and conditions of employment at any time with or without the consent of the employees.


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Byon May 9, 2013
I am not entirely dismissive of the notion that the president has not done all he can with the powers (persuasive and otherwise) bestowed upon him by virtue of his having been elected president, you know, twice already. I believe he has not done enough to break the power of weaponized lunacy in the other party and weaponized cowardice in his own, and his fealty to the Wall Street crowd leaves me absolutely cold. But it's getting to the point where, if another pundit tells me that the president's primary failure is that he hasn't been able to persuade congressional vandals to drop their spray-paint cans and back slowly away from the subway car of government, I might start sending Rahm Emanuel a card every year on Political Carnivores Day.
The McCarthy circus is by far the more revelatory of the two. Her confirmation hearing before the Senate's Environment AND Public Works Committee was a month ago. She's already answered more than 1000 questions. The EPA needs a permanent director. And still she's hanging out there in the wind to twist simply because someone like David Vitter can arrange it. Someone will have to explain to me, in detail, what the president could have done to keep this from happening, other than bring Anne Gorsuch back from the dead.
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(Photo : REUTERS/Mario Anzuoni)
In the past months, photos and videos from the set of "The Amazing Spider-Man 2" have been slowly making their way into the hands of the public. The videos have provided fans a glimpse into the epic sequel, but have steered clear of spoiling any of the Spidey action, until now. The most recent video to scour the Internet features the graduation ceremony of both Peter Parker (Andrew Garfield) and Gwen Stacy (Emma Stone), with a little something extra tacked on the end. Watch the video below, but beware, a potential spoiler appears in form of an ominous foreshadow.
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The video features Gwen's graduation speech, where she shares some inspiring words with her fellow students as she looks ahead into the future. "I know we all think we're immortal. And we should feel that way. We're graduating. The future is and should be bright. But like our brief four years in high school, what makes life valuable is that it doesn't last forever."
As MTV points out, this could clearly serve as a foreshadow to Gwen's rumored death that could very well take place in "The Amazing Spider-Man 2."
In a recent interview, Stone touched upon the possibility of her character's death in the Spidey sequel. "Essentially the argument is that Spider-Man kills her by accident," Stone told SFX Magazine. "So the person she loves is the person who kills her, which is the most horrifying thing. Apparently people unsubscribed to the comic book when that happened because they were just so flipped-out over it. But of course, I want to stay true to that."
Stone doesn't confirm or deny her character's death, but she clearly hints at a morbid ending. Check out the set photos featuring Gwen moments before her potential plunge here.
We'll have to wait and see. Director Marc Webb could very well be faking out fans with the alluding foreshadow, but then again, it's a very pivotal moment in Spider-Man history, so why not play it up?
In "The Amazing Spider-Man 2," for Peter Parker, life is busy - between taking out the bad guys as Spider-Man and spending time with the person he loves, Gwen, high school graduation can't come quickly enough. Peter hasn't forgotten about the promise he made to Gwen's father to protect her by staying away - but that's a promise he just can't keep. Things will change for Peter when a new villain, Electro, emerges, an old friend, Harry Osborn, returns, and Peter uncovers new clues about his past.
"The Amazing Spider-Man 2" is set to hit theaters on May 2, 2014.
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Gorgeous bathroom with freestanding tub, marble mosaic tiles floor, marble washstands with brass base and brass fixtures.
Gorgeous bathroom with freestanding tub, marble mosaic tiles floor, marble washstands with brass base and brass fixtures.
Marble bathroom with marble double washstands with brass base, brass faucets, gold ...The Greenwich Hotel
Lovely bathroom with Acquatinta Pendant Murano Glass Pendant, marble washstand ...The Greenwich Hotel
Chic, modern spa bathroom design with glossy white soaking tub, beveled mirror, ...Jennifer Worts Design
Fantastic bathroom design with beautiful gray walls paired with marble slab ...Lonny Magazine
Splendid master bathroom with blue grasscloth covered walls and wall-mount ...Gardiner and Larson Homes
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Stunning bathroom with marble pedestal tub framed by oversize marble tiled walls ...The Greenwich Hotel
Stunning spa-like modern bathroom design with double sided marble mosaic tiled ...BHG
Kirsty Froelich - Ceramic wall tile mixed with glass, marble floorKirsty Froelich
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Cascade Valerie Vest
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Top Palestinian officials on Friday filed a complaint to the International Criminal Court (ICC), accusing Israel of war crimes in Gaza. Palestinian Justice Minister Saleem Al-Saqqa and Gaza court public prosecutor Ismail Jabr started legal proceedings over the 18 days of fighting between Hamas ...[read more]
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The UN Special Rapporteur for human rights in the Occupied Palestinian Territories Richard Falk called Wednesday on the international community to investigate the death of Palestinian Prisoner Arafat Jaradat. Jaradat died while in interrogations at an Israeli facility. Initially, Israel claimed ...[read more]
The Israeli government on Sunday unanimously rejected the recent UN General Assembly resolution upgrading Palestine's UN status to non-member observer state. In response to the UN action Israel passed its own domestic resolution that rejects the General Assembly's decision entirely and claims it ...[read more]
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JURIST Guest Columnist Wael Lafee, an LL.M. student at the Univeristy of Pittsburgh, is the author of the twelfth entry of a 14-part series from the LL.M. students of the University of Pittsburgh School of Law. He explains Palestine's unique legal history and reviews how that history has impacted ...[read more]
The US Supreme Court ruled unanimously Wednesday in Mohamad v. Palestinian Authority that political organizations including the Palestinian Authority and the Palestine Liberation Organization are immune from liability under the Torture Victims Protection Act of 1992 (TVPA). The petitioners, ...[read more]
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