Thursday, December 26, 2019

Essay on The Future of Nursing - 689 Words

The Future of Nursing Ami Randall July 24, 2010 Upon considering the past and future of nursing, many changes have already taken place, and even larger changes are expected. With the recent rate of technological development, the heath care system is certain to follow in its advances at nearly the same pace. Many predictions for the future of medicine are based on computerized technology. The use of telemonitoring, video and â€Å"smart houses† are already being used by some companies today, and will be utilized more frequently in the future. This will enable one nurse to care for many more patients than he/she is capable of safely caring for currently. This is very important due to the baby-boomer generation growing older and the†¦show more content†¦These personal companions are able to monitor every human reaction to physical and emotional stimuli, as well as, how a specific disease process is affecting the different systems of the body, and how medications are systemically treating any disease process. This sy stem will detect disease processes much earlier than is capable at the present time. This information is then transmitted to this global health care network, as previously mentioned, and the data used to better understand disease processes and help to find cures for these diseases. The human genome has also been decoded by computers, for the cost of around one-hundred dollars. With this technology, medical professionals can better understand why some people, and who these people are specifically, are more susceptible to different types of cancer, heart disease, diabetes and so on. These chronic conditions and diseases will be cured and prevented and the larger problem will be mutating viruses and â€Å"super bugs†, for which pharmaceutical companies have put very little effort into developing curative or nonresistant medications. Looking forward to contributing to these medical advances through research, I hope to be wearing a lab coat or personal protective equipment while practicing in 2035. The clients I hope to be servicing through my professional practice are the entire human race, through research and development of preventative and curativeShow MoreRelatedThe Future of Nursing966 Words   |  4 PagesThe Future of Nursing In 2010 the Robert Wood Johnson Foundation (RWJK), a subsidiary of the Institute of Medicine (IOM), issued a report on nursing called, The Future of Nursing: Leading Change, Advancing Health, (http://www.iom.edu/Reports/2010/The-Future-of-Nursig-Leadership-Change-Advancing-Health.aspx). According to the IOM official website, (http://www.iom.edu/), â€Å"†¦the IOM provides independent, objective, evidence-based advice to policy makers, health professional, the private sectorRead MoreThe Future of Nursing999 Words   |  4 PagesFUTURE OF NURSING * SUTHA FERNANDO – DATE: 12-23-2012 GRAND CANYAN UNIVERSITY ABSTRACT The Institute of Medicine has thoroughly analyzed the Future of Nursing and submitted report. The Institute of Medicine (IOM) is a nonprofit organization that works independently, provides unbiased and authoritative advice to general public as well as government. In this essay we would discuss about the significance of report and recommendations of IOM. In 2010 the IOM has advised the GovernmentRead MoreThe Future of Nursing940 Words   |  4 Pagesï » ¿ The Future of Nursing Grand Canyon University Professional Dynamics NRS-430V The Future of Nursing Looking back over 150 years ago, the nursing profession has changed drastically. Even just the uniform of nurses changed from the white dresses with panty hose and a white cap to scrubs with pants. Here are a few other examples of change in the profession: â€Å"there was a time in the past when only physicians took blood pressures, performed phlebotomy and administered blood; andRead MoreThe Future of Nursing1402 Words   |  6 Pagesï » ¿Future of Nursing Introduction ONE: Discuss the work of the Committee of the Robert Wood Johnson Foundation (RWJF)†¦that led to the IOM report, Future of Nursing: Leading Change, Advancing Health†¦ The committee was led by former Department of Health and Human Services Secretary Donna Shalala, and was asked to create basically a blueprint for how the nursing profession can transform itself into a more potent and relevant force, Harvey V. Fineberg wrote (on page ix). The nursing committee wasRead MoreFuture of Nursing1315 Words   |  6 PagesThe Future of Nursing July 14, 2013 The Future of Nursing According to the Institute of Medicine (IOM), the nursing profession is the largest population in the nation s health care workforce with over three million members. Because of this, nurses have a fundamental role in the transformation of the nation s rapidly changing health care environment. To achieve this role, the IOM addressed several key recommendations to serve as a guide to the direction of the future of nursing (InstituteRead MoreThe Future of Nursing1170 Words   |  5 PagesThe Future of Nursing Carrie Curell Grand Canyon University: NRS-430-0191 Professional Dynamics 02/23/2013 The Future of Nursing The Institute of Medicine (IOM) has researched how nursing as we know it will and is changing. They have written a report called â€Å"The Future of Nursing: Leading Change, Advancing Health† that outlines the impact of these changes on education, nursing practice, and nurses as leaders and made recommendations on the necessary changes. Regarding the impact of educationRead MoreFuture of Nursing1378 Words   |  6 Pages2010 IOM report on the future of nursing 1. Running Head: PROFESSIONAL DEVELOPMENT OF NURSING PROFESSIONALS Professional development of nursing professionals: 2010 IOM report on the future of nursing Awudu BraimahRead MoreFuture of Nursing1041 Words   |  5 PagesThe Vision for Nursing is a Bright Nur/391 Sharon Berry Facilitator Arlene Leyba December 1, 2014 United ICN, the nurses of all nations speak with one voice. We speak as advocates for all those we serve, and for all the unserved, insisting that prevention, care and cure be the right of every human being. We are in the vanguard of health care progress, shaping health policy around the world through our expertise, the strength of our numbers, the alignment of our efforts, and ourRead MoreThe Future of Nursing834 Words   |  4 Pagesï » ¿Running head: The Future Nursing The Future Nursing The Future of Nursing The Affordable Care Act of 2010 (ACA) will have a great effect on nursing. According to this article nursing will have to change it role in the ACA and the three main categories that need to be changed and redeveloped is transforming practice, education and leadership. â€Å"The ACA outlines some new health care arrangements, and with these structures will come new opportunities for new rolesRead MoreThe Future of Nursing1181 Words   |  5 PagesThe Future of Nursing Grand Canyon University NRS-440V 3.24.13 Introduction This paper will discuss various aspect of the future of health care focusing on the future of how nursing will play an ever-important role in the reformation of health care. Presentation regarding, the Robert Wood Johnson Foundation Initiative on the future of nursing, at the Institute of Medicine report entitled, â€Å"Future of Nursing: Leading Change, Advancing Health,† will help set the stage for this paper. Discussion

Wednesday, December 18, 2019

The Root Of Female Subjugation - 1258 Words

Marlee Taylor Taylor1 02/26/15 ANT3302 SEC9618 Dr. Khadidja Arfi Paper One: Marx Engels Identifying the root of female subjugation in society is a conundrum that extends over numerous decades and on into present day, time and time again. Some scholars and feminists have frequently deemed the biological make-up of woman and their aptitude to reproduce the source of gender oppression. It seems the natural ability to give birth is often contended whether or not to be a restrictive factor of female activity. In a modern society as industrialized and innovative as present day where attention is much more focused on supple thoughts, the masculinity of the physical male becomes an untenable reason for superiority over the organic†¦show more content†¦Karl Marx rationalizes why he blames the social shift in production as one of the seeds that generated female coercion and began the destruction of the societal kinship. In order to understand the development of woman subjugation, one must first understand how exchanging production and private prop erty steered the growth of a bourgeoisie society, an amateur system of capitalism. In part one of his text â€Å"The German Ideology† Marx declares, â€Å"†¦the class which is the ruling material force of society, is at the same time its ruling intellectual force. The class which has the means of material production at its disposal, has control at the same time over the means of mental production, so that thereby, generally speaking, the ideas of those who lack the means of mental production are subject to it† (Marx, 2). This is often justified as a pivotal moment in the emergence of male gendered domination among society. The development of the small patriarchal groups separating from the clan commanded each member be responsible for the economical upkeep in the unit, and for woman that meant giving birth to offspring and nurturing new generations. This erupts the conception of female becoming confined to domesticated work and the development of the women’ s â€Å"thought to be† gender role in society. As one flips through the collaborated research of Marx and Engels in â€Å"The Family, Private Property and the State†, it can be noticed that Engels implied that the subjugation of women can

Monday, December 9, 2019

Bryan free essay sample

The Locos were a radical faction of the Democratic Party that existed from 1835 until the mid-asses. ;The faction was originally named the Equal Rights Party, and was created in New York City as a protest against that city regular Democratic organization Tammany Hall. In general, Locos supported Andrew Jackson and Van Burden, and Were for free trade, greater circulation of specie, legal protections for labor unions and against paper money, financial speculation, and state banks. Specie Circular ; The Specie Circular, or Coinage Act, was an executive order issued by U. S. President Andrew Jackson in 1836 and carried out by succeeding President Martin Van Burden. ; The Act was a reaction to the growing concerns about excessive speculations of land after the Indian removal, which was mostly done with soft currency. Long Cabin campaign, Tippecanoe and Tyler too, ND the election of 1840 Tippecanoe and Tyler too was a very popular and influential campaign song of the Whig Partys colorful Log Cabin campaign in the 1840 United States presidential [->l]election. We will write a custom essay sample on Bryan or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page Its lyrics sang the praises of Whig candidates William Henry Harrison (the hero of Tippecanoe) and John Tyler, while denigrating incumbent Democrat Martin Van Burden. ; The United States presidential election of 1 840 saw President Martin Van Burden fight for re-election against an economic depression and a Whig Party unified for the first time behind war hero William Henry [->garrison and his log bin campaign. Second Great Awakening ; The Second Great Awakening was a Protestant revival movement during the early 1 9th century in the United States.

Monday, December 2, 2019

Ion Channel Disease Essay Example

Ion Channel Disease Essay MECH A NIS MS OF D IS EASE Review Article Mechanisms of Disease F R A N K L I N H . E P S T E I N , M. D. , Editor ION CHANNELS — BASIC SCIENCE AND CLINICAL DISEASE AND MICHAEL J. ACKERMAN, M. D. , PH. D. , DAVID E. CLAPHAM, M. D. , PH. D. I ON channels constitute a class of proteins that is ultimately responsible for generating and orchestrating the electrical signals passing through the thinking brain, the beating heart, and the contracting muscle. Using the methods of molecular biology and patch-clamp electrophysiology, investigators have recently cloned, expressed, and characterized the genes encoding many of these proteins. Ion-channel proteins are under intense scrutiny in an effort to determine their roles in pathophysiology and as potential targets for drugs. Defective ion-channel proteins are responsible for cystic fibrosis,1 the long-QT syndrome,2 heritable hypertension (Liddle’s syndrome),3,4 familial persistent hyperinsulinemic hypoglycemia of infancy,5,6 hereditary nephrolithiasis (Dent’s disease), and a variety of hereditary myopathies,7-9 including generalized myotonia (Becker’s disease), myotonia congenita (Thomsen’s disease), periodic paralyses, malignant hyperthermia, and central core storage disease (Table 1). Elucidating the mechanisms of these diseases will benefit medicine as a whole, not just patients with a particular disease. For instance, although the inherited long-QT syndrome is not common, identifying the underlying defects in the KVLQT1 and HERG potassium channels and the SCN5A sodium channels may benefit the study of ventricular arrhythmias, which are responsible for 50,000 sudden deaths each year in the United States. Likewise, al- hough a defect in the recently cloned epithelial sodium channel (ENaC) is the basis of a very rare form of inherited hypertension (Liddle’s syndrome, or pseudoaldosteronism), normal ENaC may serve as an alternative target in attempts to correct the physiologic defects created by the cystic fibrosis transmembrane regulator (CFTR), which is mutated in patients with cystic fibrosis, and work with ENaC may provide insight into the mechanism of essential hypertension. This review focuses on ion channels as functioning physiologic proteins, sources of disease, and targets for therapy. We will write a custom essay sample on Ion Channel Disease specifically for you for only $16.38 $13.9/page Order now We will write a custom essay sample on Ion Channel Disease specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will write a custom essay sample on Ion Channel Disease specifically for you FOR ONLY $16.38 $13.9/page Hire Writer We will discuss two prominent diseases caused by defects in ion-channel proteins, as well as two specific ion channels whose recent molecular identification raises new prospects for pharmacologic manipulation. PHYSIOLOGY OF ION CHANNELS From the Department of Pediatrics and Adolescent Medicine, Mayo Foundation, Rochester, Minn. (M. J. A. ); and the Department of Cardiology, Children’s Hospital Medical Center, Department of Neurobiology, Harvard Medical School, Boston (D. E. C. ). Address reprint requests to Dr. Ackerman at the Department of Pediatrics and Adolescent Medicine, Mayo Eugenio Litta Children’s Hospital, Mayo Foundation, Rochester, MN 55905.  ©1997, Massachusetts Medical Society. Ion channels are macromolecular protein tunnels that span the lipid bilayer of the cell membrane. Approximately 30 percent of the energy expended by cells is used to maintain the gradient of sodium and potassium ions across the cell membrane. Ion channels use this stored energy much as a switch releases the electrical energy of a battery. They are more efficient than enzymes; small conformational changes change (gate) a single channel from closed to open, allowing up to 10 million ions to flow into or out of the cell each second. A few picoamps (10 12 A) of current are generated by the flow of highly selected ions each time the channel opens. Since ion channels are efficient, their numbers per cell are relatively low; a few thousand of a given type are usually sufficient. Ion channels are usually classified according to the type of ion they allow to pass — sodium, potassium, calcium, or chloride — although some are less selective. They may be gated by extracellular ligands, changes in transmembrane voltage, or intracellular second messengers. Conductance is a measure of the ease with which ions flow through a material and is expressed as the charge per second per volt. The conductance of a single channel, g, as distinguished from the membrane conductance (G) of all the channels in the cell, is defined as the ratio of the amplitude of current in a single channel (i ) to the electromotive force, or voltage (V): g i . V The direction in which ions move through a channel is governed by electrical and chemical concentraVol ume 336 Numbe r 22 575 The New Engla nd Journa l of Medicine TABLE 1. HERITABLE DISEASES MODE OF INHERITANCE* OF ION CHANNELS. NO. OF AMINO ACIDS DISEASE ION-CHANNEL GENE (TYPE) CHROMOSOME LOCATION COMMON MUTATIONS†  Cystic fibrosis Familial persistent hyperinsulinemic hypoglycemia of infancy Hypercalciuric nephrolithiasis (Dent’s disease) Liddle’s syndrome (hereditary hyperten sion; pseudoaldosteronism) AR AR X-linked CFTR (epithelial chloride channel) SUR1 (subunit of ATP-sensitive pancreatic potassium channel) CLCN5 (renal chloride channel) 7q 11p15. 1 Xp11. 22 480 1582 746 AR ENaC (epithelial sodium channel) a subunit b subunit g subunit 12p 16p 16p 1420 640 649 F508 (70 percent of cases) and 450 other defined mutations Truncation of NBD2 (nucleotidebinding domain 2) 1 intragenic deletion, 3 nonsense, 4 missense, 2 donor slice, 1 microdeletion R564stop, P616L, Y618H (all in b subunit); premature stop codon in b and g subunits; C-terminal truncation Long-QT syndrome (cardiac arrhythmia) LQT1 LQT2 LQT3 Myopathies Becker’s generalized myotonia Central core storage disease Congenital myasthenic syndrome AD KVLQT1 (cardiac potassium channel) HERG (cardiac potassium channel) SCN5A (cardiac sodium channel) 11p15. 5 7q35–36 3p21–24 581 1159 2016 1 intragenic deletion, 10 missense 2 intragenic deletions, 5 missense KPQ1505–1507, N1325S, R1644H D136G, F413C, R496S R163C, I403M, Y522S, R2434H T264P L269F , G153S T698M, T704M, M1585V, M1592V R528H, R1239H G341R, G2433R G1306A Q552R V1293I, G1306V, T1313M, L1433R, R1448C, R1448H, V1589M S804F, G1306A, G1306E, I1160V D136G, G230E, I290M, P480L AR ? ? Hyperkalemic periodic paralysis Hypokalemic periodic paralysis Malignant yperthermia Masseter-muscle rigidity (succinylcholine-induced) Myotonia levior Paramyotonia congenita Pure myotonias (fluctuations, permanins, acetazolamideresponsive) Thomsen’s myotonia congenita AD AD AD ? AD AD AD AD CLCN1 (skeletal-muscle chloride channel) RYR1 (ryanodine calcium channel) nAChR (nicotinic acetylcholine receptor) e subunit a subunit (slow channel) SCN4A (skeletal-muscle sodium channel) CACNL1A3 (dihydropine-sensitive calcium channel) RYR1 SCN4A CLCN1 SCN4A SCN4A CLCN1 7q35 19q13. 1 17p 2q 17q23–25 1q31–32 19q13. 1 17q23–25 7q35 17q23–25 17q23–25 7q35 988 5032 473 457 1836 1873 5032 1836 988 1836 1836 988 AR denotes autosomal recessive, and AD autosomal dominant. † Missense mutations are represented by the standard nomenclature (AxxxB, meaning that at amino acid position xxx, amino acid A has been replaced by amino acid B). tion gradients. Ions flow passively through ion channels down a chemical gradient. Electrically charged ions also move in an electrical field, just as ions in solution flow to one of the poles of a battery connected to the solution. The point at which the chemical driving force and the electrical driving force are exactly balanced is called the Nernst potential (or reversal potential [Erev]). Above or below this point of equilibrium, a particular species of ion flows in the direction of the dominant force. The net flow of electricity across a cell membrane is predictable given the concentrations of ions and the number, conductances, selectivities, and gating properties of the various ion channels. Electrophysiologic concepts are simplified by recalling the Nernst potentials of the four major ions 1576 May 2 9 , 1 9 9 7 across the plasma membrane of cells. These are approximated as follows: sodium, 70 mV; potassium, 98 mV; calcium, 150 mV; and chloride, 30 to 65 mV (Fig. 1). The positive and negative signs reflect the intracellular potential relative to a ground reference electrode. When only one type of ion channel opens, it drives the membrane potential of the entire cell toward the Nernst potential of that channel. Thus, if a single sodium-selective channel opens in a cell in which all other types of channels are closed, the transmembrane potential of the cell will become ENa ( 70 mV). If a single potassium channel opens, the cell’s transmembrane potential will become EK ( 98 mV). Because cells have an abundance of open potassium channels, most cells’ transmembrane potentials (at rest) are approximately MEC H A NIS MS OF D IS EASE Extracellular Cell membrane Intracellular Ca2 Ion channels 2. 5 mM Depolarization 0. 0001 mM Nernst potential (Erev) 150 mV Control mechanisms 142 mM Depolarization 10 mM Na 70 mV Gating †¢ Voltage †¢ Time †¢ Direct agonist †¢ G protein †¢ Calcium Depolarization Nonselective Repolarization 0 mV Modulation †¢ Increases in phosphorylation †¢Ã‚  Oxidation–reduction †¢ Cytoskeleton †¢ Calcium †¢ ATP 101 mM Repolarization Cl Depolarization 5–30 mM Cl 30 to 65 mV 4 mM Repolarization 155 mM K 98 mV Figure 1. Physiology of Ion Channels. Five major types of ion channels determine the transmembrane potential of a cell. The concentrations of the primary species of ions (sodium, calcium, chloride, and potassium) are millimolar. The ionic gradients across the membrane establish the Nernst potentials of the ion-selective channels (approximate values are shown). Under physiologic conditions, calcium and sodium ions flow into the cells and depolarize the membrane potential (that is, they drive the potential toward the values shown for ECa and ENa), whereas potassium ions flow outward to repolarize the cell toward EK. Nonselective channels and chloride channels drive the potential to intermediate voltages (0 mV and 30 to 65 mV, respectively). 0 mV, near EK. When more than one type of ion channel opens, each type â€Å"pulls† the transmembrane potential of the cell toward the Nernst potential of that channel. The overall transmembrane potential at a given moment is therefore determined by which channels are open and which are closed, and by the strength and numbers of the channels. A cell with one o pen sodium channel and one open potassium channel, each with the same conductance, will have a transmembrane potential halfway between ENa ( 70 mV) and EK ( 98 mV), or 14 mV. The result is the same when there are 1000 equal-conductance, open sodium and potassium channels. Ion channels are both potent and fast, and they are tightly controlled by the gating mechanisms of the cell (Fig. 1). The modern way to see an ion channel in action is to use the patch-clamp technique. With this method,10 a pipette containing a small electrode is pressed against the cell membrane so that there is a tight seal between the pipette and the membrane (Fig. 2). In essence, the electrode isolates and captures all the ions flowing through the 1 to 3 mm2 of membrane that is defined by the circular border of the pipette. In this fashion, the ionic current passing through a single ion channel can be collected and measured. Several geometric configurations can be used if a mechanically stable seal is formed. The current passing through the attached patch (cell-attached configuration), a detached patch (inside-out or outside-out configuration), or the whole cell can be measured, providing information about ion channels within the Vol ume 336 Numbe r 22 1577 The New Engla nd Journa l of Medicine A Cellattached mode B Electrode Pipette Insideout mode C Wholecell mode Acetylcholine Acetylcholine Cell membrane IK. ACh g 40 pS to 1 msec Closed pA Closed Gbg protein pA msec Open Open msec msec Figure 2. Patch-Clamp Measurement of Ion-Channel Activity, with the Acetylcholine-Sensitive Potassium Channel (IK. ACh) Used as an Example. In the â€Å"cell-attached† mode (Panel A), a pipette is pressed tightly against the cell membrane, suction is applied, and a tight seal is formed between the pipette and the membrane. The seal ensures that the pipette captures the current flowing through the channel. In the cell-attached membrane patch, the intracellular contents remain undisturbed. Here, acetylcholine in the pipette activates the IK. ACh, which has a characteristic open time (tO) of 1 msec and a conductance (g) of 40 picosiemens. In the inside-out mode (Panel B), after a cell-attached patch has been formed, the pipette is pulled away from the cell, ripping off a patch of membrane that forms an enclosed vesicle. The brief exposure to air disrupts only the free hemisphere of the membrane, leaving the formerly intracellular surface of the membrane exposed to the bath. Now the milieu of the intracellular surface of the channels can be altered. In this figure, adding purified Gbg protein to the exposed cytoplasmic surface activates the IK. ACh. In the whole-cell mode (Panel C), after a cell-attached patch has been formed, a pulse of suction disrupts the membrane circumscribed by the pipette, making the entire intracellular space accessible to the pipette. Instead of disrupting the patch by suction, a pore-forming molecule, such as amphotericin B or nystatin, can be incorporated into the intact patch, allowing ions access to the interior of the cell but maintaining a barrier to larger molecules. In this figure, the net current (IK. ACh) after the application of acetylcholine is shown. environment of the cell, in isolation from the rest of the cell, or over the entire cell, respectively. MOLECULAR BLUEPRINTS OF ION CHANNELS Many ion channels have been cloned by assaying their function directly with the use of oocytes from South African clawed toads (Xenopus laevis). 11 These oocytes are large enough to be injected with exogenous messenger RNA (mRNA) and are capable of synthesizing the resulting foreign proteins. In â€Å"expression cloning,† in vitro transcripts of mRNA from a complementary DNA (cDNA) library derived from a tissue known to be rich in a particular ion channel are injected into individual oocytes. Subsequently, the currents in the oocytes are meas1578 May 2 9 , 1 9 9 7 ured by two-electrode voltage clamp techniques. The cDNA library is serially subdivided until injected mRNA from a single cDNA clone is isolated that confers the desired ion-channel activity. Moreover, mutant cDNA clones with engineered alterations in the primary structure of the protein can be expressed and the properties of the ion channel can be studied to determine which regions of the protein are critical for channel activation and inactivation, ion permeation, or drug interaction. Most ion-channel proteins are composed of individual subunits or groups of subunits, with each subunit containing six hydrophobic transmembrane regions, S1 through S6 (Fig. 3A). 13 The sodium and calcium channels comprise a single (a) subunit containing four repeats of the six transmembrane-span- A M ECH A NIS MS OF D IS EASE A C-type slow inactivation B K Extracellular S4 S1 S2 S3 S4 S5 H5 S6 S4 S4 S4 Cell membrane †Ball and chain† N-type fast inactivation P N S4 voltage sensor H5 channel pore C K Intracellular P P K Figure 3. Structure of Ion Channels. Panel A shows a subunit containing six transmembrane-spanning motifs, S1 through S6, that forms the core structure of sodium, calcium, and potassium channels. The â€Å"ball and chain† structure at the N-terminal of the protein is the region that participates in N-type â€Å"fast inactivation,† occluding the permeation pathway. The circles containing plus signs in S4, the voltage sensor, are positively charged lysine and arginine residues. Key residues lining the channel pore (H5) are found between S5 and S6. The genes for sodium and calcium channels encode a protein containing four repeats of this basic subunit, whereas the genes for voltageactivated potassium channels (Kv) encode a protein with only a single subunit. The genes for Kir channels encode a simple subunit structure containing only an H5 (pore) loop between two transmembrane-spanning segments. P denotes phosphorylation. Panel B shows four such subunits assembled to form a potassium channel. Although no mammalian voltage-dependent ion-channel structure has been revealed at high resolution by x-ray crystallography, the dimensions of the pore region shown here were derived by using high-affinity scorpion toxins and their structures (as determined by nuclear magnetic resonance imaging) as molecular calipers. 12 The pore region appears to have wide intracellular and extracellular vestibules (approximately 2. 8 to 3. 4 nm wide and 0. 4 to 0. 8 nm deep) that lead to a constricted pore 0. 9 to 1. 4 nm in diameter at its entrance, tapering to a diameter of 0. 4 to 0. 5 nm at a depth of 0. 5 to 0. nm from the vestibule. ning motifs. Voltage-gated potassium channels (Kv; this nomenclature refers to K channel, voltagedependent) are composed of four separate subunits, each containing a single six-transmembrane–spanning motif (Fig. 3B). 14 The subunits are assembled to form the central pore in a process that also determines the basic properties of gating and permeation charact eristic of the channel type. The peptide chain (H5 or P loop) between the membrane-spanning segments S5 and S6 projects into and lines the water-filled channel pore. Mutations in this region alter the permeation properties of the channel. S4 contains a cluster of positively charged amino acids (lysines and arginines) and is the major voltage sensor of the ion channel. Voltage-dependent â€Å"fast inactivation† of the channel is mediated by a tethered amino-terminal– blocking particle (the â€Å"ball and chain†) that swings in to occlude the permeation pathway. 15 The most recently discovered family of ion-channel proteins is that containing the inwardly rectifying potassium-selective channels (Kir, for K channel, inward rectifier). These channels determine the transmembrane potential of most cells at rest, because hey are open in the steady state. Kir channels are known as inward rectifiers because they conduct current much more effectively into the cell than out of it. Despite this biophysical property of the Kir channels, the physiologically important current is the outward one that accompanies the efflux of potassium ions. The topography of Kir channels resembles that of Kv channels, but the su bunits in Kir channels lack the S1 to S4 segments present in Kv channels. 16 With only two transmembrane-spanning segments, Kir channels have a deceptively simple domain surrounding the conserved H5 pore. However, pore formation by different combinations of subunits, direct gating of G proteins, and interactions with other proteins adds considerable complexity to the behavior of the Kir channels. HERITABLE DISEASES ASSOCIATED WITH ION-CHANNEL MUTATIONS Cystic Fibrosis One in 27 white persons carries a mutant CFTR gene, and 1 in 2500 to 3000 is born with cystic fiVol ume 336 Numbe r 22 1579 The New Engla nd Journa l of Medicine A B Cell membrane TM1 TM6 TM7 Extracellular TM12 Skin †¢ Cl , 60 mmol/liter Lungs †¢ Bronchiectasis †¢ Pneumothorax †¢ Hemoptysis †¢ Cor pulmonale N F508 NBD1 ATP ADP Pi NBD2 ATP ADP Pi Liver †¢ Obstructive biliary tract disease Pancreas †¢ Enzyme insufficiency †¢ Insulin-dependent diabetes mellitus Regulatory domain S I P Reproductive tract †¢ Male infertility †¢ Congenital absence of vas deferens PKA PP2A C 1 Gene therapy to replace CFTR gene (phase 1) Extracellular Cell membrane 3 Activate mutant CFTR with NS004 (experimental) 2 Direct CFTRprotein delivery (in vitro) 5 Activate non-CFTR chloride channels with aerosolized UTP (phase 3) 6 Decrease sodium uptake by blocking ENaC with aerosolized amiloride (phase 3) Na CFTR P2R R P lCI. ATP Cl P Intracellular I †¢ Meconium ileus S Small intestine P ENaC P ATP Intracellular Cl 4 Chaperonins (none tested yet) 1580 May 2 9 , 1 9 9 7 P S I P Endoplasmic reticulum S I P S I P P M EC H A NIS MS OF D IS EASE Figure 4. Cystic Fibrosis and CFTR. In cystic fibrosis, defective apically located membrane chloride channels (CFTR) in a variety of epithelial cells do not allow the egress of chloride ions into the lumen. Control over epithelial sodium channels is also lost, increasing the reabsorption of sodium from the lumen. Thick, desiccated mucus results, which accounts for the primary clinical manifestations of the disease (Panel A). 7 CFTR contains 12 transmembrane segments (TM1 through TM12, Panel B), several of which (TM1, TM6, and TM12) contribute to the chloride-channel pore. There are also two nucleotide-binding domains (NBD1 and NBD2) and a regulatory domain. The chloride channel is regulated by ATP binding and hydrolysis at the nucleotide-binding domains and by the phosphorylation (P) of serine residues (S) in the regulatory domain. The most common mutation in cystic fibrosis, found in more than 70 percent of cases, involves a deletion of a single amino acid (phenylalanine) in NBD1 ( F508). PKA denotes protein kinase A, PP2A protein phosphatase 2A, and Pi inorganic phosphorus. Molecular strategies to treat cystic fibrosis (Panel C) include replacing the mutant chloride channel by gene therapy (1) or protein delivery (2); improving the secretion from the existing mutant CFTR protein with CFTR-channel openers, such as NS004 (3) or â€Å"chaperonins† for F508 in the endoplasmic reticulum (4); bypassing the CFTR defect by activating other chloride channels with aerosolized uridine triphosphate (UTP) (5); and blocking the increased reabsorption of sodium through epithelial sodium channels (ENaC) with aerosolized amiloride (6). The investigational stages of these strategies are given in parentheses. P2R denotes type-2 purinergic receptor, and R regulatory domain. brosis (among blacks the incidence is 1 in 14,000, and among Asians it is 1 in 90,000). The manifestations of cystic fibrosis stem from a defect in a chloride-channel protein, CFTR, that does not allow chloride to cross the cell membrane (Fig. 4A). 7 The CFTR gene encodes a chloride channel that is activated by the binding of ATP to its nucleotide-binding domains and by the phosphorylation of key serine residues in its regulatory domain; the phosphorylation is mediated by cyclic AMP and protein kinase A (Fig. 4B). 18-21 CFTR also appears to regulate the absorption of sodium through ENaC, the epithelial sodium channel, and to activate other â€Å"outwardly rectifying† chloride channels. More than 450 mutations have been identified in CFTR, which contains 1480 amino acids. A deletion of phenylalanine at position 508 ( F508) accounts for more than 70 percent of cases of cystic fibrosis and is associated with severe pancreatic insufficiency and pulmonary disease. The F508 CFTR channel conducts chloride reasonably well when it is incorporated into a cell membrane, but because of improper folding the mutant protein becomes stuck in intracellular organelles and is not inserted into the cell membrane. 2 The majority of mutant CFTR proteins are processed abnormally, like the F508 mutant, but some mutations cause either defects in regulation or defective conduction through the CFTR channel. 23 Different CFTR genotypes may provide opportunities to develop unique therapeutic strategies. For instance, misfolded mutants could be escorted to the membrane by yet-to-be-invented â€Å"chaperonins,† whereas the action of poorly conducting mutant proteins may be enhanced by CFT R-specific channel openers. Molecular genotypes are correlated with the severity of pancreatic insufficiency, but not with the severity of pulmonary disease. 24 An exception is the A455E CFTR mutant (in which alanine is changed to glutamic acid at position 455), which has been associated with mild lung disease and accounts for 3 per- cent of cases of cystic fibrosis in the Netherlands. 25 In addition, a primarily genital phenotype of cystic fibrosis that involves the congenital bilateral absence of the vas deferens has been described in otherwise healthy males who are heterozygous for the F508 CFTR mutation. 6 Pulmonary disease accounts for over 90 percent of mortality from cystic fibrosis, and therefore treatment is mostly directed at ameliorating lung disease. Therapy includes antibiotics to eliminate common respiratory pathogens (Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Staphylococcus aureus), recombinant human DNase to decrease the viscosity of secretions, and antiinfl ammatory drugs to reduce the inflammatory response. 7 The recognition of the ion-channel defect in cystic fibrosis has led to novel approaches, such as replacing the defective channel gene by gene transfer with either viral carriers such as adeno-associated virus or nonviral carriers such as cationic liposomes (now in phase 1 trials)28; stimulating the activation of reduced numbers of functional ion channels with a CFTR-channel opener (NS004, a substituted benzimidazolone)29; mobilizing mutant CFTR proteins to the cell surface30,31; counteracting the defect in chloride efflux by blocking the influx of sodium with amiloride32,33; and bypassing CFTR-mediated conductance of chloride by activating other chloride channels, such as ICl. Swell, ICl. Ca, and ICl. ATP34 (Fig. 4C). Long-QT Syndrome A more detailed understanding of cardiac arrhythmogenesis is emerging as the workings of most of the types of ion channels underlying cardiac action potentials are elucidated. 35,36 The various long-QT syndromes are the first genetically determined arrhythmias known to be caused at the molecular level by defects in myocardial ion channels (Fig. 5). The congenital long-QT syndrome has an estimated incidence of 1 in 10,000 to 1 in 15,000. It is characterized by prolongation of the QT interval Vol ume 336 Numbe r 22 1581 The New Engla nd Journa l of Medicine A C LQT1 (11q15. 5) KvLQT1 IKs C Long-QT Syndrome Prolongation of QT (QTc 460 msec1/2) †¢ Syncope †¢ Sudden death N 1 581 Cell membrane LQT2 (7q35–36) HERG IKr Prolonged QT N 1 C 1159 LQT3 (3q21–24) Torsade de pointes II III IV SCN5A INa C P N 1 2016 KPQ P P P P B 47 mV 1 0 Current clamp 85 mV 0 100 2 Prolonged cardiac action potential 3 LQT4 (4q25–27) 4 ? 200 300 400 Milliseconds 500 corrected for heart rate (QTc) to more than 460 msec1/2, and it is an important but relatively rare cause of sudden death in children and young adults (Fig. 5A). The majority (two thirds) of persons with the long-QT syndrome are identified during routine electrocardiographic screening or after the evaluation of a primary relative who is affected. Approximately one third of subjects are identified during a clinical evaluation for unexplained syncope or cardiac or respiratory arrest. These subjects are at an annual risk of 5 percent for an abrupt syncopal episode. Without treatment, symptomatic subjects have 1582 May 2 9 , 1 9 9 7 a 10-year mortality rate approaching 50 percent. Often the arrhythmia is a torsade de pointes polymorphic ventricular tachycardia, typically triggered by adrenergic arousal. 37 Genetic origins were suggested for this syndrome by descriptions both of the autosomal recessive form associated with congenital deafness (Jervell and Lange-Nielsen syndrome)38 and of an isolated autosomal dominant form (Romano– Ward syndrome). 9,40 Substantial progress has been made toward elucidating the molecular basis of the most common inherited subtypes of the long-QT syndrome (Fig. M EC H A NIS MS OF D IS EASE Figure 5. The Long-QT Syndrome. A person with the long-QT syndrome may have unexplained syncope, seizures , or sudden death (Panel A). More likely, the person will be asymptomatic and identified by electrocardiographic screening during a routine evaluation or the screening of a primary relative who is symptomatic. The strict electrocardiographic definition of a prolonged QT interval varies according to age and sex, but generally a QT interval corrected for heart rate (QTc) greater than 460 msec1 ? 2 is considered abnormal. According to Bazett’s formula, the QTc is calculated by dividing the QT interval by the square root of the R-R interval. In patients with the long-QT syndrome, the T-wave morphology is often abnormal. This base-line rhythm can degenerate into a polymorphic ventricular tachycardia, classically a torsade de pointes, as shown here, after a stimulus that is not precisely understood but that often takes the form of adrenergic arousal. The prolonged QT interval as measured on the electrocardiogram results from an increased duration of the cardiac action potential (Panel B). The ventricular action potential is maintained at a resting membrane potential (approximately 85 mV) by inwardly rectifying potassium currents (IK1, phase 4). Once an excitatory stimulus depolarizes the cell beyond a threshold voltage (for example, 60 mV), sodium currents are activated that quickly depolarize the cell (INa, phase 0). These sodium channels are rapidly inactivated, allowing transient potassium currents to return the action potential to the plateau voltage (phase 1). The plateau lasts about 300 msec and provides time for the heart to contract. The plateau is maintained by the competition between outward-moving potassium currents and inward-moving calcium currents (phase 2). Progressive inactivation of calcium currents and increasing activation of potassium currents repolarize the cell to the resting membrane potential (phase 3). On a molecular basis, the autosomal dominant LQT1 and LQT2 are caused by defects in potassium-channel genes (KvLQT1 and HERG) involved in phase 3 repolarization (Panel C). LQT3 is caused by a defective sodium-channel gene, SCN5A. A common SCN5A mutation in families with LQT3 involves a deletion of three amino acids ( KPQ) in the III–IV cytoplasmic linker loop, which is known to regulate inactivation. The mutant sodium channel fails to become completely inactivated, resulting in sustained depolarization and prolonging the cardiac action potential. The linear topology of the proteins responsible for LQT1, LQT2, and LQT3 is shown, with the amino acids numbered beginning with the N-terminal — a total of 581, 1159, and 2016 amino acids, respectively. The chromosomal locations for these genes are shown in parentheses. 5C). 2,36 Recent studies of 16 families with chromosome-II–linked long-QT syndrome type 1 (LQT1) implicated KvLQT1, a 581-amino-acid protein with sequence homology to voltage-activated potassium channels. 41 One intragenic deletion and 10 missense mutations were identified. The combination of the KvLQT1 and ISK subunits (the latter of which contains 130 amino acids, also known as minK) appears to reconstitute the cardiac IKs current. 42,43 IKs (â€Å"s† denotes â€Å"slow†) is one of the principal delayed-rectifying potassium currents responsible for phase 3 repolarization in the heart (Fig. 5B). LQT1 may account for half the incidence of the long-QT syndrome in its autosomal dominant forms. Mutations in a second potassium channel, the human ether-a-go-go–related gene (HERG), have been identified in subjects with the long-QT syndrome type 2 (LQT2), which has been linked44,45 to chromosome 7q35–36. HERG is responsible for the other major potassium current (IKr [â€Å"r† denotes â€Å"rapid†]) that participates in phase 3 repolarization. It is a unique voltage-gated potassium channel; its secondary structure is that of a typical voltage-activated (Kv) potassium channel (Fig. 3A), but it behaves more like an inwardly rectifying (Kir) potassium channel. 6 The role of HERG in normal cardiac physiology appears to be to suppress depolarizations that lead to premature firing. Subjects with LQT2 may therefore be prone to sudden cardiac death, because they lack protection from arrhythmogenic afterbeats. Class III antiarrhythmic drugs block HERG channels. In addition, antihistamines such as terfenadine and antifungal drugs such as ketoconazole have been implicated in acquired cases of the long-QT syn- drome because of their ability to block IKr (HERGmediated) current. The third subtype of the long-QT syndrome (LQT3) has been linked to the gene for the cardiac sodium channel (SCN5A) on chromosome 3p21– 24. 47 This channel is responsible for the fast upstroke of the cardiac action potential (phase 0, Fig. B), which ensures contractile synchrony by causing the potential to spread rapidly throughout the heart muscle. A deletion of three amino acids, KPQ1505– 1507, in a region thought to control rapid inactivation has been demonstrated in LQT3-linked families. The mutant sodium channel fails to inactivate completely, resulting in reopenings of the channel and long-lasting bursts of channel activity. 48,49 The resulting prolonged inward current lengthens the action potential (and thus the QT interval). Finally, a fourth heritabl e type of long-QT syndrome (LQT4) has been linked to chromosome 4q25–27. Its causative gene has not been identified, although a gene encoding a calcium–calmodulin kinase has been proposed. 0 Current therapies for the long-QT syndrome include b-adrenergic–antagonist drugs, cardiac pacing, and left cervicothoracic sympathectomy. The majority of families with heritable long-QT syndrome have type 1, 2, or 3, offering the prospect of genetic screening and directed antiarrhythmic therapy. Theoretically, therapies that augment potassium-channel activity may be used in subjects with potassiumchannel defects (LQT1 and LQT2),51 and those with sodium channel–linked defects (LQT3) may benefit from drugs that decrease sodium-channel activation (such as mexiletine). 52 Vol ume 336 Numbe r 22 1583 The New Engla nd Journa l of Medicine TABLE 2. ION CHANNELS AND DRUGS THAT AFFECT THEM. Calcium channels Antianginal drugs (amlodipine, diltiazem, felodipine, nifedipine, verapamil) Antihypertensive drugs (amlodipine, diltiazem, felodipine, isradipine, nifedipine, verapamil) Class IV antiarrhythmic drugs (diltiazem, verapamil) Sodium channels Anticonvulsant drugs (carbamazepine, phenytoin, valproic acid) Class I antiarrhythmic drugs IA (disopyramide, procainamide, quinidine) IB (lidocaine, mexiletine, phenytoin, tocainide) IC (encainide, flecainide, propafenone) Diuretic drugs (amiloride) Local anesthetic drugs (bupivacaine, cocaine, lidocaine, mepivacaine, tetracaine) Chloride channels Anticonvulsant drugs (clonazepam, phenobarbital) Hypnotic or anxiolytic drugs (clonazepam, diazepam, lorazepam) Muscle-relaxant drugs (diazepam) Potassium channels Antidiabetic drugs (glipizide, glyburide, tolazamide) Antihypertensive drugs (diazoxide, minoxidil) Class III antiarrhythmic drugs (amiodarone, clofilium, dofetilide, N-acetylprocainamide, sotalol) Drugs that open potassium ch annels (adenosine, aprikalim, levcromakalim, nicorandil, pinacidil) TARGETING ION CHANNELS Drugs that target ion channels include calciumchannel blockers (used in patients with hypertension), potassium-channel blockers (used in patients with non-insulin-dependent diabetes mellitus), some diuretics and antiseizure medications, and essentially all antiarrhythmic drugs (Table 2). Recent progress in the basic understanding of the ATP-sensitive potassium channel (IK. ATP) and the G-protein–activated potassium channel (IK. ACh) shows the opportunities for drug design. The ATP-Sensitive Potassium Channel The IK. ATP current has been characterized in heart, skeletal muscle, pituitary, brain, smooth muscle, and pancreas. 55 In the pancreas, it plays a major part in regulating glucose homeostasis and the secretion of insulin. 56 Rising plasma glucose concentrations increase intracellular concentrations of ATP in islet beta cells, which in turn inhibit IK. ATP channels. As these potassium channels close, the cell’s membrane potential depolarizes away from EK and enters the range in which voltage-dependent calcium channels are activated. The resulting influx of calcium triggers insulin secretion. As plasma glucose concentrations decline, intracellular concentrations of ATP decrease and IK. ATP channels become more active, hyperpolarizing the cell, closing the calcium channels, and terminating the secretion of insulin. Oral hypoglycemic drugs (such as glyburide) bind to the sulfonylurea receptor to inhibit the activity of IK. ATP and promote the secretion of insulin. 57 Drugs that open potassium channels include nicorandil, pinacidil, aprikalim, levcromakalim, and diazoxide. In vascular smooth muscle these drugs open IK. ATP channels, hyperpolarize cell membranes, and reduce calcium-channel activity, thus decreasing vascular tone. The drugs are therefore potentially cardioprotective and may provide novel therapeutic approaches in patients with cardiac disease or hypertension. 58-60 The subtype specificity of sulfonylurea receptors (SUR1 in the pancreas and SUR2 in the heart) may be exploited to develop more specific drugs. The G-Protein–Activated Potassium Channel The ATP-sensitive potassium channel IK. ATP is a multimeric complex of inwardly rectifying potassiumchannel subunits (Kir 6. 2 K. ATP-a) and the sulfonylurea receptor (SUR1 K. ATP-b). 53,54 The genes for both are located on chromosome 11p15. 1. SUR1 binds sulfonylurea drugs. Mutations in the SUR1 gene are responsible for persistent hyperinsulinemic hypoglycemia of infancy. 5,6 Kir 6. 2 is an inwardly rectifying potassium channel. Like other such channels, it has two transmembrane-spanning segments surrounding a pore domain. Expression of both SUR1 and Kir 6. 2 results in a potassium channel that is sensitive to intracellular ATP inhibited by sulfonylurea , drugs, and activated by diazoxide, as is consistent with the known properties of IK. ATP channels in pancreatic beta cells. The cardiac sulfonylurea receptor, SUR2, has a lower affinity for sulfonylurea drugs than does SUR1, and it may form the cardiac IK. ATP channel by combining with a homologue in the Kir 6 family. 1584 May 2 9 , 1 9 9 7 Vagally secreted acetylcholine binds to cardiac muscarinic type 2 receptors. Activating these G-protein– linked receptors slows the heart rate by opening a potassium-selective ion channel (IK. ACh) composed of G-protein–activated inwardly rectifying Kir subunits. In turn, IK. ACh decreases spontaneous depolarization (pacemaker activity) in the sinus node and slows the velocity of conduction in the atrioventricular node. 61,62 Muscarinic stimulation of IK. ACh can terminate arrhythmias, particularly supraventricular tachycardias, providing the basis for carotid massage and other vagotonic maneuvers. 5 Another G-protein–linked receptor agonist, adenosine, activates the same cascade in atria and pacemaking cells through type 1 purinergic receptors. Because muscarinic stimulation has many systemic effects, adenosine has become a favored treatment for supraventricular tachycardia; it is also useful in determining the underlying arrhythmic mechanism (usually a reentrant one). 63 The molecular mechanism of the activation of IK. ACh (IK. G) is known. 64 Cardiac IK. ACh is a heteromultimer of two inwardly rectifying potassium-channel subunits, GIRK1 (Kir 3. 1) and GIRK4 (CIR or Kir 3. 4),65 and it is activated after the direct binding of the bg subunits of G protein (Gbg). 66 Similar IK. ACh currents and GIRK proteins are present in the brain. M EC H A NIS MS OF D IS EASE Neuronal GIRK channel proteins are formed by heteromultimers of GIRK1 and GIRK2 in the cerebellum, midbrain, and cortex. In homozygous weaver mice that have profound ataxia due to the loss of granule-cell neurons during cerebellar development, a single point mutation in the highly conserved pore region of GIRK2 results in granule-cell death and failure of migration. The mutated weaver-mouse channel loses its potassium-ion selectivity and sensitivity to Gbg, converting a regulated repolarizing potassium channel into a constitutively active, nonselective depolarizing channel and resulting in increased excitotoxic cell death. 67 CONCLUSIONS A growing number of heritable diseases are known to be caused by ion-channel mutations. Chloridechannel defects underlie cystic fibrosis, certain myotonias, and heritable nephrolithiasis. Mutant sodium channels give rise to the long-QT syndrome and other myotonias, potassium-channel malfunction increases susceptibility to arrhythmias, and calciumchannel mutations can result in hypokalemic periodic paralysis, malignant hyperthermia, and central core storage disease. Identifying the structural framework of the major ion-channel proteins and resolving the precise relations between structure and function should make it possible to develop new therapies for patients with these disorders. We are indebted to David A. 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Krapivinsky G, Gordon EA, Wickman K, Velimirovi„ B, Krapivinsky L, Clapham DE. The G-protein-gated atrial K channel IKACh is a heteromultimer of two inwardly rectifying K -channel proteins. Nature 1995;374: 135-41. 66. Krapivinsky G, Krapivinsky L, Wickman K, Clapham DE. Gbg binds directly to the G protein-gated K channel, IKACh. J Biol Chem 1995;270: 29059-62. 67. Navarro B, Kennedy ME, Velimirovi„ B, Bhat D, Peterson AS, Clapham DE. Nonselective and Gbg-insensitive weaver K channels. Science 1996;272:1950-3. Lake District, Northern Italy KEITH J. QUINTON, M. D. 1586 May 2 9 , 1 9 9 7

Wednesday, November 27, 2019

Lift Every Voice and Sing essays

Lift Every Voice and Sing essays "Lift Every Voice And Sing" is a high-spirited gospel song that was written by the famous black poet and civil rights leader, James Welden Johnson. Performed by Melba Moore and a few others, I downloaded a version of the song to play. Originally in honor to celebrate Lincoln's birthday, it was performed in a Florida school to children who were being educated in a segregated environment. I happen to think it also has something to do with Martin Luther King Jr. and the marches he led in order to overcome discrimination and prejudice. Indeed, this song can be considered uplifting and courageous to the people that think God has left them during their times of trial. Specifically, this message focuses on the hard times of African Americans, during segregation and slavery. The speaker is someone who is trying to be inspirational and uplifting to those who need it. The audience is not only concentrated on blacks that went through or viewed hate crimes, but also to anyone that has felt the t errible burden of intolerance and hatred. The writer of this song entitled it "Lift Every Voice And Sing" because of the fact that he's telling all blacks to do the very same thing. Blacks were told to be quiet when they were slaves; they were there for service. Moreover, blacks were to be seen, not heard, like children. James is telling blacks to speak up, not to be ignored, or disregarded. His plea is to empower the oppressed so that the world is forced to notice the beauty and integrity of you as a person, as a fellow human being. The first stanza and chorus of "Lift Every Voice and Sing" reads: Ring with the harmonies of liberty; Let it resound loud as the rolling sea In this stanza, James is advising blacks to let people know they're here. The lines "Till earth and heaven ring, Ring with the harmonies of liberty;" (1.2-3) encourages blacks to make sure everyone hears what they have to say. It's also telling them that their words can teac...

Saturday, November 23, 2019

Biography of Michelle Obama, U.S. First Lady

Biography of Michelle Obama, U.S. First Lady Michelle Obama  (born January 17, 1964) was the first African-American first lady and the wife of Barack Obama, the 44th president of the United States and the first African-American to serve as president. She is also a lawyer, the former vice president of community and external affairs at the University of Chicago Medical Center, and a philanthropist. Fast Facts: Michelle Obama Known For: First Lady of the United States, wife to 44th President Barack ObamaBorn: January 17, 1964 in Chicago, IllinoisParents:  Marian Shields and Fraser C. Robinson IIIEducation: Princeton University (BA in sociology), Harvard Law School (JD)Published Works: BecomingSpouse: Barack Obama (m. October 3, 1992)Children: Malia (born in 1998) and Natasha (known as Sasha, born in 2001) Early Life Michelle Obama (nee Michelle LaVaughn Robinson) was born on January 17, 1964, in Chicago, Illinois, the second of two children of Chicagoans Marian Shields and Fraser C. Robinson III. She describes her parents as important early role models in her life, whom she proudly identifies as working class. Her father, a city pump operator and Democratic precinct captain, worked and lived with multiple sclerosis; his limp and crutches did not affect his abilities as the family breadwinner. Michelles mother stayed home with her children until they reached high school. The family lived in a one-bedroom apartment on the top floor of a brick bungalow on Chicagos south side. The living room- converted with a divider down the middle- served as Michelles bedroom. Michelle and her older brother Craig, now an Ivy League basketball coach at Brown University, grew up hearing the story of their maternal grandfather. A carpenter who was denied union membership due to race, Craig was shut out of the citys top construction jobs. Yet the children were taught they could succeed despite any prejudices they might encounter over race and color. Both children were bright and skipped second grade. Michelle entered a gifted program in sixth grade. From their parents, who had never attended college, Michelle and her brother learned that achievement and hard work were key. Education Michelle attended Whitney M. Young Magnet High School in Chicagos West Loop, graduating in 1981. Although she was discouraged from applying to Princeton by high school advisors who felt her scores werent adequate, she was accepted and graduated from the college with honors and a bachelors degree in sociology and a minor in African-American studies. She was one of very few black students attending Princeton at the time, and the experience made her acutely aware of the issues of race. After graduation, she applied to Harvard Law School and once again faced bias as college counselors tried to talk her out of her decision. Despite their doubts, she matriculated and excelled, obtaining her J.D. in 1985. Professor David B. Wilkins remembers Michelle as forthright: She always stated her position clearly and decisively. Career in Corporate Law After graduating from Harvard Law School, Michelle joined the law firm of Sidley Austin as an associate specializing in marketing and intellectual property. In 1988, a summer intern who was two years older than she by the name of Barack Obama came to work at the firm, and Michelle was assigned as his mentor. They married in 1992 and later had two daughters, Malia (born in 1998) and Natasha, known as Sasha (born in 2001). In 1991, the death of her father from complications related to MS caused Michelle to re-evaluate her life; she subsequently decided to leave corporate law to work in the public sector. Career in Public Sector Michelle first served as assistant to Chicago Mayor Richard M. Daly; later she became assistant commissioner of planning and development. In 1993 she founded Public Allies Chicago, which provided young adults with leadership training for public service careers. As executive director, she headed up a nonprofit named by President Bill Clinton as a model AmeriCorps program. In 1996, she joined the University of Chicago as Associate Dean of Student Services and established its first community service program. In 2002, she was named the University of Chicago Hospitals executive director of community and external affairs. Balancing Career, Family, and Politics Following her husbands election to the U.S. Senate in November 2004, Michelle was appointed Vice President of Community and External Affairs at the University of Chicago Medical Center in May 2005. Despite Baracks dual roles in Washington, D.C., and Chicago, Michelle did not consider resigning from her position and moving to the nations capital. Only after Barack announced his presidential campaign did she adjust her work schedule; in May 2007 she cut her hours by 80 percent to accommodate the needs of the family during his candidacy. Although she resists the labels feminist and liberal, Michelle Obama is widely recognized as outspoken and strong-willed. She has juggled career and family as a working mother, and her positions indicate progressive ideas on the roles of women and men in society. First Lady Michelles husband Barack was elected U.S. president in November 2007. During her first term as first lady, Michelle spearheaded the Lets Move! program, a concerted effort intended to reduce childhood obesity. Although it has been difficult to gauge the success of the program overall, her efforts led to the passage of the Healthy, Hunger-Free Kids Act in 2010, which allowed the U.S. Department of Agriculture to set new nutritional standards for all food sold in schools for the first time in more than 30 years. During Barack Obamas second term, Michelle focused on the Reach Higher Initiative, which aimed to help students identify future careers and enable them to complete coursework past high school- whether its at a professional training program, a community college, or a four-year college or university.  That initiative continues, with a focus on school counselor training, raising awareness about college access tools, and social media outreach and flagship events such as College Signing Day. Post-White House Since the Obamas left the White House in January 2016, Michelle worked on and published her memoir Becoming, published in November 2018. She has also worked on the Global Girls Alliance, an education project intended to help provide tens of millions of adolescent girls worldwide who were not given a chance to finish high school; Global Girls is an outgrowth of Let Girls Learn, which she started in 2015 and left with the White House. She has actively supported the Chicago-based Obama Foundation charity, and been a spokesperson for When We All Vote, to increase voter registration. Sources: Obama, Michelle. 2018. Becoming. New York: Crown, 2018.Saulny, Susan. Michelle Obama Thrives in Campaign Trenches. New York Times, 14 February 2008.Bennetts, Leslie. First Lady in Waiting. VanityFair.com, 27 December 2007.Gewertz, Catherine. Michelle Obamas Reach Higher Initiative Merges With the Common Application. Education Week Blog High School Beyond, 27 September 2018.  Ross Johnson, Steven. Gauging the public health value of Michelle Obamas Lets Move campaign. Modern Healthcare, 23 August 2016.Rossi, Rosalind. The woman behind Obama. Chicago Sun-Times, 22 January 2008.Slevin, Peter. Michelle Obama: A Life. New York: Vintage Books, 2015.Michelle Obama’s vacation is over. Now she’s claiming her own spotlight. The Washington Post, 11 October 2018.

Thursday, November 21, 2019

Issues in Strategic Management Strategic Audit Exercise Essay

Issues in Strategic Management Strategic Audit Exercise - Essay Example Apple experienced good success during the late 1980s but after that there were testing times during the 90s. John Sculley, previously the CEO joined Apple in 1983. Sculley came to Apple with the valuable experience of the 'Cola-War' between Coke and Pepsi. Steven Jobs, more of technology oriented initially found this approach little weird, but later gave Sculley a free hand. Gradually, over the years, Apple has succeeded in regaining the lost glory to a great extent. Feb 27 edition of Business Journal (2007) points out that the ipod helped in this transformation process with the sale of over 90 million ipods since its launch in 2001. After this successful parade of its ipod, Apple has now taken up another ambitious product called 'iphone'. This gadget is an integration of an iPod, a mobile phone, a portable computing machine and a digital camera. With touch controls and an internet communication device the iphone is an innovative product from the armory of Apple. Slated for a full-fl edged launch in June 2007, iphone also has the Wi-Fi connectivity and Bluetooth features and it is based on quad-band GSM + EDGE technology. Now it is to be seen how Apple can mobilize its resources to convert this venture into another success story. Over the years Apple has also established a dependable value chain with strong links with its suppliers and distributors, but the spat with its arch rival Microsoft will not allow Apple to take things lying down, it'll have to be on the path of innovation with regular inputs from market. Though the iphone promises to be a cult item that may influence the industry to follow suit, yet there are certain finer edges which need to be smoothened before Apple expects an ipod like revolution. For example ipod became such a craze owing to its compatibility with the most popular music format-MP3, and the most popular operating system-Windows. But it at the moment industry analysts are keenly watching the verbal dual between Apple and Microsoft. O n the one hand Apple has issued a warning about MS Vista being a security threat to the ipods while on the other hand Microsoft chief Bill Gates underlined the importance of the 'software part' when asked for his views on Apple iphone. He sought to downplay the technological advancement and innovative features that Apple has put in it. This dual promises more fireworks in near future. Resources Audit Such an audit is done to identify different types of resources available to the company. Some of the resources that Apple Inc. could mobilize for carrying out its business are; Financial resources: The Company has been able to post a record revenue billion and record net quarterly profit of $1.0 billion, or $1.14 per diluted share for its fiscal 2007 first quarter ended December 30, 2006 (Apple, 2007). During the operations Gross margin was 31.2 percent, up from 27.2 percent in the year-ago quarter. What is the source of strength is that the International sales accounting for 42 percent of the quarter's revenue. The very fact that the company has been able to sustain the onslaught of Microsoft and IBM provides an insight into the strength of its financial resources. Company's consistent track record of dividend indicates that Apple values its

Tuesday, November 19, 2019

Critically assess theories of Transaction Cost Economics and Resource Essay - 1

Critically assess theories of Transaction Cost Economics and Resource Based View in terms of their usefulness in explaining firm - Essay Example This is a theory that tries to explain why companies exist, why they outsource activities to the external environment, and why they expand.The theory argues that companies try to minimize the bureaucratic costs of exchanges within the company, and that companies try to minimize the cost of exchanging resources with the environment.In their operations, the companies therefore, analyse the bureaucratic costs of conducting in-house activities, and the costs of exchanging resources with the environment (Williamson, 2010; Boneta, Peris-Ortizb & Gil-Pechuanb, 2010; McIvor, 2009). The market and the institutions are considered different forms of coordinating, and organizing economic transactions. The firm makes a decision basing an analysis on this theory to find out an appropriate move; whether to outsource or use internal resources. If such an analysis reveals high external costs, the firm will not outsource since it will have determined that it has the capability to perform its operation s cheaply. This means the firm will grow. When the external costs are lower than the internal bureaucratic costs, it is advisable to outsource the activities to be performed in the market. Such acts lead to minimized transaction and bureaucratic costs. Using the internal bureaucratic means of operation when the cost is higher than the transaction costs in the market reduces the firm’s growth rate or intentions.... After creation of the competitive advantage, a firm is able to sustain it over longer periods of time. The firm will then be able to protect itself against resource transfer, imitation, or substitution (Revilla, Cordeiro & Sarkis, 2011; Flynn, Morita & Machuca, 2010). When firms in a specific industry are competing in a market, these respective firms must have some unique resources that improve performance more that other companies. This creates the competitive advantage of a firm. If for example a firm has a unique strategy of acquiring customers, it will beat the other firms in the market, and gain more market share. This will be its competitive advantage. Not all firms therefore, should have the same resources that give a certain firm a competitive advantage. Such a resource or resources must be difficult to duplicate or imitate through other means (Flynn, Morita & Machuca, 2010). Usefulness in Explaining Firms’ Internationalising Strategies The transaction cost economics t heory explains why firms exist, expand and outsource certain activities. Internationalising a strategy means using the same strategy internationally. A firm may have its headquarters in Atlanta, but has found ready market in various other states, and countries outside United States. If this firm analysed its strategies, and found out that using one type of strategy, or by using certain strategies, the transaction costs and the internal bureaucratic costs are minimized, it will continue to use the same strategies internationally. Specific strategies therefore, ensure a new firm exists in a region; a firm expands to certain regions and survives or outsources to survive in the market. Analysing this considering the Resource Based

Sunday, November 17, 2019

Public Health of the Developing Country of South Africa Essay Example for Free

Public Health of the Developing Country of South Africa Essay Abstract Studies and statistics have put the cost of one year requirement of standard essential medicines needed for the treatment of AIDS at $ 4000 to $ 6000 in developing countries like South Africa. This cost puts the medicines out of the reach of most of the people infected by HIV in the developing countries. In order to make the medicines available to all the needy people the cost should have been at least 95 percent less. The exorbitant price is because of the cost of the patents. The drugs protected by the intellectual property rights were required to treat diseases like Tuberculosis, in addition to the treatments of HIV/AIDS. Such drugs also included Hepatitis-B Vaccine. There has been a continuous criticism by the social activists and other public health associations, of the action by the World Trade Organization in making the developing countries implement the Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement which deals with the protection of Intellectual Property rights relating to the essential drugs. They have also been condemning the attitude of the multinational companies in indulging in excessive lobbying to insist on the implementation of the IP rights protection which will have the effect of enhancing their earnings by charging exorbitant prices for the drugs and for putting the essential drugs and health care beyond the affordability of scores of people in the developing nations including South Africa. However under such circumstances the relationship between the government of South Africa and the international pharmaceutical companies had not been a conducive one – thanks to the implementation of the provisions of TRIPS Agreement. On the decision of the South African Government to pass the Medicines and Related Substances Amendment Act in the year 1997, 39 drug companies joined to initiate legal action against the government. The plea of the drug companies is that the Act gave too much freedom of action to the Health Minister and he acted beyond the legitimate interpretation of TRIPS. It was the endeavour of South Africa to make life saving drugs available at affordable prices. The country wanted to effectively utilize the compulsory licensing opportunities opened by TRIPS so that the prices of the drugs could be put under check. But since the action of the government posed a threat to the earning capacity of the international pharmaceutical companies they went to the extent of entering into litigation with the government of South Africa. Introduction TRIPS (Trade Related Aspects of Intellectual Property Rights) under the authority of the WTO were founded to protect worldwide intellectual property rights. The agreements, governing not only more general intellectual property rights but also those of the pharmaceutical industry, are fairly stringent causing many problems for developing countries especially South Africa which is being ravaged by epidemics which includes AIDS. According to a statistical survey by United Nations[1] 20 percent of the adult population in South Africa tests positive for HIV. The impact of the disease is such that the more than half a million children have been declared orphans. It is also reported that HIV/AIDS related diseases expect to reduce the average life expectancy in South Africa by 20 years in the year 2010. Therefore it can be inferred that the provision of treatment of HIV/AIDS in South Africa is a high priority issue[2]. It has been necessary for South Africa to circumvent part of the TRIPS agreements in an effort to protect its population.   AIDS is taking great toll of the country leaving families without parents and health care hospitals totally unable to cope. The United States currently insists on the TRIPS agreement being strictly adhered to and seems unable, or unwilling, to find a way to help the developing nations with this problem. There have been some efforts made to help them in this respect, for example compulsory licensing and parallel pricing and these methods will be examined in a later section. The negotiation of the TRIPS Agreement has been construed as one that was forcibly introduced by the developing countries against the objection of many of the developing nations. The industrial lobbies (multinational and transnational corporations) have convinced the governments of the developed countries to link the international trade with Intellectual Property Rights (IPR) so that the industrial advancement of the developing countries would be curtailed. This would automatically prevent imitation of technologies and increase the returns on research and development for the developed countries. Monopoly rights granted under IPR were mainly intended to deter the developing countries from advancing on the industrialization. Thus TRIPS Agreement and the protection of IPR have been used to ensure the comparative advantage of the developed countries in terms of the technological development. Under TRIPS countries like India, Brazil which manufactures generic medicines would not have the right to export such medicines with effect from 01 January 2005. This is so despite the fact that the importing countries do have the respective patents covering the drugs. Specifically the least developing countries have put a strong resistance to the requirements of TRIPS especially in the matter of granting the protection rights for the products and processes. While developing countries were required to implement the provisions within one year of reaching the Agreement, the developing countries were given time until the end of the year 2004. In the matter of protection of rights of pharmaceutical products the lease developing countries have been allowed to delay the implementation of TRIPS Agreement provisions till the year 2016. The peculiarity with the provisions of TRIPS is that it allows any country to override the patent right under certain specific circumstances by using the compulsory licensing procedure. For instance when there is a shortage of drugs or the prices of the drugs are too high to make them unaffordable the country can override the patent if the prescribed procedures are followed. This provision of TRIPS presupposes that all the countries do possess the required manufacturing facilities which enable them to use the provisions to produce generic medicines under extraordinary circumstances. But unfortunately many of the developing and least developing countries do not posses such facilities, and hence they would be left with shortage of such drugs. In addition they are also not allowed to import the generics from those countries that possess them. In any case these countries do not have enough power and administrative capabilities to invoke the TRIPS Agreement either due to the reason that they do not possess the know-how required to reengineer the drugs or they fear sanctions from the US and the West[3]. TRIPS Agreement under WTO The TRIPS Agreement is often thought of as one of the three â€Å"pillars† of the WTO (World Trade Organization), trade in goods and services being the other two.[4] TRIPS, initially part of GATT. But becoming part of the WTO brief, was founded to ensure that protection of intellectual property rights was not, of itself, an obstruction to trade and to increase cooperation between members. Under the TRIPS agreement each member state has an obligation to treat all other member states equally. The WTO negotiates between members and helps them to understand and carry out the rules and regulations they have signed up to. It also aids cooperation between members and acts as a watchdog to ensure that the agreement is adhered to. Marketing rights of a patent, when first applied for, are given for a period of 5 years or until the patent is finally approved (whichever is the shorter period) but even during this period members must comply with the rules and regulations as set out in Articles 3 and 4. Because of the nature of the agreement especially as regards pharmaceuticals, it was decided that minimum standards could be used, the USA prefers the higher standards but accepts the minimum as the developing world does not have the capacity to work to the higher standards at the present time. Public awareness of the serious issue of AIDS and other diseases has led to the belief   (by the WTO) that health must, in the final analysis, come before agreements since the spread of AIDS cannot be the sole responsibility of one country. In trying to bridge the gap between the pharmaceutical companies and the developing nations, TRIPS has endeavoured to bring the two sides together by allowing extensions to drugs’ patents but has also allowed some compulsory licensing. Article 3(a) under the TRIPS Agreement states that treatment of all members must be equal,   but Article 3(b) is a get-out clause and Article 4(b) states that all members are equal, unless an †¦agreement was entered into before the WTO agreement.   However, the Council for TRIPS must be informed of any non-observance of Article 3(a) under Article 3(b). The TRIPS Agreement ensures that members discharge their commitments to the World Intellectual Property Organisation (WIPO). Part of the United Nations WIPO was set up in 1974 specifically to direct international treaties and agreements. The Paris Convention on Industrial Property and the Berne Convention on Copyright, two of the major treaties have been brought under the TRIPS umbrella.   The former states that â€Å"members must comply with the obligations they have towards each other† and â€Å"nothing must stand in the way of such obligations†.  Ã‚   However, as noted, there is a get-out clause in cases of emergency which has to be acknowledged by members to the agreements. There is also an agreement that member countries monitor each other for infringements.   Most important in terms of worldwide health problems is Article 67 of TRIPS which states   that developed countries must assist developing countries with the development of their intellectual property rights, it states: â€Å"In order to facilitate the implementation of this Agreement developed country Members shall provide, on request and mutually agreed terms and conditions, technical and financial cooperation in favour of developing and least-developed country members† â€Å"Such cooperation shall include assistance in the preparation of laws and regulations on the protection and enforcement of intellectual property rights as well as on the prevention of their abuse, and shall include support regarding the establishment or reinforcement of domestic offices and agencies relevant to these matters, including the training of personnel.†Ã‚  Ã‚  Ã‚  Ã‚     Programmes to assist the developing nations have already been promoted and are being assisted by the WTO secretariat and WIPO. TRIPS Agreement in Relation to Medicines   Since most pharmaceutical research and development is carried out in developed countries the organisations involved feel that they should be better protected.   Most drugs cost millions and take years to test and develop before being allowed onto the market, the industry naturally want returns by way of profits on sales. AIDS medication has been a particularly important breakthrough since: ‘HIV infects an estimated 45 million persons worldwide†Ã‚   but there are also â€Å"†¦1.86 billion cases of infection with mycobacterium tuberculosis†[5] therefore, it is imperative that something be done to help alleviate this type of suffering which, with the ever growing number of tourists, should be the concern of not only those countries in which these epidemics are raging but every nation whose borders are open to travel from other countries. The TRIPS agreement, currently, seems to err on the side of the drugs’ companies, probably because they have such powerful lobbies and are part of the new world-wide elite of corporations which, according to Janet Dine, are increasingly importing their own ethics into the developing countries and virtually taking over, creating in the process an impoverished and unhealthy nation, they, the indigenous population have to take what is offered often at less than subsistence wages and become more dependant on the corporations who have moved into their countries in search of ever increasing profits. The money the corporations make from taking over in developing countries returns, not to the people of that region, but to their own countries.  Ã‚   With tax incentives and a population who take any work they can get to survive at the lowest rates offered, these Corporations appear to be fuelling a crisis in health for some of the poorest nations in the world.[6] Although The TRIPS agreement does allow for compulsory licensing in an emergency, each country must first negotiate with rights’ holders and must use those drugs obtained under such a license only for the emergency period and not for any commercial gain. Specific areas, such as South Africa, are going through a health crisis which needs the drugs already available to ameliorate it, however, in spite of clause 3(b), they are getting no further forward in their fight to help their citizens to overcome unprecedented death rates that the epidemics are producing. In spite of Articles 30/31, which allow for compulsory licensing, the poorest and least developed nations are fighting against the cost of the use of patents and the epidemics themselves. Compulsory licensing does not adequately cover the needs of such nations in   â€Å"sub-Saharan Africa since they do not have facilities to manufacture their own drugs.†[7] Protection of intellectual property is not part of the culture of many countries, nevertheless, the TRIPS Agreement was signed on 15th April 1994 by 117 nations. The agreement allows intellectual property rights to be â€Å"enforced by trade sanctions†[8] and, although some countries were not in complete agreement, international trade is vital to their economic growth so, however reluctantly, they signed.   Inhibitors, which have done much to control AIDS in the west, cost as much as $10.000 per head annually but international trade is the life blood of developing nations therefore they had little choice but to do so.[9] 4. TRIPS and Developing Countries It has been observed that implementing TRIPS Agreement and recognizing IPR on pharmaceutical products and processes would result in the following problems to the developing countries[10]: The minimum 20 years protection to the IPR would grant a virtual monopoly for a pharmaceutical company over its patented drug and the company would be able to charge exorbitant prices on the drugs without competition which in turn would keep the drug prices very high during the period of protection. It is also not possible to bring any generic equivalent into the market due to the TRIPS Agreement. This would deny the patients cheaper alternative drugs. The product and process patents provide for the protection of the product as well as the technology. Under the TRIPS Agreement the countries are given the right to make application for the protection of patent rights on drugs for a period extending up to twenty years. After the expiation of this period the countries can get the protection extended for further periods to the processes being employed in the manufacture of the drugs. This no doubt creates a monopoly situation on the drugs. Such protection also throw the domestic pharmaceutical producers in the developing countries out of market as they have to compete with large multinational pharmaceutical manufacturers which is not possible for small producers in the developing nations who use cheaper generic alternatives. Moreover such production may not be carried out by them during the 20 year protection period. Under TRIPS Agreement patent rights need to be granted irrespective of the fact that the products are imported or domestically manufactured[11]. This implies that the transnational corporations can supply global markets under the monopoly of patent rights even without producing any medicines in the developing countries by simply importing them into the developing countries. There will be no flow of technology or foreign direct investments into the developing countries as envisaged by the WTO However under Article 66 of the TRIPS the least developed countries were allowed to postpone the application of the provisions relating to the patents for a period of 10 years on specific application.[12] 5. Exceptions to the Patent Protection of Pharmaceuticals    Parallel importing – implying that the developing counties are allowed to import the drugs from the cheaper markets for resale in their respective countries and thereby lower the prices of drugs. Compulsory licensing – under compulsory licensing scheme, the government acting through the courts of law is empowered to provide a license in favor of a third party. Such license may be granted by the government even without the prior consent of the license holder. However the compulsory licensing can be resorted to in cases of national emergencies. The license may also be compulsorily transferred to a third party in case of an extremely emergent situation or where there are circumstances implying any anti-competitive movements by the manufacturers. The compulsory licensing is resorted to by the governments to make the drugs easily available to the poor and needy people at affordable costs. It also ensures that the patent holder is provided adequate compensation for use of the patent. 6. Public Health in South Africa and the Impact of TRIPS Agreement The need for cheaper drugs in South Africa can not be undermined. The impact of AIDS in the country poses the situation of an extreme emergency forcing the implementation TRIPS. The economy of South Africa is likely to get affected by a reduction of 1 percent every year because of the work force getting disintegrated. It is estimated that the life expectancy would be lowered to 50 years in 2010 from 70 years currently. These threats to the economy and population growth would as well be a threat to ‘peace and order’ situations in the country of South Africa[13]. In this context all the problems enumerated above for the developing nations have been faced by South Africa also. In addition when the government wanted to implement the Medicines and Related Substances Control Bill, the US Government vehemently objected to the passing of the law which allowed for parallel importing and compulsory licensing. However amidst lot of pressure on the government and the Parliament the South African government enacted the law in the year 1997.The pharmaceutical lobby backed by the transnational companies in the South Africa not only filed a suit against the promulgation of the law but also indulged in negotiations and threats   to the government to change its stand. The pressure was intense after the year 1997 when the South African government tried to implement a number of policy measures to lower the prices of drugs used in public health. â€Å"The SA policies have focused on such issues as mandatory generic drug substitution, restrictions on inappropriate marketing efforts, registration of generic versions of the cancer drug Paclitaxel (sold as Taxol by Bristol-Myers Squibb), parallel-imports, and compulsory licensing†[14]. It may be noted that despite Article 31 of the TRIPS Agreement that provides for the parallel importing and compulsory licensing the transnational pharmaceutical companies have vehemently opposed the attempts by developing countries like South Africa taking measures for implementing parallel importing and compulsory licensing as these practices would allow these countries to have their requirements of the medicines at cheaper prices which in turn would affect the profits of these transnational companies[15]. It was after the intervention of the AIDS activists and health activists that US came to an understanding in the issue. The government of South Africa insisted that it retains all the original provisions defending its position be retained. The government also wanted to make the fullest use of compulsory licensing and parallel importing which were considered as detrimental to the interests of the American Transnational Companies[16]. How American Corporations Control the Business World A- Business lobbies: Large and small businesses in the United States have been organised into various associations, for example Business Round Tables are national Associations which include membership of the Chief Executive Officers (CEOs) of all the most important trans-national companies and the National Chamber of Commerce includes all sizes of firms.[17] Round Tables have been in existence since 1972, the first was formed by forty-two of the (then) biggest and most important U.S. companies including banks, retailers, Insurance, transport and most of the utilities’ companies. They were designed to enable business to proceed without the destructive competitive basis of the business world. They were described as: â€Å"An association of chief executive officers who examine public issues that affect the economy and develop positions which seek to reflect sound economic and social principles. †¦ the Roundtable was founded in the belief that business executives should take an increased role in the continuing debates about public policy.†[18] The raison d’etre for these firms was the idea that ‘what ever is good for business is good for the American people’. They argued that, employees, purchasers, suppliers etc all have an interest in a business. These associations, they say, represent a cross section of the American public.[19] The idea that ‘what is good for business is good for America’ is patently nonsense since most people are in fact excluded from any rights in this elite world.  Ã‚   Employees have little or no say in the running of their firms and consumers must pay the prices asked, they do have the right ‘not to buy’ which is a somewhat negative view of the process of inclusiveness. David C Korten says that most of the memberships of the Round Tables are confined to white males over the age of 50 whose salaries are enormous. They do not, as claimed, consider that what is good for business is good for America but rather endeavour to maximise their own profits and those of their shareholders by seeking to globalise in areas where they can have an almost free hand to carry out their business practices almost unhindered by the laws of any country they move into. [20] Free Trade has long been an ideal of the American Corporate world which is why the Round Tables campaigned vigorously for the North American Free Trade Agreement (NAFTA and created USA-NAFTA to front their interests, the American public, nervous at so much control in so few hands, have been given country-wide blanket assurances through the media.   In spite of the fact that NAFTA was supposed to be a really broad church of interests it is really part of the elite Round Table Associations and has many representatives on advisory committees. The country might have been even more nervous if they had realised that at the time of the creation of these Round Tables the major companies were in fact laying aside their competitive differences to â€Å"reach a consensus on issues of social and economic policy for America†.[21] B- Influence of U.S. Democracy Janet Dine claims â€Å"no single idea is more deeply embedded in modern culture than the belief that economic growth is the key to meeting most important human needs, including alleviating poverty and protecting the environment† [22] which accounts for the greatest growth area in Washington being public relations firms. These firms work hard to protect the images of their corporate clients against a rising tide of discontent which is now manifesting itself throughout the world. It could be thought that they are fighting a losing battle but â€Å"the top fifty public relations firms billed over $1.7 billion dollars in 1991†[23] which gives rise to the question, why are these PR firms so necessary? There is probably no single answer to this question but very little news is given directly to the public without some corporate employee looking at the effect it will have, news and advertising, according to Korten, are almost synonymous.[24] The political system of America has greatly changed in the post war period of more general affluence. The Democratic party has lost its basic identity   the party of the people – as opposed to the Republicans who have always represented business and the wealthier side of the electorate – this being so the Democrats are far more dependant on the need to raise funds for their electioneering and have turned to the corporations who inevitably want quid pro quo for their donations. The mass media are heavily behind the elitist values of corporate America and the amount they are able to pay to PR firms to put across an extremely one-sided policy and both the leading parties needing the financial backing of corporate America, this, says David C Korten, â€Å"This is the sorry state of American democracy†.[25]   He says that voters tend to be seen as a passive homogeneous mass of potential customers who can be told not only what to buy but also what to think and feel.   What is worse, this idea of corporations is spreading, many trans-national companies rely heavily on the corporate idealism of what is good for them is good for the people they sell to.   Mexico and Japan both use those same American firms to tell their populations what they should think and feel and ultimately what they should buy. C- American Democracy   for Sale: â€Å"The Mexican government spent upwards of $25 million and hired many of the leading Washington lobbyists to support its campaign for NAFTA. †¦ Japanese corporations were spending an estimated $100 million a year on political lobbying in the United States and another $300 million building a nationwide grassroots political network to influence public opinion†. [26] Canada, Britain and the Netherlands’ governments employ public relations’ firms in America to help them lobby and draft laws that will be favourable to the business elites in their own countries. These companies try to sell the idea of ‘corporate libertarianism’ [27]which is supposed to allay the fears of those who have an idea that all is not well in the corporate world of business, it is possible to claim that these corporations are in fact in the act of ‘taking over the world’ and with the resources piling up behind them it could well happen in the not too distant future. The United States and Higher Levels of Protection. To add to this theme of a world take-over by corporate America, the signatories to TRIPS have begun to rethink intellectual property protection.[28] This is bad news for those under-developed countries which rely on drugs from the western world to protect their citizens from ravaging epidemics. Rosalyn S Park says: â€Å"Poor, developing nations have been most affected by the patent protection laws and resulting high drug prices, yet these nations also harbor the highest number of HIV-positive people. Consequently, the vast majority of people in need of HIV/AIDS medicines simply cannot afford them†. [29] In 2006 new protection laws will come into force which all members must adhere to. This will have a devastating effect on the millions of people in countries too poor to have their own drugs’ businesses, they will become more reliant upon those better protected, developed countries making vast profits from the countries least able to pay. Neither the USA nor the European Union appear greatly interested in aiding those countries with the greatest needs and the least ability to pay.   Admittedly concessions have been made as regards agricultural and textile concessions but this has been at the cost of allowing higher property rights which is a swings-and-round-a-bouts situation.   It would be much more useful to South Africa specifically and to the developing world in general, if the costs of patented drugs could be either brought down or, as a common sense gesture of good will, eliminated completely until such time as the AIDS epidemic was at least brought down to manageable proportions. In spite of â€Å"several different types of drugs on the market which help combat AIDS and AIDS related illnesses†[30] not enough are getting through to the developing countries as the multinationals are still insisting on not just the status quo as regards intellectual property rights but even higher levels.[31] They appear to be driven only by the profit motive and the perceived necessity for free trade paying little attention to the suffering caused in the developing world. Nor are they taking a long term view, highly contagious diseases are rife in the developing world, therefore, with the modern freedom of travel, no country can ever be safe from the same epidemics.   Even with modern drugs to combat them, new strains will develop, new drugs will have to be found and costs will escalate. Drugs now exist which allow people with AIDS to live a reasonably normal life including returning to work, it would in fact be in the interests of the drugs’ companies to allow South Africa to use them, dead people have no use for drugs nor anything else that the multi-nationals may wish to sell them. Conclusion The TRIPS Agreement was a milestone in patent protection of intellectual property rights and was considered to be a financial safeguard for research investment, however, it also had the effect of pricing some pharmaceuticals out of the reach of many nations most in need of the most recently patented medicines.   Before the TRIPS agreement, governments had been able to make compulsory licence orders to produce drugs at lower prices in their own countries, after the agreement, although still possible, it is much more difficult and thus more difficult to protect their citizens from the epidemics which are wreaking havoc in their countries. It is important to protect intellectual property rights but it is far more important to protect people’s lives but the balance currentlppears to be largely towards the greater protection of pharmaceutical industries. TRIPS allows compulsory licensing and parallel pricing but underdeveloped countries such as South Africa are being prevented from using them because of the threat of trade sanctions and trade is vital to their economies. It is necessary to protect peoples’ work and investment and research must be encouraged especially into life-threatening diseases. Corporations who invest time and money into producing drugs to cope with these scourges should reap the rewards of their labour.   However, many drugs’ companies are seeing such enormous returns on their investments that concessions should be made to underdeveloped countries which so desperately need the medications produced by these huge giants of industry. In spite of concessions in the TRIPS agreement, corporations do appear to be protected at the expense of people’s lives. Public health should be and is a priority in the west where governments can afford to buy the health of their citizens. Unfortunately, this is not the case in the poorer, less developed countries where governments are struggling to find ways to access drugs and yet to maintain a healthy trading relationship with the countries which hold the patents to these drugs. Good health is the basic right of every citizen of every country wherever possible. More goodwill is necessary on the part of the western world and America in particular to allow compulsory licensing and parallel pricing to be used without the threat of trade sanctions.  Ã‚   Epidemics do not respect borders, they can be carried by people to all corners the world, what was a third world problem yesterday is our problem today, world health is an issue that no country can ignore therefore although corporations must be allowed fair returns on their investments it must not be at the expense of world health. It is quite apparent that TRIPS Agreement has not taken into account the public health needs of the developing nations while formulating the clauses relating to the protection of IPR in respect of pharmaceutical needs. The Agreement has not specified any particular obligations towards those governments granting the IPR for pharmaceutical products. The Agreement has also not considered the need for public health in the developing countries and grossly ignored the interests of the patients of these countries. There are a number of factors that the developing countries have to take into account including the implication of the TRIPS Agreement and the patent protection under the Agreement in the provision of medical facilities and adequate public health to the people of the respective developing countries. â€Å"At the end of the day it must be recognized that the poorer residents of the world’s least affluent nations cannot pay even the marginal cost of drugs that might save their lives or permit them to become productive workers†[32]. Bibliography    Conceicao Soares (2007)‘The HIV/AIDS crisis and corporate moral responsibility in the light of the Levinasian notions of proximity and the Third’ Business Ethics: A European Review Vol. 16 No 3 p 280 David C Korten, When Corporations Rule the World, Earthscan Publication Ltd. London, p.144 Duane Nash, â€Å"†¦VI, Foreign International Law South Africa’s Medicines and Related Substances Control Amendment Act of 1997† 15 Berkeley Tech. L J. 485(lexis) Fact Sheet ‘Developing Countries’ Transition Periods’ http://www.wto.org/english/tratop_e/trips_e/factsheet_pharm04_e.htm#pharmsandags p1 F.M. Scherer and Jayashree Watal ‘Post-Trips Options for Access to Patented Medicines in Developing Nations’ Journal of International Economic Law (2002) p 939 Janet Dine, The Governance of Corporate Groups, Cambridge University Press, 2000.p.157 J H Reichman, The TRIPS Agreement Comes of Age: Conflict or Cooperation with the Developing Countries? P.6 John A. Harrelson, â€Å" IV. Note: Trips, Pharmaceutical Patents, and the HIV/AIDS Crisis: Finding the Proper Balance Between Intellectual Property Rights and Compassion† 7 Wid. L. Symp. J . 175(lexis) Kara M. Bombach ‘The South African Medicines and Related Substances Control Amendment Bill and TRIPS’ http://academic.udayton.edu/health/06world/africa01.htm p1 Lisa Foreman (2007)‘Trade Rules, Intellectual Property and the Right to Health’ Comparative Program in Health and Society Munk Centre for International Studies University of Toronto Ethics International Affairs Vol. 21 No3 p 342 Louise Sylvan ‘TRIPS: Protecting Intellectual Property or Putting Profits Before People’ Online Opinion http://www.onlineopinion.com.au/view.asp?article=1968   p1 Medecins sans Frontieres (1999) Access to HIV/AIDS medicines in Thailand, Medecins sans Frontieres Report to the National AIDS Committee of Thailand, August 1999, MSF website, www.accessmed-msf.org/msf/accessmed/accessmed.nsf/html/4DTS2? Open Document.p1 N.B. Zaveri (1999) Success often comes to those who dare and act, paper presented at Brainstorming Workshop on WTO Agreements and Peoples Concerns, New Delhi, Oct/Nov 1999 p1 Patric Bond ‘US Policy toward South Africa and Access to Pharmaceutical Drugs’ Alternative Information and Development Centre http://www.aidc.org.za/?q=book/view/156 p1 Ross Brennan and Paul Baines (2005) ‘Is there a morally right price for anti-retroviral drugs in the developing world’ Business Ethics: A European Review Vol. 15 No 1 p32 Rosalyn S Park, The International Drug Industry: What the Future Holds for South Africa’s HIV/AIDS Patients, Minnesota Journal of Global Trade, p.3 Z. Mirza (1999) WTO/TRIPS, pharmaceuticals and health: impacts and strategies, The Networks Drug Bulletin, Sept-Dec 1999, Vol. 8, No. 5/6, Association for Rational Use of Medication in Pakistan p 27       [1] United Nations (2004) Report on the Global AIDS Epidemic. Geneva: United Nations [2] Ross Brennan and Paul Baines (2005) ‘Is there a morally right price for anti-retroviral drugs in the developing world’ Business Ethics: A European Review Vol. 15 No 1 p 32 [3] Conceicao Soares (2007)‘The HIV/AIDS crisis and corporate moral responsibility in the light of the Levinasian notions of proximity and the Third’ Business Ethics: A European Review Vol. 16 No 3 p 280 [4] www.wto.org (Frequently asked questions about TRIPS in the WTO). [5] Duane Nash, â€Å"†¦VI, Foreigh International Law South Africa’s Medicines and Related Substances Control Amendment Act of 1997† 15 Berkeley Tech. L J. 485(lexis) [6] Janet Dine, The Governance of Corporate Groups, Cambridge University Press, 2000.p.157 [7] John A. Harrelson, â€Å" IV. Note: Trips, Pharmaceutical Patents, and the HIV/AIDS Crisis: Finding the Proper Balance Between Intellectual Property Rights and Compassion† 7 Wid. L. Symp. J . 175(lexis) [8] Ibid [9] Ibid [10] Z. Mirza (1999) WTO/TRIPS, pharmaceuticals and health: impacts and strategies, The Networks Drug Bulletin, Sept-Dec 1999, Vol. 8, No. 5/6, Association for Rational Use of Medication in Pakistan p 27 [11] Medecins sans Frontieres (1999) Access to HIV/AIDS medicines in Thailand, Medecins sans Frontieres Report to the National AIDS Committee of Thailand, August 1999, MSF website, www.accessmed-msf.org/msf/accessmed/accessmed.nsf/html/4DTS2? Open Document. p1 [12] Fact Sheet ‘Developing Countries’ Transition Periods’ http://www.wto.org/english/tratop_e/trips_e/factsheet_pharm04_e.htm#pharmsandags p1 [13] Kara M. Bombach ‘The South African Medicines and Related Substances Control Amendment Bill and TRIPS’ http://academic.udayton.edu/health/06world/africa01.htm p1 [14] Patric Bond ‘US Policy toward South Africa and Access to Pharmaceutical Drugs’   Alternative Information and Development Centre  Ã‚  Ã‚  Ã‚  Ã‚   http://www.aidc.org.za/?q=book/view/156   p1 [15] Louise Sylvan ‘TRIPS: Protecting Intellectual Property or Putting Profits Before People’ Online Opinion http://www.onlineopinion.com.au/view.asp?article=1968 p1 [16] N.B. Zaveri (1999) Success often comes to those who dare and act, paper presented at Brainstorming Workshop on WTO Agreements and Peoples Concerns, New Delhi, Oct/Nov 1999 p1 [17] David C Korten, When Corporations Rule the World, Earthscan Publication Ltd. London, p.144 [18] Ibid [19] Ibid [20] David C Korten, When Corporations Rule the World, Earthscan Publication Ltd. London, p.144 [21] Ibid [22] Janet Dine, The Governance of Corporate Groups, Cambridge University Press, 2000.p.156 [23] David C Korten, When Corporations Rule the World, Earthscan Publication Ltd. London, p.146 [24] Ibid [25] David C Korten, When Corporations Rule the World, Earthscan Publication Ltd. London, p.147 [26] Ibid [27] David C Korten, When Corporations Rule the World, Earthscan Publication Ltd. London,pp.147-148 [28] Rosalyn S Park, The International Drugs Industry: What the Future Holds for South Africa’s HIV/AIDS   Patients, Minnesota Journal of Global Trade, 2002.p.1 [29] Ibid [30] Rosalyn S Park, Minnesota Journal of Global Trade, 2000, p.2 [31] J H Reichman, The TRIPS Agreement Comes of Age: Conflict or Cooperation with the Developing Countries? P.6 [32] F.M. Scherer and Jayashree Watal ‘Post-Trips Options for Access to Patented Medicines in Developing Nations’ Journal of International Economic Law (2002)   p 939