Boosting Key Milk Nutrients May Help Lower Free Essays

The report (ScienceDaily screen 1) chiefly centered around the significant commitments of nutrient D, calcium and magnesium in hazard anticipation for diabetes; most particularly the sort 2 diabetes. (qtd in ScienceDaily, screen 1) The language utilized is genuinely extensive with the utilization of comfortable words and with just a couple of specialized terms. The author’s comprehension of the recently announced discoveries is adequate to permit him or to permit her to altogether clarify the discoveries of the investigations introduced. We will compose a custom paper test on Boosting Key Milk Nutrients May Help Lower or on the other hand any comparable subject just for you Request Now In the two investigations directed by Pittas et al. furthermore, Larsson et al., meta-investigations approaches were directed to get the outcomes. (qtd in ScienceDaily, screen 1) Studies performed were chiefly founded on American eating routine, in this way comparable investigations might be led to assess whether these discoveries apply for other racial and ethnic populaces. These data would truly be valuable for people who have diabetes or are in danger of creating diabetes; just as everyone for the advancement of wellbeing and anticipation of infection. Nonetheless, to a peruser without broad wholesome foundation, consequences of this investigation might be deceiving. The report may misdirect by giving the peruser the thought that drinking milk alone will be avoidance enough against diabetes. Other preventive measures for diabetes ought to have been remembered for the report to maintain a strategic distance from distortion. Reference: ScienceDaily. â€Å"Boosting Key Milk Nutrients May Help Lower Type 2 Diabetes Risk†. (13 July 2007). 16 July 2007 http://www.sciencedaily.com/discharges/2007/07/070711001452.htm. Web address: http://www.sciencedaily.com/discharges/2007/07/070711001452.htm More on: Diabetes, Dietary Supplement, Vitamin, Hormone Disorders, Nutrition, Osteoporosis Boosting Key Milk Nutrients May Help Lower Type 2 Diabetes Risk Science Daily †Most Americans neglect to get the calcium and nutrient D they need, however this setback could be influencing more than their bones. It might, in any event to a limited extent, be one purpose for the scourge of type 2 diabetes, recommends new examination directed at Tufts University. Drinking more milk †a main wellspring of calcium and nutrient D in the American eating regimen †could help decline the danger of type 2 diabetes by about 15 percent, as indicated by the new meta-investigation and survey distributed in the Journal of Clinical Endocrinology Metabolism (1). In the exhaustive examination of recently distributed investigations, the analysts discovered incessantly low degrees of nutrient D were connected to as high as 46 percent more serious danger of type 2 diabetes. However boosting nutrient D alone would probably have little impact in sound grown-ups. Rather, the scientists proposed that a blend of nutrient D and calcium, similar to that found in milk, would have the best potential to help forestall diabetes, particularly among those at most noteworthy hazard for the infection. Looking at the admission of milk and milk items explicitly, the specialists discovered there was almost a 15 percent lower chance for type 2 diabetes among people with the most elevated dairy consumption (3-5 servings for every day) contrasted with those getting under 1  ½ servings every day. The vast majority of the investigations surveyed were observational and the predetermined number of intercession preliminaries makes complete ends troublesome, yet the Tufts analysts recommend calcium and nutrient D may influence the body’s capacity to deliver or use insulin, the hormone the body makes to process sugar that is impeded in those with diabetes and pre-diabetes. Close to calcium and nutrient D, milk is the essential drink wellspring of magnesium, which a second meta-examination found may likewise lessen the danger of type 2 diabetes (2). The investigation infers that for each 100 milligram increment in magnesium up to the suggested dietary admission, the danger of creating type 2 diabetes diminished by 15 percent. Type 2 diabetes and insulin opposition condition (or pre-diabetes) influence a stunning 75 million Americans and demise rates from diabetes have expanded almost 45 percent in the course of recent years, lifting the significance of finding better approaches to treat and forestall this fatal illness. Milk is an essential wellspring of calcium and nutrient D in the American eating routine. Truth be told, government reports demonstrate that in excess of 70 percent of the calcium in our nation’s food gracefully originates from milk and milk items. Moreover, milk is one of only a handful not many food wellsprings of nutrient D, which is quick developing as a â€Å"super nutrient.† The suggested three servings of lowfat or sans fat milk gives 900 mg of calcium, 300 IU of nutrient D and 80 mg of magnesium day by day. Reference: (1) Pittas AG, Lau J, Hu FB, Dawson-Hughes B. Audit: The job of nutrient D and calcium in type 2 diabetes. An orderly audit and meta-examination. Diary of Clinical Endocrinology Metabolism. 2007;92:2017-2029. (2) Larsson SC, Wolk A. Magnesium admission and danger of type 2 diabetes: a meta-examination. Diary of Internal Medicine. 2007. doi: 10.1111; epub in front of print. Note: This story has been adjusted from a news discharge gave by Weber Shandwick Worldwide The most effective method to refer to Boosting Key Milk Nutrients May Help Lower, Essay models

Ole Mac Essay Example For Students

Ole Mac Essay I live near a town called, Hot Coffee, somewhere near the Mississippi River with my family on a little ranch. I have two siblings and one sister. At the point when we return home from school we have errands sitting tight for us. My task is to take care of chickens and gather the eggs for Mama. My more seasoned sibling Bobby, cleaves wood for our warmth and cooking. Mike, the most youthful sibling is ten and the sharpest of us kids. Well in any event we thought he was. His activity is taking care of the donkey Ole Mac. Ole Mac is nine years of age and the best donkey Daddy at any point had. Daddy talked well of Mac, about how solid he is, and that he is so natural to furrow. Daddy is continually saying best darn donkey in the district. Macintosh stands 14 hands tall and 4 feet over the back. He is the greatest donkey Ive ever observed, and as per Daddy he is additionally the sharpest. One day Mike stopped by the chicken coop originating from the horse shelter with a major grin. Why you grinning Mike? I approached opening the coop entryway heading for the house as well. Gracious nothin, nothin by any stretch of the imagination. He said with that large smile. Gracious please what's going on here? Nothin I said and disregard me. He said running in front of me toward the house. Here you are Mama. I said giving her the ten eggs Id gathered. Not awful Jimbo. I adored my Mama more than anything, yet I wished she would quit calling me Jimbo. On the off chance that she kept it up everyone would begin doing it. She mixed my hair seeing my glare, she transmitted and stated, Sorry I mean James. I grinned at her, Thanks Mama. You go wash up for dinner now. Your daddy will be in from the fields soon. Alright. I said going down the lobby to the washroom. I could hear her conversing with Mike. Kid, what on the planet are you so cheerful about. Nothin Ma, Im just smilen. Cant I grin? Kid, when you grin, I get stressed. Gracious Ma, I aint done nothin for you to stress over. I could hear the grin in his voice. I dont realize what Mike did, yet I knew it wasnt great. Mike was a shrewd child, yet here and there he was unreasonably savvy to his benefit. Bobby was the most seasoned, at 14 an a half as he called himself. He wasnt the most brilliant kid youd need to meet, yet at 14 and standing 510 all muscle, and let me state this no one at school said a cross word to him. His size additionally helped Mike and me, since they realized Bobby would go to our guide. On the ends of the week marry go to the fields with Daddy, and digger the corn. That season Kekulebusrs were terrible. The Kekulebur is a plant that turns around the corn and murders it. So we needed to make war on them consistently during the developing season. Bobby would accomplish double crafted by Mike and me. Daddy was glad for every one of us, which he revealed to all of us the time. We realized he had more pride for Bobby, on account of the work he could do. I heard Daddy disclose to Bobby one day hed make a decent rancher. He never said that to Mike or me, however Mike was acceptable at his school fill in as I seemed to be. Bobby could barely peruse or compose, however he was a conceived rancher and he cherished it. We heard Daddy coming in light of the fact that Ole Mac was causing his typical to cut hawing sound realizing he was going to be taken care of. I went out onto the yard and watched Daddy taking the bridle off Ole Mac. Daddy waved for me to go to the horse shelter. I recognized what he needed me for. Two times per week Ole Mac gets a brush down. Daddy said brushing help keep the takes off Ole Macs rear end. We generally giggled when he said that. It wasnt what he said it was the manner in which he said it. That was one thing Daddy can do, he made all of us giggle. James, you traverse brushing Mac put him in his slow down. Dont take too long brushing him or damnation nibble you. Ole Macs hungry and aint going to stand by long. Alright Daddy Ill be snappy. With a grin Daddy stated, You better or Mac will remove a piece from your arm. He said snickering toward the tack live with the outfit. Daddy consistently soaped the outfit once per week. He said it shielded the cowhide from breaking. You completed at this point? Daddy inquired. Indeed sir, Im done. Very much put Mac into his slow down and let him eat, and you get to the house so we can have our dinner. Indeed sir, Ill be there in no time flat. I drove Ole Mac into his slow down and he went directly to his trough. I watched him for only a second. He stuck his head down into the trough and afterward pulled it back rapidly. I figured I ought to go in and check his feed however Ive seen rodents get into the trough previously and Ole Mac would run them out with no issue. So feeling that it was a rodent I made a beeline for the house for dinner and pondered it. What we eating this evening Mama? I asked pulling the cover off the stew pot. Kid, you know not to do that. Where you been at any rate? I thought you were in your live with your siblings doing schoolwork. I was down in the outbuilding brushing Ole Mac. Well you better go wash up once more. Dinner will be on the tabl e in one moment. Alright. I said by and by going down the lobby to wash my hands. James. Did Ole Mac begin eating? Daddy solicited coming out from the unrivaled restroom each of the six of us needed to utilize. No sir I think there was a rodent in his feed trough. Ole Mac realizes how to deal with a little rodent. Truly sir, he does Ive seen him get them and nibble them directly into equal parts. I feel sorry for any rodent that annoys Macs food. Daddy said with a grin. You hustle just a bit now before all the food is no more. You know how your siblings are about squirrel hash. Squirrel hash? Goody gumdrops we havent had that in quite a while. James, you like anything your Mother makes. Daddy said with a pat to my shoulder. I got to the table not long before Daddy asked the gift, which he accomplished for each dinner. Pam my sister and Mama got up after the gift to get the stew pot of squirrel hash. Pam removed the top of the pot and the smell was brilliant. Schindler’S List Essay PaperIm not distraught at you. Diminished I went to the tack room and found the mallet. I need you to proceed to get Mike at the present time. He transformed returning into Macs slow down. As I was heading off to the house for Mike I heard some pounding in the outbuilding. I thought it amusing for Daddy to begin building something after hed been in the fields throughout the day. Mike was in our room getting his work done. Daddy needs to see you in the outbuilding. I saw Mikes face go white. Whats Daddy need with me? Mike said getting up and strolling to the window looking toward the outbuilding. I dont know, however he sure looked furious. Really? Mike said heading for the room entryway. Will you accompany me? Mike inquired. For what reason do you need me with you? Gracious never, mind. Sick pass without anyone else. I could see Mike must be in a difficult situation so I went with him. At the point when we got to the outbuilding, the pounding had halted. Daddy did you need to see me? Mike asked in a blameless voice. I do youngster. Come into the slow down I need to ask you an inquiry. Mike took a gander at me and opened the slow down entryway. I strolled in directly behind him. Ole Mac was in another slow down eating like Id never observed Mac eat. He ate like he was famished. Daddy was remaining close to the trough. Daddy asked Mike, Did you feed Mac yesterday? Mike took a gander at the trough and stated, Yes sir I did. Daddys face went red out of nowhere. Kid, what were you considering? Daddy shouted. I dont know. Mike said practically crying. I didnt comprehend what was happening. You realize you could have executed Ole Mac. He encourages this family to get by, and you pretty much slaughtered him. What do you have to state for yourself? Mike was currently crying and he rambled out, Im sorry Daddy I didnt figure it would hurt for some time. Wouldnt hurt? You could have starved Ole Mac to death. That Ole donkey buckles down ordina ry, and the main thing he gets is his feed, and you toke that away from him. Im sorry Daddy I didnt consider that. Daddy strolled nearer to Mike. Mike supported up intuition Daddy was going to hit him. Daddy halted directly before him and stated, Dont stress child Im not going to hit you, yet I figure you will wish I had. For the following a half year, youll not just feed Mac youll likewise brush him down ordinary. You will likewise cleanser the bridle once per week. On the ends of the week you won't go angling or chasing, on the grounds that youll be excessively bustling working. Youll do all the tasks aside from slashing wood. Do you comprehend what Im saying? Mike with his head down and as yet crying stated, Yes sir, I comprehend. Indeed, Mike and Daddy saw, however I didnt. Daddy left the slow down with his hand on Mikes shoulder. It had something to do with Ole Macs feed. I took a gander at the trough, and couldnt see whatever would clarify what was happening. I bowed down and looked under the trough and incredibly observed twenty heads of 16 penny nails standing out of the base of the trough. That was what the pounding was about, Daddy had driven the nails out of the trough. Mike had stuck nails up into the trough so Ole Mac couldnt eat, thus he wouldnt need to take care of Ole Mac ordinary. Mike wasnt as savvy as he suspected he might have been.

How to Write an Essay With Me First and Johnny Chuck Find the Best Thing in the World Essay Sample

How to Write an Essay With Me First and Johnny Chuck Find the Best Thing in the World Essay SampleNot many people are able to write an essay, but with careful and repeated practice you can learn how to create a simple but effective Me First and Johnny Chuck Find the Best Thing in the World Essay Sample. By reading this article you will be able to get the best possible information about this essay topic and what it takes to write a good paper. Your university advisor or your college guidance counselor will be very happy to hear you are considering doing an essay in English.The most important thing that you need to do before writing is to start reading. Reading will give you a great background and outline about writing essays and how they work. You will also need to familiarize yourself with the different types of essays and what is required in each one. By understanding how they work you will be able to understand the type of essay that you should be doing. Essays that are written by people with no experience at all will not be successful.Take some time and learn about the different genres and the different rules. This will help you understand the skill of writing an essay. This is a very specific type of writing and you need to have a thorough knowledge of what writing is all about. Learning as much as you can about the different types of essay and the different elements will help you come up with the best Me First and Johnny Chuck Finds the Best Thing in the World Essay Sample that you can.One effective way to begin is to ask for some assistance from a college instructor. If you do not have a class instructor, you can find many classes that offer their students the ability to work with a professor on a specific assignment. It is vital that you research this and look at the instructor's background. If the professor has a reputation for writing the best essay topics then you should be looking for a course such as this.Another approach is to hire a tutor or writi ng teacher. These people are used in all aspects of writing. They will teach you how to compose effective paragraphs and how to formulate the right sentences to describe your thesis. They can help you express your ideas in a way that the professors will appreciate. They can also help you write the best thesis statement examples that you can use.If you do not have access to a traditional classroom setting you can still work on writing a thesis statement. All you need to do is purchase a journal or a notebook and place each idea that you come up with in a separate spot. Start by thinking about the fact that you can sit down and write the idea that you are experiencing right now.This is very effective and practical ways to start to build your writing skills. It is also important to give your ideas focus so that they are clearly written. The key to this is to keep things organized and go through your notes carefully and systematically.Most importantly is to start writing the paper. Give it some time and you will be amazed at the results. If you want to know how to create a Me First and Johnny Chuck Find the Best Thing in the World Essay Sample then you should consider learning the skill yourself.

The Treatment of Cystic Fibrosis using gene therapy, in particular Adeno-Associated Viruses

Sample details Pages: 25 Words: 7507 Downloads: 4 Date added: 2017/06/26 Category Statistics Essay Did you like this example? In this dissertation we shall consider the field of gene therapy in specific relation to cystic fibrosis. We examine the different delivery vector mechanisms that have already been explored and concentrate primarily on the adeno-associated vectors. We examine the current state of research and consider the advantages and drawbacks of the various methods considered. Don’t waste time! Our writers will create an original "The Treatment of Cystic Fibrosis using gene therapy, in particular Adeno-Associated Viruses | Physics" essay for you Create order We conclude with a discussion and analysis of our findings and make anumber of assumptions relating to the future direction of the researchin the field. The rate of progress in the field of gene therapy has been enormous. We must remind ourselves that the first clinical gene transfer experiment took place in 1989 when a patient with malignant melanoma received genetically modified auto logous T cells. (Rosenberg SA et al1990) Gene therapy encompasses two major areas. The in vivo field, where genes are incorporated into the target cells of the living body and the ex-vivo field where the target cells themselves are genetically modified outside the body and then re-implanted. Medical science has been using the basic techniques of gene transfer for a long time. The technique has been exploited when viral genes are introduced to human cells when a viral vaccine is administered. The key technologies that allowed the transition from vaccination to gene therapy were the evolution of methods that allowed the genes to be isolated and replicated (cloned) and manipulated (engineered) prior to transfer into human cells (Freeman SM et al 1996) The key principle in this process is the efficient transfer of the manipulated therapeutic genes into the nuclei of target cells usually be means of various vectors. This dissertation will be considering the utilisation of these vectors in some detail. In broad terms, the new or modified genetic material is able to produce new proteins which can restore deficient or abnormal functions of genetically diseased tissues, to generate tissues that have entirely new properties or to create transplantable tissues for the controlled release of therapeutic proteins. (Russell SJ1997) In terms of viral vectors, prior to 1996 science was dependent on the use of modified retroviral vectors (eg.MMLV) to effect gene transfer into the chromosomes of a target cell and the adenovirus vectors when such integration was not needed. Neither vector was particularly successful as the intact nuclear membrane (in then on-dividing state) was a major barrier for chromosomal gene integration. (Sikorski R et al 1998). A breakthrough came with the realisation that lentiviruses (e.g. HIV) have the same ability to transfer genetic coding into the cellular genome but could do this in the non-dividing or dormant phase cells. (Amado R G et al 1999) In vitro, lentiviruses have been shown to change the target cells expression of proteins for up to six months. importantly, they can be used for terminally differentiated cells such as respiratory epithelium. The only cells that the lentivirus cannot penetrate the nucleus are those in the quiescent (G0) state as this blocks the reverse transcription stages of protein synthesis. (Amado R G et al1999) Cystic fibrosis Cystic fibrosis is the most commonly lethal inherited recessive inthe caucasian population. It affects about 1 per 2,500 livebirths. Thetreatment of cystic fibrosis has improved enormously in the last fiftyyears with the life expectancy increasing from an average 10 years to30-40 years now. The prime cause of death in affected individuals is the repeatedcycle of infection, inflammation and fibrosis of the respiratory tractwhich eventually culminates in respiratory failure and death. The disease itself is caused by mutations in the single gene forthe cystic fibrosis transmembrane conductance regulator (CFTR) whichproduces a protein found in sweat and pancreatic ducts, gut,seminiferous tubules, lungs and many other tissues. The mutationsresult in an abnormal protein which, when expressed in the lungs,produces thick viscous and dehydrated secretions. This does not allow for the efficient expulsion of bacterial pathogensfrom the lungs and a number of highly resistant forms of bacteria arecommonly found in cystic fibrosis (viz pseudomonas aeruginosa)(Porteous DJ et al 1997). An individual must receive a defective copy of the cystic fibrosisgene from each parent in order to develop the clinical picture ofcystic fibrosis. Following normal genetic principles, if two carriersconceive a child, there is a 25% chance that it will have cysticfibrosis, a 50% chance that it will be a carrier and a 25% chance thatit will have two normal cystic fibrosis genes. Viral and non viral vectors Viruses have an ability to enter a host cell and combine their owngenetic material with that of the host cell. This is the basicrationale behind the science of gene transfer therapy. As we shalldiscuss in some detail in this dissertation, there are a number ofpotential viral vectors that have been explored, evaluated andexploited in the search for an efficient and safe form of therapy.Viruses are not the only vector that can be utilised . Simply placingDNA in the nasal mucosa will produce some incorporation into theepithelial cells (Knowles MR et al 1998). This absorption can bedemonstrably enhanced further by the combination of the DNA withvarious plasmid or lipid complexes(Zabner et al 1997) The advantages of lipid or plasmid assisted transfer mechanisms arethat they do not appear to generate the immunological responses thatare seen with the viral vectors. They can also be used to facilitatethe transport of much larger pieces of DNA which would otherwise belimited by the packaging consideration incumbent on the viral vectors.(Felgner P 1997). The use of retroviral vectors is far from straightforward. The heavilypublicised case in April 2000 brought some of the problems to theattention of the media. A retroviral manipulation of a case of X-SCID(X linked severe combined immunodeficiency) was treated by gene therapywith an apparent degree of success (BBC 2002). This particular diseaseprocess is caused by a mutation on the gene which codes for the C chainof the cytokine receptors which is situated on the X chromosome andvital for the functional development of T Killer lymphocytes which aretherefore completely absent in the condition A multinational team used a retroviral vector to insert a functionalcopy of the gene into bone marrow stem cells which were thenre-transfused back into the patient. (Cavazzana-Calvo M et al 2000).This particular case resulted in a return to normal levels of T cellsin a comparatively short period of time. This was hailed in both thepopular media and the peer reviewed journals as a major success and itcan indeed be considered a landmark as it pioneered the successful useof an ex-vivo procedure that avoided direct in vivo transfer of thevector. The reason for specifically highlighting this particular case isthat following the initial optimism of the clinical team, two of thefirst ten patients with this condition who were treated in the same waysubsequently developed a leukaemia-like illness. Genetic analysis ofthe malignant cells suggested that the retroviral vector used in thetransfer had also activated an oncogene LIM-only2 (LMO2) which is knownto be associated with some forms of leukaemia. The clinicians reviewingthe situation felt that, although it was not the only cause of themalignancy it was one of the events that triggered it. Similar concernshave been raised in respect of other clinical trials. (Lehrman S 1999) The prime reason for presenting these events is to demonstrate thefact that there is both a theoretical and practical risk of insertionalmutagenesis. Reduction of the risk requires greater specificity of thetargeting of the genetic deficit perhaps by directing the expressionof the therapeutic genes to various specific tissues utilising bothtransductional and transcriptional targeting. Relph K et al 2004), In terms of specific considerations of the arguments in favour of theuse of retroviral vectors, one can cite the fact that they have ahighly efficient mechanism of gene transfer together with lowimmunogenicity. It is a well researched and well studied system and isknown to selectively infect actively dividing cells. The conversearguments reflect their disadvantages including their ability todisturb or activate oncogenes, the fact that they are difficulty tospecifically target and it is difficult to obtain high titres in theclinical situation (after Olsen, J. C. 1998). In broad terms, the principles behind the use of retroviral vectorsare that they must be modified in order not to be able to transmit anyovertly pathological coding. This involves the deletion of viral helpergenes such as gag, pol and env to render the replication processinvalid. This is done by utilisation of a producer or packaging cellline. (Nichols, E. K 1998). An example of a commonly utilised and extensively researched vector isthe MoMuLV. It is an engineered vector which can store 8 kb of RNAwithout compromising packaging efficiency. It is a hybrid cell lineeasily grown in mouse fibroblast cells There is a subdivision of the retroviral vectors known as thelentivirus, which is the only retroviral vector capable of integratinginto the chromosomes of non-dividing cells. This has been effectivelydemonstrated in vitro (Naldini L et al 1996). The biggest problem with the lentivirus vectors is that theyappeared to only produce very low titres. Some recent researchsuggested that a modification to a amphotropic envelope protien wascapable of allowing higher titre levels. (Rolls M et al 1999) At about the same time that the scientific press was learning aboutthe problems with retroviral transfer (see above) other investigatorswere working with adeno-associated viruses (AAVs). A similar processwas invoked using adeno-associated viruses to correct a genetic defectinvolving coagulation factor IX. The adeno-associated viruses were usedas they were considered to be amongst the safest candidates for genetransfer. They do not naturally cause disease processes in humans andhave only rarely been found to incorporate in a random fashion into thehuman genome. Although it is noted that adenoviruses do cause oncogeneactivation in rodents although it has not been found in humans(Blacklow NR 1988). The trial had a very positive outcome. (Kay MA et al 2000), but thetrial author (in later research work) published a study which suggestedthat, in study mice, the vector used in the trials actually integrateditself into gene containing regions of DNA more frequently that it didinto non-coding regions (Kay MA et al 2003). The findings were reportedas the fact that new genetic material was randomly distributed amongstall of the chromosomes particularly at sites of gene activity. On thisbasis, there appears to be at least a theoretical basis for thepossibility of similar cellular defects such as occurred in the X-SCIDpatients. Adenoviruses are comparatively simple structures. They arecategorised as double stranded DNA viruses. They have icosahedralcapsids with twelve vertices and seven surface proteins. The virionitself is spherical and non-enveloped and in the region of 70-90 nm insize. Their natural history is that they are spread easily in the naturalstate by the faeco-oral route and also by respiratory inhalation whichclearly has great implications for the treatment of cystic fibrosis. A theoretical analysis would immediately suggest that the adenovirus should be a suitable candidate for gene therapy as they can codefor specific proteins and they do not produce infection pathogenicviral offspring. The early trials into this particular area were reviewed by Griesenbach(Griesenbach U et al 2002) who pointed out that the cystic fibrosisgene was first cloned in 1989 and in the subsequent years, 18different trials were carried out, all with rather low degrees ofsuccess. They collectively trialed three different vectors, namelyadenoviruses, adeno-associated viruses 2 and cationic liposomes, andalmost universally found that each vector had a very low rate ofclinically significant gene transfer and none was sufficient to achieveclinical benefit Plasmid Complexes At its most basic level, a plasmid is a small accessory collection ofDNA which is found in the cytoplasm outside of the nucleus. They arecapable of independent replication and can be manipulated with rathermore ease than nuclear DNA. Early investigations into the field of gene transfer explored thepossibility of plasmid vectors and demonstrated the feasibility of themethod to effect CFTR gene transfer in vitro (Alton EW 1993). Otherteams had demonstrated the fact that, in clinical use theplasmid-liposome is both nontoxic and non-immunogenic (Hyde,SC et al1993). This appeared to raise the possibility that many of theimmunological problems encountered by teams working with viral mediatedgene transfer mechanisms might be circumvented. In vivo work (Yoshimura,K et al. 1992) had demonstrated that genescould be transferred into the cytoplasm by this method and Stribling, R(et al 1992) demonstrated that, once there, they would then replicatenormally. Alton experimented with a CFTR-plasmid preparation in miceand demonstrated that it was capable of correcting the chloride levelsin cystic fibrosis mice back to normal levels (Alton EW 1993) Although the initial results were encouraging, clinical trials weredisappointing as the plasmid complex could not easily penetrate thethick mucous residues in the diseased lungs of patients with cysticfibrosis. (Erickson,R 1993) The plasmids typically have a positively charged head-group which isable to bind to the DNA strand and a hydrophobic tail group whichfacilitates the transfer of the complex across the cellular membranes.Initial studies suggest that between 100-1000 times more DNA isrequired to effect successful gene transfer when this method iscompared to viral vectors. (Santis,G et al 1994). One alternative adaptation has been reported by Stern M (et al 2003)who points out that one of the solution of delivery is to ensure thatthe respiratory epithelium is exposed to the DNA over a long period.Their solution was to encapsulate the CFTR-plasmid in a slow releasebiocompatible polymer. Clinical trials are underway but not yetreported. The adeno-associated vectors appear to have (at least on atheoretical basis) a number of advantages over the vectors that we havealready discussed. They are based on a virus vector that is alreadynon-pathogenic (Berns, KI et al 1995) and has a mechanism that allowsit to be a long-term persistent entity in human cells (Blacklow, NR etal 1989). The adeno-associated vectors are particularly useful indealing with disease process that involve single gene mutations. This,therefore makes it particularly suitable for single gene disorderssuch as cystic fibrosis and alpha 1 antitrypsin deficiency. (Flotte, TRet al 1998). In addition, some workers have also developed vectors which are capableof producing either inducible or constitutive expression of thecytokine, interlukin-10 (IL-10) which is an importantanti-inflammatory protein which, on a theoretical basis, could beuseful not only in cystic fibrosis but in other disease process whichhave chronic inflammation as their prime manifestation (viz Type Idiabetes mellitus or inflammatory bowel disease) (Egan, M et al 1992).These manifestations have been studied and have now reached the stageof early clinical trials (Wagner J et al 2002). With specific reference to the implications of cystic fibrosis, wecan point to trials which have resulted in the expression of cysticfibrosis transmembrane conductance regulator (CFTR) from rAAV(recombinant adeno-associated vectors) in cell cultures (Flotte, TR etal 1993), in animal models (primates) (Afione, SA et al 1996), andagain in early phase I clinical trials (Wagner, J et al 1998) The rAAV-IL-10 model has been studied in bronchial cell culturesfrom cystic fibrosis patients, to determine the functional consequencesof CFTR complementation. This has not yet been demonstrated in vivowith humans but in both mice (Song, S et al 1998), and monkeys (Conrad,CK et al 1996) The overall results of these (and other) studies have shown that itis possible to achieve long term gene transfer and functionalexpression of the replaced gene (some studies for as long as 18 months)without any overt pathological findings. The histological findings are something of a surprise however, as,at least in both primate and mouse studies, the vector-introduced DNAin this form does not appear to be assimilated into the geneticmaterial of the chromosome, but persists in log strings or concatemersthat are episomal, which is in complete contrast to what happens whenthe naturally occurring agent infects the cell. There is some evidenceto suggest that host cell intrinsic factors such as DNA-dependentprotein kinase play some role in this process (Song, S 2001). The significance of this finding could be that the exclusion of thefunctional, newly introduced DNA from the rest of the nuclear gene poolmay be less likely to produce effects that could be either potentiallydisruptive to the host cell and less likely to activate oncogenes.Phase I trials have demonstrated significant rises of CFTR levels inboth sinus and lung tissue with no evidence of vector-related toxicity.(Wagner, JA et al 1999) The adeno-associated vectors are constructed from proviraladeno-associated vectors plasmids, which have the Rep and Cap proteinsdeleted and substituting the appropriate gene (CFTR or equivalent)between the rAAV2 inverted terminal repeats together with other signalsequences such as promoter and polyadenylation sequences (Flotte, TR etal 1994) The packaging processes allows for about 5 kb of rAAV genomes to becarried in the vectors which are prepared using a cotransfectiontechnique utilising human embryonic kidney cells (HEK-293) where thevector plasmid is cotransfected into the cells with helper agents(plasmid pDG) being used to encode the rAAV2-rep and -cap genestogether with the adenovirus helper functions (Grimm, D et al 1998).These are incubated for between 48 and 72 hrs. The cells are then lysedand the resultant agents are then separated by ultracentrifugationagainst a density gradient and affinity chromatography (Zolotukhin, Set al 1999). The vectors are thereby amenable to being separated by both theirphysical characteristics and also their biological characteristics(infectious units). They are carefully screened to ensure the absenceof any possible contamination from non-modified (replication competentAAVs) prior to clinical usage. (Muzyczka N 1994) The comparatively small payload of the adeno-associated vectorsis proving to be a significant problem. The vector itself is small whencompared to the comparatively large size of the CFTR gene. (Flotte TRet al 1993) It does not leave any room to manoeuvre to manipulate thevector-specific sequences in the way that we have described with theretroviral and adenoviral groups. (Flotte TR et al 2001). A number of authors have characterised the problem with theobservation that the rAAV is typically about 20 nm across which allowspackaging of about 4.7 kb (kilobases) of transferable modified gene(exogenous DNA). (Dong JY et al 1996), If it is combined with otherenhancers such as the promoter, the polyadenylation signal, thisclearly reduces the capacity for the DNA component. (Duan D et al2000). The Yan paper (Yan Z et al 2000) has outlined a novelexploitation of the unique ability of the rAAV genomes to link togetherin strings which appears to have the ability to bypass this particularlimitation.( Flotte TR 2000). The mechanism itself is the capacity of two distinct rAAV genomes thathappen to simultaneously infect the same target cell to undergo anintermolecular recombination insider the transduced nucleus of thetarget cell. This was a chance finding which arose from work involvingrAAV-derived episomes (Kearns WG et al 1996) in primate airways. It wasfound that some of these episomes were configured as circular head totail concatemers (Duan D et al 1999). This could have been either froma rolling circle replication from a single vector or alternatively,from an intermolecular recombination of material from multiple cellularpenetrations which combined within the palindromic inverted terminalrepeat sequences that are an intrinsic part of the AAV genomestructure. The authors were of the opinion that it was likely to be thelatter eventuality (Duan D et al 1998) It was a logical progression to try to exploit this phenomenon andthereby bypass the limitations imposed by the relatively smallpackaging capacity of rAAV. The adeno-associated vectors capsid onlyhas a capacity of about 5 kb. If we consider that the 145 nucleotidestretch of the AAV-ITR (inverted terminal repeat) sequence has to be inplace at both ends of the single-strand DNA for the vector DNA to beboth replicated and packaged, this only leaves in the region of 4.7 kbof genetically active material in each rAAV particle. As we have cited earlier in relation to the Dong paper (Dong JY et al1996) the CFTR gene accounts for about 4.5 kb which leaves very littlespace for other enhancing material. Because of this, the actual CFTRvector that has been used in the clinical trials to date uses only theminimal promoter activity of the AAVs-ITR itself to actually activateand drive the CFTR expression (Flotte TR et al. 1993). To look at this potentially important development in a little moredetail we can consider Duans original paper (et al 2000) and theauthors describe what they call a superenhancer. They describe acombination of a potent simian virus (SV40) and CMV immediate earlyenhancer elements as being packaged in one rAAV vector and a luciferasegene assisted by a small minima;l promoter in another rAAV vector. Invitro experiments suggested that either the SV40 or the intrinsicpromoter activity of the AAV-ITR was sufficient for this purpose. Theintermolecular recombination described above, was found to occur inboth vitro and in vivo experiments and was found to be sufficient tohave a greater than additive effect. Initial results from these varying methods are encouraging insofaras they are producing results of transgene expression which are 100-600times greater than with the unenhanced vector alone. (Yan, Z et al2000) Although not directly referable to our considerations of cysticfibrosis, we should note that Yans group and other workers have doneexperimental work which has culminated in the long term expression offunctional levels of erythropoetin with this two vector method in micein vivo. (Naffakh N et al 1995), This basic principle has been further enhanced by Sun (Sun L et al2000) with an ingenious manipulation of the system. They triedinserting the promoter and the first half of the coding sequence in onerAAV vector, immediately followed by a splice donor and then theupstream half of an intron. In the other rAAV vector was the downstreamhalf of the intron, the splice acceptor, the second half of the geneand the polyadenylation signal. To quote the author verbatim: This strategy is efficient enough to mediate high-level expressionand the intermolecular junctions are apparently stable enough tomediate expression for several months in vivo. Although this is clearly an ingenious augmentation of the sameprinciple , we should note that there are both advantages anddisadvantages to both pathways. The strategy that adopts the superenhancer takes its strengths fromthe fact that the recombination mechanisms optimise theposition-independent and orientation-independent functions of theenhancers. Consideration of the options would suggest that there arefour potential recombination outcomes from the process described.Either of the two vectors could be on the 5 end of the heterodimericmolecule and clearly either molecule could be in either orientation. With the superenhancer option, all four of these possibleintermolecular recombination outcomes should be functional fortransgene expression whereas if compared to the split intron strategy,by using the same reasoning, it is clear that only one out of the fourcould work. On the other side of the argument, the superenhancer option has thedisadvantage that the actual coding sequence of the gene to betransferred must still fall within the packaging capacity of the vectoritself whereas the split intron allows for a greater functionalexpansion of the packaging capacity. (after Flotte TR et al 2000) In either event it can be seen that these ingenious modificationseffectively eliminate the main size limitation of the rAAV deliverysystem. Although initial pre-clinical work is encouraging it appearsthat there is still some potential for a degree of immune responseparticularly if the host organism has not experienced the newlyproduced protein before. A number of studies have been done on animal (vertebrate andprimate) with only minimal success. Different administration methodshave been studied including direct administration into the lung (WagnerJ et al 1999), IM injection (Song, S et al 2001 B) and hepatic portalvein infusion (Song, S et al 2001 A) Human clinical trials have taken place with these vectors (Flotte T etal 1996)(Wagner J et al 1998) (Virella-Lowell, I et al 2000). Thestudies were done on adult male and female patients (18-47 yrs) whowere pseudomonas free and had recently been hospitalised for IVantibiotic infusions The disappointing results were probably a reflection of the factthat the CFTR defect is also interconnected in some way with aproinflammatory phenotype which appears to be triggered by the abnormalprotein via an unfolded protein response. The authors were able to showevidence that the rAAV-CFTR mechanism was able to correct the proteinproduction defect, they found it clinically difficult to transduce asufficient number of cells in the airway to reverse the inflammatoryresponse. It is proposed to run further experimental work which combines theCFTR expression with an anti inflammatory gene such as the IL-10.There is some in vitro work to suggest that this may be a possibleworkable approach (Teramoto, S et al 1998). Other work on ways ofenhancing the phenotypic expression of the modified genotype hassuggested that the use of various promoters and the rAAV-CMV/beta-actinhybrid promoter (CB-AAT) was found to be tone of the most efficient, atleast when it was compared to the other tested options such as the CMV,E1, U1a and U1b promoter constructs (Teramoto, S et al 1998) Overall, the initial results appear to be encouraging. A singleinjection of an rAAV-CB-AAT vector in animal studies has resulted inhigh level, stable transgene expression which has persisted over thelife span of the experimental animals and that there was no detectableinflammatory response in the animals who had received this form oftreatment (Flotte TR 2002) Flotte (et al 2002) reports that four human clinical trials at bothPhase I and Phase II level are currently underway examining the effectsof the rAAV-CFTR vector. They had an entry cohort of seven patientswith the vector being applied to the nasal lining, the maxillary sinusand the bronchus. The authors report no adverse effects being found andthat they have observed transgene expression at doses of 6 x 108 drp inthe sinus or 1 x 1013 drp in the lung. There are no reported interimfindings from the Phase II trials as yet. There is clearly a potential for clinical benefit on the basis of theresults found to date if one can extrapolate from in vitro and animalexperiments. The authors comment that, in contrast to the adenovirusvectors there is a marked lack of inflammatory toxicity with the rAAVvectors. Despite these positive comments, we should not, however, overlook thepotential limitations of this particular delivery system. These havebeen identified by various authors as: The inhibitory effect of preexisting airway inflammation on rAAV transduction in the lungs (Virella-Lowell, I et al 2000) A relative paucity of receptors on the apical surface of airway epithelial cells (Summerford, C et al 1998), The relatively weak nature of the minimal promoters used in the first-generation rAAV-CFTR vectors(Flotte, TR et al 1993), The potential for adverse long-term effects from rAAV vector DNA persistence. (Wu, P et al 2000) The Flotte group are currently investigating this problem by examiningthe hypothesis that the barriers in the airways of the cystic fibrosissufferer are primarily due to the neutrophil-derived -defensins (HNP1and HNP2) and are actually reversible by the mechanism of AAT proteindelivery (Virella-Lowell, I 2000) Wu and his co-workers have been looking at ways of manipulating thegenetic make up of the rAAV2 capsid and thereby trying to enhance thetargeting ability so that the vector specifically targets the serpinenzyme complex receptor on IB31 cells which is virtually specificfor the Cystic fibrosis bronchial cells Zabner, J (et al 2000), have considered alternative rAAV serotypesin the hope of finding one that will bind more specifically to thebronchial cells Other peripheral adjuncts have also been explored includingpromoters to enhance the effects of complementation and superenhancerswhich have been shown to improve the ability of the rAAV toconcatermerise with the help of smaller amounts of promoter agents(Duan, D et al 2000). Perhaps it is appropriate to conclude this section on considerationof adeno-associated vectors with a critical analysis of a very recentmulticentre, double-blind, placebo-controlled trial (Moss RB et al2004) This was a well constructed, fully statistically significant anddouble blinded trial which considered both the safety and thetolerability of repeated doses of adeno-associated serotype 2 vectorrepeatedly given by aerosol inhalation. The vector contained cysticfibrosis transmembrane conductance regulator (CFTR) complementary DNA(cDNA) [tgAAVCF], an adeno-associated virus (AAV) vector encoding thecomplete human CFTR cDNA. The entry cohort was comparatively small with 42 patients, of whom20 received the active agent. A number of indices of airway functionwere measured. Of particular interest to our considerations in thisdissertation was the fact that vector shedding was found in alltreated subjects up to 90 days after inoculation. And that all subjectswho received the active agent exhibited at least a fourfold increase inthe serum AAV2 neutralising antibody levels. Of the 20 treated patients, six subsequently underwent bronchoscopy.Of those six, gene transfer but not gene expression was demonstrated inall of them. On this basis, it would appear that the actual transfermechanism is effective, but there are other factors present whichappear to interfere with the subsequent expression of the gene in termsof protein production. The study did not comment on the possiblereasons for this. The authors were able to conclude that the delivery system workedwell with no evidence of adverse effects and that treated patientsdemonstrated an encouraging trend in improvement in pulmonary functionin patients with CF and mild lung disease. Lipid 67 We have discussed the various shortcomings of the virus-associatedvectors and this has prompted researchers to explore and consider otheroptimising options for facilitating gene transfer. Zabner (J et al1997) considered the use of cationic lipids in this process and foundone GL-67:DOPE (colloquially known as lipid 67) which appeared to beparticularly helpful in the process. Cationic lipids appear to show a degree of promise as possible vectorsfor CFTR cDNA transfer into respiratory epithelial cells of cysticfibrosis patients. Zabners group developed a preparation of plasmidencoding CFTR (pCF1-CFTR) and cationic lipid (GL-67:DOPE) whichappeared to facilitate the gene transfer to a significantly greaterextent than previously tested lipid complexes. They performed in vivostudies which compared the gene transfer rate to the epithelial cellsof the nasal mucosa of DNA-lipid complex and DNA alone. In generalterms, their findings indicated that the DNA-lipid complex was far moreeffective in achieving gene transfer than was simply giving DNA. Theauthors felt able to conclude that: These results indicate that nonviral vectors can transfer CFTR cDNAto airway epithelia and at least partially restore the Cl- transportdefect characteristic of CF. However, improvements in the overallefficacy of gene transfer are required to develop a treatment for CF. In this dissertation we are primarily considering the issues ofgene therapy in direct relation to cystic fibrosis. Inevitably, thishas meant considering the issues on a wider front, as many areasoverlap on a theoretical or practical basis. The prime biochemical cellular defect in cystic fibrosis is anabnormality in the cystic fibrosis transmembrane conductance regulator(CFTR). From a theoretical perspective it should be obvious thatreplacement of the defective gene with a working alternative would bebest achieved in the neonatal period before the body had time todevelop substantial fibrotic changes in the lungs that were secondaryto repeated episodes of infection (Dark J et al 1996). If successful, this could be expected to reduce both morbidity andmortality for cystic fibrosis. We have been able to cite evidence thatgene transfer has been accomplished both in vitro and in vivo. We havediscussed the results of a number of research groups who haveinvestigated various delivery systems which, to varying extents, haveproved able to deliver at least a small quantity of functional respiteto the cystic fibrosis sufferer. It is also important to be fully aware of the possibility ofinadvertent side effects in the field of gene manipulation. We havehighlighted the problems with oncogene activation. But this appears tobe associated with some vectors more than others. In short, it wouldappear that the problems and limitations that appear with this type ofprocedure are a function of the parent virus. The initial work with adenoviruses appeared promising as genetransfer could be accomplished but the major drawback was the doselimiting inflammatory effects which arose primarily as a result of thelarge amount of viral protein which was required to achieve atherapeutic dose. The subsequent modifications which had a greaternumber of coding sequence deletions appeared to be more effective inanimal experiments as they generated a lesser response from the cellmediated immunity mechanisms and therefore had a greater duration ofaction. (Caplen NJ et al 1995). It seemed a logical step from there to produce vectors that had noviral genes at all. This did not produce any significant benefits orimprovements from the previous agents. A number of research teamsacross the world tried different subsidiary strategies including druginduced immunosuppression or modifications of various immunogenicepitopes. The plasmid-lipid complexes appeared to have a number of clinicallyimportant advantages insofar as they did not appear to generate anyimmunological response which is in distinct contrast to many viralvectors. Initial optimism did not appear to be translated intopractical application as the delivery systems explored appeared to beunable to deliver sufficiently large quantities through thepathological mucous layer that is the main feature of the cysticfibrosis patient. (Crystal RG 1992). The adeno-associated vectors have received a large amount of attentionwhen it became clear that alternative vectors were needed to optimisethe therapeutic effect. They have now reached the stage where animaltesting has lead to human Phase I and II clinical trials. As a group,they appear to have the advantage that they dont trigger theinflammatory reaction in the same way, or to the same extent as theadenovirus group. The major practical difficulty with this grouphowever, is the fact that because they are so small compared to thecomparatively large size of the CFTR gene it leaves no space forvector-specific sequences on which to base assays to help todistinguish the endogenous RNA from the vector-expressed RNA. (FlotteTR et al 2001) All the evidence that we have seen appears to suggest thatadeno-associated vectors have a satisfactory safety profile andcertainly appear to produce a longer duration of clinical effect thanthe other modalities. Another variable, and indeed challenge, in the field of genetherapy, is to find the optimum delivery vehicle. We have cited studiesthat have tried direct insufflation to the bronchial epithelium. Thisappears to be a superior mode of delivery to the aerosol which appearsto have the ability to cause agent specific reactions in the alveolarmembranes. There is continuing work which is currently looking at therelative merits of nebuliser delivery mechanisms as compared toconventional aerosol delivery systems. Others that have tried avoidingthe bronchial tree and utilising the respiratory epithelium byintroduction to the maxillary sinuses through intranasal antrostomies. Conclusion including future of gene therapy. In this dissertation we have presented evidence of from a number ofdifferent approaches to the problem of gene therapy in tacklingmonogenic conditions such as cystic fibrosis. As with most areas ofscientific exploration many blind alleys have to be explored beforean appropriate avenue of research becomes apparent. The initial enthusiasm the greeted the exploration of theplasmidDNA vector did not appear to be well founded although it isclear that further exploratory work is continuing in the field. The area of adeno-associated vectors appears to be currently themost promising with, at least in vitro, suggestions that many of thecurrent limiting problems may be on the verge of being solved. The major stumbling blocks at the moment are the difficulties ofproducing a high vector titre in the clinical situation and the longterm safety considerations, particularly those relating to mutagenesisof ongogenes. On this point the Flotte group are optimistic and feelable to make the comment: The data from our laboratory strongly indicate that the bulk of rAAVDNA in the lung, muscle, and liver is episomal and that rAAV genomesinteract with host cell proteins such as the DNA-dependent proteinkinase in the formation of stable high-molecular weight concatemers. It is the episomal situation of the gene that is currently thoughtto be the best insurance against inadvertent iatrogenic oncogenesis(Flotte et al 2002) but this is clearly no substitute for long termcareful and rigorous safety studies. It is often assumed, quite incorrectly, that the field of genetherapy is a discrete and academically isolated field. Progress in thisarea, as in so many other areas of research, is completely dependent ofdiscoveries and improvements in other areas of science. The future direction of research will be determined, to a degree,by improvements in our ability to manipulate cell types and cell linesoutside of the body as this will inevitably aid our ability to implantgenetically engineered agents. Reflection over the advances inknowledge from just the last decade indicates that new and innovativedelivery mechanisms will be developed, explored and evaluated. It islikely that the known short term problems of immunogenicity, low titredelivery and inefficient packaging will be addressed, very possiblywith new delivery vectors. It goes without saying that these investigations are hugelyexpensive in terms, not only of money, but of time, expertise andinvestment generally and therefore it is likely that the limitingfactor in terms of development will be the availability of resources(Russell S 1997) References Afione, SA, Conrad, CK, Kearns, WG, et al (1996) In vivo model of adeno-associated virus vector persistence and rescue. J Virol 70,3235-3241 Alton,EW et al. 1993 Nature Genetics. vol 5. 1993 Amado R G Chen YJS 1999 Lentiviral Vectorsthe Promise of Gene Therapy Within Reach? Science. 285 (5428): 674-76. BBC Online News. Bubble boy saved by gene therapy. 3 April 2002, Berns, KI, Linden, RM (1995) The cryptic life style of adeno-associated virus. Bioessays 17,237-245 Blacklow NR. 1988 Adeno-associated viruses of humans. In: Pattison JR, ed. 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Human History Literacy Rates Have Continued Essay

Human history literacy rates have continued to hike. Children now attend school than at any other point in history. Although nations have made immense progress, many are still far from reaching the universal goals of education. The importance of early education cannot be emphasized enough. As famous scholars had noted in human history, education is the precondition for success and unconstrained prospects. Educated citizens are the foundation for a nation’s sustainable economic and social development (Park 23). According to a study done by UNESCO and World Bank, currently there are over 400 million children at the elementary level who are not attending school. Even the rest of the millions who are attending schools are not being prepared adequately for life after school. Solving these problems ought to be the utmost goal for any nation. As a parent, one cannot fail to see how important education is for a child. As a politician, one recognizes the importance of having a governme nt with highly equipped labor force. Transforming education, however is not an easy task bearing in mind that there are challenges everywhere from the shortage of teachers, resources and use of inadequate curricula. It is therefore imperative that nations rise and act consequently before they expose another generation to the same problems (Awa Plaumann 101). This paper shall carefully examine early childhood education and the effectiveness of the universal interventions made globally. There have beenShow MoreRelatedThe Human Right Of Literacy Essay1355 Words   |  6 Pagesinnovations have advanced, the ability to read and write has become a means of survival. Today, 135 countries around the world provide a non-discriminating education for all. In the developing world, literacy is now recognized as a human right. When a person is denied that right, injustice is manifested. The millions of illiterate adults and children living in our world today are not only being denied educational opportunities, they are being denied the basic human right of literacy. Nine out ofRead MorePfizer Tested A New Antibiotic1483 Words   |  6 Pageslicense Trovan due to side effects such as joint pain and liver damage. As a result, five children died. One such child, a three year-old known only as â€Å"Patient #69,† became so alarmingly sick, that her father begged the doctors to help her. She continued to be given Trovan, rather than the tried and tested cephalosporin. She died. Many consent forms were found to be falsified, and some families were not informed that they were taking part in a drug trial, a clear violation of the Nuremberg Code andRead MoreThesis : Teach Back Methodology Is A Motivatational And Interactive Way For Healthcare1597 Words   |  7 Pagesare many acronyms that are used. Some of the acronyms used throughout this paper will include COPD (chronic obstructive pulmonary disease), MDI (metered dose inhaler), DPI (dry powder inhaler) and Centers for Medicare and Medicaid (CMS). Low health literacy is another discussion within this paper. Hospitals are held to high standards of practice by providing safe, consistent quality care. To be sure that practices occur, hospitals are inspected by different regulatory bodies such as JACHO (Joint CommissionRead MoreThe Language And Oral Communication Essay1638 Words   |  7 Pagescommunicated orally, as best explained by Goody and Watt in The Consequences of Literacy. In a related essay, Writing is a Technology that Restructures Thought, Ong reveals that the creation of the phonemic alphabet allowed humans to create new words that more accurately expressed their thoughts, which translated to their actions and speech. So in a sense, oral communication, as we know it today, is a form of literacy. Written and oral communication both can convey the same message, the only majorRead MoreAnalysis of African American Culture in the Health and Human Services2001 Words   |  9 Pages1 An Analysis of African American Culture in the Health and Human Services Setting Introduction ​Communication has often been defined by scholar as the process by which people send messages and generate meanings across various contexts, cultures, and media. The process of communicating does not stop; it occurs cycle after cycle. Whether through verbal or non-verbal messages, the transaction takes place and is inevitable, named by scholars as The Principle of Communication Inevitability.Read MorePersuasive Essay On The Atomic Bomb1656 Words   |  7 Pagespath along with homes, stores and anything else. The United States could have also put the bomb on display for Japan, possibly scaring Japan into a surrender. There is also talk about if the second bomb was even necessary. They believed that for Japan to surrender, they must accept inevitable defeat and clarification of an unconditional surrender. Many believe that if they were allowed to keep their Emperor they would have surrendered much earlier. Hiroshima Bombingï’ £ The first atomic bomb was droppedRead MoreRehabilitation of the Felony Offender Essays1468 Words   |  6 Pageslow-level offenders, have little education, job experience, limited social skills and a drug or alcohol dependence (May and Pitts 21). That coupled with the fact they have a criminal record, reduces their chances of finding suitable housing or a decent job. Like it or not this affects all of us in one way or another. As taxpayers, we pay the costs of the justice system, incarceration, and there is the issue of public safety. This problem is not just going to go away, as history shows there has alwaysRead MoreEssay On Superstitions In Huckleberry Finn1084 Words   |  5 Pagesconsidering Jim, a slave, as a human being rather than property. Thus, showing how historically White American’s within southern culture and society have never viewed people of color, specifically African Americans, as human beings but as objects of oppression. Huck’s inner turmoil caus es him to completely challenge the traditional white southern society by not wanting to be â€Å"sivilized† (Twain, 3), and coming to terms with the fact that Jim although a slave is a human being and not property. HuckRead MoreLiberi A Cultural Overview2942 Words   |  12 PagesLiberia: A Cultural Overview Liberia s political system and history has been strongly based and influenced on American and English common law. This is due in part to Liberia s initial colonization of freed American slaves starting around 1820. Initially 86 immigrants, also known as â€Å"Americo-Liberians† settled in the now named Monrovia, named after President James Monroe. In the following years thousands more freed slaves and free African-Americans resettled by a campaign created by the AmericanRead MoreEconomic Growth And Its Effect On Society1737 Words   |  7 Pages For most of human history, life remained pretty much the same. The conditions of living were almost completely stagnant, and there was no such thing as economic growth to the general public. This all changed when two different events occurred that greatly impacted the course of history. The first of these being the British industrial revolution in 1750, and then the more prominent American industrial revolution in 1870. Acting li ke a catalyst, these two events created a boom of economic growth unlike

Essay about Book VIII of John Miltons Paradise Lost

Book VIII of John Miltons Paradise Lost As Book VIII of John Milton’s Paradise Lost begins, the â€Å"new-waked† human Adam ponders the nature of the universe and the motion of the stars (ll. 4-38). When Adam has finished his speech, Milton takes the opportunity to describe Eve, who is listening nearby. We find Eve reclining in the Garden, but with grace, not laziness: â€Å"she sat retired in sight,/With lowliness majestic from her seat† (41-42). This â€Å"lowliness majestic† is the central phrase to understanding Eve’s character—she is both humble and glorious. Everything that beholds her is captivated by her â€Å"grace that won who saw to wish her stay† (43). Even in this paradise, every other beautiful creation is drawn to Eve. She walks†¦show more content†¦Though she is, of course, majestic, Eve carries herself with a lowliness that does not assume too much about her own majesty. Eve’s â€Å"lowliness majestic† is perhaps what enchants Adam the most. He is captivated and totally mystified by Eve’s very nature. Adam seems to understand the nature of humanity based on the qualities that he sees in himself, which at first seems safe, as he is the first man. However, he is perplexed by Eve’s completeness—perhaps because the qualities that Eve lacks are the ones that Adam values most in himself! Beholding his wife, he remarks that by design and intention she is his â€Å"inferior† (541): her â€Å"inward faculties† (542) are not as useful as his own, and she does not as closely resemble the Maker as he does (543-44). She is not designed, as Adam is, with the desire or capacity to rule over the other creatures (544-46). These things are not true of Eve, so Adam finds it difficult to understand why she seems â€Å"in herself complete† (548). He marvels that even as she lacks the qualities that res emble the Maker, she seems â€Å"so absolute,† not lacking anything (547). Eve is complete, she is a â€Å"guard angelic placed† to Adam—one sent as a helper and a protector (559). He is captivated by how â€Å"what she wills to do or say,/Seems wisest, virtuousest, discreetest, best,† even though the man was intended to be the wisdom-giver (549-550). Adam’s attitude can beShow MoreRelatedAdam and Eve: Breaking the Social Construct With John Miltons Paradise Lost1306 Words   |  6 Pagesman? For the entirety of human civilization, this question of gender hierarchy has been divisive issue. Regardless, Milton does not hesitate to join the heat of the battle, and project his thoughts to the world. Since the publication of Paradise Lost, many of Milton’s readers have detected in his illustration of the prelapsarian couple, particularly of Adam, a powerful patriarchal sentiment: â€Å"he for God only, and she for God in him† (Milton, IV.299). In essence, this idea declares that Adam and EveRead MoreMiltons Paradise Lost and His Justification of the Ways of God to Man.1418 Words   |  6 PagesBy Lee A. Zito When John Milton decided to write, he knew from the start he wanted his creation to be that of an epic. Paradise Lost is just that. It is Miltons own take on the biblical story of Satans fall from grace as well as mans fall. Milton was not only armed with an extensive knowledge on the Bible, but in everything a man of his time could learn. With his wisdom he emersed himself into his work, making Paradise Lost not only a tale of epic perportions, but one that would Justify theRead MoreJohn Milton s Negative Portrayal Of Monarchy1142 Words   |  5 PagesJohn Milton’s Negative Portrayal of Monarchy in Paradise Lost In Paradise Lost, Milton argues against monarchy by portraying it in its purest form using the kingdom of heaven. Heaven is portrayed in Paradise Lost as a blatant monarchy. As with all monarchies, heaven does not offer true political freedom as it is ruled by one monarch, God. Milton portrays heaven to be a true monarchy and visibly displays the shortcomings of such type of government. He does this in various ways by comparing societiesRead More Essay on John Milton’s Paradise Lost - Defense for the Allegory of Sin and Death1574 Words   |  7 PagesDefense for the Allegory of Sin and Death in Paradise Lost Milton claims his epic poem Paradise Lost exceeds the work of his accomplished predecessors. He argues that he tackles the most difficult task of recounting the history of not just one hero, but the entire human race. However, he does not appear to follow the conventional rules of an epic when he introduces an allegory into Paradise Lost through his portrayal of Sin and Death in Book II. Some readers denounce his work for this inconsistencyRead MoreLiterary Analysis : Paradise Lost By John Milton1542 Words   |  7 Pagesof feminised fluff, a kind of pseudo-human placeholder stuck into a poem or plot to motivate the (male) protagonist to action. This over-simplified, often underdeveloped characterisation is turned completely on its (rather, her) head in John Milton’s Paradise Lost: Eve, the woman known to all of Christianity as the Fallen Woman who was tricked by Satan into sampling the forbidden fruit of God’s Tree of Knowledge and therefore leading to Man’s expulsion from the Garden of Eden into the world of painRead MoreThe Role of Eve in Paradise Lost1589 Words   |  7 PagesThe importance Milton attached to Eve’s role in Paradise Lost and in the Garden of Eden is now recognised and acknowledged. (Green, 1996) Milton’s treatment of Adam and Eve’s relationship is complex. Sometimes referring to them in ways that indicate equality, (ibid) sometimes stressing their separateness as individuals (ibid) and other times they are complementary halves of a whole. (ibid) Taking on the view that many support; that Milton intended Eve to seem completely inferior to Adam, we can examineRead MoreMovie Analysis : Paradise Lost By John Milton Sets Up Adam And Eve1636 Words   |  7 PagesGender Binary in Paradise Lost Paradise Lost by John Milton sets up Adam and Eve in complete binary opposition, with dominance and gender as the controlling factors. There is a struggle between Adam, who believes Eve to be inferior, and Eve, who can control Adam through his desires; this is used by Milton to show that women and men have equal strength, but their skills lie in different areas. This would make them opposite, indeed, but not truly very different. However, despite this realization ofRead More John Miltons Paradise Lost Essays2127 Words   |  9 PagesJohn Miltons Paradise Lost John Milton’s Paradise Lost is a religious work, and is in many ways an autobiography of Milton’s own life. John Milton was raised catholic and converted to Protestantism. Later in life he became a Calvinist. His strong Calvinists beliefs can be seen throughout Paradise Lost. It was Milton’s desire to be a great poet, but he did not believe that was his purpose in life. He believed that he had been put here to serve God, and that any thing that he wrote shouldRead MoreAnalysis of the Consequences of the Disobedience to the Great God/Gods in Paradise Lost and â€Å"Pandora’s box†2496 Words   |  10 PagesIn John Milton’s Paradise Lost, Milton narrates the story of Adam and Eve, but on a deeper level, figuring out the motives, feelings, and emotions of each character while also introducing the story of Satan/Lucifer and all of his complexities. At the same time Milton gives the story a twist when he relates how sin and death is brought into the human world. Greek Mythology gives a similar anecdote which compares with John Milton’s story very much: the story of Pandora and Epimetheus. â€Å"Pandora’s Box†Read MoreParadise Lost By John Milton2137 Words   |  9 Pagessaid that the â€Å"paradise† that was lost in Paradise Lost was the equality of man and woman. In John Milton’s, Paradise Lost, Milton gives a fictional, inside look of the fall from grace. He explains the events that led up to the fall, the thoughts and inner workings of God and Satan, and the crumbling of Adam and Eve and their seemingly perfect relationship. Milton proves how Adam’s blind devotion and Eve’s uncertainty of her own self cause humanity to fall. In doing so, Paradise Lost has challenged

Passport Program In The Success Of Hero Honda Commerce Essay Example For Students

Passport Program In The Success Of Hero Honda Commerce Essay Hero Honda Motors Limited, based in Delhi, India is a joint venture between the Hero Group of India and Honda of Japan. Verification. It has been referred to as the universe s biggest maker of 2-wheeled motorised vehicles since 2001, when it produced 1.3 million minibikes in a individual twelvemonth. During the financial twelvemonth 2008-09, the company has sold 3.28 million motorcycles and the net net income of the company stood at Rs. 1281.7 crore, up 32 % from the old financial twelvemonth. The company s most popular theoretical account is the Hero Honda s Splendor, which is the universe s largest-selling bike, selling more than one million units per twelvemonth. The company introduced new coevals bikes that set industry benchmarks for fuel thrift and low emanation. A legendary Fill it Shut it Forget it run captured the imaginativeness of commuters across India, and Hero Honda sold 1000000s of motorcycles strictly on the committedness of increased milage. Over 20 million Hero Honda two Wheelers tread Indian roads today. These are about every bit many as the figure of people in Finland, Ireland and Sweden set together! Hero Honda has systematically grown at dual figures since origin ; and today, every 2nd bike sold in the state is a Hero Honda. Every 30 seconds, person in India bargain Hero Honda s top -selling bike Luster. This gay season, the company sold half a million two Wheelers in a individual month-a effort unparalleled in planetary automotive history. Hero Honda motorcycles presently roll out from its three globally benchmarked fabrication installations. Two of these are based at Dharuhera and Gurgaon in Haryana and the 3rd provin ce of the art fabrication installation was inaugurated at Haridwar, Uttrakhand in April this twelvemonth. These workss together are capable of bring forthing out 4.4 million units per twelvemonth. Hero Honda s extended gross revenues and service web now spans over 3000 client touch points. These consist a mix of franchises, service and trim points, trim parts stockiest and authorised representatives of traders located across different geographicss. Hero Honda values its relationship with clients. Its alone CRM enterprise Hero Honda Passport Program, one of the largest plans of this sort in the universe, has over 3 million members on its roll. The plan has non merely helped Hero Honda understand its clients and present value at different monetary value points, but has besides created a loyal community of trade name embassadors. Having reached an impregnable pole place in the Indian two Wheeler market, Hero Honda is invariably working towards consolidating its place in the market top ographic point. The company believes that altering demographic profile of India, increasing urbanisation and the authorization of rural India will add 1000000s of new households to the economic mainstream. This would supply the growing ballast that would prolong Hero Honda in the old ages to come. As Brijmohan Lall Munjal, the Chairman, Hero Honda Motors compactly points out, We pioneered India s bike industry, and it s our duty now to take the industry to the following degree. We ll make all it takes to make at that place. Outline1 Company profile2 History3 List of theoretical accounts4 Hero Honda Passport programme.5 What are the benefits of having a hero Honda passport?6 For how long is the Hero Honda Passport valid?7 decision8 Reappraisal of literature Company profile Hero is the trade name name used by the Munjal brothers for their flagship company Hero Cycles Ltd. A joint venture between the Hero Group and Honda Motor Company was established in 1984 as the Hero Honda company, India. During the 1980s, the company introduced bikes that were popular in India for their fuel economic system and low cost. A popular advertisement run based on the motto Fill it Shut it Forget it that emphasized the bike s fuel efficiency helped the company grow at a double-digit gait since origin. Hero Honda has three fabrication installations based at Dharuhera and Gurgaon in Haryana and at Hardware in Uttarakhand. These workss together are capable of churning out 3.9 million motorcycles per twelvemonth. Hero Honda s has a big gross revenues and service web with over 3,000 franchises and service points across India. Hero Honda s client trueness plan, the Hero Honda Passport Program, claims to be one of the largest plans of its sort in the universe with over 3 million members. The 2006 Forbes 200 Most Respected companies list has Hero Honda Motors ranked at 108. History India became the 2nd largest two Wheeler maker in the universe and get downing in the fiftiess with the Automobile Products of India ( API ) that manufactured the Lambrettas and Bajaj Auto Ltd. with its association with Piaggio of Italy ( maker of Vespa scooters ) as the largest makers within the state commendation needed. The licence raj that existed between the 1940s to 1980s in India did non let foreign companies to come in the market and imports were tightly controlled. This regulative labyrinth, before the economic liberalisation, made concern easier for local participants to hold a marketer s market. Customers in India were forced to wait up to 12 old ages to purchase a scooter from Bajaj. The Chief executive officer of Bajaj commented that he did non necessitate a selling section, merely a despatch section. By the twelvemonth 1990, Bajaj had a waiting list that was 26 times its one-year end product for scooters. The bike section had the same long delay times with three makers: Royal Enfield, Ideal Jawa, and Escorts. Royal Enfield made a 350cc Bullet with the lone four-stroke engine at that clip and took the higher terminal of the market but there was small competition for their clients. Ideal Jawa and Escorts took the center and lower terminal of the market severally. In the mid-1980s, the Indian authorities ordinances changed and permitted foreign companies to come in the Indian market through minority joint ventures. The two-wheeled market changed with four Indo-Japanese joint ventures: Hero Honda, TVS SUZUKI, Bajaj Kawasaki and Kinetic Motor Company ( Kinetic Honda ) . The entry of these foreign companies changed the Indian market kineticss from the supply side to the demand side. With a larger choice of two-wheelers on the Indian market, consumers started to derive influence over the merchandises they bought and raised higher client outlooks. The industry produced more theoretical accounts, titling options, monetary values, and different fuel efficiencies. The foreign companies new engineerings helped do the merchandises more dependable and with better quality. Indian companies had to alter to maintain up with their planetary opposite numbers. List of theoretical accounts Achiever Ambition 133, Ambition 135 Prevent Computer Crime EssaySo wholly you have to make to gain points A ; wagess is merely maintain keeping your Hero Honda bike, purchase echt Hero Honda Spare Parts and accoutrements and we ll give you one point for every rupee you spend! A Star Club and Treasured Rewards This alone nine has been introduced for those members who get their motorcycles serviced on a regular basis from authorized Hero Honda Service Centers. The Star Club rank non merely identifies the member as particular for the HHPP household, but besides brings in some added benefits like: 30 % price reduction on labourA A 7.5 % price reduction on spares, till the cogency of the Passport Introducing Treasured RewardGood intelligence for all Passport Programme members who have crossed the 1 hundred thousand point grade in the Hero Honda Passport Programme.A A new wagess construction has been introduced for all such members The HHPP Treasured Rewards. The HHPP Treasured Rewards will be available at 8 prescribed mileposts get downing from 1.25 lakh points and stoping at 3 hundred thousand points, with each milepost at a spread of 25,000 points. In other words, the new mileposts are placed at 1.25 hundred thousand, 1.5 hundred thousand and so on boulder clay 3 lakhs Each clip a member reaches a milepost a Motorcycle Privilege Voucher of Rs. 1250/- will be given to him. This verifier may be used to avail a price reduction on the purchase of a new Hero Honda bike. This verifier is movable and can be given to friends or relations who may be be aftering to purchase a new Hero Honda bike Under the new Rewards Programme, the manner of entering points will alter. The points will now be recorded in 2 books one would be the old Passport with Additional Treasured Rewards sheets for come ining points earned through service, spares and accoutrements and the other would be a Referral Book which will be used for come ining referral points. The R eferral Book will get down from 1 lakh points. On traversing 1 lakh points the members need to retain a photocopy of their old Pass with them and direct the passport to the HHPP Programme Centre instantly. On reception, the old Passport with Additional treasured wagess sheets and the new Referral Book will be sent across to the members enabling them to get down redeeming wagess beyond 1 lakh points. decision Hero Honda, the World No. 1 two-wheeled company, today announced that it has late achieved a landmark member base of more than 2 million clients for its Passport Programme . Extending across 1000 authorized Hero Honda franchises and SSPs, the plan has now become India s largest Customer Relationship Management ( CRM ) Program. The unprecedented success of the CRM plan is a testimony of the religion that the clients repose in the company and its merchandises. It was born out of a demand to maximise committedness and beef up the emotional value that binds our diverse set of clients to the Hero Honda trade name. With its disposed tagline Rishta Dil Ka , the Passport Programme is a strong platform for the company to construct long-run relationships with its clients, beyond the point of sale, and pass on its trade name image of trust and reliability . The Hero Honda Passport Programme rank is a alone inaugural unfastened to the proprietors of Hero Honda bikes. The plan offers man y touchable and intangible benefits to both the clients every bit good as to the traders. Members earn points for incurring outgo at the Hero Honda dealership/workshop, which can subsequently be redeemed against benefits. On the juncture of the memorialization of the 2 million-passport plan milepost, Mr. Pawan Munjal, Managing Director, Hero Honda Motors Ltd. said, At Hero Honda our enterprise is to offer the best in merchandise quality to our clients ensuing in highest degrees of client satisfaction. The Passport programme non merely builds digesting relationships with our clients but besides offer them some extra value , beyond merely the touchable benefits of our merchandises. This milepost merely reaffirms our clients religion in us, which has been polar in the company s growing . The Hero Honda Passport programme was rolled out nationally in the twelvemonth 2001, after a successful pilot in four provinces in the twelvemonth 2000. A alone characteristic of the programme is i ts reward theoretical account, harmonizing to which every rupee spent by the member translates into a wages point. These reward points can so be redeemed for exciting gifts. One of the most important benefits of this plan is a free personal accident policy worth Rs. 1 hundred thousand. Insurance claim of over Rs. 6 crore has already been disbursed to dependent households, representing Hero Honda s concern non merely for the safety of its clients, but besides their household members. With the aid of this plan, the company has already received over 900,000 referrals therefore besides giving a bonus to gross revenues through favorable word of oral cavity. Reappraisal of literature With a member base of more than 20 lakh clients widening across 1000 authorised traders and SSP s, Hero Honda Passport Program is today the state s largest Customer Retention Management ( CRM ) plan. Under the disposed tagline Rishta Dil Ka , the plan has become a strong platform for us to construct long-run relationship with our clients beyond the point of sale, and take frontward our trade name image of trust and reliability . It was born out of a demand to maximise committedness and beef up the emotional value that binds our diverse set of clients to the Hero Honda trade name. The plan represents a cardinal alteration in looking at the client as a long-run plus instead than a mere mark for gross revenues dealing. Marketing plan designed to heighten trade name trueness by cultivating an ongoing relationship between a seller and his client. Successful trueness plans encourage the consumer to purchase often, to increase the sum spent each clip, and to concentrate all or most of their related purchases on that trade name. Most loyalty plans offer fringe benefits for rank in a nine or plan and wages purchases. Wagess may be based on the dollar value of purchases made or on the frequence of purchases. The most well-known trueness plans are air hose frequent-flyer plans that offer price reductions against future travel called award stat mis. Most big supermarket ironss now have frequent-buyer nines that offer no-coupon price reductions every bit good as newssheets and affiliate price reductions. Loyalty plan tactics besides include regular communicating with clients such as reminder mailings, private recognition cards, cross-sell and up-sell offers, satisfaction and sentiment studies, and aggregatio n of information for member databases. See besides frequency price reduction.