The Sound Systems Of Language English Language Essay

The Sound Systems Of Language English Language Essay Phonology is one of the core fields that compose the discipline of linguistics, which is defined as the scientific study of language structure. One way to understand what the subject matter of phonology is, to contrast it with other fields within linguistics. A very brief explanation is that phonology is the study of sound structure in language, which is different from the study of sentence structure (syntax) or word structure (morphology), or how languages change over time (historical linguistics). A common characterization of the different between phonetics and phonology is that phonetics deals with actual physical sounds as they are manifested in human speech, and concentrates on acoustic waveforms, formant values, measurements of duration measured in milliseconds, of amplitude and frequency, or in the physical principles underlying the production of sounds. On the other hand, phonology is an abstract cognitive system dealing with rules in a mental grammar: principles of subconscious thought as they relate to language sound. CONCERNS OF PHONOLOGY: The most important to appreciate at this moment is that the sound which phonology is concerned with is symbolic sounds- there are cognitive abstractions which represent but are not the same as physical sounds THE SOUNDS OF A LANGUAGE: One expect of phonology considers what the sounds of a language are. We would want to take note in a description of the phonology of English that we lack a particular vowel that exists in German in words like schon beautiful, a vowel which is also found. In French (Spelled eu, as in jeune Young) or Norwegian (beer). Similarly, the consonant spelled the in English thing, path does exist in English as well as in Icelandic where it is spelled with the letter p, or Modern Greek where it is spelled with O, or Saami where it is spelled ) but his sound doesnt occur in German or French and it is not used in Latin American Spanish, although it does occur in continental Spanish in words such as cerveza beer, where by the spelling conventions of Spanish, the letters c and z represent the same sound as the one spelled the (in English) RULES FOR COMBINING SOUNDS: Another aspect of language sound which is phonological analysis would take account of is that in any given language, certain combinations of sounds are allowed, but other combinations are systematically impossible. The fact that English has the words brick, break, bridge, bread is a clear indication that there is no restriction against having words begin with the consonant sequence br; besides these words one can think of many more words beginning with br such as bribe, brow and so on. Similarly, there are many words which begin with bl, such as blue, blatant, blast, blend, blink, showing that there is no rule against words beginning with bl. It is also a fact that there is no words blink in English, even though the similar words blink, brick do exit. The nonexistence of blick is English is accidental, the exclusion from English of many other imaginable but nonexistent words is based on a principled restriction of the languages. VARATIONS IN PRONOUNCIAITON In addition to providing an account of possible versus impossible words in a language, a phonological analysis will explain other general patterns in the pronunciation of words. For example, there is a very general rule of English phonology which dictates that the plural suffix on nouns will be pronounced as (iz), represented in spelling as es, when the preceding consonant is one of the certain set of consonants including (S) spelled (sh) as in bushes, (c) (spelled as ch) as in churches, and (j) (spelled j, ge, dge) as in cages, bridge. This pattern of pronunciation is not limited to the plural, so despite the difference in spelling, the possessive suffix s2 is also subject to the same rules of pronunciation: thus, plural bushes is pronounced as same as the possessive bushs and plural churches is pronounced same as the possessive churchs. This is the sense in which phonology is about the sound of the language. From the phonological perspective, a sound is a specific unit which combin es with other such specific units and which represent physical sounds. PHONETICS Phonetics is about the concrete, instrumentally measurable physical properties and production of these cognitive speech sounds. The two basic aspects of speech sounds as there are studied in phonetics, namely acoustics which is the study of the properties of the physical sounds wave that we hear, and articulation, which is the study of how to modify the shape of vocal tract, thereby producing a certain acoustic output(sound) ACOUSTICS A sound is a complex pattern of rapid variation in air pressure, travelling from a sound source and striking the ear, which causes a series of neural signals to be received in the brain: this is true of speech, music and random noices. WAVEFORMS A concrete way to visually represent a sound is with an acoustic waveform. A number of computer programs allow one to record sounds into a file and display the results on the screen. This means one can visually inspect a representation of the physical pattern of the variation in air pressure since we are interested in the part which makes this two words sound different, we might get a clearer picture of the physical difference by expanding the scale and looking just at a part of the vowel. Vowels are periodic, which means that the pattern of their wave form repeats over time. A portion of the vowels from the middle of the words seed and Sid, involving around 30 milliseconds (ms) of each of the words. We can indeed see that there is a pattern which is repeated. Though there are visible differences between the waveforms, the basis for distinguishing these vowels remain unclear. SOUND SPECTRA: All sound waves are definably, namely in terms of three properties that characterize a sine wave familiar from trigonometry, namely frequency measure in cycles per second also known as Hertz (Hz), amplitude measure in decibels and phase measured in the angular measure radians. These characteristics suffice to define any sine wave, which is the analytic basis of sounds. The property phase, which describe how far into the infinite cycle of repetition a particular sine wave is, turns out to be unimportant for the study of speech sounds, so it can be ignored. Simple sine waves (termed pure tones when speaking of sounds) made up of a single frequency are not commonly encountered in the real worlds, but can be created by a tuning fork or by electronic equipment. Speech sounds (indeed all sounds) are complex wave forms which are virtually impossible to describe with intuitive description of what they look like. Fortunately, complex wave can be mathematically relate to a series of simple waves which have different amplitudes at different frequencies, so that we can say that complex wave from is build from asset of simple waves. Inaccuracy in spectral data has three main sources. Half of the information in the original signal, phase, has been discarded. Frequency information is only approximate and its related to how much speech is analyzed. Finally, a spectrum assumes that sound properties are constant during the period being analyzed. If too large a piece of speech is taking for analysis, a misrepresentative blending of a continuously changing signal results. SPECTROGRAM: The spectrogram shows both frequency and amplitude properties as they change over time, by adding a third dimension of information to the display. A spectrogram can be made by a mechanical spectrograph, which uses an adjustable filter to select different frequency ranges and display the changes in amplitude at each frequency ranges; or, it can be created by a computer program, which use fouler analysis to determine these component amplitudes. A spectrogram is a reasonably informative accurate display of properties of sound. It is less accurate than the spectrum at a single point. Spectrograms are created either by special machinery or specials computer programs, which are not always available. It is therefore quite impractical and also unnecessary to base the scientific study of languages sound systems exclusively on spectrograms. CONCLUSION: Phonetics and phonology both study language sounds. Phonology examines language sound as a mental unit, and encapsulated symbolically for example as (ae) or (g) and focus on how these unit function in grammars. Phonetics examines how symbolic sounds are manifested as a continuous physical object. The conversion from physically continues event to symbolic representation requires focusing on the information that is important, which is possible because not all physical properties of speech sounds are cognitively important. One of the goals of phonology is than to discover exactly what these cognately important properties are how they function in expressing Regularities about languages. CHAPTER TWO PHONETIC TRANSCRIPTIONS PREVIEW: This chapter gives an overview of phonetic transcriptions. It: Gives the important transcriptional symbols Introduces the two major schemes of phonetic transcriptions Present the main articulators classification of sounds Surveys the main variations in phonetic properties exploited by the languages Further develops the relevance of phonetics for the study of phonology INTRODUCTION: In phonetic transcription, speech is represented a small set of symbols with a standard interpretation. This chapter looks at the different systems for phonetic transcription. They are two major schemes, the informal American schemes used in especially North America, sometime known as APA (American Phonetic Alphabet), and the IPA (International Phonetic Alphabet) promulgated by the international Phonetics association. VOWELS: The first division in speech sound is made between vowels and consonants. Symbols for vowels will be considered first because they are fewer vowels than consonant. Some dialects English make no distinction in the pronunciation of the words cot and caught; even among speakers who distinguish the pronunciation of cot and caught, the precise pronunciation of the two vowels differs considerable. An important point is that the transcriptional symbols are approximations representing a range of similar values, and that symbols do not always have absolute universal phonetic values. CONSONANT: There are many more consonant than vowels, English only has a fraction of the full range of possible consonants, so illustration of many of these symbols involve more extensive consideration of languages other than English. Consonants symbols are treat as the place of articulation where the major constriction occurs as one axis, and treating properties such as voicing, being a continuant, or nasality as the other axis. Eleven places of articulation for consonants are usually recognized: bilabial, labiodentals, dental, alveolar, alveopalatal, retroflex, palatal, velar, uvular, pharyngeal and laryngeal, and arrangement which proceeds from the furthest forward to furthest back points of the vocal tract. MANNER OF ARTICULATION: largely independent of the place where a consonant constriction is formed, the manner in which the constriction is formed can be manipulated in various ways. If a constriction is formed which completely blocks the flow of air, the resulting sound, such as t, is called a stop? A consonant can be produced by forming a narrow constriction which still allows air to pass through the vocal tract, resulting in noise in at the constriction, and such consonants, for example s and v are called fricatives. A combination of complete constriction followed by a period of partial constriction is termed an affricate. SYLLABICITY A phonetic property of consonants that may be transcribed is whether the consonant is syllabic. There is a phonetic difference between the n of American English cotton and that of con: the n of cotton is syllabi, where as the n of con is no syllabic. A syllabic consonant is indicated by placing a vertical tick under the consonant, so cotton is transcript (Ka? n) and con is transcribed (Kan). The main phonetic correlate of the distinction between syllabic and no syllabic consonant is duration, where syllabic consonants are generally longer than their no syllabic counterparts. Especially in tone languages, syllabic consonants can have distinctive tone. SYMMENTRY IN CONSONANTS The symmetrical universal table consonants were we to list all the consonants found in human languages. In some instances, the gap reflects physiological impossibility, such as the fact that one cannot produce a nasal pharyngeal, analogous to velar nasal but at a pharyngeal place of articulation. A nasal involves making a complete obstruction at a given point of articulation and also requires air to flow through the velum. In order to make a pharyngeal nasal, it would be necessary to make a complete constriction at the pharynx. But since the pharynx lies below the velum, no air can flow through the nasal passages if the pharynx is totally constricted. However a nasalized pharyngeal continuant, i.e. the consonant produced with simultaneous nasal airflow, would not be a physical impossibility, since that consonant doesnt not require complete constriction of the pharynx. In other cases the gap indicates that no such sound has been found, but there is no immutable physical reason for suc h a sound not to exist. Thus bilabial affricated not seem to be attested, nor to plain no affricated alvepalatal stops, nor do nasalized pharyngeal fricatives. Similarly, while pharyngeal zed consonant exist and rounded consonants exist, there are apparently no cased of consonants which are both rounded and pharyngeal zed, though such segments are not logically impossible. These lacunae may be an indication of a deeper constraint on sound systems however; it is also possible that these segments do exist in some languages which have not been studied yet, since there are many languages in the world which remain uninvestigated. PLACE OF ARTICULATION The place of articulation of consonants is divided into primarily place of articulation something that every consonant has and secondary place of articulation-something some consonants may add to primary place of articulation. LINGUAL CONSONANTS: The tip or blade of the tongue is the active articulators in the production of many consonants, including dental, alveolar, alveopalatal, retroflex and palatal consonants. These consonants form constrictions involving the tongue and an appropriate place on the teeth, or hard or soft palates. The contract is with the teeth in the case of dentals, on the hard palate behind the teeth in the case of alveolar, behind the alveolar ridge in the case of alveopalatals and retroflex consonants, and with the blade of the tongue at the boundary between the hard and soft palate in the case of palatals. In many traditional organization in segments, retroflex consonants are classified as a separate place of articulation from alveolar and alveopalatals. This traditional concept of place of articulation combines properties with both active articulators and a passive articulator- the target towards which an active articulator moves. What unifies that various kinds of retroflex consonants across langua ges is not the specific location of the constriction on the hard palate, but rather the manner in which just the tongue tip approaches the palate. SECONDARY ARTICULATIONS: Consonants may have more than one point of constriction: generally, one of these constrictions is the major (most radical) constriction and other constrictions are less radical more vowels like in nature. CONCLUSION: Phonology views speech sounds symbolically, knowledge of the system of symbols for representing speech is a prerequisite to doing a phonological analysis. It is also vital to know the phonetic parameters for describing the sounds of human languages which have been presented here. The main characteristic of vowels involve fronting of the tongue (front, central and back), rounding, and vowel height (high, mid and low, with tense and lax variant of high and mid vowels. Other properties of vowels include stress, tone and the phonation types creaky and breathy voice. Primary consonantal places of articulation include bilabial, labiodentals, alveolar, alveopalatal, retroflex, palatal, velar, uvular, pharyngeal and laryngeal. These may be supplemented by vowel like secondary articulations including palatalization, valorization, and pharyngealization and rounding. Consonant may be produced with a number of constrictions and release types, and is stops. Fricatives or nasals and stop consonant s may be unreleased or released, the later type allowing plain versus affricate release. Differences in the laryngeal component for consonants include voicing and aspiration. And the distinction between ejectives and implosives. Vowels and consonant may also exploit differences in nasalization and length.

Use of HPV Vaccines for Cervical Cancer Prevention

Use of HPV Vaccines for Cervical Cancer Prevention HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: Vaccine efficacy Vaccine Cost/affordability/practicality of administration Production and Distribution Government backing and financial commitment Other support organisations such as the WHO, UNICEF, Gates Foundation, Social factors Media effects Public awareness Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location http://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. Table 3 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease Use of HPV Vaccines for Cervical Cancer Prevention Use of HPV Vaccines for Cervical Cancer Prevention HPV Vaccines: Will They Prevent Cervical cancer Introduction Human papilloma viruses (HPV) belong to the papillomaviridae family, they are double stranded DNA viruses. HPV is the most common sexually transmitted infection (STI) in the world (Urman et al. 2008). HPV is strongly associated with cervical cancer; more than 99% what are the other causes/factors please of cervical cancer cases are positive for HPV DNA and indeed, cervical cancer is the second most common malignancy in the world (Wang et al. 2007). In developed countries the incidence of cervical cancer has been reduced significantly by the introduction of a cervical screening programme. In developing countries where 83% of mortalities due to cervical cancer occur, there are no such programmes (Parkin et al. 2006). Can the introduction of a vaccine against HPV further reduce globally the incidence of cervical cancer? Many diseases caused by viruses are controlled in the developed world by ongoing successful vaccination programmes; Polio, Measles, Mumps and Rubella are a few examples. Smallpox caused by Variola virus was eradicated in 1979 through a successful worldwide vaccination programme. The factors that affect the Polio and MMR vaccine programmes success and those that affected the successful smallpox programme may also be contributory to the success of the HPV vaccination program. Vaccination of HPV is complex and multi factorial. This investigation studies a number of factors including: Vaccine efficacy Vaccine Cost/affordability/practicality of administration Production and Distribution Government backing and financial commitment Other support organisations such as the WHO, UNICEF, Gates Foundation, Social factors Media effects Public awareness Safety, and perceived fears Currently two prophylactic vaccines against HPV types 16 and 18, the most prevalent causes of HPV have been approved by the food and drug administration (FDA). Many developed countries have already introduced vaccination programmes using one of these vaccines. Can the vaccines and programme prevent cervical cancer? In order to effectively understand the implication of such a vaccination programme we must first fully examine the causative agent (HPV) and the consequential potential diseases including the biology, history and prevalence. Human Papillomavirus Approximately 200 types of HPV are identified of which around 40 infect the genital tract (McCance 2004). The majority of HPV types cause no symptoms, some types can cause warts and a minority may lead to cancer. Genital HPVs are transmitted via sexual contact, mainly intercourse, with an infected individual, and the risk of developing an HPV infection generally increases with the number of sexual partners, the sexual history of that partner or the introduction of a new sexual partner. Studies have shown that at least one type of HPV infection occurs soon after sexual debut, with around 30% of women infected with at least one high risk type within two years (Winer et al 2003; Winer et al 2008). HPVs are classified as either high risk or low risk, on the basis of association with cervical cancer. There are 15 types classified as high risk and three as probable high risk. High risk types include 16,18,31,33,35,39,,45,51,52,56,58,59,68,73,probable high risk types include 26,53,66 Low risk types include 6,11,40,42,43,54,61,70,72,81 and CP6108. More than 99% of cervical cancers are associated with HPV, of these 70% are associated with HPV type 16 and 18, with HPV 16 causing 50% and HPV 18 causing more than 15% in Europe (Smith et al..2007). HPV 16 is thus the single, most common high risk HPV. Interestingly HPV types 16 and 18 also cause 80% of anal cancer and 30% of vaginal and why the difference in % oper area research needed here.vulvar cancer and are associated with cancers of the, oropharynx and some rare cancers of the head and neck. (add reference form cervical cancer burden worldwide paper) The majority of HPV infections are asymptomatic, self limiting, and transient, with 70% of new HPV high risk type infections cleared within one year (with the median duration of an infection at 8 months) and 90% within two years (Ho et al 1998). The transient infection usually causes no clinical problems. A small proportion of high risk type infections persist due to host immune evasion, an evasion that results not only from restriction of HPVs to sites that are relatively inaccessible to host defences but also due to several mechanisms of preventing immune response what are these mechanisms please (a sk Dick if this is what he means . This persistence is the most important factor in the development of pre cancerous and cancerous lesions. The time span between infection by HPV and the development of pre cancerous lesions or cervical carcinoma varies from one to ten years (Moscicki et al 2006) and up to 20 years from other sources. HPV show little evidence of dramatic adaptability with phylogenic studies suggesting that the biology of HPVs has remained the same for over 200,000 years (Halpren et al 2000). While HPVs show historically the influence of point mutations, inserts, deletions and duplications, the predominant pattern of mutation within a given type is point mutation, with large scale rearrangements within the most conserved genes of HPVs such as L1 being rare (Myers et al 1996). Intra patient variation within HPV types is uncommon due to their low mutation rate. This low mutation rate is directly linked to the HPV replication strategy that requires host cell machinery, which has stringent proof reading mechanisms that avoid the incorporation of errors, conferring slow mutagenesis. All HPVs exhibit extreme specificity for infection of epithelial cells and do not infect or express their gene products in the underlying dermis. Although the mechanism of infection is not fully understood, the HPV epitheliotrophy resides for the most part in the interaction of specific transcription factors with the viral regulatory region known as the long control region (LCR). Infection with HPV can result in hyperproliferation of the host cell, and with certain high risk HPV types it may lead to transformation and immortalization. This is because high risk HPVs express two or more protein products (E6, E7 and E5) that transiently disrupt the cell cycle and stimulate cell division, knocking out at the same time the cellular mechanisms for growth inhibition. For a productive infection, HPVs require terminally differentiated cells. This HPV biology feature has impeded studies on the full reproduction life cycle because of the lack of highly efficient models of epithelial terminal di fferentiation in vitro. Most of the different stages in the HPV life cycle have been established using genetic engineering and molecular biology strategies. The dsDNA of HPV exists in a non enveloped icosahedral shaped virion 52-55 nm in diameter. The dsDNA genome is circularised and around 8000base pairs in length (Fig1). The genome encodes eight proteins, six early E1, E2, E4, E5, E6, E7, and two late structural proteins L1 and L2 and the previously mentioned noncoding LCR. Fig 1 HPV type 16 Genome structure, gene and functional domain location http://www.dnachip-link.com/Eng/library/HPV.aspusg 15/11/20009 Fig 1 shows the dsDNA genome of HPV type 16, and the location of the early and late genes along with the LCR that contains the origin of replication. An initial infection requires the access of infectious particles to the basal layer of the epithelium. Some HPVs require a break in the stratified epithelium to achieve this. Such breaks are not necessarily obvious and may occur under conditions where the skin is exposed to water or abraded, or subjected to an environment where micro traumas may occur such as possibly in aswiming pool or ect (must put an example)(in fig 2 shows as a cut). Following infection and uncoating it is thought that the virus maintains its genome as an episome in low copy numbers within basal cells of the epithelium. Although the pattern of gene expression in these cells is not well understood, it is generally thought that viral proteins E1 and E2 are expressed to maintain the viral DNA episome (Wilson et al.2002) and possibly to facilitate the segregation of genomes during cell division (You et all.2004). It is not known whether viral transformation proteins E6 and E7 are also expressed in the basal layer, but it does appear that initial infection is followed by a proliferative phase that results in the increase in the number of basal cells harbouring viral episomes. In normal uninfected epithelium, basal cells leave the cell cycle soon after migration into the superbasal cell layers where they undergo a process of terminal differentiation. During infection E6 and E7 are expressed in these cells stopping normal differentiation (Sherman et all.1997). E6 and E7 are believed to work together to achieve this and in lesions caused by high risk HPV types. During a natural infection the ability of E7 to stimulate S-phase progression is limited to a subset of differentiated cells with low levels of p21/p27, or which express high enough levels of E7 to overcome the block in S-phase entry. The viral E6 protein is thought to prevent apoptosis in response to unscheduled S-phase entry brought on by E7. The association of E6 with p53 and the inactivation of p53 mediated growth suppression and apoptosis is well documented, E6 may also associate with other pro-apoptotic proteins including bak (Thomas and Banks,1998) and bax (Li and Dou,2000). E6 is thus considered a predisposing factor in the development of HPV associated cancers, allowing the accumulation of chance errors in host DNA to go unchecked. Furthermore the E6 protein of high risk HPVs can stimulate cell proliferation independently of E7 via a c-terminal PDZ ligand binding domain. E6 PDZ is enough to mediate superbasal cell proliferation and may contribute to the formation of metastatic tumours by disrupting normal cell adhesion (Nguyen et al.2003) Amplification of the viral genome and the ability to package these genomes into infectious particles is essential for the production of infectious virions. For most HPV types this occurs in the mid or upper epithelial layers following an increase in activity of the late promoter. The late promoter gene is located within the E7 open reading frame, and the upregulation of the late promoter is thought to lead to increased expression of proteins involved in viral DNA replication, without directly affecting the expression of E6 or E7 necessary for S-phase entry. The amplification of the viral genome begins in a subset of cells in the proliferative compartment and requires the expression of all viral early gene products, these include E4 and E5 whose role in replication is not yet clearly understood. Binding of E2 to the HPV upstream regulator region is essential for viral DNA replication that is dependent on the differentiated state of epithelial cells. E2 recruits the E1 DNA helicase to the viral origin of replication. Throughout the virus life cycle, the relative levels of viral proteins are controlled by promoter usage and by differential splice site selection, with an increase in E1 and E2 allowing an increase in viral copy numbers in the upper epithelial layers. Current models suggest that a small increase in promoter activation during differentiation may lead to an increase in the level of E1 and E2 and a subsequent increase in genome copy number. The newly replicated genome could then serve as a further template for expression of E1 and E2, facilitating the amplification of viral genome and in turn further expression of E1 and E2 replication proteins. Viral DNA remains latent (not integrated) in basal cells of benign lesions. Replication occurs in the differentiating cells where capsid proteins and viral particles are found. Viral DNA is integrated in cancer cells, which contain no replicating virus. Once viral genome replication is completed, the expression of two virally encoded structural proteins, expressed in the upper layers of infected epithelia may occur. L1 the major capsid protein is expressed after L2 in a sub set of cells that express E4 (fig 2), this allows the assembly of infectious particles in the upper layers of the epithelium (Florin et al.,2002). A successful infection requires the virus to escape from the infected skin cell and survive extracellularly prior to re-infection. HPVs are non-lytic and are as such not released until the infected cells reach the epithelial surface. The intracellular retention of HPV antigen until the cell reaches the uppermost epithelial layers may contribute the compromised immune detection, especially as the virus has molecular mechanisms that limit the presentation of viral epitopes to the immune system in the lower epithelial layers (Ashrafi et al 2002). What are these mechanisms Figure 2 Papillomavirus type 16 Life Cycle and gene expression location within epithelium Taken from, The papillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Figure 2 diagrammatic representation of the skin with HPV type 16 gene expression incorporated, colour of arrows are representative of genes expressed within epithelial cells. The frequent detection of high risk HPV DNA in cervical lesions in the absence of any obvious disease, may be explained by the presence of the virus in a latent state, with only very few cells able to support the productive virus life cycle during epithelial cell differentiation. Following immune regression, HPV DNA is thought to remain in the basal epithelial cells waiting to be reactivated once levels of immune surveillance decline there are conflicting opinions (Zhang et al.1999). If regression is not achieved lesions may persist and in some instances progress to cancer. The number of lesion that progress to cancer is very low when compared to the prevalence of high risk HPV infection in the general public. The Progression of productive lesion to high grade lesions may result from the deregulation ( what happen to allow thes proteins to be deregulated intergrattion loss of E2 adn p53 association, be specific add biochemistry here please. in the expression of transforming proteins E6 and E7. The inability of a cell to support the whole virus life cycle is often associated with the development of cancerous lesions. The transformation zone (Fig 3) is particularly susceptible to cervical cancer; it appears that high risk types of HPV such as type 16 cannot complete their life cycle at this site Progression from CIN3 to cancer usually occurs in lesions that contain integrated copies of the viral genome in which E7 expression is elevated. Suggesting that retention of E6 and E7genes and the loss of E2 and E4 genes (that exert negative effect on cell growth) usually accompanies the development of invasive cancer. (reference) Remember for CIN refer to in that section or here but Cin must be corrulated with what causes the cancer and with whats happening with the virus that causes the change in CIN or the causes in CIN to occur. Cervical cancerisa considerable contributor to morbidity and mortality. Being the second most common cancer worldwide and the twelfth most common cancer in women in the UK. Cervical cancer in 2002 was the cause of 274,000 deaths worldwide (the most current data available)REF THIS FIGURE and continues to causes more than 1000 deaths in the UK each year. There are two main types of cervical cancer squamous cell cancer (the most common) and adenocarcinoma, although they are often mixed. They are named after the types of cell that become cancerous through neoplasia. Squamous cells are flat cells covering the cervix; adenomatous cells are found in the passageway from the cervix to the womb. Other rarer cancers of the cervix include small cell cancer. Deaths from cervical cancer in the UK have fallen over the last 20 years mainly because of the NHS cervical screening programme that reduced the mortality rates by 62% between 1987-2006. Screening may detect changes in the cells of the cervix at a pre-cancerous stage. Fig 3 TITTLE Showing location of transformation zone. Cell samples are examined for abnormalities, these abnormality are described in a standard format covering cytology and/or histology. What are these standard format CIN 1 CIN2 CIN3 LISL LGSIL HSIL HGSIL USE FIG 4 and explain whats happening with the proteins expressed and genome intergration where CIN number progression is concerned please. MUST DO From Lowy Schiller, J Clin Invest, 116:1167-73, 2006 Low grade squamous intraepithelial lesion (LSIL or LGSIL) indicates possiblecone biopsy, or laser ablation. High grade squamous intraepithelial lesion (HSIL or HGSIL) indicates moderate or severeCIN 2 or CIN3 (fig 3). While cervical screening has reduced the mortality significantly in the developed world cervical cancer is still a significant burden worldwide. Fig 4 Taken from, The popillomavirus life cycle by John Doorbar published in the journal of clinical virology 32S (2005) S7-S15 Fig. 5. CIN 1 resembles productive infections caused by other HPV types and as such is the most benign form of cervical intraepithelial neoplasia , it is confined to the basal 1/3 of the epithelium, CIN 2 Moderate dysplasia confined to the basal 2/3 of the epithelium,CIN3 Sever dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. INCIDENCE An estimated 493,000 new cases and 274,000 deaths in 2002 were caused by cervical cancer. The vast majority, some 83% of these cases, occur in developing countries, where cervical cancer amounts to 15% of female cancers with a risk before age 65 of 1.5%. In developed countries cervical cancer accounts for only 3.6%, with a risk of 0.8% before age 65. REF The highest incidence rates are observed in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South-Central Asia, and South East Asia (fig 6) Fig 6 Worldwide Burden of HPV related Cervical Cancer Figures from 2002. Parkin MD et al 2006 The burden of HPV-related cervical cancers The vast majority of cervical cancers are squamous cell carcinoma adenocarcinomas being less common (fig 6). Generally the proportion of adenocarcinoma cases is higher in areas with low incidence of cervical cancer, accounting for up to 25% of cases in western countries (fig 6). This higher incidence of adenocarcinoma may be partially explained by cytological screening, which historically, had little effect in reducing the risk of adenocarcinoma of the cervix, because these cancers, and their precursors, occur within the cervical canal, and were not readily sampled by scraping of the epithelium of the ectocervix. Fig 5 Fig 5 showing the higher % of adenocarcinoma in counties that have screening programmes such as the UK and Denmark What is this showing? Make it clear.do you really need it. MORTALITY RATES Mortality rates are substantially lower than incidence rates. Worldwide 55% (could you double chek that this is the case please misses) of all those that develop the disease die, the figures vary significantly from the developed to the developing world. Low risk regions of the west such as Europe have a death rate of 37% while in developing countries where many cases present at relatively advanced stages, death rates are significantly higher increasing to 70%. Cervical screening programmes in the developed world identify pre-cancerous lesions at a stage where they can be easily treated accounting for the difference in mortality rates. TITTLE IF and figure number staying and refer to in text As cervical cancer affects a relatively high number of young women, it is a significant cause of years of life lost (YLL) in the developing world. Yang et al 2004 found that cervical cancer was responsible for the 2.7 million (age weighted) years of lives lost world wide in 2000, and that it is the single biggest cause of years of life lost from cancer in the developing world. In Latin America, Eastern Europe and the Caribbean, cervical cancer makes a greater contribution to YLL than disease such as Tuberculosis or AIDS. HPV is also associated with many other forms of cancer that could possibly be prevented with use of HPV vaccines; cancers of the penis, anus, vulva, vagina, oropharynx and some rare cancers of the head and neck are included. However cancer of the cervix is by far the most significant, in terms of incidence and mortality (table 1). Cancer of the vulva and vagina have a significantly lower incidence rate compared to cervical cancer, however since 80% of the incidence are caused by HPV types 16 or 18 women vaccinated against these types would also be protected against these forms of cancer. Incidence of squamous cell carcinoma of the anus are twice as common in females as males with HPV types 16 and 18 accounting for 83% of all cases. There is a particularly high incidence of anal cancer among homosexual males, shown by the high incidence rate in populations such as Sanfransisco, where gay incidence are higher than average (fig 7). Globally cancer of the penis is relatively rare accounting for 0.5% of cancers in men (table 1). HPV DNA is detectable in 40-50% of all penile cancers and serological studies have confirmed the role of HPV 16 and 18 (IARC 2005). Cancers of the mouth and oropharynx caused by HPV are very low at 0.06% of all cancers with 0.05% being caused by HPV types 16/18. Due to the small size of most studies and the absence of comparable measurements of prevalence of infection in normal subjects conducted for cancers of the vulva, vagina, penis and anus true prevalence is difficult to quantify. The figures shown in table 1, imply that we are dealing with a virus that discriminates primarily through disease aginst women, in particular young women. Gay men, however are also clearly an at risk group. Currently only young women are vaccinated aginst HPV types 16 and 18, however the JCVI (joint committee on vaccination and immunisation) have noted that the vaccines has not been conclusively trialled on men, and that there is insufficient evidence that the vaccine available would protect against anal, penile or head and neck cancer. However when more data becomes available they will consider vaccinating, high risk groups such as men who have sex with men. Add what this implies for prophylactic use of vaccine with other cancers cause by HPV And what you think about the ue of vaccine on highrisk men and its effectivity against other cancers caused by HPV types 16 and 18. Fig 7 TITTLE add Figure 6 showing that cancer of the anus are more prevalent in women than men with the major noted exception being San Francisco, where the increased incidence can be explained by a large number of homosexual men. Table 3 VACCINATION An effective vaccine should stimulate a suitable range of immune responses, mimic or improve on the protection gained from a wild type infection with little side effects. Critically the vaccine should be inexpensive, easily administered, transported and stored to further reduce cost and maximise convenience, this is especially relevant in the case of HPV vaccine as those that are not protected by the screening programmes of the developed world would benefit the most, ease of administration and storage is paramount in the developing world as stability and healthcare is more sporadic, and people are often more remote. There are many different kinds of vaccines available, and different vaccines have a variety qualities and limitations. Live attenuated vaccines contain a version of the pathogenic microbe that is avirulent, they often elicit an excellent cellular and antibody response with good longevity that can be lifelong with few doses. However there is always the possibility that the vaccine may revert to its virulent form, causing disease. For this reason a live attenuated vaccine is not appropriate for use against oncogenic HPV types. Recombinant vaccines can include one or more proteins that may illicit an immune response. A process has been developed to allow the removal of the genome from an attenuated or avirulent viral vector allowing the insertion of selected genetic material or proteins from another virus. The carrier viruses then ferry that viral DNA into host cells where the genes are expressed. Recombinant vaccines closely mimic a natural infection and therefore illicit a strong immune system. Inactivated vaccines are produced by killing the disease causing microbe by chemical (formaldehyde eg just double check), heat or radioactive means. These vaccines are more stable than live vaccines, and as there is no risk of reversion to virulence. They are also safer than live vaccines. Most inactivated vaccines stimulate a weaker immune response than live vaccines and several doses or boosters may be required to maintain immunity. DNA vaccines dispense with both the whole organism and its parts. They only include the essential part of the microbes genetic material. In particular, DNA vaccines use the genes that code for immunogens. Researchers have found that when the genes for a microbes antigens are introduced into the body, some cells will take up that DNA. The DNA then instructs those cells to make the antigen molecules. The cells secrete the antigens and display them on their surfaces. In other words, the bodys own cells become vaccine-making factories, creating the antigens necessary to stimulate the immune system. A DNA vaccine against a microbe would evoke a strong antibody response to the free antigen secreted by cells, and also stimulate a strong cellular response against the microbial antigens displayed on cell surfaces. The DNA vaccine is unable to cause disease

My personal Goals Essay -- essays research papers

  Ã‚  Ã‚  Ã‚  Ã‚   The personal goals that I want to achieve as a student of the University of Phoenix are in the education and career areas of my life. In my education, my major goal is to gain knowledge in computers and network administration, eventually culminating in a Bachelor of Science in Information Technology. I also wish to strengthen my grammar and interpersonal skills. In my career, my goal is to either advance from my current career as a paralegal to that of an office manager or to enter into a different career as information technology department administrator. I will use staff and university services in order to achieve my goals in a reasonable timeframe with limited obstacles. To achieve these goals I plan on using the University of Phoenix’s classes and academic services and to eventually use the degree I will receive from the university. To achieve my education goals I plan on using classes and academic services provided by the University of Phoenix. To strengthen my grammar and interpersonal skills, I plan on taking classes at the University of Phoenix that will give me more confidence and experience in writing and communication. I also plan on attending writing workshops that the University of Phoenix offers and use of the Center for Writing Excellence to help me as well. To gain knowledge and training in computer and network administration I plan on taking the computer courses that the University of Phoenix offers. I plan on taking computer-...

Changing Roles of Women Essay -- Sociology

Since the beginning of the 1800's, women had been fighting for the rights that they wanted. Women should be able to vote, control their own property and income, and they should have access to higher education and professional jobs. Women also had many roles in society. Women had very important parts in jobs as they took up more responsibilities. Girls, young ladies, and women of all ages were working harder to bring home income. Most women thought the pay and the conditions were unfair. These arguments grew as women fought more and more for social equality. Women found jobs wherever they could. Women's work on farms and at home was essential but the younger women moved from rural areas to cities to work in factories. Immigrant women also turned to the factories for work. While some women were working hard in factories, other women were building volunteer organizations that took roles in rapidly reforming education, labor relations, public health, and other areas of society. Women that did neither of these jobs still worked in the home cleaning. More urban women made their own brea...

Light and Dark Imagery Depicted in Shakespeares Macbeth Essay

The natural order of the world is disrupted; this is made obvious from the start of the play. Even though they generally speak in riddle, the three witches are significant characters because of their foresight and knowledge of future atmosphere. ‘Fair is foul and foul is fair.’ ~Act 1, Scene 1~ Because this chant is towards the beginning of the play, the audience immediately see the supernatural control over things. Throughout the play of Macbeth the audience is made aware of the differences in dark and light. This could be seen as being metaphorical for many other binary oppositions one of which being good and evil. This example supports the power of the witches, representing evil and the dark. Another scene that shows Macbeth is a play of light and dark is act 1 scene 4 Macbeth whispers to himself. ‘Stars; hide your fires / let not light see my black and deep desires’ ~Act 1, Scene 4~ The dark is seen as a mask that can disguise and hide, this is foreshadowed when King Duncan at the announcement of his successor says; ‘but signs of nobleness, like stars, shall s...

My Desires for and Commitment to a College Education Essay

Thirteen years ago my father came to America with no money or education believing that he would surely make something of himself. With his very low education he received a job washing dishes at a restaurant to put food on his plate and to pay for the one room apartment that he rented. After four years he was able to bring me along with my brother, two sisters and my mother to come stay with him. With all of us together he had to work two jobs to support all of us and that truly was difficult for him. He soon was able to send my mother to a school for adults so she have a diploma and help out with the bills and purchase some new attire for us to wear. Once I saw first hand how hard it was for my parents to survive with their low education my one desire and commitment was focused on my college education and coming from a family with does not receive much income I recognize how important it would be to me to receive my education which is why I will strive to receive it. My sister was also a big influence when I saw her graduate from FAMU with a bachelor’s degree and now is the credit manager of sears. Watching how successful she has become I knew I could do the same by going through any impediments which may stand in my way. After receiving a bachelor’s I will also head for a master’s to further open my education. As of right now I am currently employed as a student library for the Broward County Main Library in Florida. I was hired because of my integrity, intellectual personality, and my commitment to the job. This job has given me the opportunity to save up some money for college to pay for some of the books and tuition costs. Having this job has made my commitment toward my education the more important to me, as well as giving me a better understanding of hard work and dedication. I now feel confident that I have gained valuable experience with my work however, I now that earning a bachelor’s degree will further enhance the skills I need to work in my field of business. Once in college I will take the courses of Business Administration since IÂ  have always desired a career that requires innovation, educated risk, and foresight. I learned to respect these qualities from my father through his example I have learned firsthand the advantages and challenges of a person with a low education and a person with a high education -the reward to be gained and the total commitment required. Having a degree in Business Administration would be a significant asset in my account just in case if I were to plan on working for a business which involved management, finance, or marketing. Upon my second year in college I plan to enroll in the track courses of Entrepreneurial Studies. These classes will teach me advanced business techniques and their successful implementation. In addition, academic entrepreneurial organization would be both are both educational and enjoyable since I view these as an opportunity to meet students or teachers who share similar goals.

Iago Manipulates Essay

In the play Othello, written by William Shakespeare, the antagonist Iago manipulates other characters. He makes them act in ways that benefits his plan of destroying Othello by making him believe that his wife, Desdemona, is having an affair with his lieutenant, Michael Cassio. In the beginning of the play, Roderigo who is in love with Othello’s wife, Desdemona, comes to Iago for help. Iago manipulates Roderigo by promising him Desdemona’s attention and love if he â€Å"put money in thy purse,† as Iago says. Roderigo gives money to Iago in the mistaken belief that Iago is using his money to help him get to Desdemona, but Iago is using it to finance his own plan. Roderigo is a desperate character in the play and is easy tricked by Iago, because he doesn’t think he has anything to lose and because he would do anything to get Desdemona. His desperate feelings for Desdemona and Iago’s convincing manner make Roderigo easy to deceive. Iago has also a wife, Emilia. He doesn’t really manipulate her, because she is unaware of what’s going on between Othello and Desdemona during almost the whole play, but he makes her do thinks that benefits his plan. For example, he makes her steal Desdemona’s handkerchief, which ended being the â€Å"icing on the cake† for Othello’s suspiciousness on Desdemona’s and Cassio’s love affair. Everyone likes and trusts Iago, and so do Desdemona. Iago is seen as an honest man, which helps him manipulate people, because they always believe him. Iago manipulates Desdemona by acting on her side and by sympathizing with her. When Othello starts to get very suspicious, he gets very angry at Desdemona, but he refuses to tell her why. Iago convinces her that Othello is angry on a letter he got earlier and not on her. Desdemona believes this lie, which probably stops her from questioning Othello’s behavior. Iago’s plan is to make Othello think that Desdemona and Cassio are having an affair together. His first move to manipulate Cassio is to get him in trouble. He gets Cassio in trouble by making him drunk and by developing a fight for him. When Othello hears what happened, he removes Cassio from his post. Othello asks Iago what Cassio did, but Iago refuses to tell him anything, he says, â€Å"I had rather have this tongue cut from my mouth than it should do offense to Michael Cassio. By doing this statement in front of Othello and Cassio, he earns Cassio’s trust. Iago uses this trust to manipulate Cassio later in the play. He tells Cassio that the best way to get his position back is to talk to Desdemona and get her on his side. Cassio does what Iago told him, and Desdemona is happy to help him because she knows him and she thinks he is a noble friend to Othello. But when Iag o and Othello come near, Cassio leaves because he doesn’t want to face Othello personally. Iago uses this situation to plant his seed of doubt, and tells Othello that Cassio fled when Othello came near. This is what starts Othello’s suspiciousness. Iago is a smart man who knows how to act and what he should say to manipulate the people around him. The character that Iago manipulates the most is Othello. He makes Othello believe that Cassio talks about Desdemona, while he is actually talking about Bianca and his sexual relationship with her. Iago makes up a story that he heard Cassio talking about Desdemona in his sleep. He also tells Othello that he has seen Cassio wipe his brow with Desdemona’s handkerchief. As a result of this, Othello gets livid and really frustrated, and wants to kill both Desdemona and Cassio. This clearly shows how Iago manipulates Othello. Iago is an intelligent character that is strongly talented in improvising and he has a clear feeling for timing. His most important skill is his acting ability. He’s a perfect actor. Although Iago plants his suspicion step by step by lying and by supplying â€Å"evidence† when it is needed, he always pretends to be a moral and loyal friend who everyone can trust. One of his strategies is to let other people make their own conclusions. Iago is smart enough to use other people’s actual weaknesses and to let them draw wrong conclusions themselves. All these strategies and abilities help him manipulate other characters in the play.