Infection

1.Introduction

Tuberculosis is a very serious infectious disease that primarily affects the lungs, causing cough and breathing difficulties. The infection also causes systemic effects including fever, night sweats and weight loss (Ellner, 2011). In some cases, the infection can spread beyond the lungs and affect the bone/joints, lymph nodes, abdomen and blood stream (Ormerod, 2003). The disease is caused by the bacteria mycobacterium tuberculosis (WHO, 2014), which is spread through respiratory droplets. These droplets are passed when an infected individual coughs or sneezes and the droplets become inhaled by another person (NHS, 2014). Despite this easy method of transmission, tuberculosis is not readily transmitted, and therefore is most likely to affect those in close contact such as family or household members (Castillo-Chavez & Feng).
Tuberculosis represents a significant risk of morbidity and mortality and represents a significant cost to society to treat and manage. Tuberculosis has particularly shown to be a problem in cities, whereby the rates of increase are greater than those of rural areas (Anderson et al. 2006). This essay will address the reasons as to why tuberculosis affects urban areas (the sick city hypothesis), and look in to why tuberculosis contributes to this urban health penalty.

As an exemplar of an urban environment suffering from the burden of tuberculosis, this essay will focus on the London borough of Newham. Newham has a tuberculosis rate 8 times higher than the national average and 3 times that of London. This essay aims to investigate the aetiology behind the incidence, and to find ways of reducing the rates of tuberculosis among individuals in the London borough of Newham. The paper will include the intervention strategies and how they should be implemented in order to reduce the rates of new infections and encourage men to get tested and get early treatment before the spread of infection.

2.Tuberculosis in an Urban Environment

Tuberculosis tends to be regarded as a problem of the past, and was responsible for 20-30% of all mortality in 17th-19th century Europe (Dye & Williams, 2010). The incidence of tuberculosis declined throughout the 20th century (Watson & Maguire, 1997), however, the disease has been slowly returning to London since the 1980’s (Great Britain 2008, p. 19). The problem seems to be worsening in urban areas. This is illustrated by the example of London, where 3,302 new cases of tuberculosis (TB) were reported in 2010 (Fullman & Strachan 2013, p. 25), a figure that has more than doubled since 1992 (Anderson et al 2006). In 2006, the incidence of tuberculosis in London was 41.5 people in 100,000, a figure that represented the highest number of new cases in any major city in Western Europe (Anderson et al, 2006). Dyer (2010, p. 34) claims that the London borough of Newham is the most affected with some people already referring to it as the TB capital of the affluent western world. In fact, the rates of tuberculosis in Newham are currently higher than that in some impoverished countries. Vassall (2009, p. 48) suggest that Newham has 108 cases per 100,000 and Anderson et al suggest a 2001 figure of 116/100,000, figures that are more than half that in India (174 cases per 100,000) (Public Health England, 2012).
Newham has a population of 308,000 with a population density of 85.1 per hectare as compared to 31 in central London (UK Census, 2012). These figures suggest that even in the populated city of London, Newham is an area of urbanisation, with a large number of people concentrated into a relatively small area.

The increase of tuberculosis has been described as a ‘penalty for high density urban living’ (Dye 2010, p.859), likely due to the increased potential for transmission in overcrowding, and the increased rates of immigration to inner-city areas. Bhunu and Mushavabasa (2012) propose that tuberculosis thrives in conditions of overcrowding and poverty, issues that are common in urban areas.

The high rates of tuberculosis in cities such as London, and areas of urbanization such as Newham, suggest that the incidence of tuberculosis is indeed an urban issue. Newham fulfills the criteria of high immigration rates and being an area of deprivation..

Newham has a diverse ethnic population, with 61% of the people being non-white (Farrar & Manson 2013, p. 54). The population of ethnic minorities continues to grow along with the increasing numbers of refugees and asylum seekers in greater London.

Another aspect of urbanisation illustrated in the borough of Newham is that of deprivation and overcrowding. Farrar & Manson (2013, p. 16) claim that Newham ranks as the third most deprived borough in inner London. Most of the people here live in tower housing and overcrowded conditions that are the perfect condition for the spread of tuberculosis. There is a positive correlation between poor housing and poverty and the prevalence of tuberculosis, which is very clear in Newham as evidenced by the findings of 108 and 116 cases per 100,000 people (Vassal, 2009; Anderson et al., 2001). The aetiology of the issue of tuberculosis is highlighted when considering the distribution of the disease across Newham. The occurrence of disease is not evenly spread across the borough, with 70% of cases coming from Manor Park, Green Street and East Ham. These boroughs represent areas of population increase, overcrowding and higher levels of those living in poverty. Manor Park and Green Street also show differing dynamics of tuberculosis incidence, representing an overall increase of 40% since 2006 whilst all other areas of Newham either remained static or showed slight decrease (Malone et al 2009, p. 23).
It can be seen that tuberculosis presents a significant urban issue, especially when comparing incidence in an urban area such as Newham to those less urbanised areas. Bromley has a population of 309,000 and a population density of 20 per hectare, in comparison to Newham’s population density of 80 per hectare (UK Census, 2012). Tuberculosis incidence in Bromley is between 0-19 per 100,000 compared to that of Newham, which is five times greater at 80-100 per 100,000 (Anderson et al., 2006).
It is for this reason that necessary intervention strategies need to be formulated and implemented to help reduce the rates of tuberculosis among individuals living in Newham.

3. The Influence of Urbanisation on Tuberculosis Incidence

While the global rates of tuberculosis are declining, the disease is showing steady increase in the United Kingdom. In 2012, 8751 new cases of the disease were identified in the country with 39% coming from London (Fullman and Strachan 2013, p. 43). Indeed London has the highest rates of the disease in Western Europe with Newham borough having the highest rates in the UK. Jindal (2011, p. 55) claims that the rate of tuberculosis in some London boroughs is more than twice higher than the threshold used by the world health organisation to define high rates. These higher incidences support the notion of a sick city hypothesis where there are greater levels of ill health than in rural areas, and may be due to the presence of factors in an urban environment that contribute to ill health (an urban health penalty).
One factor that may contribute to the urban health penalty is that of immigration. Cities are easier to access than rural areas, provide areas of congregation and provide more facilities for immigrating families and individuals. The majority of individuals suffering from tuberculosis are people born outside the United Kingdom, with 75% of cases in 2003 being born abroad (Anderson et al., 2006). A reason for the high incidence in those born abroad but now living in the UK is exacerbated by the nature of tuberculosis. On initial infection, tuberculosis is confined by the immune system with only around 5% of cases experiencing symptoms within the first two years of infection (Narasimhan et al., 2013). The remainder of cases harbour a latent infection which may reactivate later in life, with about 10-15% of those infected going on to develop an active disease (Narasimhan et al., 2013). This insidious nature combined with the later activation of the disease explains why many people do not get the disease until later in life. It is likely that it is contracted in their country of birth, however then manifests much later once they have moved to the UK.
Statistics indicate that over 90% of the residents in Newham diagnosed with the disease in 2011 were born outside the United Kingdom (Fullman and Strachan, 2013, p. 33). Among these, 50% arrived in the country in the last five years. In the same year tuberculosis diagnosis increased by 25% compared to 2010 (Fullman and Strachan, 2013), possibly as a reflection of the increased immigration.
Additionally to a high immigrant population bringing significant disease burden from their countries of birth, London and Newham both represent many of the other issues of urbanisation and urban health penalty that can contribute to the high incidence of tuberculosis.
Studies have shown that low vitamin D levels are associated with an increased risk of developing tuberculosis (Campbell and Spector, 2012; Chan, 1999). This is an important association in urban populations, as the living and working conditions foster less access to sunlight (the major source of vitamin D). Additionally, Asian immigrants present a problem of low vitamin D due to vegetarian diets, and a tendency to cover up their skin, not allowing to take advantage of the small amount of sunlight available (Chan, 1999). As previously mentioned, Newham is an area of both high urbanisation and with a large immigrant population, and 38.6% of the population being of Asian descent (London Borough of Newham, 2010).
The immigrant population of urban areas such as Newham also present a non-vaccinated proportion of society. Whilst the BCG vaccine against tuberculosis was introduced in the UK in the 1950s and was shown to provide a reduction in risk of contracting tuberculosis (Colditz et al., 1994), those immigrating were less likely to receive this vaccination on moving to the UK.
London also represents cases of tuberculosis that are socially and medically complex. As a hugely populated area, London includes those with HIV infection and presents other risk factors such as onward transmission and poor treatment. HIV is one of the most powerful risk factors for tuberculosis, with a incidence rate of 20 times higher in those that are HIV positive (Dye and Williams, 2010). People’s attitudes towards and access to healthcare also present a complex mix of factors which contribute to an increased incidence of many health problems, including that of tuberculosis. Those in impoverished areas have reduced access to healthcare, which may stem from many reasons such as complex needs, chaotic lifestyles, location of services, user ignorance, and language and literacy barriers (Szczepura, 2005). These can affect the disease process of tuberculosis from prevention, treatment of active disease, adherence to treatment and prevention of the health consequences.
Especially problematic are misconceptions and a lack of understanding of the disease, leading to late presentation and delayed access to treatment (Figuera-Munoz and Ramon-Pardo, 2008)
With the close living quarters in areas such as Newham, the spread of tuberculosis is facilitated. With poverty, poor housing and overcrowding, these areas concentrate several risk factors and lead to a greater spread of tuberculosis (Bates et al., 2004).
These determinants therefore suggest that the incidence of tuberculosis in urban areas is a complex issue. Controlling and preventing tuberculosis in London requires effective social and economic tools that must be incorporated in the development of policies of control in treatment initiation.

4. Consequences and implications of tuberculosis on the general population

Tuberculosis ranks with HIV/ AIDS and Malaria as one of the three main health challenges currently facing the world. The Commonwealth Health Ministers Update 2009 (2009, p. 41) indicates that 8 million new cases are reported globally each year. As previously mentioned, when combined with HIV, tuberculosis can prove lethal as the two diseases enhance the progress of each other. It is for this reason that tuberculosis is the major cause of death among HIV patients with the rate standing at 11% globally. The World Health Organization (2009, p. 27) indicates that tuberculosis is responsible for more deaths today than ever before, with approximately 2 million lives claimed by the disease annually.
As well as the significant mortality contributed by tuberculosis, the morbidity of the disease can be extremely detrimental both socially and economically. Those with the active disease that are not receiving treatment have been shown to go on to infect 10-15 others every year (WHO, 1998). Those who do receive treatment face a long (up to six months) and complex treatment regime involving several medication side effects. This can affect adherence to the treatment regime, and lead to the disease developing a resistance to the treatment, with this drug resistant tuberculosis contributing to greater mortality and increased expense to treat (Ahlburg, 2000).
As well as the significant morbidity and mortality, it is important to consider the economic impact of tuberculosis. The World Health Organisation estimated the cost to treat tuberculosis in 2000 as $250,000 US dollars (?150,000) in developed countries (Ahlburg, 2000). This presents a significant burden to the UK NHS, not to mention the time lost through not working which can dent the economy.
London is a global world trade centre whose economy is shaped by global forces, particularly in terms of trade, labour and capital. As a gateway to both the UK and other parts of Europe and the rest of the world, London records a very large number of tourists and immigrant populations. This high number of people accelerates the spread of the disease as people carry it to the country from other parts of the world is indicated by the new infection patterns and is highlighted by the prevalence in immigrant populations.
5. Strategies and intervention for addressing tuberculosis

Current UK guidelines for tuberculosis intervention were made by NICE in 2006 (updated 2011). The recommendations propose strategies for identifying those with latent (non-active) tuberculosis to prevent spread or reactivation and also specify criteria for treatment (NICE, 2011). Those recommended for screening for latent tuberculosis include close contacts of infected individuals, immigrants from high incidence countries, immunocompromised individuals, and healthcare workers. Whilst this strategy targets prevention of the spread of tuberculosis, they are only targeting specific groups, and it is likely in high incidence areas such as Newham, people will slip through the net. These guidelines have only changed minimally since 2006, and since then tuberculosis incidence has been on the increase in areas such as Newham, suggesting that changes may need to be made.
High incidence areas of the UK such as Newham could learn from New York experience and copy the strategy it used in dealing with the disease. With the implementation of broadened initial treatment regimes, direct observed therapy, and improved guidelines for hospital control and disease prevention, the city managed to halt the progression of an epidemic (Frieden et al., 1995). As mentioned in the previous chapter, adherence to the lengthy treatment regime as well as a lack of understanding may contribute to the spread of tuberculosis. Directly observed therapy (DOT) involves observing the patient take each dose of their medication, with outreach workers travelling to their homes. Evidence from New York showed that through DOT, only 3% of patients in therapy were infectious, compared to a proposed 20% if not receiving DOT (Frieden et al., 1995). Current UK guidelines (NICE, 2006) do not recommend DOT, although they do state that it may be used in cases of patients with previous issues with adherence or at high risk. Although an expensive and time consuming process, if DOT can reduce infectious cases, this would also work as a preventative measure. There could be one allocated outreach nurse for the borough of Newham and other high-risk areas.
Another method implemented in New York was the downsizing of large shelters for the homeless. These were breeding grounds for tuberculosis, and the subsequent reduction in overcrowding led to a decrease in transmission of the disease (Frieden et al., 1995). Whilst it is not possible to split people up from living with their families in crowded homes in terms of Newham, education about keeping those with tuberculosis from interacting with too many others in crowded conditions may be of benefit.
The model should also borrow from those used by other cities like Paris and the rest of Europe in controlling tuberculosis with intervention at the level of the agent, individual and community levels.
In Paris, Rieder (2002) suggested that prophylactic treatment could be used to prevent the disease occurring in those at risk, for example those in the household of an identified case of tuberculosis. Additionally, Rieder (2002) proposed that early or neonate vaccination be used especially in those in areas where tuberculosis is frequent, rarely diagnosed, and adequate contact examinations rarely feasible. It may be possible that in cases where lots of people are vaccinated that they may infer herd immunity and thus protect unvaccinated individuals from the disease. Once the populations have been protected and the incidence (number of new cases) of tuberculosis has been reduced, this allows for a reduction in the prevalence of tuberculosis (number of ongoing cases at any one point in time) with preventative chemotherapy that can treat sub-clinical, latent tuberculosis in the population. This preventative chemotherapy is likely to be extremely relevant to Newham due to the large immigrant population likely harbouring latent tuberculosis.
On a country- or city-wide scale, these recommendations from New York and Paris provide excellent models for preventing the increase of tuberculosis any further. It is also important, however, to consider the individual communities in Newham, and to promote health awareness and an attitude towards taking responsibility for their health. Their needs to be an encouragement at the level of primary care where immigrant populations feel that they can approach healthcare, and education to encourage tuberculosis prevention and adherence to treatment.
The strategy should be all-inclusive in order to encourage people to not only go for testing but also start and finish the treatment process.

6. Recommendations and conclusion

Tuberculosis presents an important urban issue in the area of Newham. Incidence is greater than other areas of the UK, and is over half that of India. There are several factors contributing to this including a large immigrant population, crowding and overpopulation, access to healthcare and comorbid health problems such as vitamin D deficiency and HIV.
The disease has considerable effect on morbidity and is responsible for high levels of mortality. Further consequences of the disease manifest as economic problems such as cost of treatment and loss of work.
London and the UK already have policies and structures for controlling tuberculosis in place; however the implementation process is patchy across the city, and often dependent upon budget. In high-risk areas such as Newham, there is poor access of healthcare due to inaccurate beliefs on the disease, language and cultural barriers, and complex needs of the population. In the case of tuberculosis, these contribute to poor disease prevention, delayed diagnosis and poor treatment adherence. All of which lead to an increase in transmission and health consequences. The area of Newham would benefit greatly from further education into tuberculosis, how to look for signs and how to get treatment. Encouraging good relationship with healthcare professionals and promoting access to healthcare through outreach programmes and targeting pharmacies may be helpful.
Additionally, Newham should look to employ techniques used in New York and Paris, including DOT, prophylactic treatment and neonate vaccination to reduce both the prevalence and incidence of tuberculosis.

References

Ahlburg (2000). The economic impact of TB: ministerial conference Amsterdam, WHO
Bates, I., Fenton, C., Gruber, J., Lalloo, D., Lara, A. M., Squire, S. B., … and Tolhurst, R. (2004). ‘Vulnerability to malaria, tuberculosis, and HIV/AIDS infection and disease. Part II: determinants operating at environmental and institutional level’. The Lancet Infectious Diseases, vol. 4(6), pp. 368-375.
Bhunu, C. P., and Mushayabasa, S. (2012). ‘Assessing the effects of poverty in tuberculosis transmission dynamics’. Applied Mathematical Modelling, vol. 36(9), pp. 4173-4185.

Campbell, G. R., and Spector, S. A. (2012). ‘Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy’. PLoS pathogens, vol. 8(5).

Castillo-Chavez, C., and Feng, Z. (1997). ‘To treat or not to treat: the case of tuberculosis. Journal of mathematical biology’, vol. 35(6), pp. 629-656.

Colditz, G. A., Brewer, T. F., Berkey, C. S., Wilson, M. E., Burdick, E., Fineberg, H. V., and Mosteller, F. (1994). ‘Efficacy of BCG vaccine in the prevention of tuberculosismeta-analysis of the published literature’. Jama, vol. 271(9), pp. 698-702.
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Introduction

Measles virus (MV) is a member of the paramyxovirus family and has a single stranded RNA genome. The viral genome encodes for six structural proteins: Haemagglutin (H), Fusion (F), Nucleoprotein (N), Phosphoprotein (P), Large (L) polymerase protein, and Matrix (M) protein and two non-structural proteins: C and V (Griffin, 2010). The structure of the virus is shown below.

Fig 1. The structure of the Measles virus

Ref:http://www.microbiologybytes.com/virology/Paramyxoviruses.html

The majority of measles cases occur in children and in those who are fit and healthy, results in life long immunity without complications. Measles virus has been eliminated in the western world since 2000 through an efficient vaccine programme, however, it is a different scenario in developing countries were deaths arise due to lack of vaccine administration and malnourishment of children (Fontana et al, 2008).For example in 2008, 164 000 people died from measles virus of these 95% were in low-income countries (www.who.int/mediacentre/factsheets/fs286/en/). Although infection with MV produces an efficient immune response that is maintained for the rest of the individuals life, it also results in a transient state of immunosuppression that can last for several weeks. This leaves the patient susceptible to secondary infections by opportunistic pathogens which account for the majority of measles associated deaths (Sevet-Delprat et al, 2000).The exact mechanism of the immunosuppression is still unknown however many theories have been suggested.

Infection and Spread

The MV is spread through aerosol transmission in the cough or sneeze of an infected person. The virus is extremely contagious and can remain in the air or on a surface for up to two hours (Stalkup, 2002). The route of entry for the virus is through the respiratory tract and once infected, the virus will incubate for an average of 10-12 days before any symptoms are seen. Infection is initiated by the attachment of the H protein to the host cell receptors, which results in the fusion of the envelope of the virus with the host cell membrane. This fusion of membranes causes the release of viral RNA into the host cell cytoplasm. After the RNA has replicated, using host cell machinery, new virus particles are assembled using the M protein and bud from the host cell membrane to infect other susceptible cells (Swart, 2008). The host cell receptors for the measles virus are CD46, a complement regulatory protein that is found on all nucleated cells and the Signalling Lymphocytic Activation Molecule (SLAM/CD150) which is found on the surface of both T and B lymphocytes as well as macrophages and mature Dendritic cells (DC) (Yanagi et al, 2006). In vitro studies have found that vaccine strains of the measles virus use CD46 and SLAM as their receptor however wild-type MV only recognizes CD150 (Ferreira et al, 2010). There has been some debate over the exact cell that is involved in the initial infection with MV. It had previously been thought that the virus infected epithelial cells lining the nasopharynx (Stalkup et al, 2002) however more recent studies have shown that these cells do not bear the MV receptors SLAM which facilitate wild-type viral infection therefore further studies are required to identify this unknown receptor . It has been suggested that alveolar macrophages and DC lining the respiratory tract are the initial cells involved in measles infection.This was demonstrated in a study using mice that expressed humanized SLAM. These mice were infected intranasally with wild type measles virus expressing green fluorescent protein. The nasal associated lymphoid tissue (NALT) was then extracted from these mice at different time points (1,2 or 3 days). Results showed that alveolar macrophages were the first cells to be infected by the measles virus and not the epithelial cells (Ferreira et al, 2010).

DC’s are the main antigen presenting cells of the immune system and are used by other viruses to infect lymphocytes for (example the HIV virus) (Witte et al, 2008). Therefore DC may provide an important route of transport for MV to secondary lymphoid tissue. The role of DCs in measles infection is further indicated by the identification of DC-SIGN which is an accessory receptor that has been identified on MV susceptible cells and is thought to assist MV infection of CD150 expressing DCs (Yanagi, 2006). Furthermore, large numbers of DC-SIGN positive DCs have been found to be present in the epithelium of the respiratory tract which demonstrates their potential primary role in MV infection of (Ludlow et al, 2010 ; Witte et al, 2008).

An alternative theory is that epithelial cells are infected in the latter stages of infection by lymphoid cells facilitating viral spread by the respiratory route. This would mean that epithelial cells are infected at the basolateral cell surface rather than the apical surface. This was demonstrated by a study that looked at mutated MV strains that could not bind to the as yet unidentified Epithelial Cell receptor (EpR) but could still recognise the SLAM receptor. Results showed that the macaques developed the rash but could not shed the virus which suggests that the EpR is a basolaterally expressed protein that is important for the spread of the virus at the infective stage (Leonard, et al, 2008). A study by Ludlow (2010) supported these findings by showing that wild type MV could not infect primary columnar epithelial cells by the apical surface further demonstrating the potential role of epithelial cells in latter stages of infection rather than initial stages as previously thought.

In response to viral infection the innate immune system responds by producing inflammatory cytokines to protect cells from viral infection. These cytokines include type 1 interferons (IFN) such as IFN? and ? which are induced in response to RNA viruses. IFNs induce an anti-viral state in neighbouring cells and increase the expression of class 1 Major Histocompatibility Complex (MHC) molecules on the infected cell surface which will present the viral antigens to CD8+ T cells. CD8+ T cells clear the infection by cytotoxic T cell mediated killing of the infected cell (Abbas & Ltchtman, 2005). To overcome these host cell defences, viruses have ways to evade the immune system. MV virus protein V and C have been shown to downregulate IFN production in vitro and this includes both attenuated and wild type strains (Fontana et al, 2008). Through the inhibition of the proinflammatory cytokines MV can infect more host cells. MV may also use the innate immune system to enhance viral spread and pathogenesis by using Toll like receptors (TLRs) which are found on the surfaces of cells that activate the immune system by recognising bacterial and viral pathogens. The binding of TRL2 on human monocytes by MV H protein has been shown to induce production of interleukin 6 (IL-6) which upregulates expression of SLAM the primary receptor for MV (Beiback et al, 2002).

Once the virus is picked up by antigen presenting cells it is carried to the secondary lymphatic tissue were it can replicate in T cell, B cells and activated monocytes with lymphocytes being the main target cell of MV infection (de Swart et al, 2007). These infected cells can be seen in the blood 7-9 days after infection (Griffin, 2010). It is thought that through these infected lymphoid cells that the virus is able to infect epithelial and endothelial cells lining organs including the liver, brain and skin (Moench et al, 1988). In order for MV to infect these organs it must overcome these endothelial cell barriers.It has been shown in cell culture that wild type MV infection may infect endothelial cells by increasing the expression and activation of leukocyte integrins which bring infected T cells into close contact with these cells leading to their infection (Dittmar et al, 2008).

Symptoms

The initial symptoms of MV are very similar to those of the flu including runny nose, conjunctivitis and cough which is accompanied by a fever of 104-1050F that lasts up to 4 days (Stalkup, 2002). The characteristic feature of MV is the red rash that appears beginning on the face and behind the ears, which spreads to the rest of the body (please see Fig 2 below). During this time the person is highly contagious and remains so until the rash disappears (www.cdc.gov/vaccines/pubs/pinkbook/download/meas.pdf).

Fig 2 shows a child with an extensive rash caused by the Measles virus.

Ref: http://www.vaccineinformation.org/measles/photos.asp

Small white spots known as Koplik spots may also be seen in the inside the mouth which is a diagnostic indicator of measles and appear one day before the rash (Perry & Halsey, 2004). The appearance of the rash is due to the immune systems attack of the systemic infection of epithelial cells and biopsies of the rash have shown infiltration of CD8+ and CD4+ T lymphocytes in the rhesus monkey (Permur et al, 2003). An individual who in infected with measles virus will recover within about 10-14 days but may remain vulnerable to secondary infections including pneumonia and diarrhoea for a few weeks.This was first noted by von Pirquet who noticed that individuals recently infected with the MV failed to respond to the tuberculin skin test and this has led to many studies into the reasons for this immune suppression (Griffin et al, 1994).

One reason for the immunosuppression seen after a measles infection is the switch from a T helper 1 (Th1) CD4 response to a T helper 2 (Th2) CD4 response. Initial MV infection results in the production of a Th1 response which is necessary to eliminate the pathogen and is marked by increased production of IFN? however as the rash is cleared this changes to a Th2 response which is important in the production of measles specific antibodies (Moss et al, 2004). Th2 cytokines IL-4 and IL-10 have been shown to be elevated for weeks in those who have had MV (Moss et al, 2002). IL-10 suppresses the immune system by inhibiting lymphocyte proliferation and macrophage activation therefore may have a key role in failure to generate a Th1 response after MV infection (Sato et al, 2008).

IL-12 is primarily produced by activated macrophages and DCs and has a pivotal role in the generation of a cell mediated immune response as well as directing CD4+ T cells to differentiate into Th1 cells (Abbas & Lichtman, 2005). Studies have shown that MV infection of DCs inhibits IL-12 production which would lead to an environment favouring a Th2 cell response (Servert-Delprat et al, 2000). Furthermore peripheral blood monocytic cells taken from patients with measles have been shown to have a prolonged decrease in IL-12 (Atabani et al, 2001). Stimulation of DCs through TLR4 also results in inhibition of IL-12 in mice expressing human SLAM receptor (Hahm et al, 2007).

As lymphocytes are the main targets for MV infection and replication the immunosuppression seen after infection may be due to as decrease in circulating lymphocytes. However, studies have shown that lymphocyte numbers quickly return to normal levels and therefore cannot account for the immune suppression seen weeks after infection (Griffin, 2010).

Subacute Sclerosing Panencephalitis (SSPE)

SSPE is a rare neurological complication of MV infection that affects 1 in a million measles cases although there is an increased risk with children infected with the measles virus before age 2 and males more than females (Norrby & Kristensson, 1997). The characteristic symptoms of SSPE are deterioration of mental and motor functions as a result of destruction of brain tissue. These symptoms typically begin to manifest 7-10 years after primary viral infection and ultimately result in death within 2 years (Stalkup, 2002). Patients with SSPE have high levels of measles specific antibody circulating in their blood and cerebrospinal fluid (CSF) yet the virus is not eliminated (Barrero et al, 2003). It is thought that the virus mutates inside the neurons which allows it to evade the immune system however these mutations may alter the host cells leading to the generation of the immune response (Gutierrez et al, 2010). However the mechanism by which neurons are infected is still unknown as no receptors have been identified. There is no cure for SSPE although treatment of individuals with Interferon ? and Isoprinosine has been shown to slow down the progression of symptoms in some individuals (Gascon et al, 1993).

Vaccination

The first MV vaccine was produced in the 1960s which was formalin-inactivated with alum. This vaccine produced a condition known as atypical measles which resulted in some individuals experiencing symptoms which were often worse than wild-type measles, when they came into contact with someone who had measles (deSwart, 2008). In 1963, Enders measles vaccine was developed which was a live attenuated vaccine (Stalkup, 2002). This vaccine is grown in cell culture fibroblasts from chicken embryos and is unable to produce its full pathogenic effect but induces an adequate life long immune response (P?tz et al, 2003). The measles vaccine has resulted in a 99% fall in the number of measles cases that were previously seen annually in the United States (Stalkup, 2002). MV could potentially be irradicated but this is dependent on high vaccine coverage. The World Health Organization (WHO) has a policy in place which has set a goal of reducing the death rate from MV in children under 5 by 2015 (http://www.who.int/mediacentre/factsheets/fs286). MV infection can also lead to blindness in children who are Vitamin A deficient and the WHO have recommended that all children with measles are given vitamin A supplementation to combat blindness (Semba and Bloem, 2004).

The measles vaccine is part of the Measles Mumps and Rubella (MMR) vaccine that is given in two doses. The vaccine is administered intramuscularly and the first injection is given to children around 13 months (http://www.nhs.uk/conditions/mmr/Pages/Introduction.aspx). The vaccine is not given before this age because these children will have maternal antibodies which would interfere with the vaccine and not generate an appropriately high enough immune response (Moss et al, 2004). A second dose of the MMR vaccine is given to preschool children as a booster as 2-5% of individuals fail to produce an appropriate protective immunity to the first inoculation

(http://www.cdc.gov/vaccines/vpd-vac/combo-vaccines/mmr/faqs-mmr-hcp.htm). New methods of delivery of MMR vaccine have been investigated such as the use of aerosol vaccine which would mimic natural measles infection and the use of DNA vaccine administration. Aerosol vaccine has been found to generate an effective immune response that is equal to that of the currently used vaccine and may also overcome the interference from maternal antibodies however clinical trials are still in progress (Heno-Restrepo et al, 2009). Furthermore, trials into the use of DNA vaccines have proposed a potential to vaccinate children as young as four months (Pasetti et al, 2009).

The MMR vaccine has been in the public eye for many years as a result of a paper by Wakefield and colleagues in 1998 which claimed that there was a link between the administration of the MMR vaccine and the development of autism (Farrington et al, 2001). Many studies have been carried out to either prove or disprove this study as these claims led to fear amongst parents regarding vaccination of their children and uptake fell to 80% between 2003 and 2004 as a result of this (Bedford & Ellimen, 2010). As stated in the introduction MV is so contagious even a minor drop in vaccine coverage can lead to a large number of cases. In 2010 after an extensive investigation by the General Medical council it was finally confirmed that the paper by Wakefield was unfounded (Godlee et al, 2001).

Conclusion

Although cases of MV are rarely seen in this country it results in the death of many children in the developing countries. Currently vaccination is given at 13 months of age however many studies are ongoing that could potentially provide a vaccine that could be administered earlier resulting in children being protected earlier and limiting hosts for the virus. Furthermore, malnutrition is one of the major contributing factors in the deaths from measles virus, tackling this problem would also decrease the mortality rate. As stated above MV poses a problem in that infection generates a life long immune response but also leaves the host susceptible to secondary infections. The exact mechanism for this is not yet known therefore more work is needed to answer this problem and potentially combat this immune suppression.

Introduction

In this article, we will discuss a case scenario related to diabetic mellitus patient. After understanding the case, we will state what is our main concern in this scenario and why will we focus on this aspect rather other aspect. Also we will introduce some tools to do an assessment in order to predict the outcome. If we understand the possible outcome, we may anticipate the outcome of this patient and understand the possible worse situation too. In this scenario, foot assessment will be focused on.

Case scenario

Ms Wong, 47 years old woman who was a housewife, arrived at hospital due to get dizzy, fatigue and fall in the floor at home with little bleeding. After she arrived at emergency department, nurse discovered she got a wound in the left heel but she didn’t feel pain, nurses suspected she got the wound during she fell in the floor. Her vital sign was normal; body temperature was37.5C, pulse 70/min, blood pressure 126/80 mmHg, respiration 18/min. After having a blood glucose test, we knew that she was suffering from hypoglycemia and her blood glucose index was 2 mmol/d. As nurse provided glucose water and wound dressing to her, she recovered and transferred to ward for continuing observation. Her past history was that she was suffering diabetic mellitus for 7 years and having regular oral diabetic mellitus medication without daily blood glucose test by herself and her BMI was over 25, she was overweighed. Her parents had diabetic mellitus too but they passed away.

After tackling her emergency problem which is lower blood glucose level, we will focus on the further investigation in order to find out the reason why she don’t get any feeling of her wound as well as to investigate how the sensation change and what is the possible outcome so as to give some recommendations to her and prevent the serious consequences. As early detection and treatment of diabetic foot complication could reduce the prevalence of negative outcome. (Prakash, 2011) In the following part, we will focus on the foot assessment.

For foot assessment

Foot assessments include the following aspects such as demographics, musculoskeletal system, neurologic system, peripheral vascular system and skin. Assessments will though inspection, palpation, sensation and using tools so as to obtain the result.

For demographics

To obtain data from interview, it includes regarding type of diabetes, gender, any smoking habit, presence of hypertension, retinopathy, nephropathy and suitability of footwear. (Thompson, Nester, Stuart & Wiles, 2004)

For musculoskeletal system

Assessment includes postures, gait, strength, flexibility, endurance and range of motion. It includes evaluation for any deformity because imbalance of foot muscles frequently. (Khanolkar, Bain & Stephens, 2008) Other muscles problems like claw toes, hammer toes, heel spurs, calluses, cracks and corns. (Chan, Yeung, Chow, Ko, Cockram & Chan, 2005) The website shows how to have the musculoskeletal assessment to the patient. (BJSM, 2008)

Inspection and palpation can be applied into this assessment, note the size and contour of the joint which is including knee and ankle, inspect the skin and tissue of the foot for color, swelling and any masses, any lesion or deformity, pay attention of the skin integrity.

Palpation is including skin for temperature, muscles, bony articulations and area of joint capsule, notice any heat, tenderness, swelling. The most important is to palpate radial and brachial pulse. If the peripheral pulse is weak, we need to have a further assessment.

Neurologic system

Assessment should include asking neuropathic symptoms such as burning, tingling, numbness and nocturnal leg pains. Assessment related to sensory assessment, pressure assessment, and vibration sensation too.

For sensation

Pinprick sensation test is used to test pain. Lightly apply the sharp point or dull end to the foot skin randomly, unpredictable order and ask the patient to say sharp or dull depending on the sensation felt. If the result of pinprick sensation test is abnormal, temperature sensation test will be applied. Fill two test tubes, one with hot water and one with cold water and apply the bottom ends to the patient’s skin randomly and ask them to say which temperature is felt. Another method to test sensation is light touch. Apply a wisp of cotton to the skin, stretch a cotton ball to make a long end and brush it over the skin in a random order and irregular intervals and ask the patient to say yes when touch is felt. (Jarvis, 2004) Pressure sensation is usually assessed by using the10gnylon Semmes-Weinstein monofilament. (Khanolkar, Bain & Stephens, 2008)

For vibration

Tuning fork can be used to test vibrations over bony prominences. Strike the tuning fork on the heel of your hand and hold the base on a bony surface of the fingers and great toe and ask the patient to indicate when the vibration starts and stops. If no vibrations are felt, move proximally and test ulnar processes and ankles, patellae. Also compare the vibration of both sides. (Jarvis, 2004)

For peripheral vascular system

The Doppler ultrasonic stethoscope is a device to detect a weak peripheral pulse and to measure a low blood pressure or blood pressure in a lower extremity. The Doppler stethoscope magnifies pulsatile sounds from the heart and blood vessels. Place a drop of coupling gel on the end of the handheld transducer. Place the transducer over a pulse site, swiveled at a 45-degree angle. Apply very light pressure and locate the pulse site by the swishing, whooshing sound. (Jarvis, 2004)

Nurses should apply both Doppler ultrasonic stethoscope and ankle-brachial index. The Ankle-brachial Index is to apply a regular arm blood pressure cuff above the ankle and determine the systolic pressure in either the posterior tibial or dorsalis pedis artery. Then divide that figure by the systolic pressure of the brachial artery. The normal ankle pressure is slightly greater than or equal to the brachial pressure. However, the ankle-brachial index may be less reliable because of calcification which makes their arteries non-compressible and may give a falsely high measurement. (Jarvis, 2004)

Skin assessment

If patient have wound or skin impair, nurses should do wound assessment to record the size and the characteristic such as redness, edema, pain and heat. It is used to follow the wound healing progress. If necessary, nurses may have a bacteria test to confirm either the wound have microbe or not. (Worley, 2006)

The outcome of having foot assessment

The assessment findings can be used to indicate or predict the problems of their diabetic foot. The most positive outcome is no diagnostic findings. It is including integrated skin with normal sensation. However, other possible findings are neuropathy, ischemia, ulceration, infection and necrosis. The most serious alive consequence is amputation.

Outcome of musculoskeletal syste

The possible finding of musculoskeletal system is foot deformity. Deformity should be recognized early and accommodated in properly fitting shoes before ulceration occurs. If nurses assess the footwear, the chance of foot deformity will be reduced. Deformities include the Charcot foot which refers to bone and joint destruction that occurs in the neuropathic foot. Early diagnosis is important to prevent severe deformity. The foot presents with unilateral erythema, warmth and edema. (Edmonds, 2008)

Outcome of neurologic assessment

The outcome of neurologic assessment is either absent of sensory neuropathy or not. If patient loss of sensory neuropathy, they cannot sense pain or pressure and has a lack of identity with their feet. Also, motor neuropathy where muscular loss results in the clawed toes, high arch, foot drop and an absent ankle reflex. Due to absence of sweat and sebum production of autonomic neuropathy, the skin is dry and inelastic. In addition, pressure sensation test can be further confirmed their pain sensation is true or not. If patient can feel the pressure from the filament, the protective pain sensation is present. It is important to avoid areas of callus when carrying out this procedure as applying the filament to a plaque of callus may lead to a false diagnosis of neuropathy being recorded. (American Diabetes Association, 2010)

Outcome of peripheral vascular assessment

The outcome of Doppler ultrasonic stethoscope is to indicate the presence of peripheral vascular disease though listen the pulse qualities. The normal range of ankle-brachial index is 1.0 to 1.2. If the ankle-brachial index is of 90% or less, it indicates the presence of peripheral vascular disease. If the index is 0.9 to 0.7, it indicates a mild claudication, 0.7 to 0.4 indicates moderate to severe claudication, and 0.4-0.3 indicates severe claudication usually with rest pain except in the presence of diabetic neuropathy. The most serious outcome of this assessment is the index less than 0.3; it is diagnosing ischemia with impending loss of tissue. (Jarvis, 2004)

Ischemia or peripheral arterial occlusive disease is the possible outcome too. It eventually will reduce in arterial perfusion severely and result in vascular compromise of the skin, often precipitated by a major trauma. Also ischemia is always associated with neuropathy. (Wilson, 2003)

Infection process is the main reason for major amputation following ulceration. It can complicate the neuropathic and the neuro-ischemia foot ulcer. As infection originate from skin trauma or ulceration, often spreading to soft tissue then bone. Associated with neuropathy or ischemia, mean infection is often missed because of an absence of pain or loss of ability to mount an inflammatory response. Also there is no increase in temperature, white blood cell count and C – reactive protein. (Wilson, 2003)

Outcome of skin assessment

The most positive skin assessment outcome is integrated skin and no wound. However, if diabetic patient have wound, healing is usually protracted. It is because patients with neuropathy continually traumatize their foot wounds by walking freely upon them. It is difficult to tell patient to take rest when they don’t feel pain during walking. Also patients with ischemia cannot mount an adequate inflammatory response to fight infection and achieve healing. Another reason is related to the healing process. Macrophages and neutrophils are important agents in wound healing, particularly at the inflammatory stage which is fundamental to all ensuing stages. However, the above function of diabetic is impaired. Thus the wound will hard to heal. If the wound decay, it will become foot ulceration. (Bentley & Foster, 2007)

Necrosis is a grave implication that diagnosis necrotic foot, threatening the loss of the lumbs, and is caused by infection or ischemia or both. It is classified as either wet or dry, each with its specific management. If it is in the neuropathic foot, necrosis is invariably wet initially and is nearly always due to a septic arteritis secondary to soft tissue infection complicating a digital or metatarsal ulcer. The arterial lumen is often occluded by a septic thrombus. Both wet and dry necrosis can occur in the neuroischemic foot. The common cause of a black toe is again septic arteritis, exacerbated by large vessel disease in the leg. Dry necrosis can also develop in the neuroischemic foot and is secondary to a severe reduction in arterial perfusion. (Edmonds, 2008)

For Amputation

The combined impact of neuropathy, ischemia and infection are so great that is amputation. It is preceded by foot ulceration and infection. It is because diabetic related to an artery disease which reduces blood flow to the feet. If the blood flow reduces, the healing process will be slowly. Even with preventative care and prompt treatment of infection and complications, there are instances when amputation is necessary to remove infected tissue in order to save a limb or even save a life. (Wilson, 2003)

If missing the above assessment, nurses cannot diagnosis the problem of this patient. The most serious consequence will be happened.

Conclusion

Diabetic foot assessment indicates lots of different outcomes. Patient with diabetic should not look down upon their wound; it will be have a serious consequence which is amputation. In order to have a quality of life, an impaired skin’ diabetic patient must need the further foot assessment so as to prevent the negative outcome.

Reference

1. American Diabetes Association. (2010). Foot Complications. Retrieved Mar 23, 2011, from http:// www.diabetes.org/living-with-diabetes/complications/foot- complications.html
2. Bentley, J., & Foster, Ali. (2007). Multidisciplinary management of the diabetic foot ulcer. Wound Care, S6, S8, S10, S12.
3. BJSM. (2008). Knee Exam (5 of 27): Neurovascular evaluation: supine. Retrieved Mar 23, 2011, from http://www.youtube.com/user/BJSMVideos#p/u/38/xe W7dwcBZCI
4. Chan, C. N. J., Yeung, T. F. V., Chow, C. C., Ko, T. C. G., Cockram, C. S., & Chan, N. N. (2005). A manual for management of diabetes mellitus a Hong Kong Chinese perspective (revised ed.). Hong Kong: TheChineseUniversity ofHong Kong.
5. Edmonds, M. (2008). A natural history and framework for managing diabetic foot ulcers. British Journal of Nursing, 17(11), S20, S22, S24, S25-S29.
6. Jarvis, C. (2004). Physical Examination & Health Assessment (4th ed.).Philadelphia:Elsevier
7. Khanolkar, M. P., Bain, S. C., & Stephens, J. W. (2008). The diabetic foot. Q J Med, 101, 685-695.
8. Prakash, S. (2011). Early Screening to Cure from Type 2 Diabetes. Retrieved March 23, 2011, from http://topnews.us/content/237118-early-screening-cure-type-2 -diabetes
9. Thompson, L., Nester, C., Stuart, L., & Wiles, P. (2004). Interclinician variation in diabetes foot assessment- a national lottery?. Diabetic Medicine, 22, 196-199.
10. Wilson, D. J. (2003). Amputation and the diabetic foot: learning from a case study. Wound Care, S18, S20, S22, S24.
11. Worley, C. A. (2006). Neuropathic Ulcers: Diabetes and Wounds, PartI.Etiology and Assessment. Dermatology Nursing, 18(1), 52-53.

Introduction

Measles is one of the most important contagious diseases of mankind. It remains one of the leading causes of infant deaths in developing countries. In 1998 the world health organization (WHO) estimated that despite all the efforts to eradicate measles it still accounted for more than 30 million infections and 1 million deaths every year. Most the infections, it is believed are from countries where vaccination has not been taken up properly and developing countries where vaccination programs are not that robust.

Measles is very infections with an infection rate of 90% when susceptible individuals are exposed to the organism that causes measles. This organism is an RNA virus of the genus morbillivirus, hence measles sometimes being referred to as morbilli. This virus belongs to the virus family of the Paramyxoviridae. The measles virus is transmitted through bodily fluids mainly as aerosols (airborne exposure) or droplets. It enters the host through the respiratory tract and immediately starts to replicate in the epithelial cells of the respiratory tract, from here the virus start to invade some cells of the immune system in the lymph nodes particularly the monocytes through which it then spreads to rest of the host body.

Measles is a self-limiting disease, which means it will normally resolve itself after a few weeks, but because measles also induces transient profound immunosuppression, most of its victims succumb to fatal opportunistic infections. Without these infections, the host will normally clear the virus from its system as illustrated by the graph below.

It should be noted that in very rare cases the measles virus cannot be cleared from the host and persist in the host system in what is termed persistent measles virus (PMV). This is the cause of most measles complications which includes subacute sclerosing pan encephalitis (SSPE) which may occur in about 1:10 000 measles cases and inclusion encephalitis which may occur if the host does not have adequate cellular response to the infection.

Infection and Spread

Clinical symptoms of measles include fever, malaise, coryza (runny nose), conjunctivitis, and tracheobronchitis. Other symptoms that appear at a later stage during infection are the Koplik’s spots, 10-12 days post-exposure, and erythematous maculopapular rash which appears at around day 14. Symptoms like diarrhea and pneumonia, which are from opportunistic infections, will not be discussed here as they are not a direct result of the measles virus. The direct results will be discussed later in this essay after discussing how the virus infects and spread around the host body. To fully understand the mechanism of measles virus infection, one has to understand the measles virus structure.

The Virus

As a morbillivirus in the paramyxoviridae family, the measles virus is a negative, single-strand enveloped RNA virus. It is about 150-300 nm in diameter and has a lipid bilayer surrounding the RNA forming the envelope. Protruding from this envelope are two glycoprotein ligands called haemagglutinin (H) and fusion (F), necessary for virus attachment to host cells. The RNA is enclosed in a nucleoprotein (N) and associated with two proteins called phosphoprotein (P) and large protein (L).

The lipid envelope on the outside of the virus is acquired from the host cell during budding, because this outer layer is made up of host material it becomes difficult for the body’s immune system to detect the virus as non-self in the initial stages of infection enabling the virus to gain a foothold.

Directly beneath the lipid envelop is the matrix (M), a protein that is important in virus replication as it facilitates the assembly of virus particles to the cell surface membrane during budding.

The nucleoprotein (N) forms a protective sheath around the virus RNA called the nucleocapsid. The associated proteins P and L have been suggested to act as virus polymerase by some studies, helping in RNA replication.

Then there are the two glycoproteins H and F. As their names suggest, they are responsible for anchoring the virus to the host cell and penetration of the cell membrane. The haemagglutinin binds (agglutinates) the virus to the host cell receptor (CD46, to be discussed later) and the fusion protein fuses the virus envelope with the cell membrane.

Infection

The infective process occurs in two key stages of attachment and fusion. In order for the virus genome to gain entry into the host cell and start replicating it needs to “catch” and “inject” host cells with its genome.

The “catching” of host cells occurs when the virus haemagglutinin protein (H) attaches to the host cell receptor CD46. CD46 in the human cell act as a co-factor for serine protease degradation of C3b and C4b, these are the complement proteins of the immune system hence immunosuppression by the measles virus. Studies suggest that there exist more undefined virus receptors that enable the virus to attach to its host cells. The formation of syncytiae, cell-to-cell contact, also allows virus to spread to other cells.

The “injecting” of host cells with the virus genome occurs during fusion, and the processes are less understood. It is thought that the same fusion processes occur for all enveloped virus, and studies on human immune-deficiency virus (HIV) has shed some light into this. Two glycoproteins are involved, gp41 and gp120. gp41 is anchored onto the virus envelope and gp120 attaches to the host cell CD4 receptor next to the CCR5 co-receptor. Structural changes then occur whereby the gp41 is driven into the membrane of the host cell thereby linking the two cells (virus and host). The whole structure of gp41, gp120, co-rector CCR5 and CD4 receptor then collapses leaving the two membranes in apposition for fusion.

Spread

As discussed earlier, the virus enters the host through the respiratory tract, where it replicated in the epithelial cells. Then it infects cells of the immune system, monocytes are the most affected cells. B and T lymphocytes are also infected but at less proportions as compared to monocytes. This amplification of the virus occurs in the lymph nodes of the host. Monocytes, B and T lymphocytes are cell of the peripheral blood and therefore circulate around the body, carrying with them the virus and spreading the infection to other parts of the body including the skin, gastrointestinal tract, liver and the central nervous system. Disseminated virus proliferation occurs in the epithelial and endothelial cells of the blood vessels and other infected organs. Another mode of spread (mentioned earlier) is the formation of syncytia, not only do infected cells aggregate together, but they can also form syncytia with noninfected cells, therefore, infecting them in the process.

Symptoms

The symptoms of measles infections as mentioned earlier are fever, malaise, coryza, conjunctivitis, cough, and Koplik’s spots in the oral cavity, later on, the erythmatous maculopapular rash appears. These symptoms are tied with the immune response as the virus infection progresses. From day 0 when the virus first enters the host to around day 8, the first response from the immune system is the innate one, which is characterized by inflammation, giving rise to fever and general body malaise. As the virus continues to replicate in the epithelial cell of the host especially the nasal cavity (causing coryza), the trachea and bronchus (causing coughs), the nasolacrimal duct (causing conjunctivitis) and the oral epithelial cells (causing Koplik’s spots), it irritates these mucosal surfaces and causes their inflammation. The appearance of Koplik’s spots is diagnostic of measles and it signals the appearance of early symptoms and viral load start to peak in the blood (refer to fig 1 for the measles timeline in-host infection). These spots are transient and last for only about 3 to 4 days; also it is about this time that the adaptive immune response starts to kick in. At day 14 the viral load is at its peak and the adaptive immune response is fully operational and is clearing the pathogen from the system, the formation of the immune complex on the skin as the virus gets cleared result in the measles rash signaling cytotoxic T cell clearance of virus-infected cells. After peak levels of the virus, following successful adaptive immune response, the virus levels drop and the immunological memory begins. In rare circumstances the virus can persist in the host, causing complications. One of these complications is subacute sclerosing panencephalitis (SSPE), discussed below.

Subacute Sclerosing Panencephalitis

This is one of the complications of persistent measles virus infection; it affects the central nervous system of children who are infected by measles virus at a very early age. These children normally lack the maternal antibodies in their circulation to help combat the infection at its early stages. Studies found that 50-75% of children who develop SSPE had measles infection before the age of two and also the prevalence rates of SSPE are 1:10 000 cases. This complication can take a very long time to manifest itself, with an average time of 8 years before SSPE symptoms appear and the reported range is between 9 months and 30 years. The disease leads to neurological deficits and eventually the patient dies. The other two measles complication worth mentioning are progressive measles inclusion body encephalitis (MIBE) which can occur in patients who are immunocompromised, and the post-infection encephalomyelitis which is an autoimmune disorder that attacks the myelin sheath covering neurons.

Recovery from measles (assuming opportunistic infections have not prompted medical intervention) requires both the humoral and cell-mediated immune response. Cytotoxic T lymphocytes clear infected host cells and measles antibodies reduce free viral load by serum neutralisation these antibodies can also be directed directly against the virus. The humoral response as usual is mostly for preventing re-infection and is involved in building immunity, a process taken advantage of by vaccine developers. After cytotoxic clearance of infected cells; there follows an immunologic type 2dominance where cytokines IL4, IL5, and IL10 are secreted by type 2 CD4+ T cells.

Vaccination

Many virus infections are untreatable, they are either self limiting, maim, or kill the host, so the only intervention that is available is to prevent infection in the first place. As noted from fig 1, after day 21 when the pathogen has been cleared, immunological memory is activated. This activation of immunological memory can only happen after the host has encountered the measles virus. Subsequent infections are met with a robust humoral response and the virus does not progress to cause infection. This is the basis of immunisation, the host immune system has to be introduced to the virus first, and as there is a risk of the virus overwhelming the immune system most virus used in vaccines are “controlled”.

Attenuated Virus Vaccine

Once the measles virus was isolated and cultivated by Enders and Peebles it was then able to be manipulated. They found that the virus once cultured in chick embryos was attenuated in virulence and immunogenic enough to stimulate the host immune system to produce antibodies against it and remembering it.

Work to produce a licensed measles vaccine begun in 1958 and by 1963 the first licensed measles vaccine, RUBEOVAX®, was available. In 1968 a more attenuated vaccine ATTENUVAX® was licensed. As more vaccines for viruses e.g. mumps and rubella were developed there was a need to combine the doses into one single shot. In 1971 a trivalent vaccine with all three vaccines, measles-mumps-rubella was licensed. In recent times a fourth vaccine has been added to the MMR vaccine, resulting in a tetravalent vaccine MMRV. The fourth vaccine is a chicken pox vaccine, varicella.

Other Virus Vaccines

Other less favourable virus vaccines exist. Experiments were done on high titre vaccines by Sabin et al. These were aimed at infants who are at risk because they have circulating maternal measles antibodies which prevent vaccine uptake by neutralising it. The other vaccine, an inactivated measles virus vaccine produced by killing the virus in formalin was produced and licensed in 1963. It fell out of favour because the immunity if offered lasted for only one year and it had to be taken in three doses.

With vaccination and great knowledge gained from studying measles it can be said that total eradication of the virus is possible. It is the beliefs and cultures of people that are slowing this up because they are not taking up vaccination.

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24. Pediatr Infect Dis J (2007) 26 (7): 632–8

Gonorrhea is a bacterial disease that is an infection caused by gonococcus bacteria. This bacteria is round shaped and can live only in dark, warm, moist places.

These places would include; inside your body, cervix, penis, throat, and rectum. It usually involves the urethra in males, and vagina, cervix, and fallopian tubes in females. For 2-9 days there are no symptoms of Gonorrhea. There can a lot of burring during urination and thick green-yellow discharge from the penis or vagina.Also, there may be rectal discomfort and discharge, joint pain, a mild rash, or sore throat and swollen glands. For men, the opening of the penis may be red and sore. Symptoms of gonorrhea show up more in males than in females, in fact, about half of the women with gonorrhea have no symptoms.

Effects of this disease could include; gonococcal eye infection, blood poisoning, infectious arthritis, pelvic inflammatory disease, epididnmitis, endocarditis, sexual impotence in men, and infertility in women.Also, pregnant women can infect unborn babies. In females the infection occurs in the urethra, the vagina, or the cervix. Although discharged and irritation of vaginal mucous membranes may be severe, and fatal.. Gonorrhea is diagnosed by staining a smear of the discharge to expose the bacteria. Treatment in the early stages is usually effective.

In females gonorrhea seems to strike selectively at the cervix. Eighty percent of females with gonorrhea have no immediate signs or symptoms. One symptom in women is a foul smelling vaginal discharge.Since vaginal discharges are not uncommon, women should be alert to any change in the color, odor, or other appearance of discharges. If gonorrhea has affected the urethra, women may experience a burning sensation upon urination. Gonorrhea can be diagnosed by tests that include blood studies. There could be laboratory cultures and microscopic analysis of the discharge from the reproductive organs, rectum, or throat.

You will have to obtain some of the symptoms before the doctor will confirm that the tests be administered. This disease is transmitted by sexual contact.Any form of sexual penetration, oral, anal, and vaginal can transmit gonorrhea. There are other ways you can catch the disease, but they are not common. A person with gonorrhea can infect another area of their body by touching the infected area and transferring the excretions. Gonorrhea can also spread through clothing or wash clothes if used by an infected person, and then by someone who isn’t infected. Sometimes infected secretions from the vagina drip down around the anus can cause infection in women.

Gonorrhea is treated with antibiotics.Common ones include: ciprofloxacin, ofloxacin, cefixime, certriaxone, azithromycin, you can also take non-prescription drugs such as Tylenol or aspirin to reduce discomfort and inflammatory pain. The period of communicability for gonorrhea is uncertain but can last as long as discharge continues anywhere from three to six months. Precise diagnosis of gonorrhea requires cultures of discharge specimens. Under most circumstances gonorrhea is easily treated. It is now clear that great amounts of penicillin may be necessary to kill some resistant strains.Untreated gonorrhea may result in irreversible complications.

Infertility and sterility can develop in males and females. Gonococcal arthritis in major joints is a generalized infection that irreversibly damages the brain, heart, liver and other key organs and can be present in either sex. The most reliable form of protection is the use of condoms during sexual episodes. STD’s is a very serious matter and it can be fatal, the sexually active individual should also be selective about sexual partners and stay alert to obvious signs and symptoms of disease.Not being wise in your selections can cause you to be infected by the STD, and not being wise in your selections can cause death. No matter what situation your in always use a condom, that is The best way to avoid sexual transmitted disease like Gonorrhea, you have a 90% chance of not getting infected. A 100 % chance of not getting infected wit STD’s is through abstinence.

Gonorrhea http://www. marchofdimes. com/pnhec/188_712. asp http://www. smartersex. org/stis/gonorrhea. asp http://www.

vdh. virginia. gov/Epidemiology/factsheets/Gonorrhea. htm http://www. womenshealth. gov/faq/gonorrhea. cfm

Introduction

Measles is a contagious human disease that mainly affects children. The measles virus (MV) that causes this systemic infection is a single stranded ribonucleic acid virus belonging to the genus Morbillivirus in the Paramyxovirus family. As transmission is via air droplets, initiation of the infection occurs in the respiratory tract, and spreads to other organs. MV affects the immune system leading to a prolonged state of immune suppression which can result in several complications involving the respiratory tract and the brain e.g. encephalitis.

Immunisation using a live attenuated vaccine is the main preventative of the infection. In 2000, the cases of infection of measles in Europe was rare due to vaccination, however in 2008 there was a total of 7,822  with Switzerland having the highest incidence rate in Europe.  Measles are increasing in Ireland, with 320 cases reported within 8 months in 2009. (7) The objective of this assignment it to review the pathogenicity of measles, the symptoms associated with the infection and how to prevent this infectious and potentially fatal disease.

Infection and spread

Infection is initiated in the respiratory tract. (The virus can then spread to the local secondary lymphoid tissues via dendritic cells of the lungs or the alveolar macrophages.  From here it can travel to the peripheral blood and spread via epithelial and endothelial cells to multiple organs. Research has suggested that in the later stages of the infection, the virus infects the epithelial cells of the respiratory tract facilitating in the spread of the virus. (9) But how does the virus invade its host?

MV is a non – segmented negative sense strand enveloped RNA virus that encodes 8 proteins: 6 structural proteins and 2 non-structural proteins.

The first 3 structural proteins are combined within the RNA. The (N) nucleoprotein protects the genomic RNA by forming the ribonucleocapsid. The phosphoprotein (P) and large polymerase protein (L) are involved in viral replication.

The non- structural proteins C and V are responsible for the regulation of viral infection by interacting with cellular proteins.

The F and H glycoproteins found on the surface of the virus envelope, are responsible for the initiation of infection to susceptible host cells. These transmembrane proteins allow the virus to fuse with the host cell, penetration of the virus into the host cell and haemolysis.  The F protein facilitates the spread of the virus from one cell to the other by inducing cell fusion.  Transcription occurs within the cell to create more negative sense RNA for assembly of new budding viruses (see figure 1).

The matrix M protein is a non-glycosylated protein found in the inner lipid bilayer of the envelope. Its function is to connect the ribonucleoprotein complex to the envelope glycoproteins during viral assembly.

The H protein of the virus surface is responsible for receptor binding. CD46 was the first identified receptor for MV and is present on all nucleated cells. (8) It was later discovered that the signalling lymphocyte activation molecule (SLAM) also known as CD150 has also been identified as receptor for MV.  In fact the receptor binding of CD46 seems to be limited to attenuated vaccine strains rather than the wild type which seems to have better affinity for the CD 150 receptor. CD150 is expressed on many immune cells including lymphocytes, dendritic cells and macrophages and is a member of the CD2 subset of the Ig superfamily.

The structure of H protein of MV is well documented consisting of a globular head group composed of 6 anti-parallel B sheets. These are stabilised by two intra- monomeric disulphide bonds and partially covered with N-linked carbohydrates. The binding regions for CD 46 and CD 150 (SLAM) are found adjacent to one another.

It has been widely documented that CD150 is the initial receptor targeted by the H protein of the virus but little is known on the receptors involved in the infection of epithelial cells as these cells do not express CD150.  Tahara et al have resulted that “MV has the ability to infect both polarised epithelial and immune cells using distinctive receptor – binding sites on the H protein”. His study used a CD150 negative human lung adenocarcinoma cell line (NCI-H358) to infect with the MV. The presence of the H protein was evident using monoclonal antibodies and suggesting that the H protein must have been using a different receptor binding site to infect the cells.

The pathogenesis of MV, initiates an immune response. It triggers a cell-mediated immune response which involves the activation of TH1 and release of interferon ? and interleukin 2 (IL-2).  In the later part of the infection an antibody- mediated response provides long term protection against future infections. TH2 lymphocytes are produced as well as IL-4 which favours the induction of a humoral response which is important for long life protection against re-infection.  However MV has the ability to dominate the immune system and use it to its advantage. The suppression of the immune system results in secondary bacterial and viral infection which attributes to the number of fatalities associated with Measles infection. Moss et al suggested that there are many mechanisms that develop to immune suppression following a MV infection.

These include:

• Lymphocyte Apoptosis
• Impaired Lymphoproliferation
• Immunomodulatory Cytokines (Increased IL-10 and IL-4)
• IL-12 down regulation
• Impaired Antigen Presentation of Dendritic cells

One of the clinical manifestations of MV is lymphopenia. This may be due to the reduction of CD4+ and CD8+ T lymphocytes. Increased surface expression of Fas (CD95) during acute measles suggests that unaffected T lymphocytes undergo apoptosis.  Abnormalities in the lymphocyte function are found during and after MV infection. The virus inhibits IL-2 dependent T lymphocyte survival and proliferation. This is in response to an impaired protein kinase B activation caused by the H and F proteins of the virus.

In the acute phase of infection a T helper Type 1 (TH1) response is induced which shifts to T helper type 2 (TH2) in the later stage of infection which accounts for viral clearance and development of antibodies respectively. The increased production of cytokines IL-10 and IL-4 in the TH2 response may be another mechanism for viral induced immunosuppression. IL-10 is an immunosuppressive cytokine which down-regulates the synthesis of cytokines and suppresses T cell proliferation and macrophage activation.  This prevents macrophage activation and TH 1 response to new infections.  As previously mentioned CD 46 is found on many immune cells including monocytes. As a result IL-12 produced by monocytes is downregulated.  IL-12 is essential for TH1 immune response. The reduction in production of IL-12 favours TH2 and suppresses TH1 immunity.

Dendritic cells play a critical role in the presentation of antigen to naive T lymphocytes. MV infection promotes maturation of dendritic cells but also alters its function (18) and mediates Fas induced apoptosis.

It is now established that the non-structural protein C and V produced by the P gene plays a role in immunosuppression by interfering with interferon  signalling pathways. These proteins of the MV inhibits phosphorylation of STAT 1 and STAT 2 which are transcription factors involved in the Interferon pathway.

Symptoms

Clinical symptoms associated with measles include a fever and rash but a cough, coryza or conjunctivitis can also be seen. (9) It is after 10-14 days of infection that this characteristic rash is present and seems to be due to the individuals’ immune response to the virus. The rash usually begins on the face and travels down to the extremities and can last for about 5 days before disappearing .Two thirds of patients show a white-marked enanthema on the buccal mucosa known as Koplik’s spot. Koplik spots were first identified by Koplik in 1896 and are the pathognomonic of measles.  Generally the resolution of the rash and fever begins after 7 to 10 days however the cough may persist for longer. In many cases complication can occur resulting in infections of the respiratory tract and brain.

Pneumonia accompanying measles may be due to the MV or a secondary bacterial infection. 60% of infants infected with measles, can die from pneumonia while older children (10 -14 years) death is associated with acute encephalitis.  It seems that viral infection of the CNS is a common feature of measles but only a proportion of patients will present with clinical symptoms.

Mild forms of measles have been observed due to passive immunity to the virus. Infants who have passively acquired antibodies to MV from the mother will present with some of the symptoms but depends on the degree of passive immunity that is achieved. A study in China determined that mothers produced low levels of antibodies due to vaccination rather than natural infection. The outcome is reduced protection to the infant which can result in measles infection before the age of receiving a vaccine.

Atypical measles is associated with patients who received a vaccine using a killed MV rather than live attenuated vaccine and subsequently was exposed to the wild-type measles virus. Patients present with a low or undetectable titre which drastically rises after a few days.  As the symptoms may vary to classic measles, it can be misdiagnosed. Atypical measles is more severe than classic measles. Research has shown that this may be due to the fact that the killed vaccine lacks the antigen to stimulate immune response by preventing the virus entering the cells.  It has been shown that the killed vaccine does not produces antibodies to the F proteins which facilitate cell entry and spread of the virus.

Immunocompromised patients present with severe measles due to their deficient cellular immunity. Secondary infections are often seen including pneumonia and encephalitis resembling SSPE. Malnourished children especially in the developing world can suffer from severe measles. This may be due to intense exposure due to crowding or the inability to produce a cell-mediated response due to malnutrition.

Measles is regarded as an infection of childhood however adults do get infected and usually develop a severe form which can have complications. During pregnancy, an infected mother is not known to cause co-genital abnormalities to the foetus but may cause abortion or preterm delivery.

Vaccines

The use of vaccines is the main preventative of Measles. The development of the first measles vaccine was in the 1960s. (20) Immunisation began with a inactivated (killed) vaccine, but resulted in short term protection and undeveloped immune system.  Immunisation with a live-attenuated vaccine can be administered as a monovaccine or in combination with mumps and rubella (MMR) or mumps, rubella and varicella virus (MMRV). It is derived from a wild type of the virus known as Edmonston and processed through chicken cells. In 1985, the measles virus was first introduced in Ireland, with the combination vaccine (MMR) emerging in 1988.  When the vaccine was first introduced in Ireland 9,903 cases of measles were reported. This dropped to 201 cases in 1987.  A two dose vaccine is essential for long lasting protection to the virus.

There are occasions when passive immunisation is required using immunoglobulin which include immunocompromised patients such as HIV positive patients.

Successful vaccination against infectious diseases depends on the vaccines ability to induce a protective response. Successful vaccination is dependent on the individuals’ human leukocyte antigen (HLA) haplotype which regulates the immune response. There are two types of HLA proteins. The first, Class I consists of A,B and C alleles. These bind to CD8+ T lymphocytes. Class II DR,DQ and DP alleles attach and present peptides to CD4+ T lymphocytes.

The measles vaccine results in an iatrogenic attenuated measles infection. As mentioned previously, the C46 molecule serves as the receptor for the H protein of MV where it is broken down and presented to the immune system by the HLA system.  Studies have shown certain HLA alleles may impact differently on the responsiveness to the measles virus.

For successful herd immunity to measles, most of the population needs to be immunised. However fears of the association of the MMR vaccine and autism have stopped parents from vaccinating their children. There is no scientific evidence to suggest any link with autism.

Research has suggested that Vitamin A supplementation may help prevent Measles infection in infants prior to vaccination.

Subacute Sclerosing Panencephalitis. (SSPE)

One of the persistent secondary infections of MV is subacute sclerosis panencephalitis (SSPE) which causes demyelination of the central nervous system (CNS).

SSPE cannot occur without the presence of a direct measles and is found to be more prevalent in males than in females. Research has shown that the earlier a patient is infected with MV the greater the risk of complications such as SSPE can occur. This is due to an immature immune system.

Conclusion

The MV invades the neurons using the CD46 receptor and using its F protein.  There have been studies to suggest that another receptor CD9 aids entry into the cell. Once inside the cell the virus changes the machinery of the cells to avoid an immune response. It undergoes mutations of its own proteins to go unrecognised and reproduces within the neurons.  The virus can live as a “parasite” within the neurons for years. Finally it will damage the cell to an extent that apoptosis will occur and the immune system is triggered.

Onset of SSPE is usually 6 years after infection and clinical symptoms present as intellectual deterioration and behaviour abnormalities. Final stages include seizures, focal paralysis and death with akinetic mutism.

There is no cure for this fatal disease only a preventative. Other fears related to the vaccine were that it may cause SSPE however there is no evidence to back this case.

Introduction:

Although the measles virus remains less of a threat in the today’s western world, it still posses a significant challenge in the under developed countries with an estimated 30 million illnesses and 770,000 deaths being reported in the year 2000.

Following a survey of 32 European Countries, the European Centre for Disease Control has reported a staggering 12,000 measles cases in the first quarter of 2010.

Although Bulgaria topping the poll, it is somewhat concerning how Ireland with a relatively low population, lies a close second in incidence rates to date.

With what has been depicted as a preventable disease, it is therefore essential to understand the concept and fundamentals on the risks of infection, likelihood of spread, associated symptoms and furthermore the importance of appropriate vaccination in a timely manner.

Symptoms:

Derived from the air, Measles is an acute viral illness originating from the paramyxovirus

Family that is commonly spread from person to person through tiny aerosol droplets.Common signs include fever, cough, sneezing, runny nose and conjunctivitis.  Initial replication of the illness occurs in the upper/lower respiratory tract through blood vessels. This prodromal stage infecting epithelial cells is assisted by the potential development of Koplik spots on the mucous membranes of the mouth and In addition the appearance of a rash on the skin. The rash is due to the Immune reactions to the virus in the endothelial cells of dermal capillaries (Mims et al. Medical Microbiology, 1993) and at this stage can be considered as a mode of diagnosis , as both IgM and IgG antibodies are produced during the on set of rash development, therefore by using sensitive ELISA IgM early detetction can be achieved.

The incubation period is approx ten days (ranging between 7 and 18 days) (Chin, 2000). The term incubation period lies very closely with that of the symptoms. As summarised from the World health organisation, After 2-3 days of r e p l i c a t i o n ,the virema escalates to the reticuloendothelial system.Further expansion of this virema for 5-7 days post infection may result in infection in organs, including the spleen, thymus, lung, liver, and kidney. The viraemia climaxes at day 11-14 days after infection and eventual declines rapidly

The most common complications of measles infection are otitis media due to increased growth in epithelia of the nasopharynx making it more susceptible (7 to 9% of cases), pneumonia due to an impaired cell-mediated immune response occuring when the F protein facilitating cell fusion at a given pH (1 to 6%), diarrhoea (8%) and convulsions (one in 200).

Infection and spread:

A number of concepts regarding the measles virus pathogenesis, including the theory of dentric cells and lymphocyte cells expressing CD150 as the official facilitator for MV infection (http://www.ncbi.nlm.nih.gov/pubmed/18820585?dopt=AbstractPlus) to others focusing more on the ethical origin linking interaction of malnutrition, proliferation and immune mechanisms as a culpret. Therories behind increase intake of Vitamin A to reduce infection and mortality rate have also sparked thoughts of remediation (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586282/?page=2 ) . As it has been scientifically proven when vitamin A (which can be sourced in the skin) is administrated in megadoses (200,000 international units on each day for two days) has significantly lowered the mortality rate in hospitalised children ranging from ages 2-5 cited from the cochrane report. Published by (Yang HM, Mao M, Wan C. 2009.) (http://www2.cochrane.org/reviews/en/ab001479.html)

The most obvious mode of infection or spread is that of direct contact with nasal or throat secretions. Measles is highly contagious and is known to affect 90% of susceptible individuals.In developing countries . This susceptibility is heightened by the overcrowding circiumstances and therefore increasing the exposure rate of high viral loads [Tu l chinsky, T.H. ,e ta l . , Me a s l e scontrolin developing and developed

countries: the case for a two-dose policy. Bull World Health Organ, 1993. 71(1): p. 93-103).

Vaccination:

Following the introduction of measles, mumps and rubella (MMR) vaccine in

October 1988 mortality due to measles has significantly declined.

Although, Infection and spread has been controlled for several decades, public fears linking the MMR vaccine with autism has significantly reduced the immunisation rate resulting in the concern of serious outbreak of the measles virus occurring.

The publication of this mis-conception has been quashed by medical experts who continue to recommend two doses of the MMR vaccine for maximum protection normally given at age 12 months and age four or five years. This has been widely illustrated for example Researchers from the Cochrane Vaccines Field reviewed 139 studies assessing the effects MMR vaccine in preventing measles, mumps and rubella (MMR) in children. It was found that MMR vaccine protects children against infections of the upper respiratory tract and is unlikely to cause milder forms of measles, mumps and rubella. No plausible association with either autism or Crohn’s disease was also determined. Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD004407. DOI: 10.1002/14651858.CD004407.pub2

Although the vaccination rate is once again steadily inclining, following a global helath response for not only developed countries, the fourth Millennium Development Goal (MDG 4) is aiming to reduce the viral rate of measles to two thirds by 2015 (6)

Sub acute sclerosing panencephalitis:

Subacute sclerosing panencephalitis (SSPE) is a brain disorder due to adverse immune response to measles or, possibly, mutations of the virus leading to brain inflammation. SSPE usually occurs in later years post infection of measles and have common Symptoms that include dementia , Gradual behavioral changes, Myoclonic jerking (quick muscle jerking or spasms) and seizures. (6)(7)

The incidence of SSPE has decreased since vaccination against measles was initiated.As SSPE is associated with defective forms of the virus in the brain and has been proven to be difficult to isolate infectious virus. Certain viral proteins such as the M protein are commonly deficient. Currently, there is no Vaccine for SSPE. Clinical trials of antiviral (isoprinosine and ribavirin) and immunomodulatory (interferon alpha) drugs have suggested that these types of remediation can assist in delaying the prognosis of the desease but the long term outcomes are still undefined. (6)

Upon diagnosis, Most individuals with SSPE will die within the first three years.Others where the disease progresses rapidly, death maybe within three months. (6)

With sufficient grants, research been carrued out by The National Institute of Neurological Disorders and Stroke (NINDS) and other institutes at the National Institutes of Health conduct research will continue to focus on finding efficient ways in treating such onsets of measles in particular SSPE (7)

References:

1. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002536/
2. http://www.irishtimes.com/newspaper/ireland/2010/0607/1224272004407.html
3. http://www.ncbi.nlm.nih.gov/pubmed/18820585?dopt=AbstractPlus
4. http://www.immunizationinfo.org/vaccines/measles
5. http://www.ncbi.nlm.nih.gov/pubmed/20561004?dopt=AbstractPlu
6. http://pathmicro.med.sc.edu/mhunt/mump
7. meas.htmhttp://www.who.int/vaccine_research/diseases/measles/en/
8. http://www.ninds.nih.gov/disorders/subacute_panencephalitis/subacute_panencephalitis.htm