Pathogenesis of measles virus infection The WritePass Journal

Pathogenesis of measles virus infection Introduction Pathogenesis of measles virus infection IntroductionSymptomsVaccinationSubacute Sclerosing Panencephalitis  ConclusionRelated Introduction Often dismissed in the developed world as a common childhood infection, measles are in fact a worrying contributor to childhood morbidity and mortality worldwide. In the UK alone, approximately 10% of cases result in complications requiring hospitalisation, 1 in 5,000 could be fatal [1]. This is much higher for the developing world where infection spreads rapidly in children that are living in close quarters, are malnourished and unable to avail of the vaccine. In 1994, under the national schools vaccination campaign all school children aged 5-16 were offered the mumps-measles-rubella (MMR) vaccine. An uptake of 92% under this campaign resulted in measles being all but eradicated from England and Wales [2]. Unfortunately a fall in immunisation uptake over the last decade, amid fears of a link between MMR vaccine and autism, now means that the number of susceptible children is such that measles are once again endemic in the UK [3]. Epidemics are prevalent throughout European countries including Italy, Austria Switzerland. Controlling a measles epidemic can be difficult, despite the availability of a safe and effective vaccine, as it is a highly infectious disease that spreads rapidly between susceptible individuals. Infection Spread The measles virus (MV) is single stranded RNA Morbillivirus from the paramyxovirus family that results in an acute infection of respiratory and lymphoid tissues. It is a highly contagious disease transmissible via respiratory droplets that can remain viral on surfaces for up to two hours [1]. Although it’s spread via the respiratory route and symptoms are well established little is actually known of the cellular events underlying the disease. Figure 1: Schematic diagram of measles structure [4] To better understand the process of infection and spread we must take a closer look at the measles virus (MV). MV is single negative-strand enveloped RNA Morbillivirus that contains 15,894 base pairs encoding 8 proteins. As shown in figure 1 hemagglutinin (H) and fusion (F) proteins are transmembrane envelope proteins and as such their primary role is to initiate infection. Antibodies to these proteins may render the virus inactive [4].   The RNA genome is encapsidated by the nucleotide (N) protein forming a ribonucleocapsid complex which acts as the substrate for transcription and regulation [5]. The large protein (L) and phosphoprotein (P) are also associated with the ribonucleocapsid complex and hence replication and transcription.   The matrix protein (M) links the ribonucleocapsid complex to the envelope proteins during virus assembly [6]. There are also two non-structural proteins, C V encoded within the P gene that act as regulators of infection by interacting with cellul ar proteins. As previously mentioned binding of H to susceptible cells is an important instigating step in measles pathogenesis. Three viral receptors for H are identifiable, CD46 a low affinity protein present on all nucleated cells, an undetermined receptor on epithelial cells and SLAM / CD150, a high affinity receptor present on subsets of lymphocytes, thymocytes, macrophages and mature dendritic cells (DCs). SLAM/CD150 is the preferential receptor for wild type strains of MV. Initially it was thought that MV infected respiratory epithelial cells which would in turn infect monocytes resulting in spread of infection to lymphoid tissues. However, this has been found not to be the case as monocytes only express CD46 low affinity receptors. Since then it has been demonstrated in vivo that lymphocytes expressing CD150 recpetors are the primary infected cells during measles in macaques [7]. However lymphocytes are not commonly found at respiratory epithelial cell surfaces hence MV target cells at transmission and throughout pathogenesis of MV are unclear. It is thought that professional antigen presenting cells (APCs) known as dendritic cells may have a dual role in mediating transmission of the measles virus [8]. Although the expected role of DCs is to capture and present MV antigens for degradation, some escape degradation and are actually protected by DCs for transportation to lymphoid tissues. Here they encounter and infect CD150+ lymphocytes allowing replication of the virus. From the primary lymphoid tissue, infected cells enter circulation. Infected peripheral blood mononuclear cells (PBMCs) are evident in the blood 7-9 days after infection [9].   From here the infection spreads to distal lymphoid tissues and to the epithelial and endothelial cells of multiple organs. Less is known about receptors used to infect these cells. There is however a number of cell surface molecules that interact with MV and as such may play an important role in MV pathogenesis, including receptor clustering, fusion, entry, cell-to-cell spread or cytokine production.   These include DC-SIGN, Toll like receptor 2 (TRL2), neurokinin-1 and Fc-ÃŽ ³ receptor II. DC-SIGN (C-type lectin dendritic cell-specific ICAM-3 grabbing non-integrin) for example is credited with binding of MV to DCs. The role of which has been previously described for HIV1 [10] and has been demonstrated in MV infected macaques [7].   TRL2 interacts with H envelope protein to induce interleukin-6 (IL-6) wh ich in turn stimulates the expression of CD150. TLR2 interaction with CD46 also inhibits IL-12 production. Symptoms Measles typically have an incubation period of 7-14 days. During the prodrome period of day 4-7 characteristic clinical symptoms of measles appear which include fever (often 104 °F), cough, conjunctivitis and photophobia. Koplik spots, which are white buccal opposite the first and second upper molars, appear 2-3 days later followed by the maculopapular rash that lasts on average of 3-5 days [11] The rash is a manifestation of the adaptive immune response, and marks the start of viral clearance. Activated T cells and MV specific antibodies are present in circulation at this time and CD4+ and CD8+ cells have infiltrated sites of virus replication. Immunocompetent individuals will be successful in clearing the virus from these sites of replication and confer life long immunity to re-infection. Interestingly, MV appears to have a contradictory effect on the immune system with acute infections predominantly linked to periods of transient immunosuppression, often lasting weeks after the disappearance of characteristic symptoms [8]. It is these periods of immunosuppression that leaves an individual susceptible to many associated secondary complications and ultimately MV related deaths. The risk of complications may increase in densely populated areas, in children infected under the age of two, pregnant women, malnourished individuals particularly those lacking in vitamin A and in individuals who have existing immunodeficiency. Complications include respiratory complications such as bronchopneumonia and giant cell pneumonitis, neurological complications such as acute demyelinating encephalitis, subacute sclerosing panencephalitis and measles inclusion body encephalitis, gastrointestinal complications like diarrhoea or clinical hepatitis and vitamin A deficiency which may manife st as xerophthalmia a leading cause of blindness worldwide [1]. The mechanisms that result in immunosuppression are not clearly understood but a number of methods are hypothesised. For example, there is noted decrease in the numbers of T cells and B cells during the rash which for the most part is attributed to an increase in CD95 mediated and lymphocyte apoptosis [9]. This may contribute to lymphopenia, however lymphocyte numbers generally return to normal as the rash clears. It is also thought that suppression of lymphocyte proliferation may be associated with G1 arrest of the cell cycle after infection with MV [12].   Similarly T-cell proliferation may be suppressed as a result of direct inhibitory signalling by the H and F1-F2 membrane viral complex which when in contact with a cell will delay S phase entry of T cells by several days leading to accumulation of cells in the G0-G1 cell cycle phase [9]. Yet another mechanism of immune suppression is type 2 skewing of CD4+ T-cells. During infection of APCs with MV there is marked decrease in production of IL-12, which plays an important role in T-cell production of type 1 cytokines [12]. Altered CD4+T production leads T cells that fail to proliferate. Immunosuppression is characterised by lymphopenia, defective response to new antigens and a loss in the delayed type hypersensitivity responses to recall antigens. Vaccination A combined live attenuated mumps, measles and rubella (MMR) vaccine is the vaccine of choice against measles in more the 90 different countries worldwide. [13] Since its introduction in the 1970s the MMR vaccine has proven its capability to eliminate its target diseases from a number of countries. Following a national vaccination programme it was reported in 1996 that measles had all but been eradicated from the UK [2]. The US had similar success prior to this in 1993 [13] as did many other countries. Numerous strains of the MMR vaccine are produced worldwide, many of which are derived from the Edmonston strain [14]. Four non Edmonston strains including Leningrad 16, Shanghai-191, CAM-70 and TD-97 are also in use [13]. The virus is generally cultured in chick embryo cells. Most vaccines also include a small dose of antibiotic. A number of combinations of these virus, mumps virus and rubella virus are used to produce a commercial MMR vaccine. There are five commonly used MMR vaccines on the market today including M-M-R by Merck, Morupar by Chiran, Priorix by Glaxo-Smith Klein, Trimovax by Pasteur Merieux Serums and Triviraten Berna. Current US guidelines regarding vaccination with MMR recommend first dose at 12 months and a second dose to be administered before the age of 4, leaving at least 28 days between doses [15]. One dose and two dose vaccination strategies have been tried and tested in many countries [16, 17]. Although one dose strategies may achieve as much as 85% efficacy a second dose is essential to achieve eradication. Unfortunately erroneous claims linking the MMR vaccine to autism and Crohn’s disease have led to a decline in uptake of MMR vaccine and as a result countries like the US, Germany, Austria and Italy are once again facing a measles epidemic [18]. Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis (SSPE) is an incurable complication of measles virus that presents itself 1-15years following acute MV infection [1]. It is most common in boys who under the age of two become infected with MV and is a far less common when MV infection occurs in adulthood [12]. SSPE occurs at the rate of 10,000-300,000 in acute MV infections. A disease affecting the central nervous system (CNS), SSPE initially presents as subtle cognitive changes, progressing to overt cognitive dysfunction, motor dysfunction, seizures, organ failure and eventual death. Neurons are initially targeted but as the disease progresses infected oligodendrocytes, astrocytes and endothelial cells have also been noted. Histologically it is characterised by cellular inclusion bodies, loss of neurons, inflammation, glial activation and deterioration of the blood brain barrier [12]. High numbers of MV specific antibodies are found in both blood and cerebrospinal fluid of SSPE patients.   Conclusion Little is actually known of how MV may cause SSPE and other associated MV complications. Early studies using brain biopsies of SSPE patients did however show that infected neurons were unable to release budding virus. Since then extensive sequencing of such cells have lead to the conclusion that point mutations of envelope associated genes, namely as H, M, and F, could result in defective protein expression and therefore do not allow infected neurons to complete the viral process [19]. How this impacts on the development of SSPE is unclear. Pathogenesis of measles virus infection Introduction Pathogenesis of measles virus infection IntroductionInfection1. Attachment2. Fusion3. RNA replication and Assembly of viral particles4. Release of virusSpread1. Changes in lymphocyte number and function2. Shift in cytokine profile3. Impaired antigen presentationSymptomsImmunosuppressionVaccinationSubacute sclerosing panencephalitis (SSPE)BibliographyRelated Introduction Measles is a highly contagious disease caused by an enveloped RNA virus of the genus Morbillivirus in the family of Paramyxoviridae (Griffin et al, 1994). It is a major cause of child morbidity and mortality, particularly in developing countries, despite the introduction of attenuated measles virus vaccines which have greatly reduced the incidences since the 1960s (WHO, 2009). The window period of infection for infants lies between the disappearing maternal antibody protection and vaccine administration (Manchester and Rall, 2001). In 2008, 164,000 measles deaths were reported and majority was children under five years old (WHO, 2009). Affected individuals combat measles by generating cell mediated immunity to clear the virus and humoral immunity to provide long-term protection (Manchester and Rall, 2001). However, measles virus (MV) induces immunosuppression during infection and for weeks after recovery, rendering infected individuals susceptible to secondary infections (Griffin et al, 1994). The evidence of immunosuppression caused was first recognized in 1908 when von Pirquet reported that children lost positive skin test for tuberculin antigen during MV infection (von Pirquet, 1908). Research has been carried in vitro and in vivo in order to define the pathogenesis pathways of MV. Immune responses to MV have been described on transgenic mice and cynomolgus monkeys models (Sato et al, 2007) suggesting that multiple potential mechanisms are linked to the virus-induced immunosuppression (Schneider-Schaulies et al, 2002). Infection Measles is transmitted via airborne exposure from coughing and sneezing or close contact with nasal and throat secretions. MV remains active in the air for up to two hours. It enters the body through the respiratory system and spread systemically by infecting lymphoid cells. Infection and spread is a complex process. The structure and proteins of MV are important determinants of virus tropism and pathogenesis (Yanagi et al, 2006). Measles virus consists of a non-segmented single negative-strand RNA genome (16,000 ribonucleotides) with a diameter of 150 to 300 nm. The outer envelope comprises with the inner matrix protein to form a lipid bilayer surrounding the viral genome. It encodes six structural proteins and two nonstructural proteins which are important for attachment of the virus to the host, replication and spreading of the virus in the body (Horikami et al, 1995). Table 1 briefly describes the functions and locations of structural components and Figure 1 illustrates the structure of a measles virus. Table 1: Locations and functions of Measles virus structural proteins Structural proteins    Locations Functions 1. Haemagglutinin(H) Both H and F proteins are surface transmembrane glycoproteins. They project from the lipid bilayer and traverse the internal matrix. Responsible for the initiation of infection. H protein: receptor binding and cell fusion F protein: cell fusion and viral entry. 2. Fusion proteins (F) 3. Nucleoprotein (N) Surround the RNA strand Form a ribonucleocapsid. 4. Phosphoprotein (P) Both P and L proteins are associated with the ribonucleocapsid The ribonucleoprotein complex acts as RNA polymerase and is responsible for RNA replication and transcription. 5. Large polymerase protein (L) 6. Matrix protein (M) Attaches to the inner surface of the envelope Assembly of the viral particles. Virus budding. Adapted from (Yanagi et al, 2006) The nonstructural protein C and V are encoded on the P gene by RNA editing and alternative translation. Patterson et al (2000) showed that C and V proteins functioned as virulence factors in CNS measles infection using YAC-CD46 transgenic mice. In addition, C protein is capable to inhibit viral transcription and enhancing MV particles assembly. These proteins have shown to be involved in inhibition of interferon production (Naniche et al, 2000). The infection process involves four steps: 1. Attachment When measles virus enters the respiratory tract, the initial infection begins with viral attachment to host cellular receptors by the haemagglutinin (H) protein. The most studied receptors are CD46 and signaling lymphocytic activation molecule (SLAM/ CD150) (Ferreira et al, 2010). CD46 is a complement regulatory molecule and is present on all nucleated human cells whereas SLAM is only expressed on thymocytes, mature dendritic cells and T and B lymphocytes (Hsu et al, 2001). Other cell surface proteins such as moesin and substance P receptor were also proposed in MV binding (Kehren et al, 2001). The primary target for early stage infection has not been clearly defined. It was originally thought that respiratory epithelial cells were firstly infected (Griffin, 2001) but following the discovery of SLAM, some studies suggested that SLAM-positive immune cells should be the initial targets (Yanagi et al, 2002). Leonard et al. (2008) suggested the presence of a basolateral epithelial recept or (EpR) is necessary for entry of MV into respiratory epithelium and infection of the epithelial cells is required for shedding and transmission. Figure 1: a) Structure of a measles virus   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   b) Measles virus genome   Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚  Ã‚   c) Membrane fusion and replication of measles virus in a cell   Take from the wed-site nature.com/nrmicro/journal/v4/n12/box/nrmicro1550_BX1.html (Moss Griffin, 2006) 2. Fusion The interaction of both H and F proteins with human receptors is important for the virus to gain access into the host cell. Fusion (F) protein mediates the fusion of viral envelop with cell membrane. Figure 1 (c) demonstrated the fusion process. When the tetramer H protein binds to its receptor, it generates a conformational change within the F protein which is composed of two subunits F1 and F2 linked by a disulphide bond. The activated F protein inserts the hydrophobic fusion peptide into the target cell membrane and provides entry of the viral genome into the host cell interior (Weidmann et al, 1999). 3. RNA replication and Assembly of viral particles The polymerase allows replication and transcription of the genome within the cell. The negative sense RNA is copied into a complementary positive strand which, in turn, acts as a template for the negative strand. Viral components are translated in the cell and are assembled at the cell surface (Yanagi et al, 2006). 4. Release of virus MV leaves the host cell in a budding form (Yanagi et al, 2006). Spread The viremic spread from the respiratory tract is carried out by infected immune cells including monocytes, dendritic cells, B and T cells which travel through the local lymphatics and are transported to the secondary lymphoid tissue where further viral replication occurs. A secondary viremia occurs when infected cells enter the circulation and viral replication continues in the endothelia and epithelia of other organs including skin, gastrointestinal tract, liver, kidney and central nervous system (Ferreira et al, 2010). A systemic spread is favored by the immunosuppression following infection. Multiple mechanisms are involved in the development of immunosuppression and a brief description below focuses on some of the important pathways. 1. Changes in lymphocyte number and function Lymphopenia of B and T cells during viremic and post-clinical recovery stages is demonstrated by many studies. Bieback et al. (2002) showed that MV can bind to Toll-like receptor (TLR) 2 on monocytes, inducing SLAM expression and interleukin-6 (IL-6) production. In addition, binding of SLAM can induce Fas (CD95)-mediated apoptosis of uninfected CD4+ and CD8+ T lymphocytes. The extracellular composition of CD46 is characterized by four short consensus repeat (SCR) and a STP domain. SCRs 2, 3 and 4 are binding regions for C3b and C4b, thereby preventing them from causing autologous complement lysis. The attachment of MV to SCRs 1 and 2 alters the normal signaling pathway resulting in down-regulation of CD46, eventually leading to increased C3b-mediated complement lysis (Manchester and Rall, 2001). MV also inhibits lymphoproliferation by causing cell cycle arrest in the G0/G1 phase in dividing lymphocytes (Niewiesk et al, 1999) and interferes with NF-kB signaling pathways and anti-apoptotic B cell lymphoma 3 (Bcl-3) proteins (Bolt Berg, 2002). Furthermore, Nucleoprotein of MV binds to the Fc-gamma receptor on antigen presenting cells and impairs their ability to stimulate T cell proliferation (Hehren et al, 2001). Figure 2 summarized the main pathways leading to immunosuppression. Figure 2: Mechanisms of immunosuppression following measles virus infection Adapted from (Moss et al, 2004) 2. Shift in cytokine profile Early evasion of the innate immune responses is the interference of interferon-alpha/beta signaling pathways (Naniche et al, 2000) due to inhibition of STAT1 and STAT2 phosphorylation by proteins V and C. However, IFN-gamma production is not affected in the acute phase of measles (Takeuchi et al, 2003). Cross-linking of CD46 by MV and direct binding of MV to CD46 on monocytes and dendritic cells inhibit the production of IL-12 (Karp et al, 1996) and hence suppress macrophage activation, T cell proliferation and delayed-type hypersensitivity (Atabani et al, 2001). The loss of IL-12 also decreases type 1 cytokines TNF-alpha and IL-2, leading to transition to type 2 cytokines IL-4, IL-5 and IL-10 by CD4+ T cells (Moss et al, 2002). Th1 to Th2 shift leads to a change of cell-mediated immunity to a dominant humoral immunity which is not sufficient to combat new infections (Kemper et al, 2003). 3. Impaired antigen presentation Dendritic cells are critical for the antigen presentation to naà ¯ve T lymphocyte. MV infected dendritic cells fail to undergo differentiation to become mature effector cells and some of them are susceptible to Fas-mediated apoptosis (Servet-Delprat et al, 2000). Marttila et al (2001) reported that antigen processing of other viruses such as rubella virus and coxsackie B4 virus is compromised in MV-infected human mononuclear cells, suggesting impaired antigen presentation to T cells. Symptoms The clinical presentation is induced by the immune responses. The initial encounter of the virus activates the innate immunity with high levels of IFN-ÃŽ ³ and IL-8 but it is not efficient to clear the virus, leading to rapid multiplication of virus (Sato et al, 2008). Figure 3 illustrates the timeline of viremia and appearance of symptoms. Figure 3: Pathogenesis of measles virus and immune responses of host. Obtained from http://pathmicro.med.sc.edu/mhunt/mump-meas.htm (Hunt, 2008) The early symptoms of measles, listed below, usually appear after an incubation period of 10 to 12 days and last for 2 to 4 days due to inflammatory reactions affecting the respiratory tract and conjunctiva (Griffin, 1995). Fever Malaise Coryza Cough Small white spots in the oral cavity (Koplik’s spots) Conjunctivitis Rash The appearance of maculopapular rash reflects the immune complex formation in the skin. It correlates with viremia and onset of adaptive immune responses. The rash starts on the face and upper back after 14 days of exposure and spreads to the entire body over the next 3 days and finally fades after 5 to 6 days indicating that Cytotoxic T lymphocytes destroy infected host cells and clear the virus. Measles antibodies also appear in the circulation around this time with IgM at day 10 and IgG at day 14. They reduce measles viral load through serum neutralization. IFN-ÃŽ ³ and IL-8 levels decrease at convalescent as cytotoxic T cells decline (Heffernan and Keeling, 2008). Immunosuppression The most important pathologic feature of measles virus is immunosuppression. Most measles-related deaths are caused by secondary bacterial and viral infections. Malnourished children with weakened immune system and vitamin A deficiency are at high risk of developing complications which include blindness, diarrhoea, bronchitis, encephalitis, ear infection and pneumonia. Patients with impaired cell-mediated immunity may not develop the rash and they are susceptible to giant cell pneumonia (Manchester and Rall, 2001) Vaccination There is no antiviral therapy for measles although medications can reduce complications. Vaccination is currently the best method to prevent the disease. The first MV called Edmonston strain was isolated in 1954 on primary human kidney cells and it was subsequently adapted to chicken embryo fibroblasts and become the progenitor for currently used attenuated live vaccines. Composition of vaccines is important to elicit long-term protective immunity but not immunologic reactions and clinically significant immunosuppression. Measles vaccine is now usually given as part of a trivalent combined vaccine, MMR which is also against mumps and rubella (Hilleman, 1999). The World Health Organization has recommended infants should have the first administration of measles vaccine at 9 to 12 months because immunity requires Th1-type response. For countries with high measles transmission, a second dose should be given at age 15 to 18 months (WHO, 2009). Vaccination campaigns are effective in promoting the use of vaccination and reducing measles deaths. Between 2002 and 2008, measles vaccination has significantly reduced 78% of measles deaths from an estimated 733 000 in 2000 to 164 000 in 2008. However, many developing countries, particularly parts of Africa and Asia, still suffer from this preventable infection due to the poor access to vaccinations and lack of facilities to properly store vaccines (Manchester and Rall, 2001). Ohtake et al (2010) has reported a spray drying method was successful to produce heat-stable measles vaccine powders. However, further tests are required to demonstrate the feasibility of these dry vaccines. Molecular epidemiology is a useful tool to monitor measles and genomic study of measles virus can provide insight in the development of new and safe vaccines (Ohtake et al, 2010). The World Health Organization is making an effort to monitor outbreaks and increase immunization coverage and hopefully can ev entually eradicate the virus in the future. Subacute sclerosing panencephalitis (SSPE) SSPE is a fatal disease caused by a persistent infection with a defected form of measles virus in the brain. The common mutated components are the matrix (M), the fusion (F) and the haemagglutinin (H) proteins. Mutations can be point mutations, deletions and biased hypermutations and are mostly found in the M gene (Gutierrez et al, 2010). SSPE has a slow progression and usually develops in an interval of 5 to 10 years after the initial infection. It is very rare. Incidence rate varies between countries but the average is about one per million. Age and sex of infected individuals can affect the frequency of SSPE. Infection before the age of 2 years is associated with higher occurrences and boys are 2 times more likely to acquire SSPE (Gutierrez et al, 2010). The development of SSPE is caused by an imcompleted eradication of MV due to inadequate cell-mediated responses caused by genetic polymorphisms (Yentur et al, 2005) and high level of IL-4 but low levels of IL-12. These cytokines favour humoral response and predispose to viral replication (Hara et al, 2006). MV enters neurons by binding to host receptors CD46 and CD9 using the F protein. It replicates inside the cells and spreads to neighbouring neurons by neurokinins synaptic receptors (Makhortova et al, 2007). In addition, sequence analysis of viral RNA showed that the virus was entered from one point and disseminate throughout the brain. The defective structural envelope proteins assist them to escape from the immune system as the mutated M, F and H proteins failed to assemble and bud out the cells. Thus, the viral particles are not recognized for many years. However, inflammatory responses are finally triggered when the virus damages the host DNA and induces apoptosis (Oldstone et al, 2004). Histological examination of the brain tissue shows evidence of widespread demyelination, infiltration of immune cells and blood brain barrier damage. Glia cells and astrocytes may be activated with increased expression of MHC class II molecules and tumor necrosis factor-ÃŽ ±. Appearance of inclusion bodies in brain tissue is also common (Akram et al, 2008). Patients are often diagnosed based on presentation and clinical findings of electroencephalography, magnetic resonance imaging and CSF serology (Koppel et al, 1996). SSPE has four clinical stages (Table 2) and most patients died within 3 years of diagnosis (Gutierrez et al, 2010). Table 2: Clinical stages of SSPE Stage Clinical manifestations I Personality changes Behaviour abnormalities II Seizures Motor decline III Rigidity Progressive unresponsiveness IV Coma Akinetic mutism (Loss of ability to speak and move) Adpated from Gutierrez et al, 2010 Word count: 2421 excluding references and plagiarism statement. Bibliography Akram M, Naz F, Malik A et al. (2008) Clinical profile of subacute sclerosing panencephalitis. J Coll Physicians Surg Pak. 18, 485-488. Atabani SF, Byrnes AA, Jaye A et al. (2001) Natural measles causes prolonged suppression of interleukin-12 production. Journal of Infectious Diseases,184, 1-9. Bolt G Berg KB (2002) Measles virus-induced modulation of host-cell gene expression. Journal of General Virology,83, 1157-1165. Ferreira CSA, Frenzke M, Leonard VHJ et al. 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The Unsolved Case of the Oakland County Child Killer

The Unsolved Case of the Oakland County Child Killer The Oakland County Child Killer (OCCK) is an unknown responsible for the unsolved murders of four or more children, two girls and two boys, in Oakland County, Michigan, in 1976 and 1977. The Murders From February 1976 to March 1977, in Oakland County, Michigan, four children were kidnapped, held for up to 19 days, and then murdered. The killer would then dress them in their freshly pressed clothing, and leave their bodies carefully positioned on blankets of snow or laying in full sight next to a road. The murders resulted in the largest murder investigation in U.S. history at that time, but it failed to produce a suspect. Mark Stebbins In the afternoon on Sunday, February 15, 1976, 12-year-old Mark Stebbins of Ferndale, Michigan,  disappeared after  leaving  the American Legion Hall to go home to watch television. Four days later, on February 19, his body was found around 12 miles from his home, laying in a snowbank in a parking lot in Southfield. He was dressed in the same clothes that he had was wearing on the day that he was abducted, but they were cleaned and pressed. An autopsy determined that he had been with an object and strangled to death. Rope burns were discovered on his wrists, indicating that his hands had been tightly bound. Jill Robinson In the late afternoon of Wednesday, December 22, 1976, 12-year-old Jill Robinson of Royal Oak, got into an argument with her mother and decided to pack a bag and run away from home. It was the last day that she was seen alive. The next day, on December 23, her bicycle was discovered behind a store located on Main Street in Royal Oak. Three days after, her body was found lying on the side of Interstate 75 near Troy within full sight of the Troy police station. An autopsy determined that Jill had died from a shotgun blast to her face. Like Mark Stebbins, she was fully clothed in the clothing that she had worn when she disappeared. Placed next to her body, police found her backpack which was intact. Like Mark, her body appeared to be carefully placed on a pile of snow. Kristine Mihelich On Sunday, January 2, 1977, at around 3 p.m., 10-year-old Kristine Mihelich of Berkley, went to the nearby 7-Eleven and bought some magazines. She was never to be seen alive again. Her body was discovered 19 days later by a mail carrier who was on his rural route. Kristine was fully dressed and her body positioned in the snow. The killer had also closed Kristines eyes and folded her arms across her chest. Although her body was left along a rural road in Franklin Village, it was left in full view of several homes. An autopsy later revealed that she had been smothered. The Task Force Following Kristine Mihelich’s murder, authorities announced that they believed that the children had been murdered by stalking the area. An official task force was formed specifically to investigate the murders. It was made up of law enforcement from 13 communities and led by the Michigan State Police. Timothy King On Wednesday, March 16, 1977, at around 8 p.m., 11-year-old Timothy King left his Birmingham home with $0.30 cents to buy candy, his skateboard tucked under his arm. He was headed to a drugstore near his house in Birmingham. After making his purchase, he left the store through the back exit which led to a parking lot where he seemed to disappear into thin air. With yet another case of an  abducted and likely murdered child on their hands, the authorities decided to perform a massive search throughout the entire Detroit area. Television news stations and Detroit newspapers heavily reported about Timothy and the other murdered children. Timothy Kings father appeared on television, pleading with the kidnapper to not hurt his son and to let him go. Marion King, Timothys mother, wrote a letter that said she hoped she would see Timothy soon so that she could give him his favorite meal, Kentucky Fried Chicken. The letter was printed in â€Å"The Detroit News.† On the night of March 22, 1977, Timothy Kings body was found in a ditch alongside a road in Livonia. He was fully clothed, but it was obvious that his clothes had been cleaned and pressed. His skateboard had been placed next to his body. An autopsy report showed that Timothy had been sexually assaulted with an object and smothered to death. It was also revealed that he had eaten chicken before he was murdered. Before Timothy Kings body was found, a woman came forward with information about the missing boy. She told the task force that on the same night that boy went missing, she saw him talking to an older man in the parking lot behind the drugstore. She described Timothy and his skateboard. Not only had she seen Timothy, but she also got a pretty good look at the man he was talking to, as well as his car. She told the authorities that the man was driving a blue AMC Gremlin with white stripes on the side. With her help, a police sketch artist was able to do a composite drawing of the older man and of the car he was driving. The sketch was released to the public. Profile of the Killer The task force developed a profile of the based on descriptions given by witnesses who saw Timothy talking to a man on the night that he was abducted. The profile described a white male, dark complected, age 25 to 35, with shaggy hair and long sideburns. Because the person seemed to be able to gain the trust of children, the task force believed that the killer was possibly a police officer, doctor, or a clergyman. The profile went on to describe the killer as someone who was familiar with the area and probably lived alone, possibly in a remote area, since he was able to for several days without friends, family or neighbors knowing. The Investigation Over 18,000 tips came into the task force, and all of them were investigated. Although there were other crimes that the police discovered while doing their investigations, the task force had not gotten any closer to capturing the killer.   Allen and Frank Detroit psychiatrist Dr. Bruce Danto  and a member of the task force team received a letter a few weeks after Timothy King was murdered. The letter was written by someone who called themselves Allen. and claimed to be the of his roommate Frank who was the Oakland County Child Killer. In the letter, Allen described himself as guilt-ridden, remorseful, scared, suicidal, and on the brink of losing his mind. He said that he had been with Allen on many road trips looking for boys, but that he was never present when Frank abducted the children or when he murdered them Allen also wrote that Frank drove a Gremlin, but that he had junked it in Ohio, never to be seen again. To offer investigators a motive for the murders, Allen said that Frank killed children while fighting in Viet Nam and was traumatized by it. He was taking revenge on rich people so that they would suffer like he did while in Viet Nam. Allen wanted to work out a deal and offered to turn over incriminating pictures that could be used as evidence against Frank. In exchange, he wanted the Governor of Michigan to sign an agreement that would give him immunity  from prosecution. Dr. Danto agreed to meet Allen at a bar, but Allen did not show up and he was never heard from again. In December 1978 the decision was made to discontinue the task force and the state police took over the investigation.

European union law Essay Example | Topics and Well Written Essays - 1000 words

European union law - Essay Example In the current context it refers to the imbalance of power between national interests in decision-making within the Council of the European Union (Ministers) and across the EU institutions as a whole. Crucially European citizens have little say in what is done in their name once they vote for their MEPs. Mitchell (2005) clarifies this: Europe’s democratic deficit, whether it be perceived or real, is largely due to the EU’s institutional architecture, which promotes a type of circulatory decision-making process, but permits little input from the European public sphere. Compounding this situation is the informal nature of negotiations that often take place among and within the key policy-making bodies of the EU, leading to a less than transparent, and sometimes unpredictable, policy-making process. The institutions ultimately take their respective mandates from the Treaties which themselves are open to interpretation. It could be argued that the EU is not a well-defined cogent democratic entity – but a hybrid of functionalism, inter-governmentalism and mult-level governance (Steiner and Woods, 2003. p13). Indeed, quoting Dr Guiliano Amato, Aveblj (2005) points out that the EU’s stakeholders have yet to determine what the European Union ought to be – and therefore cannot begin to address the wider question of how to get there. Each member state is represented by a senior Minister with the President of the Council being appointed for a six-month term, thereby ensuring that in any fiscal year 2 different member states will have the opportunity to hold the Presidency. Although the representative Minister will have been elected to a seat by a majority in his/her national constituency and appointed to high office by members of his/her political party, critics argue that the manner in which Ministers are appointed means that there is no real European philosophy at work

Final Paper Essay Example | Topics and Well Written Essays - 1500 words - 1

Final Paper - Essay Example Those who wanted to purchase homes in black neighborhoods were not covered in their mortgage even if they were financially well-off. As a result, black families and communities became trapped in these poor communities and their plight was not improved at all when other white communities were flourishing. Part of the development process in the cities also included the building of freeways cutting through many black communities and areas, prompting these people to move and settle in the suburbs or in other more convenient areas. The devastating part about the building of the freeway system is that it only cut through the black and poorer communities, but hardly through rich and white neighborhoods. This practice successfully separated black and white communities, or poor and rich communities – it successfully displaced the already disadvantaged black communities into poorer and even more dangerous neighborhoods. The government also provided much motivation for the middle class whites to leave the cities and flee to the suburbs. Motivation came in the form of mortgage and tax exemptions offered to veterans. Consequently, these individuals took advantage of these benefits and further increased the gap between the rich and the poor and increasing the concentration of poverty in some areas. These suburban communities featured successful individuals – most of them were white. In fact, the first black family to settle in such an urban community was bullied and eventually driven out of the community. In effect, the rich and the white status of said communities were maintained and the black and poor image of the urban poor was also maintained. Moreover, zoning policies further restricted the access of the poorer people to the more affluent and more progressive urban communities. New housing policies which were set forth in the aftermath of the

European History (Gender History) Essay Example for Free

European History (Gender History) Essay The history of feminism has developed into a major field in recent years. Scholars from many disciplines and writers in many countries explore the ways in which womens oppression has been represented, discussed, and resisted in the past few centuries. In Burdens of History: British Feminists, Indian Women, and Imperial Culture, Burton characterizes her book as a history of `discourse`. Antoinette Burton has revealed the intensity, the extent, the duration, and the complexity of the concern to understand significant but neglected historical extent of the relationship between feminism and imperialism. Until quite recently, feminist discussion and debate was seen fragmentary. In her work, Burton argues that it is possible to construct a more or less continuous history of British feminism, recognizing imperial feminist ideologies. Antoinette Burton developed an immense interest in the relationship between feminism and imperialism. Burton discusses the endorsement of the racism and imperialist ideals by many white feminists, and the assumption by British feminists of their own particular version of the white mans burden. This interest in the history of feminism and the sense of its expansiveness has come from a number of different fields. The writer explored the ideas, lives, and activities of feminist writers and activists. The novels of Fanny Burney, Mary Hays, Jane Austen and George Eliot, and the poetry of Elizabeth Barrett Browning, have thus been encompassed within recent discussions of the history of feminism alongside the novels of Sarah Grand, Olive Schreiner and Virginia Woolf. The feminist underpinnings, or the implications for feminism of a range of political, social, and philanthropic ideas and activities have also been examined and explored. Burton stressed the need to recognize the relationship between changing ideas about the womens role. Burtons book has served not only to expand but also to transform the history of feminism. It made clear both its immense scope and its complexity. On the one hand, it is now clear that feminist ideas and debates have existed and been elaborated more or less constantly over the last two centuries. On the other hand, the question of feminism itself of what it means and what it encompasses has become much more complex. Once feminism meant a concern with gaining equal political and legal rights for women. In Burton’s book, feminism is now seen as at best a small part of what the term covers. In recent literature far more emphasis has been placed on feminist concerns with the sexual oppression of women. They were described as objects of male desire rather than as sexual subjects seeking to articulate and express their own desires. Interrogating the meaning of sexual difference and exploring what it means to be and to live as a woman are major writer’s interests. The book establishes a variety of new challenges for anyone seeking to explore feminist ideas and debates. This is not only because of the changing frameworks. It is also because of changes and new developments which have been brought to the study of history from literary theory and from cultural studies. The shift away from authorial intention towards meaning or readings in discussing literary texts has had a significant impact on thinking about feminism. Antoinette Burton writes about mid-Victorian feminism. She argues that as mid-Victorian feminism was specific in its class base and worked with social and sexual ideals derived from that class, so too it was very specific in its sense of both national and imperial identity. Like Mary Wollstonecraft, many mid-Victorian feminists possessed a powerful sense of themselves, not so much as British, but as English women. This period saw the advent of a new form of imperial feminism. The general sense of the superiority of the West, in terms of the status of its women-which was so central for Mary Wollstonecraft and caused a particular form of feminist orientalism gave way to a specific concern with the status of Indian women. These women were seen as being in particular need and were regarded as the special responsibility of their more enlightened and more fortunate English sisters (29). The close relationship between feminism and philanthropy in the mid-nineteenth century established the framework through which feminism expanded to include imperial projects and ideals. The rate and the importance of imperial expansion in the mid-nineteenth century made the needs of the colonies significant. This occurred almost as soon as the widespread involvement of women in philanthropy came to be accepted. As Antoinette Burton has argued, our magnificent colonies became the natural ground for the practice of British womens philanthropy, offering a whole new range of avenues which provided relief from the constraints on their reform activities at home. Philanthropic work within the colonies also became a source of collective national pride (17). Following on concern about the education of Indian women, British feminists planned a scheme with send trained British lady teachers to India to preside over a number of girls schools. Feminists’ enthusiasm was effective in raising money, and in interesting British women both at home and in India in the reform of girls schooling. After an initial emphasis on sending British women to India, scholarships were provided to train Indian women as teachers as well. The concern about education was followed by one about womens health. There also was concern about the need for the provision of women doctors to Indian women who would not countenance male doctors. Here too, money was raised both in Britain and in India to provide training, initially for British women, but also for Indian women to become doctors. As Antoinette Burton points out, there was throughout all of this some recognition of the abilities and the achievements of specific Indian women. But overall, the schemes directed towards India were seen as ones necessarily begun and mainly carried out by British women on behalf of their less educated and passively suffering Indian sisters. The whole question of British women in India in the nineteenth century has become the subject of increasing discourse. On the one hand, it is clear that the significant numbers of British women who became immensely concerned about the condition of Indian women should to be revised. These women worked, sometimes quite effectively, to keep alive in the public mind their needs and interests. On the other hand, some of these women came to know and appreciate Indian women, and to make themselves mouthpieces for the goals that Indian women set. Other women both in India and in Britain assumed that their own high level of education and development made them the ones best suited to know what Indian women needed. In general, Antoinette Burton argued that the aims and objectives sought by feminists in Britain set the framework for womens emancipation everywhere. British feminists regarded themselves as experts on India after a visit. Their campaigns simply involved the application of British programs to the Indian situation. The British feminists who learned about these missionary struggles could only be strengthened in their own sense of moral and racial superiority. That consciousness, as Antoinette Burton has demonstrated in the context of India, contributed significantly to the domestic culture of imperialism. Unfortunately, feminists who responded by embracing imperialism tended to propagate generalized images of backward and oppressed Oriental womanhood. Burton has emphasized the dangers for British feminism in the assumption that a supposedly superior elite among women could speak for the less privileged and fortunate (210). In particular, the desire to emancipate women could easily become a desire to control them. Ultimately, for Burton, each new venture served more fully as a means for British feminists to show their own fitness for political rights and responsibilities through their preparedness and capacity to take on their own particular imperial burden.

The Benefits of Nursing Homes Essay -- Health Care

In the early twentieth century, what we now call nursing homes did not exist. If elderly citizens had nowhere else to go, they were sent to live in rundown poor farms. On August 14, 1935 President Roosevelt signed the Social Security Act, which provided matching grants to each state for Old Age Assistance (OAA). This in turn set in motion the opening of private homes that allowed people to live in a care facility and collect the OAA payments as well. It was not until the 1950’s when nursing homes started developing into the facilities most of us are familiar with today. It was then that nursing homes were required to follow state set standards for licensing and some even received Federal grants if they possessed a hospital like atmosphere. Throughout history, nursing homes have faced many dilemmas, laws, and legislations. However, it has been these ups and downs that have contributed to the quality of modern nursing homes. In my opinion, nursing homes are a good choice becau se they provide seniors with companionship, medical treatments, and reliable safe shelter for those who do not have a safe environment at home. Nursing homes provide companionship to elders and fun activities with people in their age group. The Four Seasons Nursing and Rehabilitation Center, offers a variety of services for the elderly. According to their website, the Four Seasons have a Therapeutic Recreation Department which â€Å"coordinates and plans all therapeutic activities for all Four Seasons residents† (2012). These activities revolve around an individual’s specific needs and can include activities such as book readings, music, arts and crafts, games, and even holiday dances. In February 2011, my grandmother suffered a stroke and needed to go to a te... ...aving their family members at home. In the end, it all comes down to the individual family deciding what would be best for their loved ones. Works Cited Four Seasons Nursing and Rehabilitation Center (2012). Recreation. Retrieved from http://www.fourseasonsnh.com/Recreation/recreation.html Kapp, M. B. (2003). Resident safety and medical errors in nursing homes. Journal of Legal Medicine, 24(1), 51. Minority Staff of the House Committee on Government Reform (2001). Abuse of residents is a major problem in U.S. nursing homes. Washington, DC: U.S. House of Representatives. PBS (2012). The Evolution of Nursing Home Care in the United States. PBS The Online News Hour. Retrieved from http://www.pbs.org/newshour/health/nursinghomes/timeline.html Stiegel, L. A. (2011). Power of Celebrity at the Senate Special Committee on Aging Hearing. Bifocal, 32(4), 43-45.

Indian Role in Afghan and Its Implication of Pakistan Essay

1.Afghanistan continues to be a proxy ‘playing ground’ for diverse outside powers with Russia in near vicinity and US in West. The decade old US meddling after the failure of Russian invasion of Afghanistan in 1979 has yielded more familiar results i.e. ethnic and cultural tensions, warlordism, drug-trafficking and rampant corruption. It is not that these traits did not exist in the Afghan society before US invaded Afghanistan but US invasion provided a surge in these attributes. 2.Afghanistan is a fault line where many outside powers are jostling for both influence and position. Some of this jostling remains overt, as in the case of US and its allies, and some of it is not, as in the case of Indian proxy war on Pakistan through Afghanistan. The Indian activities in Balochistan and FATA got a boost when US homed on to it for replicating its mandate in Afghanistan and preserve its interests post withdrawal. After intense interaction between the respective national security advisors, India agreed to fit into American boots. By doing so India would be benefited on two counts i.e. by safeguarding US interests in Afghanistan, it can accrue more American favors ranging from military to nuclear technology and it will expand its anti-Pakistan network in Afghanistan and continue sponsoring terrorist activities across borders into Pakistan. As a first step to place India in Afghanistan, US helped India sign an accord with Karzai titled ‘Strategic Partnership Agreement’ that would allow India exploit its provisions to cement its involvement in Afghan military and civil affairs. 3.AIM. 4. SEQ PART 1 INDIAN ROLE IN AFGHANISTAN PART 2 IMPACT ON PAKISTAN PART 3 ANALYSIS RECOMMENDATION PART 1 INDIAN ROLE IN AFGHANISTAN 5.The regional security dynamics in South Asia are driven by the conflict between India and Pakistan. Pakistan fears strategic encirclement by India if the Afghan government leans too much towards India, while India is afraid of Pakistan using Afghanistan as a convenient strategic staging area and a back door. Giving a military role to Indians in Afghanistan will simmer the existing tensions between the two countries on various issues while America wraps up its Afghan venture. With the added dimension of nuclear-armed India – Pakistan rivalry combined with likely strife taking place between the warlords and the central government in Kabul and a perpetual conflict between the warlords and the Taliban may create a civil war that no one would like to happen. 6.On October 4, 2011, New Delhi and Kabul have signed a historic Agreement on Strategic Partnership (ASP) which will further strengthen the relations between the two neighbors. India is the fifth highest donor in Afghanistan with $2billion of aid and also engaged in various development projects in Afghanistan and the recent visit by Afghan President Hamid Karzai also marks the collaboration of expanding the training of Afghan National Security Forces (ANSF). The growing partnership between New Delhi and Kabul has ensured some anxious moments with in Pakistan who doubts Indian presence in Afghanistan as a threat to them. 7.India is now geared up to impart extensive training to the fledgling Afghan National Army at training institutions across the country. Three areas have been identified under the ‘Agreement’ so far i.e. increase in number of Afghan trainee officers, specialized training to already serving mid and higher-level officers in ANA and training Afghan soldiers in counter insurgency and counter terrorist operations. The Indian military institutions earmarked for the purpose comprise the Commando School in Belgaum in south India, the Counter-Insurgency and Jungle Warfare (CIJW) School in Mizoram in the north East and the High Altitude Warfare School in Sonamarg, Indian Occupied Kashmir. 8.The relations between India and Afghanistan were strengthen more after the visit by Prime Minister Dr. Manmohan Singh to Kabul , which was after the gap of six years and he sent the message that, unlike the West, New Delhi has no ‘exit strategy’ from Afghanistan and will stay here to bring peace and stability in the country as well as in the region. There are also active negotiations taking place between the US and India to replace US trainers in Afghanistan for providing continuity in training of Afghan security forces once US withdraws from Afghanistan. 9.The fall of the Taliban regime in 2001 allowed India to expand its influence in Afghanistan dramatically. Its engineers and IT specialists poured in as part of its most ambitious aid package – worth more than $1.5 billion – to build remote mountain roads, establish telephone, internet, and satellite links and reopen schools and hospitals. Washington encouraged India’s involvement and believed it could use the soft power of its popular Bollywood film industry and other cultural links to encourage tolerance and pluralism in the country. Meanwhile, Delhi’s contribution towards Afghan reconstruction cannot be denied. The country’s four landmark projects are the Delaram-Zaranj road, transmission lines providing Uzbek electricity to Kabul, the hydroelectric Salma Dam and a new parliament building in Kabul – the latter two of which are still under way. The $500m newly committed aid by India will be used for development and infrastructure projects in agriculture and mining. Through its provision of education, medical treatment and small-business support, India has projected considerable soft power in Afghanistan. It provides 2,000 scholarships to Afghans annually for schooling and training in India, including for 500 Afghan civil servants. More than 100 Indian-supported but Afghan-owned small development projects are being implemented. Indian medical missions in Kabul, Jalalabad, Kandahar, Herat and Mazar-e-Sharif provided free treatment for more than 350,000 Afghans in 2009-10. PART 2 IMPACT ON PAKISTAN 10.Much distrust exists between Islamabad and Delhi over their respective activities in Afghanistan. Islamabad perceives New Delhi’s presence and influence as a deliberate attempt to encircle Pakistan and prevent it from attaining the strategic depth it needs in Afghanistan. Pakistan’s government often accuses India’s embassy and four consulates in Afghanistan of carrying out clandestine operations against Pakistan in its tribal areas and restive province of Baluchistan. Pakistan has claimed that India arms and funds Baluchi rebels and the Pakistani Tehrik-e-Taliban (TTP), which India denies. Pakistan resents the goodwill of Afghans towards Indians. For its part, Delhi sees Pakistan as attempting to force it from Afghanistan. The Indian government charges that ‘elements’ in Pakistan – essentially its Inter-Services Intelligence (ISI) directorate – planned the 2008 and 2009 terror attacks on the Indian embassy in Kabul (which Islamabad denies) and says that the Pakistan-based Haqqani terror network was responsible for carrying them out. 11.Indians replicating the role of US trainers in Afghanistan spells danger for Pakistan. The placement of Indian trainers may create more rifts in the already volatile bilateral relationship between India and Pakistan. Some of the opinion makers even go to the extent to term it on par with Kashmir. Some simplistic and narrow analyses have also linked the signing of the ASP to the worsening of US-Pakistan relations following the attack on the US embassy in Kabul, and of Afghan-Pakistan relations following the assassination of former President Rabbani and the suspension of the peace process with the Taliban thereafter. What has missed the eye is that the ASP was long in the making to address the Afghans’ long-standing demands. On the other hand, Islamababad did refrain from commenting on the Indo- Afghan partnership but the Pakistani defense analyst Ayesha Siddiqa says that â€Å"despite not commenting on this issue, the fact is that Pakistan does not like what has happened as they are crying for so long that Indian presence in Afghanistan would hurt Pakistan interests†. 12.India and Afghanistan’s problem is that Pakistan doesn’t agree and that sees India’s involvement in Afghanistan is a threat to its ‘strategic depth’ according to a concept in which Afghanistan is acknowledged as Pakistan’s backyard in which India has no right to hang out, whereas for India, which had been frozen out under the Taliban regime as a supporter of the Northern Alliance’s warlords, Afghanistan holds the keys to the Central Asian mineral and energy reserves it needs to sustain its rapid economic growth. To that end, and to increase its chances of gaining access to Afghanistan’s own rich reserves of iron ore, India has pledged another half a billion dollars in aid and the same is really affecting Pakistan’s and the things are even getting more worsen. Afghanistan is also keen to encourage India in this and it doesn’t want Pakistan to be its sole customs guard or jailer, and it has seen how vindictive its twin can be. When India’s Kabul embassy was blown up by a suicide bomber in 2008, killing 41, including India’s defence attachà ©, American officials said they had evidence that members of Pakistan’s ISI intelligence service had been involved in the plot. 13.There was a time when India was quite taken aback by that change of mood among regional neighbours that forced her to immediately seek new avenues to intervene. Indian psychological anguish, sense of alienation and feelings of failure in Afghanistan have revamped Indian diplomatic efforts with enhanced lobbying and manipulative methodology to mark their presence in Afghanistan. In this backdrop, Afghan Foreign Minister Dr. Abdullah Abdullah’s recent statement that India has a critical role to play in their country is a sign of persistent Indian clout in Afghanistan. Hence, Indian diplomatic efforts in Kabul to drive a wedge between Pakistan and Afghanistan to ensure that mutual relationship between the two inseparable neighbors remain tense. In this context, India aggressively propagates that al-Qaeda and Taliban are having safe heavens in major cities of Pakistan to show Pakistan in bad light and create ill feelings between the people of Afghanistan and Pakistan. India’s Foreign Secretary Nirupama Rao talking at a South Asia initiative talk on â€Å"India’s global role† in Harvard University a few months back said: â€Å"We have direct interest in Afghanistan, not because we see it as theater of rivalry with Pakistan but because of the growing fusion of terrorist groups that operate from Afghanistan and Pakistan and their activities in India†. PATR 3 ANALYSIS 13. The reality is what meets beyond the eyes. India has interest in Afghanistan but not in its stability and for this purpose Indian intelligence agencies have been trying to create rift among various segments of society in Afghanistan. The instability in the Afghan society will not only help India consolidate its place in Afghanistan but also facilitate in destabilizing the arch-rival Pakistan and energy rich Central Asian Republics (CARs). In the pursuance of same, India invested over a billion US dollars to have an economic clout in Afghanistan and surged its presence in terms of intelligence cooperation through opening of new consulates. These consulates are used to continue destabilization of both Pakistan and Afghanistan and their respective interests. New Delhi’s billion dollars aid to Kabul is being actually dispersed among Indian companies working in Afghanistan for use in the projects that would help India consolidate its place in Afghanistan and Central Asia. 14.For instance, construction of road linking Chahbahar Port in Iran with Afghanistan was part of the encirclement plan and to secretly ship explosives, arms and ammunition from India in the name of construction material. India has also started showing its friendly gestures to Iran as well. In a bid to make Iran forget that India voted against its nuclear programme in the IAEA and supported sanctions on Iran, New Delhi is now often found advocating that Iran has a right to peaceful uses of nuclear energy. All this flattery is to keep Afghanistan accessible through the Iranian corridor. Afghanistan is important to India to achieve its vested interests in the region. India’s long and tumultuous history of capturing and grabbing natural resources and territories, which includes valley of Jammu & Kashmir and state of Nagaland, in order to expand its size and power, is no more a hidden fact. The expansionist agenda of India disqualifies it to be a regional power what to speak of assigning her a greater role in regional peace initiatives. 15.Had India been that justified mediating power and peace lover, it would not have back-stabbed Iran on nuclear issue merely on the basis that another nuclear armed country in the region is not in India’s interest. Also Bangladesh, Sri Lanka, Nepal, Bhutan, and Maldives would not have been a victim of Indian bully. Indian occupied Kashmir is another burning example of Indian usurpation. Northeast India, a region not very well known outside South Asia, is a hotbed of Indian state terrorism and numerous armed insurgencies. Recommendations 16.It will be in the interest of the region if the US reconciles with the India-Pakistan milieu in the Afghan context and leave Afghanistan to the Afghans to decide their own fate. As the Agreement on Strategic Partnership (ASP) was signed between New Delhi and Kabul, there was an immediate reaction from Islamababad that in such an agreement â€Å"the fundamental principle of ensuring the stability in the region must be taken in the account†. This shows that how anxious Islamababad is over the growing Indian presence in Afghanistan. India’s engagement in Afghanistan has been painted by many western analysts as a zero-sum game vis-à  -vis Pakistan. Yet, despite being the largest regional donor in Afghanistan, and the fifth largest internationally, India finds it increasingly difficult to operate in Afghanistan. There have been two suicide bombings of its embassy in Kabul, the first of which killed two senior Indian diplomats, two security personnel and 50 Afghans. A terror plot targeting the Indian consulate in Jalalabad was foiled. Since 2001, 20 Indian nationals have been killed. But New Delhi is also aware of the fact that until all the groups engaged in stopping the violence the path of development and progress will not be achieved. New Delhi is also aware of the fact that the role of Pakistan is also very crucial in bringing stability in the region but is also aware of the fact that any peace process will succeed only when the violence is completely shut. CONCL In short, India has no legitimate interests in Afghanistan but is keen to have a permanent role in Afghanistan in order to fulfill its vested agenda to destabilize Pakistan – major irritant in the way of establishing Indian supremacy in the region – and to have significant influence over central Asian states. From Indian side, anything that is being projected, promoted or displayed through media and friendly gestures is merely eyewash. So in view of these bitter realities, is India worth assigning a greater role in regional peace initiatives? In view of the past experience, Iran can be fool enough to walk hand in hand and in sync with India on Afghanistan? Would Kabul keep on closing its eyes on facts and will remain in state of denial vis-à  -vis New Delhi? It is time to realise that India is not a compulsion, all that is needed to make a right choice. The relation between India and Afghanistan is entering into the new horizon and it will be interesting to see how Pakistan will respond to this new growing relationship. The coming days will be the testing times for India and Afghanistan as United States is preparing to leave Afghanistan which will enable Pakistan to use its clout in Afghanistan for their strategic interests.

Innate vs Learnt Behaviour

In your own words, detail for' and ‘against' arguments with regard to innate and learned behavior. Feel free to include your own opinion, but be sure to Justify It. Try to Include equal amount of Information for both sides. Use at least 500 words for your answer. Answer: The innate verses learnt or nature verses nurture argument is a subject that has been theorized and debated by scientists, psychologists and philosophers for hundreds of years. It Is a question that can be dated back as early as 350 BC where philosophers Plato and Aristotle had different views on whether it was nature or nurture which shaped individual behaviors.Plato believed knowledge and behavior to be innate. He theorized that all knowledge was present at birth and the environment played a unique part in shaping us. In his opinion the environment did not teach us anything we weren't born with and that Its purpose was merely to remind us of Information we already knew. Aristotle on the other hand theorized t hat behavior and knowledge had to be learnt and that we were born as tabular Rasa' or blank slate and our behavior, thoughts and actions were learnt and acquired through experiences.Although nether Plato or Aristotle theories are supported today It Is still debated hat shapes us In the people we become. Is nature or is it nurture? What is innate behavior or viewed as nature? Innate behavior is a fixed, unchangeable, untaught-of, natural behavior, which is instinctive and are born with. Behavior that is inherited or passed on through genes. Things such as reflexes are Innate behavior; a reflex Is an involuntary automatic response to a certain stimulus.Those who believe we are shaped by nature are known as nativities. Examples of innate behavior are the moor or falling reflex, the moor reflex is any sudden movement that affect the baby's neck, giving them the feeling of falling or Ewing dropped. The baby's innate reaction to this is to open their arms out wide, opening up their hands before bringing them back In to their chest almost as if to catch an object. The grasp reflex, whenever an object or fingers touches the palm of a baby's hand they will automatically grasp or grab It.The swallowing and sucking reflex, if you place something, even a finger in to the baby's mouth they will automatically suck and swallow, babies are also known to sometimes suck their fingers or thumbs whilst still in the womb, this is an instinctive reflex, something needed to survive. There are many other reflexes including blinking, breathing, sneezing and coughing. With the ability to instinctively know how to make nests, what is needed to do this and to carry the materials required to do this in their beaks.Sea turtles despite hatching on land instinctively know to head straight for the water and have the ability to swim. A very complex innate behavior can be seen in chickens. Having kept chickens since a child myself vast differences can be seen in battery hens and free range hens . Imagine this battery hens never get the opportunity to see daylight, stretch their inns, take a dust bath or forage in the dirt for worms and bugs, unlike free range hens. Yet on removing hens from the battery and giving them the gift and opportunity of a free range lifestyle, all of the natural instincts return immediately.They have always been there Just merely suppressed. Other more complex innate or instinctive behavior in animals can include hibernation and migration. Learnt behavior on the other hand or nurture is something we are not born with but which we are taught by parents, peers, teachers and can be influenced by social and environmental factors we are exposed to. These behaviors unlike innate behavior are not fixed, but flexible and can be changed at any time. Those who believe it is learnt behavior that shapes us are known as empiricists.Learnt behavior is very complex and can display itself in so many guises and can also vary diversely from one culture to another. Take for example the Europeans and the primitive mammas tribes of Africa. In Europe hunting is considered a sport whereas to the mammas tribes hunting is a necessity and way of life. Without hunting they would not be able to feed, clothe or provide for their families. To them hunting s learnt at a very young age unlike the Europeans who have the convenience of shops and no longer require learning this skill.Learnt behavior can be both good and bad, in the respect that with children a lot of learning is through copying, what they see and listen to and what they are being told about what is going on in their environment surrounding them. The good thing with learnt behavior that if it is bad such as swearing or answering back it can be rectified and changed unlike innate behavior. The body and brain combined are an amazing combination as to how it co-ordinates s, and throughout our lives we will never stop learning. Examples of learnt behavior in children include, walking, talking, lis tening, potty training to mention just a few.Babies usually makes attempts to walk from around 12 – 14 months although prior to this they have already mastered the art to get from one place to another or where they want to be. From 6 months babies may start to shuffle across the room on their bums, or lay on their front with their legs in the air trying to work out how to crawl. From 9 months babies are able to wriggle along the floor on their tummies or even rail, and by 12 months they are making attempts to walk and may even be able to when holding someone's hand. Rods are said and pronounced around them. The path to talking begins as early as 2 – 4 months when babies start to make ooh and ah sounds of pleasure. Between months 4 and 9 babies start cooing and babbling, then from 9 months they begin to point to things and vocalism with some meaning although the pronunciations is not quite there yet, by 12 – 18 months single words begin to emerge with some clarit y words such as mama or dada. Then from 18 – 24 months basic phrases and ententes start to develop with sayings like teddy gone'?From 24 months sentences begin to emerge with real meaning instead of teddy gone' it becomes Where's teddy gone'. Finally from 4 years onwards children have the same language comprehension as an adult although with basic and limited vocabulary. Some children by this age are also bilingual having parents of a different nationality are able to speak English and a foreign language having been used t hearing it during the formative years. Hearing is developmental milestone that begins whilst babies are still in the womb.From around 24 weeks gestation babies have the ability to hear sounds in the outside world, by 32 weeks they will have the ability to recognize a piece of music and move around to the beat, they are also likely to recognize the piece of music after birth. This is how we learn to listen by hearing things over and over again and through li stening to noises and people talking. Many learnt skills as a child are achieved by repetition. Although this all looks quite simple and clear cut there are problems with viewing behavior as either innate or learnt.It is relatively easy to view a singular aspect of a arson's behavior as either innate or learnt for example, hearing is innate and listening is learnt, but it would be impossible to categories a person as a whole as either innate or learnt. The main problem with trying to view behavior as either one or the other is that there are no specific scientific tests which can be carried out, and it would be practically impossible to set up such tests as people's perceptions of things are different.This would create different test results with one person viewing one thing and in the others professional opinion it could be completely different. There is also he fact that it would be seen as unethical to test such things. It has in previous years been attempted to research identica l twins, although being identical and having the same upbringing, they are unable to account for environmental and social factors, as these may be different for both of them. One spending time with one group of people going to one set of places and areas.Whilst the other twin who has a completely different group of friends, going to other places. You would also have to bear in mind the media factors the people are exposed to such as television, radio, gaming stations, the internet. It would therefore make it ritually impossible to agree whether it was nature or nurture that shaped them as individuals. Shapes us in our development from infant t o adulthood along with environmental and social factors all playing a part.Social factors may include one parent families, adopters, or where you are brought up. It is also my belief that many media factors also have a hand in what we learn things as mentioned earlier like television, internet, gaming machines, mobile phones, music, and mobile phones. I also think the social dynamics of the family also play a part too depending on what sort of upbringing you have, and who or what you learning from.

35 Genres and Other Varieties of Fiction

35 Genres and Other Varieties of Fiction 35 Genres and Other Varieties of Fiction 35 Genres and Other Varieties of Fiction By Mark Nichol A previous post detailed synonyms for story. This entry defines words identifying various genres categories of story types and similar terms: 1. Adventure fiction: stories in which characters are involved in dangerous and/or exhilarating exploits 2. Airport novel: a work of fiction, generally genre fiction, so named because of its availability at stores in international airports in order to provide airline passengers with a light diversion during a flight 3. Allegory: a story using symbolism to express truths about the human condition 4. Bildungsroman: a story detailing the emotional and moral growth of a character 5. Black comedy: a story in which the humor derives from the misfortunes and/or reproachable behavior of characters 6. Comedy: a story with elements and situations intended to amuse 7. Comedy-drama: a story with both humorous and serious elements 8. Comedy of errors (farce): a story involving energetic action revolving around humorous predicaments and coincidences 9. Comedy of manners: a story that mocks class pretensions and/or prejudices 10. Crime fiction: stories based on the commission and/or investigation of wrongdoing 11. Detective fiction: stories in which the protagonist investigates a crime 12. Epic: originally a long poem celebrating the exploits of a factual or fictitious hero, but now applied to prose works on the same theme as well 13. Epistolary fiction: stories constructed as a series of letters exchanged between characters 14. Fantasy fiction: stories involving imaginary beings in the real world or in an alternate reality and assuming suspension of disbelief about magic and/or supernatural powers 15. Fictional autobiography: a story purporting to be a first-person account of someone’s life 16. Fictional biography: a story structured to resemble a factual life story 17. Genre fiction: stories intended to appeal to readers because of adherence to a specific formula (such as adventure fiction or detective fiction), rather than on their literary merits 18. Gothic fiction: stories often taking place in an isolated setting and involving strange and/or perilous happenings 19. Horror fiction: stories incorporating supernatural and/or inexplicable elements and intended to arouse fear and dread 20. Melodrama: a story that emphasizes action over characterization and features exaggeratedly dramatic plot elements 21. Mystery fiction: stories that detail the solution of a crime or other wrongdoing 22. Pastiche: a story that imitates one or more established works, or consists of episodes of such works 23. Picaresque: an episodically structured story featuring a rogue or an antihero as the protagonist 24. Parody: a story mocking the pretensions or weaknesses of a particular author, style, or genre 25. Romance: a love story; also a tale taking place in a distant time and place and involving adventure with often supernatural or mysterious elements 26. Romantic comedy: a lighthearted story detailing a romance and its complications 27. Romp: a boisterously comical tale 28. Satire: a story that pokes fun at human shortcomings such as arrogance, greed, and vanity 29. Science fiction: stories focusing on how science and technology affect individuals and civilizations 30. Screwball comedy: a fast-paced story involving improbable situations and antics from which the humor derives 31. Swashbuckler: an adventure story in which the hero accomplishes great feats to aid a noble cause 32. Thriller: a dramatic story punctuated with action, adventure, and suspense 33. Tragedy: a story with a catastrophic and/or unfortunate outcome 34. Tragicomedy: a story with both humorous and heartbreaking aspects 35. Travelogue: a story with a plot centering on a significant amount of travel Want to improve your English in five minutes a day? Get a subscription and start receiving our writing tips and exercises daily! Keep learning! Browse the Fiction Writing category, check our popular posts, or choose a related post below:12 Signs and Symbols You Should KnowThe Possessive Apostrophe20 Ways to Laugh

Morin Surname Meaning and Family History

Morin Surname Meaning and Family History The Morin surname derives from the Old French morin, a diminutive of the name More, meaning dark and swarthy [as a moor]. It may also have originated as a topographical surname for one who lived on or near a moor. The Morin surname could also possibly originate as an adaptation of Irish surnames such as OMorahan and OMoran, or as a patronymic surname meaning the son of Maurice. Surname Origin: French Alternate Surname Spellings:  MOREN, MORRIN, MORREN, MORINI, MORAN, OMORAN, MURRAN, MORO Famous People with the Morin Surname Jean-Baptiste Morin  -  French  mathematician,  astrologer, and  astronomer.Jean-Baptiste Morin - French composerArthur Morin  -  French physicistJames C. Morin  -  American Pulitzer Prize-winning editorial cartoonistRenà © Morin  - head of the Canadian Broadcasting Corporation during World War IIJean Morin - French Baroque artistLee Morin - American astronaut Where is the Mori Surname Most Common? The Morin surname, according to surname distribution information from Forebears, is the 3,333rd most common surname in the world. It is most commonly found today in Canada, where it ranks as the 24th most common surname in the country. It is also very prevalent in France (ranked 47th) and the Seychelles (97th). WorldNames PublicProfiler indicates the Morin surname is most common in France- particularly in the regions of Poitou-Charentes, Basse-Normandie, Bretagne, Haute-Normandie, Centre, Pays-de-la-Loire, and Bourgogne. It is also fairly prevalent in Canada, particularly in the Northwest Territories, as well as Maine and New Hampshire in the United States. Genealogy Resources for the Surname Morin Morin Family Crest - Its Not What You ThinkContrary to what you may hear, there is no such thing as a Morin family crest or coat of arms for the Morin surname.  Coats of arms are granted to individuals, not families, and may rightfully be used only by the uninterrupted male-line descendants of the person to whom the coat of arms was originally granted. MORIN Family Genealogy ForumThis free message board is focused on descendants of Morin ancestors around the world. Search the forum for posts about your Morin ancestors, or join the forum and post your own queries.   FamilySearch - MORIN GenealogyExplore over 2.4 million  results from digitized  historical records and lineage-linked family trees related to the Morin surname on this free website hosted by the Church of Jesus Christ of Latter-day Saints. MORIN Surname Mailing ListFree mailing list for researchers of the Morin surname and its variations includes subscription details and a searchable archives of past messages. GeneaNet - Morin RecordsGeneaNet includes archival records, family trees, and other resources for individuals with the Morin surname, with a concentration on records and families from France and other European countries. The Morin Genealogy and Family Tree PageBrowse genealogy records and links to genealogical and historical records for individuals with the Morin surname from the website of Genealogy Today. Genealogy of Canada: Morin Family TreeA collection of links and information for Morin ancestors shared by researchers. Ancestry.com: Morin SurnameExplore over 1.2 million digitized records and database entries, including census records, passenger lists, military records, land deeds, probates, wills and other records for the Morin surname on the subscription-based website, Ancestry.com References: Surname Meanings Origins Cottle, Basil.  Penguin Dictionary of Surnames. Baltimore, MD: Penguin Books, 1967. Dorward, David.  Scottish Surnames. Collins Celtic (Pocket edition), 1998. Fucilla, Joseph.  Our Italian Surnames. Genealogical Publishing Company, 2003. Hanks, Patrick and Flavia Hodges.  A Dictionary of Surnames. Oxford University Press, 1989. Hanks, Patrick.  Dictionary of American Family Names. Oxford University Press, 2003. Reaney, P.H.  A Dictionary of English Surnames. Oxford University Press, 1997. Smith, Elsdon C.  American Surnames. Genealogical Publishing Company, 1997.

Asian Theatre and Drama Essay Example | Topics and Well Written Essays - 1000 words

Asian Theatre and Drama - Essay Example Decked up with a number of psychological and social issues, the play brought a remarkable fame to Tagore not only within the nation but across the globe as well. The combination of pathos and the humor operating hand-in-hand within the plot of the play enables a huge scope for a prolific presentation of the play on stage. Owing to this scope, a lot of modernization and improvisations have been incorporated within the plot of the original text while performance by various dramatists. PETA’s Ang Post Office which was performed in the 4th Day of the month of September in 2010, Directed by Grady Labad and Dramaturgy framed by Rustom Bharucha and the adaptation was done by Rody Vera. The entire play gives a different dimension to the language of humanity but the presentation of the ending scene, where the protagonist Amal is lying on the bed dying builds a spectacle unforgettable. The light, sound and action of the characters the moving of the bed, and the association of all the ch aracters on stage transformed the macabre of death into a panorama worth viewing that has the strength to percolate through the mundane inhibitions and comprehension of human mind and transport the audience into some space belonging to cosmic realm . Thesis Statement This essay intends to focus on the ending scene of the performance of Tagore’s ‘Post Office’ by PETA and the intensity of its presentation through which the group is able to take the viewers on a cosmic ride almost. Before analyzing the ending scene of the PETA’s ‘Post Office’ performance, it is very eventual to introspect into the original text from which the play has actually evolved; its themes, motif and most importantly a thorough judgment of its backdrop and context should also taken into consideration. Tagore’s ‘Post Office’ is a play from the pantheon of symbolic theatre. One can trace another plot running through the main plot of the play which is allegorical nature. The allegory inherent in the play, ‘Post Office’ by Tagore les at the pivotal motif of the play or the most potent theme considered. Illusion and reality at the end of the world and the eternal battle of life and death is the crux of the play. Tagore’s own fascination for the mysticism associated with death and life after death actually glossed the play, ‘Post Office’. Tagore’s idealism for the spiritual death finds profound expression through t he presentation of Post Office. The dynamics of skepticism regarding the physical and spiritual death all through his life gets a proper expression in the play, ‘Post Office’. Amal dies a physical death, but his physical death is not his actual death. Amal seems to die, but his physical extinction does not lead an end to life’s unceasing voyages2. The village doctor was about to maltreat and put him to death, but Amal feels that when a patient is visited by the royal physician, then no one can fall into the clutches of death so easily. Through the fabric of metaphors Amal awaits the King’s letter to come to him directly pondering upon the window through which he can see the Post Office. The door or the route to the endless road opens at the closing scene of the play. The royal physician himself brings the message for Amal, but the message of emancipation from the hands of the royal physicia