Human African Trypanosomiasis Treatment

Human African Trypanosomiasis Treatment THE synthesis of novel hydrazone compounds to determine the potential anti-parasitic properties and efficacy in the treatment of Human African Trypanosomiasis. ABSTRACT Human African Trypanosomiasis is caused by two sub-species of trypanosome, Trypanosoma brucei gambiense and Trypanosoma brucei rhodeisense. The protozoan parasite has complex mechanisms to evade immune destruction and hence survives in the host, leading to eventual death without treatment. Treatment such as Suramin and Melarsoprol are limited and have high toxicity, often leading to further complications. Alternative therapies are drastically needed to combat trypanosomal infection, with novel hydrazone compounds currently in development promoting trypanocidal activity. The aims and objectives of this research project include the synthesis of novel hydrazone compounds, with aims of high efficacy and low toxicity, namely against Trypanosoma brucei rhodesiense. This was achieved through a series of reactions, with proton NMR spectra used to confirm the structures of novel hydrazone compounds, and biological screening analysis used to assess the trypanocidal activity in vitro. IC50 valu es were obtained for all hydrazones synthesized, the best results coming from HD1, 9.29 ÂÂ µM, and HD6, 16.18 ÂÂ µM. Overall, the presence of chlorine in the compound typically lowered trypanocidal activity when compared to HD1, which lacked chlorine atoms. Despite other compounds in literature having much lower IC50 values, the results remain promising, demonstrating trypanocidal activity against T. brucei brucei, the infective form of trypanosome that affects animals. Trypanocidal activity against Trypanosoma brucei brucei suggests potential activity against Trypanosoma brucei rhodesiense, signifying the IC50 values obtained from novel hydrazones. Furthermore, the biological properties of hydrazone structures demonstrate the potential to develop additional analogues and derivatives, which could contribute to combatting Trypanosoma brucei rhodesiense infection. Likewise, alternative therapies that can cross the blood-brain-barrier are another interest regarding research i n the field. Trypanosoma brucei rhodesiense proceeds rapidly once an individual has been exposed to the parasite, with severe side effects and high mortality rates. This reinforces the need for better and more effective treatment and management of the disease. Key words: Trypanosomiasis, Trypanosoma brucei rhodesiense, hydrazone, Suramin, Melarsoprol, proton NMR, IC50 values 1.1. Background of Human African Trypanosomiasis Human African Trypanosomiasis (HAT), or African sleeping sickness, is a disease affecting a large proportion of Africa, with a suspected 60 million people at risk (Kennedy, 2013).It is caused by two subspecies of trypanosome, a unicellular and flagellated protozoan parasite, with Trypanosoma brucei rhodesiense (T.b.r) causing East- African sleeping sickness, and Trypanosoma brucei gambiense (T.b.g) causing West-African sleeping sickness. West African sleeping sickness is much more prevalent in terms of the whole continent, with 6228 cases reported in 2013. Incidence has decreased massively since 2000, with 25,865 reported cases, although this figure is suspected to be higher due to unreported disease incidence. It is the causative sub-species in 98% of cases. The other 2% of cases are classified as East-African sleeping sickness, with 86 cases reported in 2013, approximately 88% lower than in 2000 (709 cases reported) (Franco et al., 2014). Despite the low incidence of T.b.r infectio n, symptoms are severe and death occurs in almost all patients without treatment. Treatment for suchinfections are limited and have high toxicity, signifying the need for development. Transmission of the protozoan parasite is via the vector, the tsetse fly. Infections with T.b.r proceed rapidly, with entry of infectious metacyclic trypomastigotes into the human bloodstream, lymphatic system and cerebrospinal fluid (CSF) following the initial bite, where proliferation occurs. The tsetse fly ingests a blood meal from an infected animal, with cattle and ungulates acting as reservoirs (Palmer Wells, 2012), and hence ingests trypomastigotes. Various cell divisions and binary fission occur in the mid-gut of the fly to form procyclic trypomastigotes, and conformational changes occur to allow the trypomastigotes to bind to the salivary epithelia. Once attached, the parasite can once again replicate via asymmetric division (Pepin, 2014) to form metacyclic trypanosomes. It is in this way that a person becomes infected with T.b.r (Langousis Hill, 2014). 1.2. Immunology The causative parasite manifests in hosts due to the evasion of the immune system through antigenic variation, delaying the immune response and therefore allowing the parasite to complete its complex lifecycle (Stijlemans et al., 2016). The parasite expresses variant surface glycoproteins (VSGs) on its cell membrane via a glycophosphatidylinositol anchor to serve as a protective barrier. While the immune response induces antibody development against the VSG being expressed, the parasite can switch VSG due to the large amount of VSG genes the genome possesses. This causes new antibodies to form against the newly expressed VSG, and the parasite continues to change VSGs to avoid destruction. Furthermore, the parasites alter their energy metabolism and internal structure, presenting further issues for the immune system (Stijlemans et al., 2016). T.b.r. is resistant to human trypanosome lytic factors (TLFs) containing apolipoprotein L1 (ApoL1), and this is due to the existence of the seru m resistance protein (SRP) coded for by the SRA gene. This binds to TLF-1 and therefore prevents ApoL1-mediated lysis of the infected parasitic cells (Kennedy, 2013; Bart et al., 2015). Kato et al. noted the upregulation of certain cytokines following T.b.r infection, namely IFN-ÃŽÂ ³, IL-10, IL-6 and TGF-ÃŽÂ ² (Kato et al. 2015). Furthermore, these cytokines may play a key role in the inflammatory immune response. IL-6 and IL-10 were upregulated upon CSF examination of late stage patients, and those with CSF trypanosomes had higher levels of WBCs, positively correlating with IL-6 CSF levels. Despite this, no significant changes in levels of cytokines at different stages in HAT were noted. Both subspecies of trypanosome cause non-specific inflammatory responses, resulting in non-specific symptoms. This demonstrates the difficulty in diagnosis and staging of T.b.r infection, and therefore poses a hindrance in regards to timely treatment (Lamour et al. 2015). 1.3. Symptoms Symptoms, typically manifesting 1-3 weeks after bite, include myalgia, hyperplasia of the lymph nodes and spleen, and weight loss in the haemolymphatic stage, and there is clear central nervous system (CNS) involvement in later stages (Pepin, 2014; Kennedy, 2013). It is in this meningoencephalitic stage where patients often exhibit behavioural and motor disturbances including tremors, speech complications, anxiety, confusion, personality changes and others. Further complications may manifest, including ocular difficulties, acute renal failure, multi-organ failure and chronic lymphocytic meningoencephalitis. Death is highly likely to occur in those who do not receive treatment. Trypanosoma brucei produces an aromatic compound called tryptophol, and this induces sleep in humans. Other complications with sleep include irregular patterns of sleep or interrupted sleep, insomnia during the night and sleepiness during the daytime. 1.4. Current problem Current pharmaceutical treatment including intravenous Suramin or Melarsoprol is ineffective and potentially toxic, with patients suffering with neurological dysfunction and post- treatment reactive encephalopathy. Co-administration with eflornithine and nifurtimox has been used to treat T.b.r infection also, but remains somewhat ineffective. Suramin is provided intravenously as the first line treatment for the haemolymphatic stage of T.b.r infection, however this treatment can lead to side effects such as renal failure, peripheral neuropathy and anaphylactic shock, amongst others. It acts by binding to enzymes in the glycosome and disrupts glycolysis within the trypanosome (Babokhov et al., 2013). Should the parasite cross the blood-brain barrier in the later stages of the disease, the treatment options are toxic and limited to the arsenic compound, Melarsoprol, which acts by disrupting trypanosomal redox mechanisms. Treatment with this can lead to further complications such as post-treatment reactive encephalopathy seen in 10% of patients (Palmer Wells, 2012), subsequently causing comas, seizures and cerebral oedema for example. Co-administration of eflornithine with nifurtimox, a hydrazone of 5-nitro-2-furaldehyde, has been shown to demonstrate trypanocidal activity, and is routinely used to treat T.b.g. It has shown trypanocidal activity against T.b.b in mice, however has been relatively ineffective against T.b.r. Furthermore, although eflourthrine abides Lipinskis rule of five in theory, in practice it is a highly hydrophobic compound, and is therefore unlikely to cross inner membranes once administered (Gilbert, 2014). It is therefore administered intravenously. Due to there being no self-cure for T.b.r, treatment is required for a recovery to be made. Furthermore, many of the drugs developed are only applicable to bloodstream trypomastigotes, rather than those that have crossed the blood-brain barrier (Palmer Wells, 2012). Factors such as this demonstrate the problematic nature of the disease, as well as the need for alternative therapies to combat the infection. 1.5. Current research Currently, novel treatments are in development with the hope that toxicity is reduced and efficacy is increased against trypanosomal parasites, namely T.b.r and T.b.b. To determine whether a proposed therapeutic compound is likely to be membrane permeable and therefore orally bioavailable, the Lipinskis rule of 5 is applied. To be within the limits of the rule means that the compound is orally bioavailable and easily absorbed by the body (Leeson, P. 2012). The rules state that the molecular weight of the compound must be less than 500 Daltons, the lipophilicity value is less than 5, represented as a LogP value, the number of hydrogen bond acceptors must be less than 10, and the number of hydrogen donators must be less than 5. Hydrogen bond acceptors include highly electronegative atoms not bound to a hydrogen atom and with free electrons on its outer shell, including oxygen and nitrogen. In newer literature, fluorine may be considered and counted as a hydrogen acceptor. This contrasts with a hydrogen bond donor, any atom that donates a hydrogen atom that it is bound to break or form a bond. All novel compounds are assessed under these rules to dete rmine properties involved in pharmacokinetics (absorption, distribution, metabolism and excretion). Oral administration is non-invasive, more bioavailable and simpler for patient use, all of which is desirable for a new treatment for T.b.r infection. Furthermore, a compound designed may still be orally bioavailable if a single rule is not adhered to. Benzoxaborole compounds have recently been suggested as a new, novel treatment for Trypanosoma brucei (T.b.r and T.b.g) in vitro, namely SCYX-7158 oxaborole(Jacobs et al., 2011). The orally-active treatment is suggested to have high efficacy for both acute and chronic stages of the disease due to the treatment being permeable to the CNS, and properties such as distribution, metabolism, elimination, absorption and toxicology are apparent in vitro. A viability assay combined different whole cell T. brucei spp.and the novel compound to gain positive results of anti-parasitic activity. This treatment demonstrated concentration-dependency, and most trypanocidal activity came from the first 8 hours of a 24-hour exposure. Furthermore, the irreversibility of trypanocidal activity was noted during a short exposure. In vivo, SCYX-7158 was examined against an infection with T.b.b to monitor passage across the blood-brain barrier, with mice models providing an 80% cure rate over a 7 day-treatmen t. Benzoxaboroles, like hydrazones, have demonstrated anti-cancer, anti-fungal, anti- bacterial, anti-viral, anti-inflammatory and anti-parasitic properties with a low intrinsic toxicity similar to table salt when decomposed (Liu et al., 2014). This is due to the metabolites of benzoxaboroles being found to be boric acid and oxidative deboronation products, both with very low toxicity. Per Lipinskis law, it is an orally bioavailable drug with very low IC50 values ranging from 0.19 to 1.008 ÂÂ µM, demonstrating high trypanocidal activity in vitro. An IC50 value is value is the inhibitory concentration value at which 50% inhibition of target cells has occurred. It is important when comparing the difference in the potency of compounds. A higher value represents less efficacy, with smaller values representing good trypanocidal activity in this case. It is a pharmacokinetic parameter, measuring the relationship between drug target and drug. Other research at the forefront include the development of hydrazone compounds of 5-nitro-2-furaldehyde and adamantine alkanohydrazine (Foscolos et al., 2016). Adamantine and derivatives have been previously shown to have trypanocidal activity, increasing for the more hydrophobic, phenyl and cyclohexyl substituents. These compounds and derivatives demonstrated good trypanocidal activity, approximately 20 times greater than nifurtimox. The lowest IC50 value obtained was 0.386 ÂÂ µM. Following the same study, it was found that in the absence of the nitro group, no trypanocidal activity was demonstrated, highlighting the trypanosomal nitro reductase mechanism these novel compounds work by. In terms of the structure-activity relationship, it was seen that the selectivity of compounds against T. brucei species increased when the distance between the carbonyl group and the adamantine skeleton was increased, with derivatives containing 3-cyclopentyl and 3-phenyl being more biologically active than other compounds. In conjunction, the lipophilicity and conformational structure contributed to the efficacy of these novel compounds, with increased lipophilicity and conformational flexibility promoting trypanocidal activity. 1.6. Aims of research Better pharmaceutical treatments with high efficacy and less lethal side-effects are drastically needed for T.b.r infection. Current research demonstrates the potential use of hydrazone compounds and derivatives in combatting parasitic infections, amongst others. Guidance from project supervisor Dr A Bhambra was given throughout the project regarding the structures of compounds. Hydrazones are defined as having the structure R1R2C = NNH2, the N=H bond is conjugated with a lone pair of electrons on the functional nitrogen atom (Verma et al. 2014). Research suggests hydrazone compounds also demonstrate anticancer, anti-inflammatory and anti-HIV properties, signifying biological variety and the potential to treat other diseases (Verma et al., 2014). It is because of these properties that new hydrazone compounds are in development, with the aim of synthesising novel compounds which demonstrate similar properties when applied against Trypanosoma brucei infection, and hence a potential the rapeutic for T.b.r. 2.1. Chemistry/ experimental synthesis The synthesis of four novel hydrazone compounds of reactants A-D and Pentafluorophenyl hydrazine (PFH) (Figure 3) was performed. All solvents and reactants were commercially available. Reflux condensation reactions with relevant reactant (3 mmol) and PFH (3 mmol) were performed, with continuous heating (oil bath) and stirring of compounds at 100-150 ÂÂ °C approximately. Compounds were separated with ethyl acetate (60 ml) and distilled water (50 ml). Excess magnesium sulphate was added to remove any excess water and products were vacuum filtered. Recrystallization reactions with boiling ethanol (10 ml approximately) not in excess were performed, and compounds were vacuumed down to give final compounds. Thin Layer Chromatography (TLC) analysis was performed for all compounds throughout the stages of experiment to monitor the constituents of the final product. Prior to NMR analysis, compounds were dissolved in chloroform (800 ÂÂ µL) with exception of HD6 (with reactant D), dis solved in DMSO (400 ÂÂ µL). 2.2. Biological Screening Analysis Further viability tests were carried out to assess the trypanocidal activity of each compound. Compounds were sent to the London School of Tropical Medicine for biological screening analysis against T.b.b. Stock drug solutions were prepared in DMSO at 20 mg/ml and further diluted appropriately. All assays were performed with use of 96-well microtiter plates, each well containing 100 ÂÂ µL of parasite culture, and serial dilutions of the compound in triplicate. Wells were incubated at 37ÂÂ °C for 72 hrs in 5% CO2. Control wells contained no compound, and blanks consisted of medium only. Following this, the MIC was determined and assurance of growth in control wells. 20 ÂÂ µL of Alamar Blue was added to wells, and plates were incubated for 2-4 hrs more. Plates were read on Gemini Plate Reader with an excitation wavelength of 530 nm and emission wavelength of 580 nm. Following this, IC50 values were obtained. Four novel hydrazone compounds were synthesised, shown in table 1. The electrophilic carbonyl group of appropriate reactants A-D reacted with the nucleophilic nitrogen (hydrazine portion) of PFH by nucleophilic addition. IC50 values gained demonstrated potential, especially HD1 and HD6. Proton NMR analytical results from spectra obtained are demonstrated below, showing the amount of hydrogens (or protons) in each compound as well as their corresponding intensities. Throughout synthesis, TLC was performed for each compound to visualize the two reactants, the formed product and any other substance that may be present. Rf values and appropriate TLC analysis results are illustrated in alongside compounds in table 1. 3.1. HD1 Beige crystals (50% yield); ÃŽÂ ´H (CDCl3) 7.28 (1H, s), 7.32-7.42 (3H, m), 7.64 (2H, dd), 7.82 (1H, s). 3.2. HD4 Pink crystals (50% yield) ÃŽÂ ´H (CDCl3) 7.30 (2H, s), 7.35 (1H, s), 7.45-7.50 (1H, m), 7.62 (1H, s), 7.73 (1H, s). 3.3. HD5 Beige crystals (H (CDCl3) 7.32-7.38 (3H, s), 7.54-7.60 (2H, d), 7.78 (1H, m). 3.4. HD6 Red crystals (H (CDCl3) 7.37 (1H, s), 7.45 (2H, s), 7.70 (2H, s). 3.5. Biological screening analysis Results obtained from the London School of Tropical Medicine included IC50 values for all hydrazones synthesised. These are listed alongside appropriate compounds in table 1. HD1 had an IC50 value of 9.29 ÂÂ µM; HD4 34.37 ÂÂ µM; HD5 34.09 ÂÂ µM and HD6 16.18 ÂÂ µM. Formation of all compounds HD1, HD4, HD5 and HD6 (table 1) followed the general mechanism illustrated in appendix 1. R1 should be substituted with relevant reactant (A-D) benzene rings. Electrophilic reactants accept free pairs of electrons from the nucleophilic nitrogen atom of PFH by nucleophilic addition. The formation of a biologically active centre was documented (Verma, 2014). All compounds synthesised contain phenyl groups, which has been suggested in literature to promote trypanocidal activity (Foscolos et al., 2016). Hydrazones synthesised are also non-polar and hydrophobic compounds, meaning that they carry no net charge and are not soluble in water. Furthermore, an increase in hydrophobicity also promotes trypanocidal activity, however has been suggested to make the compound less bioavailable (Gilbert et al., 2014). Proton NMR spectra demonstrate relative intensities in parts per million (ppm) of protons or hydrogens in the compound. Despite only hydrogens being of interest, it is important to consider the other electronegative groups that exist within the compound such as phenyl groups or -OH groups, which produce different peaks. The solvent peak demonstrates as a sharp, well distinguished peak to exclude it from the compound results. Singlet, doublet and Name Reactant Structure IC50 value (ÂÂ µM) TLC (illustrated- not to scale) Rf value (cm) HD1 Benzaldehyde (reactant A) 9.29 0.73 HD4 3-chlorobenzaldehyde (reactant B) 34.37 0.48 HD5 4-chlorobenzaldehyde (reactant C) 34.09 0.43 HD6 3,4-dichlorobenzaldehyde (reactant D) 16.42 0.57 multiplet peaks were all demonstrated on the spectra. NMR analysis reflects the structures synthesised, confirming the number and positioning of hydrogens. The spectra observed demonstrated some sharp peaks and others more broad. Furthermore, some peaks were somewhat distorted due to the presence of chlorine on the aromatic benzene ring. Limitations of the experimental synthesis included low yields obtained from synthesised hydrazones. This could have been possibly due to the recrystallization step or some of the reactants not converting into product. Factors such as this could have been improved to gain better results. In addition, yields were estimated due to not weighing compounds beforehand, therefore weighing the compounds when they were initially synthesised would improve the data. 4.1. HD1 From the NMR spectra, HD1 contained 7 hydrogen atoms, one at 7.28 ppm as a singlet peak, three at 7.32 7.42 ppm as a mutliplet peak, two at 7.64 ppm as a doublet peak and one hydrogen at 7.82 ppm as a singlet peak. All novel compounds synthesised differ in terms of the aromatic benzene ring on the relevant reactants, therefore the positioning and amount of chlorine attached to this aromatic ring demonstrates the difference in IC50 values. This coincides with the biological activity against T.b.b. HD1 is formed of benzaldehyde and PFH, and therefore does not possess any chlorine atoms. The IC50 values were the lowest for HD1 at 9.29ÂÂ µM, which suggests that the presence of chlorine in the compound may decrease trypanocidal activity. 4.2. HD4 HD4 contained six hydrogen atoms, two at 7.30 ppm as a singlet peak, one hydrogen at 7.35 ppm as a singlet peak, one hydrogen at 7.45-7.50 ppm as a multiplet peak and a one hydrogen as a singlet peak at 7.73 ppm. HD4 contained a chlorine group on the 3rd carbon of the reactant benzene ring, with displacement of chlorine by (bio)nucleophiles, facilitated by the electrophilic carbon centre determining biological properties observed. However, it has been suggested that the presence of a chlorine atom at a non-reactive aromatic double bond diminishes reactivity (Naumann, 2003). The IC50 value for HD4 was 34.37 ÂÂ µM, the highest value from all the compounds synthesised. This supports the notion that chlorine atoms present in the compound reduces trypanocidal activity rather than improving it. 4.3. HD5 HD5 also contained six hydrogens, with three hydrogens at 7.32 7.38 ppm in a singlet peak, 2 hydrogens at 7.54 7.60 ppm in a doublet peak, and one hydrogen at 7.78 ppm in a multiplet peak. HD5 also contained a chlorine atom but on the forth carbon of the benzene ring, as opposed to the third. Altering the position of the chlorine atom did allow for an improved IC50 value to be obtained, which was 34.09 ÂÂ µM. This however remains much less effective than HD1. 4.4. HD6 HD6 contained five hydrogen atoms, one at 7.37 ppm as a singlet peak, one at 7.35 ppm as a singlet peak, two at 7.45 ppm in a singlet peak, and 2 hydrogens at 7.70 ppm in a singlet peak. Despite the presence of chlorine in both HD4 and HD5 causing less effective activity against T.b.b, HD6 contained two chlorine atoms attached to the benzene ring, and the IC50 value obtained was nearly half that of HD4 and HD5 at 16.18 ÂÂ µM. This suggests that the presence of one chlorine atom existing at any carbon on the benzene ring does not promote trypanocidal activity, however the presence of 2 attached chlorine atoms did aid activity. 4.5. Oral bioavailability Per Lipinskis rule of 5, all novel compounds fall within the laws except from HD1, which contains 6 hydrogen bond donors. HD1 therefore would be more bioavailable if administered intravenously, however may still be orally bioavailable as only one rule has been violated, with the rest all being adhered to. Despite this, the other novel compounds alone demonstrate progression in seeking an orally bioavailable treatment for HAT, linked with reducing toxicity amongst being easier and more accessible for those who require it. Furthermore, the use of PFH incorporates many fluorine atoms, which increases lipophilicity (Citation), increasing activity in vivo, as well as increasing fat solubility and therefore allowing the compounds to easily pass through membranes in the body. Retaining fluorine is a desirable property due to the improvement of metabolic stability as a result of the high strength C-F bond. It is a relatively small molecule, with a high electronegativity value. All properties such as this contribute to biological responses within the body. 4.6. Comparison to literature IC50 values HD1 and HD6 demonstrated the most promising results of 9.29 and 16.18 ÂÂ µM. For comparison intentions, alternative novel therapies at the forefront of science such as adamantine alkanohydrazine hydrazones and benzoxaborole SCYX-7158 have IC50 values of 0.386ÂÂ µM and 0.19 to 1.008ÂÂ µM respectively (Foscolos et al., 2016; Jacobs et al., 2011). Although the results from the synthesised compounds are promising and suggest trypanocidal activity against Trypanosoma brucei, both SCYX-7158 and the adamantine alkanohydrazine hydrazones have much lower IC50 values, suggesting that the structures of novel compounds could be improved and altered to gain better trypanocidal activity. Furthermore, current treatment Melarsoprol and Suramin have IC50 values of 0.046 and 0.004-0.009 ÂÂ µM, much lower than the compounds synthesised (Torreele et al., 2010). However, as stated above, these treatments offer high toxicity and high mortality rates following administration, and the fa ct that the novel compounds synthesised (HD1 especially) have low IC50 values remains promising. Furthermore, both Suramin and Melarsoprol are administered intravenously, posing more problems in terms of accessibility as developing countries where the disease is endemic possibly do not possess the facilities to administer treatment. This is unlike the synthesised hydrazone compounds, which all theoretically can be administered orally, therefore moving towards better treatment and management of T.b.r infection. HD4 and HD5 demonstrate lower trypanocidal activity than HD1 and HD6, therefore further progression on HD1 especially would allow for potentially more effective trypanocidal compounds, represented by lower IC50 values upon testing. Furthermore, new compounds in other literature with the highest trypanocidal activity, namely 5-nitro-2-furaldehyde and adamantine alkanohydrazine hydrazones and benzoxaboroles, provide a platform for future work and development of structural analogues of hydrazones to promote trypanocidal activity. To confirm that the novel compounds synthesised are in fact effective against T.b.r, further testing is required in a controlled level 3 laboratory where the p

The Metamorphosis of Anne in The Diary of Anne Frank Essay example --

The Metamorphosis of Anne in The Diary of Anne Frank        Ã‚  Ã‚   A young girl, Anneliese Marie Frank, receives an empty jar of a diary for her thirteenth birthday, amidst much political strife in her new home country of Netherlands. As a German-born Jew in hiding, Anne will eventually fill her diary with over 2 years of experiences of the Secret Annex. Initially, she makes use of her newfound outlet to exhibit her growing interest to become a writer. The diary, for Anne, acts as her personal confidante before her family goes into hiding, and becomes even more valued to her during their ordeal. Eventually, in 1944, Anne will hear of an opportunity for her work to be published after the war, and sets out to revise her entries. Despite this, it does not take away from the appeal for readers of her diary. The audience, as it were, is attracted to the prospect of experiencing the life and times of a person: young, female, Jewish and in hiding. As a diary, there is no foreshadowing in its content, and although in context we und erstand the inevitable end, we suspend our disbelief to immerse ourselves in the story. The narrative voices of her diary, come with several different identities too. As "Anne", herself, complete with her own feelings of awkwardness and insecurity; "Anne", the girl who ponders and philosophizes; and "Kitty", creating an identity for her diary to lay the basis for a relationship for herself. Between the duality of her personality, and the perspective of her "diary", Anne Frank demonstrates a process in realizing her own maturity as a writer.    Living in the confinement of the Annex imposes a cruel circumstance upon Anne at a critical time in her life. As an emerging teenager, dealing... ...lf, the content of her diary demonstrates how she has melded her unique experience with her personality to carve out her own sense of self. Where she began as an innocent and somewhat naà ¯ve girl, she does not lose this sense of innocence. What she does is replace this naivete with a conscious awareness of the scope of her existence, in terms of realizing the potential for her future. It's no coincidence that being the socially inclined girl she was at school, meant she adapted to life in the Annex through a diary to create a portrait of her life in hiding through her work. For Anne, not only was her diary her personal outlet, but a prism by which she could reflect on herself through her many colourful identities.    Works Cited Frank, Anne. The Diary of A Young Girl. Eds. Otto H. Frank and Miriam Pressler. Definitive ed. New York: Bantam, 1997. The Metamorphosis of Anne in The Diary of Anne Frank Essay example -- The Metamorphosis of Anne in The Diary of Anne Frank        Ã‚  Ã‚   A young girl, Anneliese Marie Frank, receives an empty jar of a diary for her thirteenth birthday, amidst much political strife in her new home country of Netherlands. As a German-born Jew in hiding, Anne will eventually fill her diary with over 2 years of experiences of the Secret Annex. Initially, she makes use of her newfound outlet to exhibit her growing interest to become a writer. The diary, for Anne, acts as her personal confidante before her family goes into hiding, and becomes even more valued to her during their ordeal. Eventually, in 1944, Anne will hear of an opportunity for her work to be published after the war, and sets out to revise her entries. Despite this, it does not take away from the appeal for readers of her diary. The audience, as it were, is attracted to the prospect of experiencing the life and times of a person: young, female, Jewish and in hiding. As a diary, there is no foreshadowing in its content, and although in context we und erstand the inevitable end, we suspend our disbelief to immerse ourselves in the story. The narrative voices of her diary, come with several different identities too. As "Anne", herself, complete with her own feelings of awkwardness and insecurity; "Anne", the girl who ponders and philosophizes; and "Kitty", creating an identity for her diary to lay the basis for a relationship for herself. Between the duality of her personality, and the perspective of her "diary", Anne Frank demonstrates a process in realizing her own maturity as a writer.    Living in the confinement of the Annex imposes a cruel circumstance upon Anne at a critical time in her life. As an emerging teenager, dealing... ...lf, the content of her diary demonstrates how she has melded her unique experience with her personality to carve out her own sense of self. Where she began as an innocent and somewhat naà ¯ve girl, she does not lose this sense of innocence. What she does is replace this naivete with a conscious awareness of the scope of her existence, in terms of realizing the potential for her future. It's no coincidence that being the socially inclined girl she was at school, meant she adapted to life in the Annex through a diary to create a portrait of her life in hiding through her work. For Anne, not only was her diary her personal outlet, but a prism by which she could reflect on herself through her many colourful identities.    Works Cited Frank, Anne. The Diary of A Young Girl. Eds. Otto H. Frank and Miriam Pressler. Definitive ed. New York: Bantam, 1997.

Phantom Limbs: A Neurobiological Explanation Essay -- Biology Essays R

Phantom Limbs: A Neurobiological Explanation Severely injuring a digit or limb can result in unrepentant damage and amputation. However, the painful sensations experienced in regard to that limb do not necessarily cease after amputation. The concept of feeling sensations in a limb that is no longer attached to the body is referred to as feeling a "phantom limb." This phenomenon is experienced by approximately 80%-100% of all patients who have lost a limb (1), and has therefore sparked wide interest in scientific community. Phantom limb sensations are common for people with missing limbs or digits. In most cases, a phantom arm hangs straight down at the side when the person sits or stands (2). The subject feels as though the limb is there even though he or she is consciously aware that it is no longer attached to the rest of the body. For example, a story by S. Weir Mitchell was written in 1866 in which a civil war soldier undergoes amputation of both legs after a battle. Before the patient knows that his legs have been amputated, he asks the nurse to scratch them for him as he feels discomfort. The nurse and doctor are surprised and dumbfounded since they both are aware that the soldier no longer has these limbs and therefore should not being feeling any pain or discomfort stemming from them (2). While the story of this soldier is fictitious, similar events occur constantly in patients who suffer the loss of a limb. There are phantom sensations that are not painful, including warmth, tingling, itching, movement, and uncomfortable positioning (1).. However, phantom pains are also common in which the subject feels stabbing, cramping, burning, and shooting pains in the phantom limb (1). The biology behind phantom limbs ... ... to uncover and understand. Perhaps after finding a definitive explanation for the sensations, subjects experiencing uncomfortable phantom pains will be able to seek some kind of therapy or treatment. The phenomenon is an excellent example of the interesting ways that neurons and the nervous system function, and it continues to question the concepts of knowing and consciousness. References This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated. Contribute Thoughts | Search Serendip for Other Papers | Serendip Home Page http://serendip.brynmawr.edu/cgi-bin/comments

Comparing The Speckled Band and Neighbourhood Watch :: Sir Arthur Conan Doyle Colin Dexter Essays

Comparing The Speckled Band and Neighbourhood Watch In this essay I' am going to compare & contrast two detective stories. A pre-twentieth century story by Sir Arthur Conan Doyle called 'The Speckled Band' & a modern story by Colin Dexter called Neighbourhood Watch. I will describe the language, characters, social and historical context, Style, the plot, similarities and differences between the two. I will also state which I prefer & why. The Speckled Band starts off with Miss Stoner going to Sherlock Holmes's house and asking for his help. She tells him of her sister's death and of how her sister had heard a whistle at night for the past week or so. On the night of her death there was a loud scream of terror and just after a whistle Miss Stoner went to inspect quickly but as she neared her sisters room she stumbled out and said silently a 'speckled band'. Miss Stoner was quite worried because her sister was soon to be married and now so is she. As soon as she left Dr Roylott came barging in wanting to know what Miss Stoner had come to see Holmes for. Holmes tried to put off answering Dr Roylott and answered with something about the weather. In disgust Dr Roylott picked up Holmes's poker and bent it then he left. Once Dr Roylott left Holmes picked up his poker and bent it back as straight as possible in one go. Holmes and Watson soon left for Stoke Moran which is the home to DR Roylott and Miss Stoner who live with one servant. But they told the dog cart driver that took them there that they were archaeologists and were interested in the building itself. They got off the dog cart near the plantation that was on Dr Roylott's land. He let some gypsies live there and often used to go with them on voyages and trips. When Holmes started to look at the rooms he began in Miss Stoners room which was supposed to be having some repairs done to the wall because the builders punctured the wall while doing repairs in the other wing of the house. When Holmes looked at it there wasn't any repairs done to the wall and nothing wrong with it either. Holmes soon went on to the next room which was currently being used by Miss Stoner Holmes automatically noticed the ventilator and told Watson that he knew that it was somewhere near due to the fact that the dead sister could smell Dr Roylott's cigars and could hear things that Dr Roylott was doing and that meant there was some kind of connection between the rooms and

Childhood Essay

Explain the sequence and rate of each aspect of development from birth- 19 years. Children develop at different rates and their progress can be measured and tracked in a variety of ways. Although every child develops at different rates the sequence will follow a pattern. This is because children will often acquire one skill before being able to move on to the next. In early years children’s sequential development can be measured against the Early Years Foundation Stage. The different aspects of development they are measured on are Physical, Communication, Intellectual/cognitive, moral, social, emotional and behavioural. Children’s Physical abilities usually develop very rapidly in the early days as they grow from a baby to a toddler. By six months of age a baby’s muscles will have developed enough to reach out and hold objects and begin exploring the world around them. They will enjoy responding to adult facial expressions and may still be shy with strangers. By the age of one a child will begin crawling and using furniture and adults for support in standing. They will be able to sit independently and become more co-ordinated with their hands. A child may have developed their first teeth and solid food will be introduced to their diet. They will begin to understand more words and respond to their name when called and may become anxious when separated from parents or carers. Jealousy of others may become apparent and they enjoy imitating actions they are shown. Between the age of one and two a child will begin walking and mark making will be explored. A child may shake their head to mean ‘no’ and they will begin to understand more words that are spoken to them. Between the ages of two and three scribbles will evolve as children start to experiment more with pencils and pens. A child will be able to throw and kick balls and build towers with blocks. Speech will have developed into longer sentences and questions will be constantly asked as they become more inquisitive. From three to four years of age children will begin to use pitch and tone in singing and their vocabulary will continue to increase. They will enjoy sorting objects into shape, colour and size and will be able to follow simple instructions. Children’s independence will continue to increase as they enjoy running, jumping, skipping and hopping. Children will now assist in dressing and undressing. From four to five years of age children’s questions become more inquisitive and their grammar more accurate. They will be able to hold pencils and pens more correctly and copy shapes and letters and draw people. Routine is very important and they will enjoy being given increasing responsibility. At six and seven years children will be able to dress unassisted and they will be ever more confident in their abilities to run, skip and hop. They may be able to do up buttons and remember events. A child will be able to hold a conversation as well as recognise sounds, words and letters. Beyond these years and heading into adolescence children will develop physically at varying rates. Children will go through puberty at very different rates. Children’s and Young People’s language and vocabulary through adolescence are greatly aided by the adults around them. From the age of seven and onwards children may begin to read aloud confidently and have an increasing knowledge of grammar and tenses. During teenage years vocabulary skills and humour will be developing in a more complex way. The use of sarcasm may be introduced. The skills to argue and debate will also progress. Teenagers will become increasingly confident in their own thoughts and ideas, however may still need reassurance as they become an adult. They will develop strong friendships and discover the opposite sex. Although Children may reach these aspects at different times and stages in their life, the same sequence will be followed. This means that a pattern of development is followed. For example, a child must learn to walk before they can develop the ability to run. 1. 2- Explain the difference between sequence of development and rate of development and why the difference is important The difference in the sequence and rate of development is important as they are used to measure a child’s development. It enables Early Years providers to monitor and track a child’s development and identify any concerns. It also allows the provider to plan at the right time for specific children. The sequence of development is the order in which a child develops. This can be different in each child. One child may begin to do things before another and skip a step in the sequence while another child may follow each step in the sequence exactly. Rate of develop is the speed in which a child develops. This can also vary from child to child as one child as one child may start doing things earlier than others. It is vital to know the difference between sequence of development and the rate of development as it helps professionals in identifying the individual needs of a child. It helps practitioners recognise where there may be special education needs and additional support required. Outcome 2Understand the factors that influence children and young people’s development and how these affect practice 2. 1- Explain how children and young people’s development is influenced by a range of personal factors. Various factors contribute to a child or young person’s development. Personal factors can include Health Problems. A child’s development begins in the Mother’s womb and can be hindered by a Mother’s drug taking or excessive alcohol consumption. It can result in premature birth and a low birth weight which consequently has an ongoing effect on the Child’s development. If a child is born with impairment such as hearing loss then this will affect their social skills and their ability to communicate. Socialising is a very important contributing factor to a child and young person’s development as children learn from each other. Learning difficulties can affect a child’s development of social skills. Children with learning difficulties will need extra support in certain areas of learning as they may become frustrated and lose confidence. A disability develops through genes. Therefore this can be a personal factor in a child and young person’s development. Physical impairments because of a disability can present social issues and different aspects of the disability can physically restrict and impair a person. 2. 2-Explain how children and young people’s development is influenced by a range of external factors. As well as personal factors, there are a number of external factors which contribute to a child and young person’s development. Poverty and deprivation can mean that a child’s life chances can often be reduced. This is especially true in other, less affluent countries where children may not have access to an education or healthcare. Family environment and background can strongly influence a child’s development. Children may not receive much support from their parents or carers and the Family may have different priorities than education for example. Personal choices can go on to affect a child and young person’s development throughout their life. If a child chooses to leave school early then this will affect their career prospects and life chances. If a young person chooses to do drugs then this will go on to affect them socially and in regards to their health. If an individual has been a ‘looked after’ Child or in care then this may be a factor in their development. Many ‘looked after’ children are moved around frequently and this can have a negative effect on their education and may cause attachment issues in childhood and throughout life. Education itself can be an external influence in an individual’s development. If a child has not attended Nursery in their Early Years then they may be held back once they begin school. The child may have learning difficulties which have not yet been identified. Explain how theories of development and frameworks to support development influence current practice. Theories of development and frameworks to support development influence current practice in various ways. Cognitive development, a theory developed by Jean Piagent, suggests that children prior to seven years of age judge their good and bad actions on the consequences of them. Children after the age of seven then begin to judge their actions on their intentions. Piagent’s theory also suggests that children’s development is sequential and that a child cannot run before they can walk, so to speak. This theory heavily influences current practice as the development of children less than five years is measured against the Early Years Foundation Stage, which recognises that the milestones which children reach may be at different times in their life but will follow the familiar pattern. Psychoanalytical Development is a theory formulated by Sigmund Freud. The theory proposes that unconscious thoughts, feelings, emotions and experiences can influence a person’s actions and that past experiences can influence and shape an individual’s future. This underlines a child’s impulses and actions. This theory influences every day practice and is demonstrated by having patience and encouraging children to share and take turns. A child must be supported in reasonable risk taking and motivation. A child must learn the skills to negotiate. This can be achieved through conflict resolution and by challenging the child’s behaviour. Abraham Maslow explained through his Humanist theory of development that individuals choices are influenced by their own perception of their experiences and that a person is able to choose their behaviour, it is not an instinctual reaction to your environment. Self-esteem, self-fulfilment and an individual’s needs are of primary importance and a person’s basic needs must be met in order to attain these. Maslow developed the ‘Hierarchy of Need’ which is utilised in current practice to measure a child’s personal development. Maslow put forward that a person’s basic needs must be met before they can achieve self-actualisation and realise their own personal potential. Albert Bandura’s theory of Social Learning advocates that children learn from others through observation and imitation. There are three aspects to this theory and these are that children learn through observation, that a child’s internal mental state is a factor and that even if a child learns something it does not mean that a child will use that learned behaviour. Bandura’s theory has had an influence on current practice as it put forward the idea that learning does not change behaviour and in order to do so both Families and Professionals need to be part of the process. It is widely understood that Parents and Teachers should be positive role models in a child and young person’s life. Burrhus Frederic Skinner’s theory of Operant Conditioning supports the concept of ‘the mind’ and that it is more productive to learn from observed behaviour than to develop from your own internal mental experience. Skinner believed that the best way to understand an individual’s behaviour is to consider the cause and effect. B. F. Skinner’s theory of Operant Conditioning was largely based on Edward Lee Thorndike’s ‘Law of Effect’ theory. Thorndike’s theory was founded through studying learned behaviour in animals. Skinner believed that reinforcement was the key to repeated behaviour and that behaviour that is encouraged will be replicated as opposed to behaviour which is not reinforced being extinguished. Operant conditioning is a theory which supports the fact that behaviour may be changed through reinforcement. This theory is demonstrated in current practice by the use of reward charts. By negatively reinforcing behaviour a child may not repeat the action so as to remove the unpleasant experience. Behaviourist theory was formulated by John B. Watson who believed that children have three main motives being fear, rage and love and the theory deals only with observable behaviour. Development is considered a reaction to given rewards and punishments. Behaviourist theory is set apart from other theories in the fact that it does not deal with internal thoughts or theories. Because of this many critics argue that Behaviourism is one dimensional and does not account for other types of learning. However, it is an effective tool in measuring a child’s behaviour and tracking their development. Although Behaviourism is widely criticised it is still a widely used notion in teaching and encouraging positive behaviour and discouraging negative behaviour. Social Pedagogy is a framework in place to support development and enforce humanistic behaviour such as respect for others, trust and equality. It promotes the development of children in areas such as emotions and feelings, intellect, and physical capability. It encourages sustained wellbeing and health, self-empowerment, to take responsibility for one’s own actions and to promote human welfare and ease social problems. This Framework supports development of children and is increasingly associated with Community and Social Work. It upholds Equality, Diversity and Inclusive practice and is enforced by looking at the child as a whole and supporting their overall development. Outcome 3Understand how to monitor children and young people’s development and interventions that should take place if this is not following the expected pattern 3. 1- Explain how to monitor children and young people’s development using different methods. There are various methods and ways of monitoring and tracking children and young people’s development. A key system is session planning and evaluation which enables practitioners to reflect on a session and introduce scaffolded learning to meet a child’s developmental needs. Assessment Frameworks within education are in the form of SATS and GCSE exams. These exams measure a child’s ability to retain information. If a child is believed to have additional needs then a Common Assessment Framework can be completed to identify a child or young person’s educational, emotional and developmental needs. In their Early Years, children undergo regular health checks to ensure their physical development is progressing at the expected rate. The Early Years Foundation Stage is used to measure children’s milestones. Through observation it can be discerned if a child is not meeting the expected pattern of development. This should be relayed to the parent or carer and discussed to ascertain if there are any concerns at home. It is best practice to share information with other professionals, colleagues and parents and carers to ensure that all information and facts are collated and everyone is concerned with the overall development of a child or young person. 3. Explain the reasons why children and young people’s development may not follow the expected pattern There are a range of reasons why children and young people’s development may not follow the expected pattern. Factors such as disability can affect various areas of development but early intervention and support can aid in a child’s development. Positive emotional development occurs when a child receives routine and structure and feels settled. Attachment issues can cause low self-esteem and motivation in children and young people and so this may hinder them in trying new things and risk taking. Physical development can be effected due to genetics. A child may be a slow learner or have problems with physical growth. This can also affect social development. Socially a child or young person’s development may not follow an expected pattern if parents and carers do not make time or prioritise interactive play with their children. An environment can result in a child’s development being affected. If a person is born into poverty then they may not have access to opportunities and education and so life chances are reduced. Culture can also play a part as the ways in which a child is brought up differs around the world. Other cultures may have different expectations or restrictions on a child. Learning difficulties may shape a person’s development pattern as they may not be identified early on in a child’s life. This may therefore hold them back. Children who have speech problems or find it difficult to read and write will find it arduous and frustrating to communicate with others. 3. 3-Explain how disability may affect development Disability can affect development in a number of ways. Learning and social development can be affected by a number of disabilities and a child may be faced with prejudice and discrimination. Learning disabilities which can affect development can include Autism, which affects an individual’s communication and interaction with others and the world around them. Autism can lead a person to feel isolated and alone and an individual may find it hard to read facial expressions and tone of voice. Dyslexia can create development issues in relation to reading and writing. If Dyslexia is undetected in childhood then this can affect a child’s self fulfilment. Children may become angry and detached and may have difficulty attending school. This in turn will affect their education and learning development. Physical disabilities such as Cerebral Palsy affect movement and posture and co-ordination. Some individuals who suffer from this particular disability can suffer from seizures and difficulty in reading and writing. 3. 4-Explain how different types of interventions can promote positive outcomes for children and young people where development is not following the expected pattern. Different types of intervention can promote positive outcomes for children and young people where development is not following the expected pattern. Social Workers are in place to help and safeguard vulnerable children and their families through Child In Need and Child Protection Plans. Speech and Language Therapists can assess and work with children and young people who have speech difficulties. The earlier the difficulty is identified the less the impact on the child’s life. Children who have behaviour and learning difficulties may be supported by a Psychologist. Once the child’s needs have been ascertained support plans can be put in place at home and within education. Psychiatrists is specialised in treating people with Mental Health issues and works alongside other professionals in supporting individuals with such issues. Youth Justice and Youth Workers work alongside Social Care in supporting young people with behavioural problems. Physiotherapists aid children in their physical development where they have restricted or little movement capability. They facilitate them in gaining the maximum movement possible. Specialist Nurses provide support to families of children with disabilities and in need of specialist medical care. Additional learning support is available to children who have specialist educational needs. Assistive technology can further aid those with learning and physical development issues. This technology can play to a child or young person’s strengths and can encourage and motivate them within their capabilities. Health Visitors are often the earliest intervention in a child’s life and the first to ascertain if development is not following the expected pattern. Regular visits from Health will ensure that the child’s development is monitored closely and any concerns are raised early on. Outcome 4Understand the importance of early intervention to support the speech, language and communication needs of children and young people. 4. 1- Analyse the importance of early identification of speech, language and communication delays and disorders and the potential risks of late recognition. Our speech, language and communication capabilities relate to how we interact and relate to others. It allows us to socialise and educate ourselves. If a child is identified as having speech, language and communication needs then it is often referred to as SLCN in short. If a child’s SLCN’s are not identified during their early years it may affect their early education and relationships in school. A child may be bullied or their own confidence issues may hold them back from interacting with others. If a child has a hearing or speech impediment then other forms of communication must be evolved and access to the appropriate support must be provided. There are many risks of late recognition regarding speech, language and communication needs. If they are not recognised early on then it can continue to result in problems with self-esteem, learning difficulties, a person feeling isolated and becoming withdrawn, anti social behaviour and an inability to express themselves effectively and a child or young person not fulfilling their full potential. 4. 2-Explain how multi agency teams work together to support speech, language and communication. Practitioners have an obligation to identify children’s needs and refer them into the right support to aid in their development. Multi agency teams work together to support SLCNs by meeting and discussing available support for the child. By multi agencies meeting together it allows all channels of support to be identified at once and discuss what each agency can provide. Minutes are taken at these meetings which allow all agencies to have up to date information and work together to achieve a common goal. 4. 3-Explain how play and activities are used to support the development of speech, language and communication. Children learn through play and different activities can support the development of speech, language and communication. This allows different language to be used within a context the child can enjoy. The activity should be themed on something a child enjoys doing to encourage interest and engagement. Instruments and shapes can lead into describing words and sensory experiences. Puppets can encourage children to talk and interact in dramatic play which allows children to express emotions and develop language. Outcome 5Understand the potential effects of transitions on children and young people’s development 5. Explain how different types of transitions can affect children and young people’s development. A child and young person may go through several types of transition during their development. Emotional transitions occur when a person’s emotional state is altered for some reason. It can occur when a child experiences bereavement, misses a parent/carer or begins or leaves care. A child experiencing an emotional transition may have angry outbursts if they are too young or incapable of expressing themselves in words. A child may experience physical transition when beginning or leaving a school or moving home and perhaps when shifting from one activity to another. It may result in a child becoming anxious and unable to interact with others. Physiological transition takes place when a child goes through puberty or develops a long-term medical condition. A young person may lose confidence and feel uncomfortable meeting new people or experiencing new situations as they develop physically and become an adult. Intellectual transition is when a child progresses from pre-school to primary school, for example. New faces and environments can impact on a child’s ability to feel comfortable and may make the child feel anxious and lose confidence. 5. 2-Evaluate the effect on children and young people of having positive relationships during periods of transition. Positive relationships are highly important to a person’s development and wellbeing. Positive relationships promote consistency and resilience in a child and young person. Good support can come from Parents, Carers, Siblings and extended family, Social Workers, Health Professionals, teachers and tutors. These affiliations will mean that a child or young person is more likely to achieve academic targets and build strong social links. A child will feel more loved and valued and be more prepared for future transitions. Positive relationships also mean that a child or young person’s needs and requirements are more liable to be identified and provided for. A child’s welfare can be monitored more effectively and plans for children’s development and education can be more effective in their outcomes.

Project Evaluation Essay

REPORT ON PROJECT EVALUATION FOR KALAHI-CIDSS PROJECT, PHILIPPINES Introduction This report considers the following project evaluation methodologies in the context of the KALAHI – Comprehensive and Integrated Delivery of Social Services (CIDSS) Project in the Philippines (â€Å"the Project†): (a) financial analysis; (b) economic analysis; (c) social cost benefit analysis; (d) other evaluation methods including willingness to pay, planning balance sheet and cost effectiveness analysis. In order to analyse the relevance of the various evaluation methods to the Project, it is appropriate to have regard to the objectives of the Project. The overarching objectives of the Project as outlined in the logical framework for the Project were to: †¢ improve local governance; †¢ reduce poverty; and †¢ improve the quality of life of the poor. By considering the various evaluation methodologies, it is possible to identify the evaluation methods that best apply to the Project, in light of its objectives. FINANCIAL ANALYSIS Overview of financial analysis Financial analysis is an essential part of project appraisal which is necessary to estimate the financial profit generated by a project. Financial analysis â€Å"†¦attempts to determine the net financial benefit (or loss) to an  agency rather than the net benefit (or loss) to the economy or society. Financial evaluations are only concerned with cash flows in and out of the organisation.† (Commonwealth of Australia 2006, p. 28) Assessing the financial benefit of a project may be achieved through a consideration of the following: (a) net present value; (b) financial internal rate of return. Page 1 ARCH1260 Net present value Net present value is calculated by â€Å"†¦discounting a project’s cash receipts using the minimum required rate of return on new investment (cost of capital), summing them over the lifetime of the proposal and deducting the initial investment outlay.† (Levy and Sarnat 1982, p.55) It is necessary to apply a discount rate, that is the minimum required rate of return on new investment, to future cash receipts to determine the present value of those profits. The minimum required rate of return often reflects interest rates at which capital could otherwise earn interest in the market if it was not invested in a project. It is then necessary to sum the present value of cash receipts and deduct the initial cash investment for the project. Where the net present value is positive, the project may be accepted as financially viable. Financial internal rate of return The financial internal rate of return is calculated by determining the rate at which the net present value of a project equals zero. (Brent 1990) In determining financial internal rate of return, future cash receipts must be time-discounted to present values to relate to the initial investment outlay for the project. Levy and Sarnat (1982, p.55) suggest that as a general principle, where financial internal rate of return exceeds the discount rate, that is the minimum rate of return on new investment, a project may be accepted. Application of financial analysis to the case study Financial analysis is an essential valuation methodology to be applied to the Project to determine its financial viability. One of the key objectives of the Project was to maximise the use of the World Bank funding in order to ensure that the Project was economically beneficial to the Philippines’ national economy. (Araral and Holmemo 2007, p. 8) The funding of the subprojects was to be provided in counterpart by provincial, municipal and barangay local governments, in addition to funding from communities and private sources. As Araral and Holmemo (2007, p. vii) indicate, such contributions were intended to reduce the fiscal impact of the project on the national government. Accordingly, it was necessary for the various investors to be confident of the profitability of the Project. Moreover, the World Bank (2001, p. 25-26) required a financial analysis of the Project in order to determine the cost effectiveness of the Project and ultimately, whether to provide a loan to the Philippines government. However, it is noted that whilst carrying out a financial analysis is an essential aspect of project appraisal, there is a degree of uncertainty surrounding financial analysis at the outset of a project. This is particularly so in the context of developing countries where economic Page 2 ARCH1260 uncertainty affects market prices. Moreover, a financial analysis does not take account of external costs or benefits. (Commonwealth of Australia Jan 2006) ECONOMIC ANALYSIS Overview of economic analysis Economic analysis has a broader focus than financial analysis, it considers â€Å"†¦ the overall impact of a project on improving the economic welfare of the citizens of the country concerned. It assesses a project in the context of the national economy, rather than for the project participants or the project entity that implements the project. Economic analysis differs from the financial analysis in terms of both (i) the breadth of the identification and evaluation of inputs and outputs, and (ii) the measure of benefits and costs.† (Economics and Development Resource Centre Feb 1997, p. 9) The focus of economic analysis is the profitability of a project for society, rather than simply the project investor. Similar to financial analysis, through economic analysis, the net present value of a project may be calculated by summing the future flow of social benefits, less social costs (discounted to present values) and deducting the initial investment outlay. A project will be viable if the net present value of the project is greater than zero, that is, social benefits exceed social costs. Moreover, the economic internal rate of return may also be calculated for a project, by considering the net present value of a project taking into account social costs and benefits. The higher the economic internal rate of return, the more beneficial the project is to society. Discounting must be factored into the calculation of these analyses, being the minimum required rate of return on new investment, as an expression of society’s preferences rather than on the basis of interest rate as is used in financial analysis. In order to measure the social costs and benefits of a project, it is necessary to determine the common unit of account or numeraire that benefits and costs should be expressed in. Thirwall (1983, p. 213) suggests that whilst the numeraire may be expressed in domestic prices or international prices, using world prices is justified as it â€Å"†¦avoids the use of the exchange rate in order to value in a single currency some goods measured at world prices (traded goods) and others measured at domestic prices (non-traded goods).† It is also necessary, when carrying out economic analysis to adopt shadow prices. Shadow prices place a value on a factor for which there is inadequate market information, given that â€Å"†¦a project’s inputs and outputs should not necessarily be valued at current market prices because the market price may not reflect the social opportunity cost of the resource†. (Devarajan et al Feb 1997, p. 36) For example, in the context of labour, a project may Page 3 ARCH1260 employ an individual at a certain wage, which represents a financial cost, however that financial cost does not represent the social cost of  employment, being the supply price of labour. As such, a shadow price may be adopted to reflect the social opportunity cost of employment generated by the project. Application of economic analysis to the case study The Project sought to achieve several benefits beyond profitability, including improved infrastructure and services, increased community participation and improved quality of life. Accordingly, economic analysis is relevant in that it evaluates the Project’s benefits to all levels of government and to the community, rather than just the investors. An economic analysis can be carried out in respect of the infrastructure subprojects, as is evident in the analysis summarised by Aral and Holmemo (2007). For example, it is possible to quantify the cost of construction and maintenance of roads against benefits such as number of households benefiting from a road and transport costs for paddy and fertilizer. (Aral and Holmemo 2007, p. 12) However, it should be noted that economic analysis is still confined to those benefits and costs that can be measured. Whilst economic analysis is clearly useful for assessing the economic benefits and costs of the infrastructure subprojects, other broader benefits, such as better access to social services and technology and possible benefits from improvements in barangay governance (Aral and Holmemo 2007, p. 21-22), are not captured through economic analysis. SOCIAL COST-BENEFIT ANALYSIS Overview of social cost-benefit analysis Cost-benefit analysis involves the application of both financial analysis and economic analysis to a project to determine the strength of the project in being profitable and contributing to society. It â€Å"†¦attempts to measure the value of all costs and benefits that are expected to result from the activity. It includes estimating costs and benefits which are ‘unpriced’ and not the subject of normal market transactions but which nevertheless entail the use of real resources.† (Commonwealth of Australia Jan 2006, p. 5) Moreover, this analysis involves a consideration of distributional issues, that is, how benefits and costs from a project are distributed amongst private and public sectors. (Little and Mirrlees 1990, p. 352) Page 4 ARCH1260 Application of social cost-benefit analysis to the case study The use of social cost-benefit analysis as a method of evaluation for the Project is beneficial in combining a consideration of the financial viability of the project and the costs and benefits of the Project for society as a whole. It is relevant to turn to the scenarios for cost-benefit analysis for the case study. For roads, the best scenario for both road construction and road improvement is scenario 3. This is because whilst the net present value and economic internal rate of return for both scenario 1 and scenario 3 is the same for both road construction and road improvement, the discount rate for scenario 3 in both instances is less than that for scenario 1. That means that the economic internal rate of return is proportionally greater than the discount rate in scenario 3 and as such the return on those projects is greater than it would be for the scenario 1 projects. Furthermore, in the case of both road construction and road improvement, scenario 2 is the worst scenario, as the net present value is significantly less than the other scenarios and also the economic internal rate of return is lower. The higher the internal rate of return, the more beneficial the project. Overall, road construction under scenario 3 is a better option than road improvement as both the net present value and economic internal rate of return is greater for road construction than road improvement. For school building, whilst scenario 1 and scenario 3 have the same economic internal rate of return (15.91%) and the net present value for scenario 1 (at 42,729 USD) is slightly higher than that of scenario 3 (at 42,000 USD), scenario 3 is the best option as the economic internal rate of return is proportionally greater than the discount rate at 10%, rather than under scenario 1 where the discount rate is 15%. Accordingly, scenario 2 is the worst option with the lowest net present value and an economic internal rate of return which is less than the discount rate. Where economic internal rate of return is less than the discount rate the project should not be considered. As such,  scenario 2 should not be considered. For school improvement, scenario 1 and scenario 3 have the same net present value (22,930 USD) and economic internal rate of return (15.10%), however scenario 3 is more favourable given that its economic internal rate of return is proportionally greater than its discount rate (10%) than scenario 1’s discount rate (15%). Scenario 2 is the worst option given that it has a lower net present value than the other scenarios and its economic internal rate of return is less than its discount rate and as such it should not be considered. Overall, school building under scenario 3 is a better option than road improvement as the net present value of the project is greater and the proportional relationship between economic Page 5 ARCH1260 internal rate of return and discount rate is higher for school building than for school improvement. OTHER EVALUATION METHODS Overview of other evaluation methods Willingness to pay Willingness to pay examines how much a person is willing to pay for a good or service. The value that a person is willing to pay is then compared to the actual cost of the good or service. This technique relies on data collection through surveying people in a community in which a project is proposed. For example, Whittington et al (1990) surveyed a village in southern Haiti regarding willingness to pay for water services. Whilst it is suggested that the viability of willingness to pay surveys is limited given the scope for bias in individuals’ responses, Whittington et al concluded that such surveys were a feasible method of estimating willingness to pay for improved water services (1990, p. 308). Planning balance sheet This evaluation methodology attempts to list ‘intangible’ benefits of a project and also involves an analysis of the distribution of project benefits amongst society. Cost-benefit analysis only considers those  benefits that can be easily measured. As Materu (1985, p. 4) suggests, â€Å"†¦the tendency to select projects on the basis of their expected quantified monetary benefits, with intangibles treated as a minor balancing factor – which is inherent in traditional forms of cost-benefit analysis, can be misleading because it may not reflect the true social value of an investment.† The planning balance sheet approach attempts to focus on all costs and benefits of a project to the community rather than simply quantifiable economic costs and benefits. Cost effectiveness analysis Cost effectiveness analysis involves an assessment of the cost of investment in a project against the benefits measured on the basis of physical units rather than monetary value, for example, number of lives saved or children provided with an education. This enables an evaluation of the effectiveness of money spent to achieve program objectives. Cost effectiveness analysis is valuable for assessing the cost-effectiveness of alternatives programmes with similar objectives, where the project objectives are clearly defined. Page 6 ARCH1260 Application of other evaluation methods to the case study Whilst the willingness to pay approach might be suitable in respect of the infrastructure subprojects that are part of the case study, this evaluation method is not suitable for taking account of the broader aspects of the Project, such as improved community participation and quality of life. However, the planning balance sheet approach is likely to be useful in analysing the benefits of those aspects of the Project, given that they are difficult to quantify in a monetary sense. In considering cost effectiveness analysis, whilst there may be some value in measuring the benefits of the Project on the basis of units such as number of people engaged in community decision-making, however this would be difficult to measure given the broad scope of the Project wherein programmes for improved governance and participation are to be tailored to local barangay communities. As such,  this method of evaluation would not produce consistent results for carrying out preliminary appraisal of the Project. Conclusions Conducting a financial analysis is an essential part of appraisal for the Project in order to determine the financial profitability of the project for the investors. However, it is relevant to examine other aspects of the project to determine its viability given the objectives were broader than merely financial objectives. Economic analysis is relevant to apply market prices to the costs and benefits of the Project to society, rather than just the investors in the project. This enables a consideration of the net benefits of the Project as against the cost of capital expenditure required to implement the Project. Financial analysis and economic analysis are both relevant to conducting a meaningful evaluation of the Project, however, they are of limited use if applied independently. As such, social cost-benefit analysis offers an effective methodology for assessing both the financial and economic costs and benefits of the Project, and enables a consideration of how those costs and benefits would be distributed amongst various sectors within society. By applying social cost-benefit analysis, it is possible to determine whether the benefits outweigh the costs of the project to the extent that the capital should not be invested elsewhere. However, whilst social cost-benefit analysis can be used to assess benefits and costs of those aspects of the Project that are easily quantifiable, such as the infrastructure subprojects, this method does not give weight to the benefits and costs associated with the intangible objectives of the Project such as increased community participation, improved local governance and quality of life. Here, the planning balance sheet approach is useful as a means to give weight to the intangible benefits of the Project to society. Page 7 ARCH1260 Aral, E. and Holmemo, C. 2007, ‘Measuring the Costs and Benefits of Community Driven Development: The KALAHI-CIDSS Project, Philippines’, Social Development Papers – Paper No. 102. Brent, R. 1990, â€Å"Investment Criteria†, Chapter 2 in Project Appraisal for Developing Countries, New York: Harvester Wheatsheaf, pp. 24-39. Commonwealth of Australia. January 2006, Introduction to Cost-Benefit Analysis and Alternative Evaluation Methodologies, Department of Finance and Administration. [online] http://www.finance.gov.au/publications/finance-circulars/2006/01.html [Accessed 9 October 2011] Devarajan, S., Squire, L. and Suthiwart-Narueput, S. February 1997, â€Å"Beyond Rate of Return: Reorienting Project Appraisal†, The World Bank Research Observer, 12(1), pp. 3546. Economics and Development Resource Centre. February 1997, Guidelines for the Economic Analysis of Projects, Asian Development Bank. [online] http://www.adb.org/Documents/Guidelines/Eco_Analysis/eco-analysis-projects.pdf [Accessed 3 October 2011] Levy, H. and Sarnat, M. 1982, â€Å"The Economic Evaluation of Investment Proposals†, Chapter 3, in Capital Investment and Financial Decisions, 2nd ed., Englewood Cliffs, NJ: Prentice Hall International, pp. 39-64. Materu, J. 1985, â€Å"A Planning Balance Sheet of a Sites and Services Project in Tanzania†, University of Sheffield Department of Town and Regional Planning Occasional Paper Number 57. Thirwall, A. 1983, â€Å"Social Cost-Benefit Analysis and the Shadow Wage†, Growth and Development with Special Reference to Developing Economies, London: Macmillan, pp. 202-216. Whittington, D., Briscoe, J., Mu, X. and Barron, W. 1990, â€Å"Estimating the Willingness to Pay for Water Services in Developing Countries: A Case Study of the Use of Contingent Valuation Surveys in Southern Haiti†, Economic Development and Cultural Change, pp. 293311. World Bank. 2010, The World Bank Annual Report 2010, The International Bank for Reconstruction and Development, The World Bank, Washington DC. [online] Page 8 ARCH1260 http://siteresources.worldbank.org/EXTANNREP2010/Resources/WorldBankAnnualReport2010.pdf [Accessed 10 August 2011] Page 9

Geographic History of Henequen in Yucatan, Mexico Essay

In Yucatan, Mexico, one of the main considered exports has been henequen that can be obtained from the plant Agave Fourcroydes. The henequen fiber has become significant to the economic stand of Yucatan since this product has conceived intense demand by international importers, such as the United States, China, Europe, etc. According to Cook (1994), during 1990s, the production of henequen has surged to a total economic export of 150,000 tons annually. In fact, the main production of henequen originates mainly from the state of Yucatan Mexico (p. 29). The state of Yucatan, Mexico, has significantly obtained economic benefits from the exports made through these henequen fibers, such as rope, rigs, sacks, and raw forms. They are usually shipped within the proximity of Merida and other cores of henequen production (Patch, 1993 p. 206). The bloom of henequen during the nineteenth century has significantly boosted the economy of the state, especially considering that they are world’s main exported of this product. From the analysis of the blooms’ occurrence, significant characteristics that have been present in the topographical condition of the state caused this immense bloom and production. The geography and climate of Yucatan State have been considered unique and very much suitable to the growth of henequen. In addition, considering the trends of exports and demands during the early 1900s, the market needs have significantly affected the consumption of the product. However, as the late nineteenth century approaches, the decline in the henequen demand in the market due to various reasons, such as competition, discovery of alternative products and conversion of haciendas in Yucatan, has become significantly noticeable. In the study, the discussion gives emphasis on the chronological history of henequen exports from Yucatan, Mexico. The study starts with the analysis of henequen bloom during the early 1900s until its significant decline during the late 20th century. The study also provides important facts on henequen growth, export historical trends contribution of climate for its growth, and the history of its market decline. Discussion Geography of Yucatan The most evident characteristic of Yucatan Peninsula is the presence of limestone shelf from the eastern to western sections that surfaces above sea level. The limestone shelf of Yucatan is present even below the sea, which is very much evident in the eastern Caribbean side. The key to the growth of Yucatan henequen is the thin limestone soils present as one of the characteristics of their lands (Sauer, 1993 p. 178). The areas of Merida and Ticul comprise the flat plains of Yucatan abundant in limestone deposits. Viewing the areas 60 km south from Merida, vast plains of Yucatan limestone are very much evident and the river areas are flow under the soil. According to Greensfelder & Dogett (2006), the significant characteristic of limestone present in Yucatan is the porous feature, which enables storage of mineral deposits as well as water source. Such features are important in promoting the growth of henequen plants, since the limestone act as the primary nutrient banks of crop roots (p. 17). The borders of the Yucatan state involve the Campeche located in the southern portion, Quintana Roo in the southeastern portion, and the Gulf of Mexico in the north and western perspective. Throughout the peninsula, lakes called lagunas are very much evident and from here on, Yucatan has also utilized cenotes or the collapsed freshwater caverns in order to obtain their freshwater. Yucatan also has their limestone pools called chenes, which also acts as their freshwater storage since the water deposits are usually brought by the underground streams. From this variety of ecologic characteristics has aroused the vast variation of exotic flora and fauna that kept the survival of Mayan civilization present in the area (Perry, 2001 p. 9). Climatology of Yucatan The Yucatan climate entails humid temperatures from November to February, while the driest season progress from November to April. Yucatan climatology is usually tropical and hot temperature progresses in an annual scope. The average annual temperatures for the Mexican Caribbean is 78 degrees F or 25. 5 degrees C with significant deviations of 5 to 7 degrees F. During the day temperatures can push into the 80s and overnight temperatures can drop as low as the 50s and low 60s degree F. The coolest months in this region are the between December to February, where the average highs are from 74 to 76 degrees F (Page, 2005 p. 10). Analyzing one of the areas where henequen is prominently produced, Merida, which is tropical and humid, obtains the annual precipitation of about 1,050mm, which signifies to potential evapotransportation of 2,000 mm (Anton, 1996 p. 118). The climatic condition of wet and dry area has been beneficial to the industry of henequen growth since this plant tend to adapt to tropical and humid environment, which describes Yucatan peninsula as the perfect place. Added by Anton (1996), the precipitation rates present in the entire peninsula accounts to a variation of 500 mm near the northwestern shore to more than 1,300 mm in the northeastern (p. 118). The Yucatan climate has been viewed as one of the contributors for the plant’s intense growth. The Agave Fourcroydes (Henequen) The henequen plant is very similar to the usual African sisal; hence, it has acquired the name Yucatan Sisal. The Agave fourcroydes plant can be easily recognized through their leaves that have a prickly and grayish green color. The leaves are processed in the same fashion as sisal, while the strands are carefully cleansed and place under the sun to dry (Cook, 1984 p. 29). The henequen stalks can extend up to 2 meters long and 10 cm to 15 cm wide. The preferential disadvantage of this plant is the presence of thorns, which is also viewed as one of the primary reasons for the preference of consumer to African sisal since stalks their stalks are free from thorns. A cultivated henequen plant can yield about 25 leaves annually from the fifth to the 16th year after its planting. Most commonly, the henequen plant can survive and grow for seven years without intensive maintenance. In fact, with the favorable topographical condition of Yucatan, the henequen plant usually survives without being attended by farmers (Greensfelder and Doggett, 2003 p. 191). The process of extracting fiber from this plant involves the cutting of their leaves and, from the factories; they grind these until the fiber strands are revealed. The main use of henequen is for the binder twine in wheat harvesting. The advantage of henequen product over synthetic fibers is its resistance to marine life propagation, such as algae, barnacles, etc (Greensfelder and Doggett, 2003 p. 191).