The social issues of the roaring twenties ( Art and Ideas, Economy, Essay

The social issues of the roaring twenties ( Art and Ideas, Economy, Technology, Science, and the Social Ferment) - Essay Example 58). This discrimination was upheld by the US Supreme Court in Plessy v. Ferguson in 1896. This decision, which supported racial segregation, was reversed in 1954, and the government made racial segregation and discrimination in any form, illegal. However, discrimination persists and until 1920, women were not permitted to exercise their franchise, when Congress passed the Nineteenth Amendment to the US Constitution that provided women with the right to vote. Despite these measures, women in the US are still subjected to discrimination (Pozzuto & Arnd-Caddigan, Mar2008, P. 58). From the early 1900s till the Second World War, the US witnessed modernism in art, design and architecture. The first skyscrapers were constructed in the 1870s. These structures generated considerable competition from architects. The first successful design was New York’s Woolworth Building. The Architects Anderson Graham, Probst, and White designed and constructed the Wrigley Building in Chicago. Howells and Hood designed the Chicago Tribune Tower. Chrysler and the Empire State Building displayed the Art Deco design. Architect Frank Lloyd Wright designed several houses in California and Japan. Art Deco lasted from 1925 to 1950. It was called as modern construction and emerged from the 1925 International Art Exposition in Paris (Whitley, 2008). Opposition to communism reached fanatical levels in the US during the 1920s. Communism was referred to as Red Scares, and communists were referred to as anarchists. In 1920, there were an estimated 150,000 communists in the nation, which was just 0.1 percent of the population. People subscribing to radical views were persecuted, as evident from the case of Sacco and Vanzetti. Americans of that period adopted provincialism, as depicted by the reemergence of the Ku Klux Klan, restrictive immigration laws and Prohibition (Roaring Twenties). The 1919, 18th amendment to the Constitution,

Designing a training programme for supervisor skills at Primark Essay Example for Free

Designing a training programme for supervisor skills at Primark Essay Type of training and how long will the training take? (on the job or off the job) Shadowing/demonstration/coaching/external or internal course 1 hour/1/2 day/ 5 days? Provider of training and Location Sales floor/store training room/Primark head office/College/Distance course. Internal training. Who will carry out? HR manager/training manager Description of training content What will the you do /learn during the training Cost of the training Physical cost of external course/cost of paying salary to trainee whilst not doing their job role/providing cover whilst trainee is on course/travel expenses – train tickets to London if going on a head office course What will the training allow me to achieve? What skills will you have learnt? How will it assist you in being successful in your new role? Why is this skill important? Consequences Shadowing for 1 hour Sales floor watching experienced supervisor complete rota Organisation of staff rota, including breaks and lunches. Watch the supervisor complete her daily rota and then complete own rota and discuss with mentor to get feedback on how to improve it No direct costs however, Primark will still need to pay us both our  £8.50 an hour salary despite the fact that both the experienced Supervisor and I will be less productive during the training. This may impact on customer service as we won’t be available to help customers during the hours training . The training may disrupt other members of staff and reduce overall productivity of the department I will be able to complete the daily staff rota ensuring all staff get the breaks and lunches they are entitled to with minimal disruption to customer service Key feature in the job description of a supervisor. Failure to complete this correctly may mean that staff do not get the correct breaks and may become demotivated and lower their productivity as a result which will trigger a fall in customer satisfaction and potentially sales and profit Demonstration for 20 minutes Shown on the sales floor by an experienced supervisor . Whilst walking around look at the trends , most common sizes and the popular items . The ability to see when a specific product is in high demand and inform head office that more stock needs to be ordered. Listening to retail sales assistants when they tell you a product is in high demand . There are no direct costs. Although the experienced supervisor and I will need to be paid  £2.52 for the 20 minutes . I will be less productive during the training, this may impact customer service as I will be too busy to help out customers. The training may disrupt other members of staff and reduce overall productivity of the department The ability to spot trends , and items that are selling out. The ability to order in new stock . Failure in ordering a high demand products would mean Primark would miss out on an opportunity to make a profit . Failure is ordering any stock means that that Primark wouldn’t have any stock to sell and the customers would go else where. 1 day off job training completing the Impact Factory Customer service course Training by Impact Factory in London. I will be taught on how to give the best customer service and be more confident with employees. Dealing with customer complaints in the most appropriate way . Talking to unsatisfied customers and seeing what they can do to help and make sure this doesn’t happen next time.  £21.10 for the ticket to London. A whole day’s pay at  £7.57 an hour for 9 hours which is  £68.13. Although it’s more expensive than getting another supervisor to do the training , the training will be a lot more formal and I will take it more seriously . The course costs  £450. I will be trained by an expert in customer service . Although resentfulness amongst other members of staff who haven’t been chosen to attend the course and become demotivated and less efficient as a result. The overall cost will be  £539.23 . I will learn how to give good customer service , deal with rude/difficult customers , advance my listening/ responding skills, make the customers point of view work for me, gain confidence in giving customer service and handling complaints with empathy/ efficiency. A good retail supervisor needs to deal with customer complaints appropriately . This is because the supervisor will be the face of the branch and if they give a bad impression , there could be a drop in customers. The customers could go to competitors with better customer service. On the job training doing 20 minutes coaching and a 10 minutes session a week later. On the sales floor at a off-peak time with HR manager Learning how to use the supervisor function on the till to be able to give customers returns / change / cancel orders. No direct costs but both the HR manager and I will need to get paid . Although because this session is short, there will be a lot of time to do more productive things. The training may disrupt other members of staff and reduce overall productivity of the department. Customers may receive poor customer service such as long wait times at tills even though it is at off-peak time which would Lower sales. HR manager will need to be paid  £10 for the 30 minutes. I will need to be paid  £3.79 for the 30 minutes. The HR manager’s journey from London will cost  £21.10. The overall cost is  £34.89. I will learn how to use the supervisor function on the till , be able to give customer returns / change and cancel orders. As I have practiced at different times, I am now very clear on how to use the supervisor function on the till . This means in peak time if a customer needs a return I can quickly use the function on the till without holding up a long queue . This means the customers will be happier as they don’t have to wait a long time and I can go do more productive things. If I was unable to do this Primark would get a reputation for poor customer service and customers would go to competitors , which would lower sales. Off the job training for 30 minutes doing Job shadowing . 30 minutes observation On the sales floor with an experienced supervisor Ensuring that the sales floor is always kept clean, the shelves are fully stocked with products and there’s no clothes on the floor. In prime time the retail sales assistant are aware how to work in the peak times including the holidays and Saturdays . There are no direct costs but I will be paid  £7.57 for the hour and so will the experienced supervisor. I will not being my job during this training session meaning a loss of productivity . I may disrupt other employees and reduce the overall productivity of the department. Customers may have to wait longer on the tills / fitting rooms as I will be unable to help them, which would lower sales. The overall cost would be  £15.14 . I will be able to deal with the sales floor at its prime time. Through observation I can be told what my weaknesses are and how I can improve on them. If I wasn’t able to manage the store at prime the customers would be left waiting unreasonable times for the tills/ fitting rooms . They would eventually get annoyed and leave to go to a competitor, meaning a loss in sales. The employees would become demotivated as they are constantly having to work in a hectic unorganised environment and may leave. If an employee leaves Primark would have to pay for the recruitment costs for the next employee. Off the job training in London doing a leadership course – 1 day course In London being taught about leadership by CIPD Making sure all the retail sales assistants are working efficiently . Motivating all the retail sales assistants to do their work to the best of their ability . This means carrying out appraisals and dealing with any performance issues appropriately . The course costs  £545 . I will have to be paid for the full day at  £7.57 which is  £68.13 . I will have to pay for a peak return ticket to London for  £21.10 . The overall cost will be  £634.23. I will be unable to any of my tasks , therefore there will be a loss in productivity. There will be Resentfulness amongst other members of staff who haven’t been chosen to attend the course and become demotivated and less efficient as a result. I will learn which leadership characteristics I need to develop , be able to select motivational ideas with the most potential to motivate and engage the retail assistants . I will be able to motivate the retail sales assistants . Therefore they will be able to give good customer service which means happy customers , they will come more frequently . This will build a better image for Primark. If I was not able to motivate employees, they would eventually find a different job. Demotivated employees give bad customer service so the customers would get annoyed and go to competitors. Once the employee leaves , more will leave increasing the staff turnover which would make it less appealing to work for Primark . Recruitment costs are also very high and this would need to be paid for. Off the job training interview skills course In London with an interviewing expert . Working alongside Human resources manager to co interview potential candidates for the role of retail sales assistant. A ticket to London is  £21.10 . I would have to be paid for the full day at  £7.57 an hour , which is  £68.13 overall . The course costs  £30 . The overall cost is  £119.23. The setting will be more formal and I will take it more seriously . There will be a loss of productivity as I will not be there for the whole day to do my job. There may be resentfulness amongst other members of staff who haven’t been chosen to attend the course and become demotivated and less efficient as a result. I will learn: the equality act 2010 , the cost of recruitment and staff turnover, the causes of poor recruitment, strategies for effective recruitment practice, the stages of recruitment, how to design a job description and person profile, how to analyse application forms and cvs , and interview techniques . I will be able to make sure when I interview a candidate for the role of retail sales assistant I will do it in the best way possible . I will be able to choose the most suitable candidate . I will be able to make sure the candidate is not discriminated against and therefore save costs and the reputation of Primark. If I was unable to interview a candidate appropriately I could ask a question that breaks the equality 2010. This would give Primark a bad reputation and they would be fined. In house training for the 3 Hours The HR manager in a meeting room Providing induction training for new retail sales assistants and making them feel welcome and at ease. No direct costs but I and the HR manager will need to be paid for the 3 hours. The HR manager will get paid  £60 and I will get paid  £22.71. The train journey from London to this Primark branch will need to be paid for which is  £21.10. The overall cost would be  £108.31. Me and the HR manager will not be productive for those 3 hours . The training may disrupt other members of staff and decrease productivity over the whole department. Customers may receive poor customer service as I will be unable to help them. I will be able to provide suitable training for the new retail sales assistants . I will educate employees about the effective use of technology ,ensure that Primark has the competitive edge, promote health and safety, create opportunities for career development and personal growth, helps employees comply with laws and regulations and improve productivity. This is important because this means the employees will give good customer service . If I trained the employees incorrectly they could decide to leave or they could injure themselves because I didn’t mention a health and safety rule. This would mean an employee would be harmed and Primark would have broken the health and safety act and could face fines. If the employees are trained badly they could give poor customer service which would drive the customers away to the competitors , which would lower sales.

The risk factors for breast cancer

The risk factors for breast cancer INTRODUCTION Breast cancer is the most common type of cancer among women in Malaysia with an overall age-standardized incidence (ASR) of 46.2 per 100,000 population [1]. The incidence of breast cancer differs among Malaysia states; it is the most common cancer among women in Penang, followed by Sabah [2]. However, there is no previous study on risk factors associated done in Penang before. Determining the risk factors of breast cancer helps to identify women who may benefit most from screening or other preventive measures, also offers hopeful promise of modifying those factors, thus preventing breast cancer occurrence. Many risk factors of breast cancer have been found and many of them have been recognized as established factors. Advancing age is one of the most important factors [3]. Reproductive factors like timing of menarche and menopause, parity play a major role in breast cancer incidence [4, 5] . Also, lifestyle factors like alcohol consumption [6-9], high fat diet [10-14] and smoking [15-17] have been identified by many studies as risk factors for breast cancer. This study aimed to determine the relationship between the socio-demographic factors, family history, reproductive factors, the life-style factors and external factors with the occurrence of the breast cancer among the study population. MATERIAL AND METHODS Study design A matched case-control study was conducted in Penang General Hospital, Penang Island, Malaysia between 20th November 2009 and 22th January 2010 using a standardized questionnaire that designed into two languages: English and Malay. Both cases and controls were matched by age group and ethnicity. Sample size was calculated according to that reported by CARIF-UM (Release New Malaysian Breast Cancer Genetic Study) which stated that 14% of breast cancer patients in Malaysia who have family history of breast cancer [18] and the relative risk for strong family history ranging from 2.5 to 4.5 [19] , the minimum sample size was 149 patients per group. Ethical Approval Our study was approved by Clinical Research Centre and Medical Research Ethic Committee of Ministry of Health Malaysia. Considering the ethical issues, written consent was signed by each case and verbal agreement for interview participation was obtained from all control subjects. All the personal information collected was considered confidential. Data Collection The cases were recruited from a convenience sample of prevalent breast cancer women who attended the oncology clinic, day-care chemotherapy center, oncology ward, and the surgical ward during the period of conducting this research. Women with confirmed diagnosis of breast cancer histologically regardless of the stage and met the following criteria; above 20 years old, non-pregnancy, without any gynecological problems (e.g., artificial menopause by hysterectomy), hormonal and psychological problems, were called for interview. Only one patient refused to participate. Our controls were non-breast cancer women who attended the outpatient clinics and outpatient pharmacy during the same period. Women who are non-pregnant, matched by age group and ethnicity to the cases recruited, without any malignancies, gynological, hormonal and endocrine, and psychological problems are eligible to be our controls. Statistical Analysis All data entry and analyses were conducted using SPSS version 15 Microsoft program. Descriptive statistics including mean and standard deviations (SD) for continuous variables, frequencies and percentages for categorical variables were used to describe the study population. Crude ORs with 95% CI were calculated using simple logistic regression models that examined the association between breast cancer status and risk factors. Significant independent variables with P values RESULTS In all, 300 women within two groups were interviewed; 150 women with breast cancer and 150 control women without breast cancer. The means  ± SD age of cases and controls were 52.81  ± 11.13 years (range 23-83 years) and 52.40  ± 11.52 years (range 22-78 years), respectively. Statistically, there is no significant difference between cases and controls in term of age (P value= 0.75) and race frequency (P value= 1.00). Among each cases and controls group, 34.7 % were Malay, 50.7 % were Chinese, 14.0 % were Indian and 0.7 % were other races. Socio-demographic Risk Factors The results of socio-demographic risk factors obtained from univariate logistic regression analysis summarized in Table 1 showed that lower educational level and occupation were significantly related to breast cancer risk (P Family History Family history of first degree relative with other types of cancer (nasopharyngeal, ovarian, Lung, bladder, stomach, or colon cancers) increased the risk significantly (P Reproductive Risk Factors According to the reproductive factors (Table 3), women with late ages at menopauses (= 55 years old) (OR=2.8, 95%CI: 1.18 6.67), or history of menstrual irregularity (OR= 3.2, 95%CI: 1.00 10.08) or who had never breastfed (OR= 1.74, 95%CI=: 1.09 2.76) were more likely to have breast cancer. The protective effect of breastfeeding found to be a duration dependent; women who had breastfed for only few months had a higher risk by 1.51 ( 95%CI: 0.83 2.77) compared to breastfed women for a total of more than 1 year, and the risk increased in non-breastfed women to 2.08 (95%CI= 1.22 3.57). Nevertheless, no statistically significant association were observed between breast cancer and the age at menarche, number of children (parity), age at first full term pregnancy, number of abortions and menopausal status. Life Style and External Risk Factors Breast cancer risk ratios were higher for women who had a history of benign breast disease (OR=2.8, 95%CI: 1.13 6.88) and who had never practiced low fat diet (white meat, white fish, skinless chicken and avoid deep fried food) (OR=1.81, 95%CI: 1.14 2.86). However, other lifestyle factors like; smoking, alcohol consumption, body mass index (BMI = 25 kg/m2) and external hormone use, like OCP and HRT were not significant statistically to be risks for breast cancer. Multivariate Results Among all factors included in the multivariable model (Table 5), occupation, breastfeeding and practicing low-fat diet play important protective roles against breast cancer; unemployed women (adjusted OR= 2.7, 95%CI: 1.59 4.61), never breastfed women (adjusted OR= 1.94, 95%CI: 1.15 3.27) and never practiced low-fat diet (adjusted OR = 1.97, 95%CI: 1.18 3.27) were found to be associated with breast cancer risk as statistically significant independent factors. Other factors contributing to breast cancer risk were: family history of distant relatives with breast cancer (adjusted OR= 3.70, 95%CI: 1.48 -9.20) and first degree relatives with other cancers (adjusted OR= 5.27, 95%CI: 1.38 20.1). Also, women with histories of benign breast disease (adjusted OR= 3.14, 95%CI: 1.17 8.40) and menstrual cycle irregularity (adjusted OR= 4.94, 95% CI: 1.42 17.26) were more likely to have breast cancer. OCP use was significantly related to breast cancer risks; however, this was not related to the duration. While using OCP for 5 years increased the risk by only 3 times (95% CI: 1.02 9.00). DISCUSSION In a pooled analysis of 150 breast cancer cases and 150 non-breast cancer controls, associations between breast cancer and various demographic, reproductive, and lifestyle factors were examined. Both cases and controls were chosen intentionally from the same hospital during the same study period. The risk of breast cancer has been reported to be associated with socio-demographic status [24-26]. Age is a very important risk factor; it was found that breast cancer incidence generally increases with age. The mean age at diagnosis for all breast cancer patients is 50.7  ± 11.0 years. The peak age reaches between 40 and 49 and thereafter the number of breast cancer patients decreases quite dramatically with only 4.0% above 70 years old (Figure 1). Also, only 2.0% of cases were diagnosed below the age of 30 which is consistent with Singletary findings [3]. According to the other socio-demographic factors studied, higher level of education has a protective effect (P Occupation status also plays an important role as a protection factor against breast cancer in both univariate and multivariate analysis (P Family history is an important factor in our population; an adjusted OR of 3.7 (95%CI = 1.48 9.2) was found for women with a distant relative with breast cancer, which is within the OR range reported by previous literature [19, 37] and higher than that reported by others [3, 38]. However, having first degree-relatives with breast cancer is not significantly related to the breast cancer risk (P > 0.05). This may be explained partially because of the high frequency of controls (7 of 150 controls vs. 16 of 150 cases) that had first-degree relatives with breast cancer. Such a high number of family histories in controls may result in an underestimation of increased risk due to the family history. Furthermore, history of first degree relatives with other cancer (gastric, pancreatic, colon, lung carcinoma.etc) is significantly more frequent in patients than in controls with the adjusted odd ratio of 5.27 (95% CI= 1.38 20.1). Recently, it has been discovered that clustering of first degree cases of breast, pancreas and stomach carcinomas in a family has been associated with mutations in the breast cancer susceptibility gene BRCA2 [39]. Breastfeeding is an important protective factor among our population; women who had never breastfed their baby have a 1.74 (95%CI: 1.09 2.76) higher risk of getting breast cancer and the adjusted odd ratio is 1.94 (ever versus never, 95%CI = 1.15 3.27) in the multivariate analysis. Our finding is in agreement with these studies [40-48], however, others failed to find any association [31, 36, 49-52]. Moreover, the duration of breastfeeding has also an important effect; found that the longer the lactation period, the least the risk of breast cancer. This inverse relationship between the duration of breastfeeding and the risk of breast cancer have been suggested by other studies [46, 53-60], however, other revealed that this is mainly confined to women diagnosed before the age of 40 with a weak trend for older patients [61]. History of irregular menstrual cycle (Polymenorrhea, Oligomenorrhea, or Amenorrhea) had an increased risk; the OR range (3.17- 4.94) and this supports the Turkish study [62] which found that menstrual irregularity increased the risk by 1.61 (95% CI 1.05-2.49). Others [55, 63, 64] did not find any significant relation between menstrual irregularity and breast cancer risk. However, it has been reported that menstrual irregularity decreased the risk [65] This study detected a significant association between oral contraceptive use and breast cancer, consistent with other local studies [27, 36, 66] and other international studies [46, 67]. Whereas we could not find any relationship between the duration of OCP used and the risk of breast cancer, so our study does not support the growing body of evidence that long-term use of oral contraceptives, especially during certain parts of reproductive life, is associated with a modest increase in breast cancer risk [46, 68]. However, most studies found no or weak association of OCP use with the risk of breast cancer [34, 69-71]. The association between OCP use and breast cancer is also related to the duration, dosage, type of OCP and the age of first use [72]. Previous history of benign breast disease is highly significant in the present study (P Practicing low-fat diet (take only white meat, white fish, and skinless chicken and avoid deep fried food) exhibited an inverse association with the risk of breast cancer, which is significant in both univariate and multivariate analysis (crude OR 1.81, 95%CI= 1.14 2.86) and (adjusted OR: 1.96, 95%CI=1.18 3.27) respectively for women who had never practicing low fat diet. Red and fried meat consumption and fatty foods were suggested as important risk factors for breast cancer [11, 73]. For each additional 100 g (3.5 oz) daily of meat consumption the risk of breast cancer increased risk by 56% in a French case-control study [13]. Another cohort study [74] reported a significant relative risk (RR) of 1.7 for women who reported eating the skin on poultry. Null high consumptions of fatty forms, namely fried fish and chicken with skin were associated with an increase of breast cancer risk [75]. Other case-control studies reported a protective effect of poultry and fish against the devel opment of breast cancer [76]. Also, there was no evidence for a positive association between total dietary fat intake and risk of breast cancer and no reduction in the risk even among women whose energy intake from fat was less than 20 percent of the total energy intake [77]. Some case-control studies and cohort studies have shown weak and inconsistent associations between high intake of dietary fat and poultry with the occurrence of breast cancer [14, 78]. Other well-established factors that have been studied; smoking cigarettes, alcohol intake, regular use of HRT, pre and post-menopausal body mass index (BMI), marital status and the level of monthly income , age at menarche, age at first full-term pregnancy, number of abortions, menopausal status and parity were found not to be significant in this study (P > 0.05). Strength and Limitation To our own knowledge, the present study is the first case-control study of breast cancer to investigate the risk factor in Penang Island, Malaysia. Both cases and control were matched by age group and ethnicity which add some strength to our study. This research studied almost all the socio-demographic, reproductive, lifestyle and external risk factors, so the confounding effects of all of these factors had been taken into consideration when getting our result by multivariate analysis. Furthermore, the questionnaire was designed into two languages (English and Malay), hence most of the three main ethnic groups in Penang (Chinese, Malay, and Indian) are fluent in either or both of them. As other case-control studies, our work has some limitations. The question regarding menstrual history (age at menarche, age at menopause) of the respondent are likely to be affected by recall bias. There was a chance of error in recall especially for age at menarche that had been many decades earlier and this may have affected the results. We tried to minimize this bias through assisting the memory of subjects. Some of the Chinese cases were excluded due to the language barrier (they cannot speak Malay or English), that may cause some selection bias. Finally, generalizability of our findings may be precluded by our population features; they have high mean ages, low educational level and belong to a mid socioeconomic class, also by the difference in the ethnicity distribution among different Malaysia states. CONCLUSION In summarily, family history with breast cancer or other cancer, history of benign breast disease, menstrual irregularity, and oral contraceptive used were found to be significantly associated with increased breast cancer risk, whereas breastfeeding, occupation and practicing low fat diet have protective effects against breast cancer. Late age at menopause and education level are significant risk factor only in the univaraite analysis. REFERENCES Lim, G. and Y. Halimah, Second report of the national cancer registry cancer incidence in Malaysia 2003. National Cancer Registry, Ministry of Health, Malaysia, 2004. Rosemawati, A. and A. Sallehudin, Cancer registration in Malaysia. 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Naieni, K., et al., Risk factors of breast cancer in north of Iran: a case-control in Mazandaran Province. Asian Pacific Journal of Cancer Prevention, 2007. 8(3): p. 395. Ebrahimi, M., M. Vahdaninia, and A. Montazeri, Risk factors for breast cancer in Iran: a case-control study. Breast Cancer Res, 2002. 4(5): p. R10. Morabia, A., et al., Breast cancer and active and passive smoking: the role of the N-acetyltransferase 2 genotype. American Journal of Epidemiology, 2000. 152(3): p. 226. Norsa adah, B., et al., Risk factors of breast cancer in women in Kelantan, Malaysia. Singapore medical journal, 2005. 46(12): p. 698. Viladiu, P., et al., A breast cancer case-control study in Girona, Spain. Endocrine, familial and lifestyle factors. European Journal of Cancer Prevention, 1996. 5(5): p. 329. Pharoah, P., et al., Family history and the risk of breast cancer: a systematic review and meta-analysis. International Journal of Cancer, 1997. 71(5): p. 800-809. Schubert, E., et al., BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. American journal of human genetics, 1997. 60(5): p. 1031. Lubin, J., et al., Risk factors for breast cancer in women in northern Alberta, Canada, as related to age at diagnosis. Journal of the National Cancer Institute, 1982. 68(2): p. 211. Layde, P., et al., The independent associations of parity, age at first full term pregnancy, and duration of breastfeeding with the risk of breast cancer. J Clin Epidemiol, 1989. 42(10): p. 963-73. Brinton, L., et al., Breastfeeding and breast cancer risk. Cancer Causes and Control, 1995. 6(3): p. 199-208. Bernstein, L., Breastfeeding Experience and Breast Cancer Risk among Postmenopausal Women. Cancer Epidemiol Biomarkers Prev, 1998. 7: p. 365-369. Newcomb, P., et al., Lactation in relation to postmenopausal breast cancer. American Journal of Epidemiology, 1999. 150(2): p. 174. Furberg, H., et al., Lactation and breast cancer risk. International journal of epidemiology, 1999. 28(3): p. 396. Wang, Q., et al., A case-control study of breast cancer in Tianjin, China. Cancer Epidemiology Biomarkers Prevention, 1992. 1(6): p. 435. AL-Shaibani, H., et al., Risk Factors of Breast Cancer in Kuwait: Case-control Study. IRANIAN JOURNAL OF MEDICAL SCIENCES (IJMS), 2006. 31(2): p. 61-64. Calderin-Garcidueias, A., et al., Risk factors of breast cancer in Mexican women. Salud p?blica de Mà ©xico, 2000. 42: p. 26-33. Ramon, J., et al., Age at first full-term pregnancy, lactation and parity and risk of breast cancer: a case-control study in Spain. European journal of epidemiology, 1996. 12(5): p. 449-453. Magnusson, C., et al., The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years. International Journal of Cancer, 1999. 80(2): p. 231-236. Sikind, V., et al., Breast cancer and breastfeeding: results from an Australian case-control study. American Journal of Epidemiology, 1989. 130(2): p. 229. Lai, F., et al., A case-control study of parity, age at first full-term pregnancy, breast feeding and breast cancer in Taiwanese women. Proceedings of the National Science Council, Republic of China. Part B, Life sciences, 1996. 20(3): p. 71. Byers, T., et al., Lactation and Breast Cancer: Evidence for a Negatwe Association in Premenopausal Women. American Journal of Epidemiology, 1985. 121(5): p. 664. Mctiernan, A. and D. Thomas, Evidence for a protective effect of lactation on risk of breast cancer in young women: results from a case-control study. American Journal of Epidemiology, 1986. 124(3): p. 353. Yoo, K., et al., ORIGINAL CONTRIBUTIONS: Independent Protective Effect of Lactation against Breast Cancer: A Case-Control Study in Japan. American Journal of Epidemiology, 1992. 135(7): p. 726. Yuan, J., et al., Risk factors for breast cancer in Chinese women in Shanghai. Cancer research, 1988. 48(7): p. 1949. Tao, S., et al., Risk factors for breast cancer in Chinese women of Beijing. International Journal of Cancer, 1988. 42(4): p. 495-498. Gilliland, F., et al., Reproductive risk factors for breast cancer in Hispanic and non-Hispanic white women: the New Mexico Womens Health Study. American Journal of Epidemiology, 1998. 148(7): p. 683. Romieu, I., et al., Breast cancer and lactation history in Mexican women. American Journal of Epidemiology, 1996. 143(6): p. 543. Newcomb, P., et al., Lactation and a reduced risk of premenopausal breast cancer. New England Journal of Medicine, 1994. 330(2): p. 81. Tryggvadottir, L., et al., Breastfeeding and reduced risk of breast cancer in an Icelandic cohort study. American Journal of Epidemiology, 2001. 154(1): p. 37. Kuru, B., et al., Risk Factors for Breast Cancer in Turkish Women with Early Pregnancies and Long-lasting Lactation. Acta oncologica, 2002. 41(6): p. 556-561. Talamini, R., et al., The role of reproductive and menstrual factors in cancer of the breast before and after menopause. European Journal of Cancer, 1996. 32(2): p. 303-310. Adebamowo, C. and O. Adekunle, Case-controlled study of the epidemiological risk factors for breast cancer in Nigeria. British Journal of Surgery, 1999. 86(5): p. 665-668. Vecchia, C., et al., General epidemiology of breast cancer in northern Italy. International journal of epidemiology, 1987. 16(3): p. 347. Lokman, R., et al., Selenium blood level and other risk factors of breast cancer among patients in HKL, in National public Health Qolloquium, M.F.U. Cpmmunity Health Department, Editor. 2001: Kuala Lumpur. Brinton, L., et al., Modification of oral contraceptive relationships on breast cancer risk by selected factors among younger women. Contraception, 1997. 55(4): p. 197-203. Pike, M., et al., Hormonal risk factors,breast tissue age and the age-incidence of breast cancer. 1983. Marchbanks, P., et al., Oral contraceptives and the risk of breast cancer. The New England journal of medicine, 2002. 346(26): p. 2025. Malone, K., J. Daling, and N. Weiss, Oral contraceptives in relation to breast cancer. Epidemiol Rev, 1993. 15(1): p. 80-97. Vessey, M. and R. Painter, Oral contraceptive use and cancer. Findings in a large cohort study, 1968-2004. British journal of cancer, 2006. 95(3): p. 385. McPherson, K., C. Steel, and J. Dixon, ABC of breast diseases: Breast cancerepidemiology, risk factors, and genetics. British Medical Journal, 2000. 321(7261): p. 624. Ronco, A., et al., Meat, fat and risk of breast cancer: a case-control study from Uruguay. International Journal of Cancer, 1996. 65(3): p. 328-331. Byrne, C., G. Ursin, and R. Ziegler, A comparison of food habit and food frequency data as predictors of breast cancer in the NHANES I/NHEFS cohort. Journal of Nutrition, 1996. 126(11): p. 2757. Ronco, A., E. De Stà ©fani, and A. Fabra, White meat intake and the risk of breast cancer: a case-control study in Montevideo, Uruguay. Nutrition Research, 2003. 23(2): p. 151-162. Franceschi, S., A. Favero, and C. La Vecchia, Influennce of food groups and food diversity on breast cancer risk in Italy Int J Cancer, 1995. 63(6): p. 785-789. Hunter, D., et al., Cohort studies of fat intake and the risk of breast cancera pooled analysis. New England Journal of Medicine, 1996. 334(6): p. 356. Toniolo, P., et al., Consumption of meat, animal products, protein, and fat and risk of breast cancer: a prospective cohort study in New York. Epidemiology, 1994: p. 391-397.

Up The Coulee :: essays research papers fc

Reconciliation   Ã‚  Ã‚  Ã‚  Ã‚  In â€Å"Up the Coulee,† Hamlin Garland depicts what occurs when Howard McLane is away for an extended period of time and begins to neglect his family. Howard’s family members are offended by the negligence. Although his neglect causes his brother, Grant McLane, to resent him, Garland shows that part of having a family is being able to put aside negative feelings in order to resolve problems with relatives. Garland demonstrates how years apart can affect family relationships, causing neglect, resentment, and eventually, reconciliation.   Ã‚  Ã‚  Ã‚  Ã‚  After a decade of not seeing his mother and brother, Howard returns to his hometown in Mississippi. It is evident how thrilled he is. As the train approaches town, he begins â€Å"to feel curious little movements of the heart, like a lover as he nears his sweetheart† (par. 3). He expects this visit to be a marvelous and welcoming homecoming. His career and travel have kept his schedule extremely full, causing him to previously postpone this trip to visit his family. Although he does not immediately recognize his behavior in the past ten years as neglectful, there are many factors that make him aware of it. For instance, Mrs. McLane, Howard’s mother, has aged tremendously since he last saw her. She has â€Å"grown unable to write† (par. 72). Her declining health condition is an indicator of Howard’s inattentiveness to his family; he has not been present to see her become ill. His neglect strikes him harder when he sees â€Å"a gray â₠¬â€œhaired woman† that showed â€Å"sorrow, resignation, and a sort of dumb despair in her attitude† (par. 91). Clearly, she is growing old, and Howard feels guilty for not attending her needs for such a long time period: â€Å"his throat [aches] with remorse and pity† (par. 439). He has been too occupied with his â€Å"excited and pleasurable life† that he has â€Å"neglected her† (par. 92). Another indication of Howard’s neglect is the fact that his family no longer owns the farm and house where he grew up. They now reside in a poorly conditioned home: It was humble enough--a small white house, story-and-a-half structure, with a wing, set in the midst of a few locust trees; a small drab-colored barn, with a sagging ridge pole; a barnyard full of mud, in which a few cows were standing, fighting the flies and waiting to be milked. (par. 74) Grant explains to Howard, who has obviously forgotten, that the mortgage on the old farm was too expensive for them to afford.

Part Seven Chapter 2

‘No problem,' he muttered. He was glad. He could not imagine what they had left to talk about. This way he could sit with Gaia. A little way down Church Row, Samantha Mollison was standing at her sitting-room window, holding a coffee and watching mourners pass her house on their way to St Michael and All Saints. When she saw Tessa Wall, and what she thought was Fats, she let out a little gasp. ‘Oh my God, he's going,' she said out loud, to nobody. Then she recognized Andrew, turned red, and backed hastily away from the glass. Samantha was supposed to be working from home. Her laptop lay open behind her on the sofa, but that morning she had put on an old black dress, half wondering whether she would attend Krystal and Robbie Weedon's funeral. She supposed that she had only a few more minutes in which to make up her mind. She had never spoken a kind word about Krystal Weedon, so surely it would be hypocritical to attend her funeral, purely because she had wept over the account of her death in the Yarvil and District Gazette, and because Krystal's chubby face grinned out of every one of the class photographs that Lexie had brought home from St Thomas's? Samantha set down her coffee, hurried to the telephone and rang Miles at work. ‘Hello, babe,' he said. (She had held him while he sobbed with relief beside the hospital bed, where Howard lay connected to machines, but alive.) ‘Hi,' she said. ‘How are you?' ‘Not bad. Busy morning. Lovely to hear from you,' he said. ‘Are you all right?' (They had made love the previous night, and she had not pretended that he was anybody else.) ‘The funeral's about to start,' said Samantha. ‘People going by †¦' She had suppressed what she wanted to say for nearly three weeks, because of Howard, and the hospital, and not wanting to remind Miles of their awful row, but she could not hold it back any longer. ‘†¦ Miles, I saw that boy. Robbie Weedon. I saw him, Miles.' She was panicky, pleading. ‘He was in the St Thomas's playing field when I walked across it that morning.' ‘In the playing field?' In the last three weeks, a desire to be absorbed in something bigger than herself had grown in Samantha. Day by day she had waited for the strange new need to subside (this is how people go religious, she thought, trying to laugh herself out of it) but it had, if anything, intensified. ‘Miles,' she said, ‘you know the council †¦ with your dad – and Parminder Jawanda resigning too – you'll want to co-opt a couple of people, won't you?' She knew all the terminology; she had listened to it for years. ‘I mean, you won't want another election, after all this?' ‘Bloody hell, no.' ‘So Colin Wall could fill one seat,' she rushed on, ‘and I was thinking, I've got time – now the business is all online – I could do the other one.' ‘You?' said Miles, astonished. ‘I'd like to get involved,' said Samantha. Krystal Weedon, dead at sixteen, barricaded inside the squalid little house on Foley Road †¦ Samantha had not drunk a glass of wine in two weeks. She thought that she might like to hear the arguments for Bellchapel Addiction Clinic. The telephone was ringing in number ten Hope Street. Kay and Gaia were already late leaving for Krystal's funeral. When Gaia asked who was speaking, her lovely face hardened: she seemed much older. ‘It's Gavin,' she told her mother. ‘I didn't call him!' whispered Kay, like a nervous schoolgirl as she took the phone. ‘Hi,' said Gavin. ‘How are you?' ‘On my way out to a funeral,' said Kay, with her eyes locked on her daughter's. ‘The Weedon children's. So, not fabulous.' ‘Oh,' said Gavin. ‘Christ, yeah. Sorry. I didn't realize.' He had spotted the familiar surname in a Yarvil and District Gazette headline, and, vaguely interested at last, bought a copy. It had occurred to him that he might have walked close by the place where the teenagers and the boy had been, but he had no actual memory of seeing Robbie Weedon. Gavin had had an odd couple of weeks. He was missing Barry badly. He did not understand himself: when he should have been mired in misery that Mary had turned him down, all he wanted was a beer with the man whose wife he had hoped to take as his own †¦ (Muttering aloud as he had walked away from her house, he had said to himself, ‘That's what you get for trying to steal your best friend's life,' and failed to notice the slip of the tongue.) ‘Listen,' he said, ‘I was wondering whether you fancied a drink later?' Kay almost laughed. ‘Turn you down, did she?' She handed Gaia the phone to hang up. They hurried out of the house and half jogged to the end of the street and up through the Square. For ten strides, as they passed the Black Canon, Gaia held her mother's hand. They arrived as the hearses appeared at the top of the road, and hurried into the graveyard while the pall-bearers were shuffling out onto the pavement. (‘Get away from the window,' Colin Wall commanded his son. But Fats, who had to live henceforth with the knowledge of his own cowardice, moved forward, trying to prove that he could, at least, take this †¦ The coffins glided past in the big black-windowed cars: the first was bright pink, and the sight robbed him of breath, and the second was tiny and shiny white †¦ Colin placed himself in front of Fats too late to protect him, but he drew the curtains anyway. In the gloomy, familiar sitting room, where Fats had confessed to his parents that he had exposed his father's illness to the world; where he had confessed to as much as he could think of, in the hope that they would conclude him to be mad and ill; where he had tried to heap upon himself so much blame that they would beat him or stab him or do to him all those things that he knew he deserved, Colin put a hand gently on his son's back and steered him away, towards the sunlit kitchen.) Outside St Michael and All Saints, the pall-bearers were readying themselves to take the coffins up the church path. Dane Tully was among them, with his earring and a self-inked tattoo of a spider's web on his neck, in a heavy black overcoat. The Jawandas waited with the Bawdens in the shade of the yew tree. Andrew Price hovered near them, and Tessa Wall stood at some distance, pale and stony-faced. The other mourners formed a separate phalanx around the church doors. Some had a pinched and defiant air; others looked resigned and defeated; a few wore cheap black clothes, but most were in jeans or tracksuits, and one girl was sporting a cut-off T-shirt and a belly-ring that caught the sun when she moved. The coffins moved up the path, gleaming in the bright light. It was Sukhvinder Jawanda who had chosen the bright pink coffin for Krystal, as she was sure she would have wanted. It was Sukhvinder who had done nearly everything; organizing, choosing and persuading. Parminder kept looking sideways at her daughter, and finding excuses to touch her: brushing her hair out of her eyes, smoothing her collar. Just as Robbie had come out of the river purified and regretted by Pagford, so Sukhvinder Jawanda, who had risked her life to try and save the boy, had emerged a heroine. From the article about her in the Yarvil and District Gazette to Maureen Lowe's loud proclamations that she was recommending the girl for a special police award to the speech her headmistress made about her from the lectern in assembly, Sukhvinder knew, for the first time, what it was to eclipse her brother and sister. She had hated every minute of it. At night, she felt again the dead boy's weight in her arms, dragging her towards the deep; she remembered the temptation to let go and save herself, and asked herself how long she would have resisted it. The deep scar on her leg itched and ached, whether moving or stationary. The news of Krystal Weedon's death had had such an alarming effect on her that her parents had arranged a counsellor, but she had not cut herself once since being pulled from the river; her near drowning seemed to have purged her of the need. Then, on her first day back at school, with Fats Wall still absent, and admiring stares following her down the corridors, she had heard the rumour that Terri Weedon had no money to bury her children; that there would be no stone marker, and the cheapest coffins. ‘That's very sad, Jolly,' her mother had said that evening, as the family sat eating dinner together under the wall of family photographs. Her tone was as gentle as the policewoman's had been; there was no snap in Parminder's voice any more when she spoke to her daughter. ‘I want to try and get people to give money,' said Sukhvinder. Parminder and Vikram glanced at each other across the kitchen table. Both were instinctively opposed to the idea of asking people in Pagford to donate to such a cause, but neither of them said so. They were a little afraid, now that they had seen her forearms, of upsetting Sukhvinder, and the shadow of the as-yet-unknown counsellor seemed to be hovering over all their interactions. ‘And,' Sukhvinder went on, with a feverish energy like Parminder's own, ‘I think the funeral service should be here, at St Michael's. Like Mr Fairbrother's. Krys used to go to all the services here when we were at St Thomas's. I bet she was never in another church in her life.' The light of God shines from every soul, thought Parminder, and to Vikram's surprise she said abruptly, ‘Yes, all right. We'll have to see what we can do.' The bulk of the expense had been met by the Jawandas and the Walls, but Kay Bawden, Samantha Mollison and a couple of the mothers of girls on the rowing team had donated money too. Sukhvinder then insisted on going into the Fields in person, to explain to Terri what they had done, and why; all about the rowing team, and why Krystal and Robbie should have a service at St Michael's. Parminder had been exceptionally worried about Sukhvinder going into the Fields, let alone that filthy house, by herself, but Sukhvinder had known that it would be all right. The Weedons and the Tullys knew that she had tried to save Robbie's life. Dane Tully had stopped grunting at her in English, and had stopped his mates from doing it too. Terri agreed to everything that Sukhvinder suggested. She was emaciated, dirty, monosyllabic and entirely passive. Sukhvinder had been frightened of her, with her pockmarked arms and her missing teeth; it was like talking to a corpse. Inside the church, the mourners divided cleanly, with the people from the Fields taking the left-hand pews, and those from Pagford, the right. Shane and Cheryl Tully marched Terri along between them to the front row; Terri, in a coat two sizes too large, seemed scarcely aware of where she was.

Important Things to Know About Before Getting a Tattoo

Important Things to Know About Before Getting a Tattoo Free Online Research Papers Tattoos are a wonderful way of expressing ones individuality, but people need to think about all the ramifications of getting a tattoo before they get it. â€Å"Tattoos are fast becoming a mark of the 21st century, with one quarter of those under the age of 30 adorning their skin with at least one.† (Healy, 2008, p.1) The American Academy of Dermatology reports that 89% of men and 48% of women who wear tattoos have conspicuous designs on their hands, necks, arms, legs, toes, and feet (Sayre, C. [2007]. Tattoo bans. Time Magazine. November 5, p. 56). Tattoos consist of a permanent design that is drawn on to the top of the skin, then pigments are inserted under the skin by way of a tattoo gun. A tattoo gun works almost like a sewing machine. Every time the needle hits the skin, it deposits tiny droplets of ink deep under the epidermis. Tattoo ink is classified as a cosmetic and, they are not â€Å"regulated or approved by the Food and Drug Administration (FDA).† (Healy, 2008, p.1) There are specific medical risks that people need to be aware of before they get a tattoo. These risks can include: 1. Blood-borne diseases: Tetanus, â€Å"Hepatitis B and C, Tuberculosis, and HIV- the virus that causes AIDS.† (Mayo Clinic Staff, 2008, p.1) These can all be transferred by equipment that has been contaminated with the blood of someone who is infected. Because of these risks, the American Red Cross has stated that no person shall be able to donate blood within 12 months of being tattooed. 2. Skin-disorders- â€Å"Tattooing can also cause areas of raised, excessive scarring (keloids). For those people that do keloid, tattooing is not recommended as these may be hard to remove. â€Å"May form bumps called granulomas around the tattoo ink.† (Forsyth County Department of Health, 2005, p.1) Sarcoidal granulomas are firm balls of reactive tissue underneath the surface of the skin.† 3. Skin infections- â€Å"Local bacterial infections. Symptoms can include redness, swelling, warmth at the infected site, and pus-like drainage.† Some of these infections are resistant to antibiotics and â€Å"can lead to pneumonia, blood infections and the flesh-destroying condition known as necrotizing fasiitis.† (Mayo Clinic Staff, 2008, p.1) Between 2004 and 2005, a sepcific type of Staph infection known as methicillin-resistant Staphylococcus aureus, or MRSA were seen in three different states. The Centers for Disease Control and Prevention (CDC) identified 34 people with MRSA who received their tattoos from 13 unlicensed tattooists in three different states. (Montgomery, 2007, para.9) 4. Allergic reactions-Dyes used in the tattoo ink, â€Å"especially red dye, can cause allergic skin reactions, causing an itchy rash at the tattoo site.† This can even â€Å"occur years after one gets the tattoo.† (Mayo Clinic Staff, 2008, p.1) â€Å"This is because the vast majority of tattoo pigments are derived from metal, which makes them a potential source for developing a skin reaction. Some pigments do have non-metallic options for those who have concerns or a past history of allergic reactions to these compounds.† Problems can also arise from the removal of a tattoo. Laser removal can be a painstaking process, and usually involves 2-3 visits and is expensive. â€Å"Treatment with the laser varies from patient to patient depending on the age, size, and type of tattoo (amateur or professional). The color of the patients skin, as well as the depth to which the tattoo pigment extends, will also affect the removal technique.† Dermabraison is also an option. â€Å"This is where the tattoo is sanded down to deep levels and generally does not hurt, but can leave a scar.† (Mayo Clinic Staff, 2008, p.1) Now there is also the option of having a doctor surgically remove the tattoo by cutting it out and stitching the edges back together. I believe that complete removal without any type of scarring may be impossible. It is also very important to make sure that the establishment one is thinking of getting his, her tattoo at follows strict health and safety guidelines. One wants to make sure that he, or she has either a state or local license. Look around the shop. Is it clean? Do the employees sterilize their equipment after each client? Do they wash their hands and put on a new pair of gloves after each client? Do they open a fresh pack of needles after each client? These are all very important things to pay attention to before one makes his, or her final decision. Never get a tattoo while under the influence of drugs or alcohol. This is because drugs and alcohol can lead to poor judgment. One wants to make sure that he, or she has a clear head when he, or she decides exactly what type of tattoo he, or she want and where they are going to get it. One also has to sign a contract or release form. If they do this while under the influence, it makes the contract null and void. Both aspirin and alcohol thin the blood and will promote excessive bleeding. Aspirin, ibuprofen or any other NSAIDS also tend to inhibit clotting. The alternatives are topical anesthetics which contain some lidocaine, or one can buy benzocaine over-the-counter. The drawback is that these do not work on unbroken skin. Once the first needle stick is made, these can be applied and can make a tremendous difference. What type of tattoo is he, or she looking for and where do they want to have it placed? It is important to do some research on the type of tattoo that he, or she wants’ and exactly where they want to put it. They do not want something they will regret later. I think the best way to make sure of this is to picture yourself at 80 years old, wrinkly, maybe even fat. If he, or she can still enjoy their tattoo when it is on their wrinkly, fat, 80 year-old self, then by all means, get it! Remember, it is important to ask many questions and truely pay attention to the type of work that each tattoo artist does. Each one has a uniquely different style so he, or she wants’ to make sure that they pick the one that is best suited for what he, or she wants. Since tattoos are no longer considered taboo, the popularity of them proves that skin is always in. I believe that if people go into it with a broad knowledge of what getting a tattoo entails, they will be able to make the best possible choices for themselves and, be happy with their tattoo for the rest of their lives. Research Papers on Important Things to Know About Before Getting a TattooPersonal Experience with Teen PregnancyMarketing of Lifeboy Soap A Unilever ProductLifes What IfsNever Been Kicked Out of a Place This NiceAnalysis Of A Cosmetics AdvertisementGenetic EngineeringThe Relationship Between Delinquency and Drug UseThe Project Managment Office SystemHip-Hop is ArtTwilight of the UAW

A characters sketch of Fowler. essays

A characters sketch of Fowler. essays Graham Greenes "The Quiet American" is considered to be one of the best novels of the 20th century. And I can honestly say that I've spent more time thinking about the events of Graham Greene's "The Quiet American" than of any other book I've read in months. His straightforward, elegant prose along with ample doses of irony and humor, make this novel a masterpiece. The story is so scathing , so insightful, that one cannot help but to be forever affected. This is no simple tale, although it can be read as one. It works on many different levels. In its simplest form, this is a story about two foreigners in Indo-China: a middle-aged British reporter, and a young idealistic American. They involve themselves in two main plots: one concerning the French Army's battle with the Vietminh, and the second, concerning the two men's relationship with a native woman and the subsequent fight for her affections. On this level "The Quiet American" , works as an effective thriller. But there are all sorts of other subtexts and subtleties going on here. I would try to make a sketch of Fowlers character. But, I suppose, it will be extremely difficult, because Greene portrays the characters in the novel in a manner in which they are extraordinarily complex and passionate beneath their seemingly quiet exteriors.And for me Fowler is one of the most engrossing literary characters I have ever read. But Ill do my best! I promise! Fowler is the embodiment of a now-faded British archetype: the suave, impeccably well-mannered man of the world who keeps a stiff upper lip and camouflages any inner torment under a pose of amused knowingness. Fowler is a man detached, a nonbeliever. He is a real islander. Fowler is completely taken with Vietnam and especially with its tropical beauty.He doesnt believe in God, only death is his absolute value in life. He possesses honesty, that can be trusted, thoughtfullness for other people. One ...

How to Ask Polite Questions in English

How to Ask Polite Questions in English There are three types of questions in English: direct, indirect, and question tags. Direct and indirect questions are used to ask for information you do not know, while question tags  are generally used to clarify or confirm the information you think you know. Each of these three question types  can be used politely, but certain indirect forms are more formal and polite than other types of questions. One form to avoid when asking for things is the imperative form. Saying Give me that (imperative) instead of Could you give me that (indirect) puts you at risk of sounding rude. To learn more about how to ask polite questions, and use each form correctly, check out the overview below. Asking Direct Questions Direct questions are either yes/no questions such as Are you married?  or information questions such as Where do you live? Direct questions ask for information immediately without including  extra language such as I wonder or Can you tell me. Construction Direct questions place the helping verb before the subject of the question:   (Question word) Helping Verb Subject Verb Objects ? Where do you work?Are they coming to the party?How long has she worked for this company?What are you doing here? Making Direct Questions Polite Direct questions can seem abrupt or even impolite at times, especially when asked by a stranger. For example, if you come up to someone and ask: Does the tram stop here?What time is it?Can you move?Are you sad? There is nothing wrong with asking questions in this manner, but to sound more polite, its very common to add excuse me or pardon me at the beginning of a question. For example: Excuse me, when does the bus leave?Excuse me, what time is it?Pardon me, which form do I need?Pardon me, may I sit here? Key Words That Make Direct Questions More Polite In informal situations, one could use the word can in a direct sentence. In the United States, can is considered to be incorrect for written English in particular because, in the past, it was not a word used when asking for something. Saying May I have instead of Can I have is preferred in the U.S. In the United Kingdom, the word is not frowned upon. Cambridge University publishes English teaching materials with the phrase Can you lend me, Can I have, etc. In both countries, questions with can are made more polite by using could: Excuse me, could you help me pick this up?Pardon me, could you help me?Pardon me, could you give me a hand?Could you  explain this to me? Would can also be used to make questions more polite: Would you lend me a hand with the wash?Would you mind if I sat here?Would you let me borrow your pencil?Would you like something to eat? Another way of making direct questions more polite is to add please at the end of the question. Please should not appear at the beginning of the question: Could you fill in this form, please?Could you help me, please?Can I have more soup, please? May is used as a formal means to ask for permission and is very polite. It is usually used with I, and sometimes we. May I come in, please?May I use the telephone?May we help you this evening?May we make a suggestion? Asking Indirect Questions to Be Especially Polite Using indirect question forms is especially polite. Indirect questions request the same information as direct questions, but they are considered more formal. Notice that  indirect questions  begin with a phrase (I wonder, Do you think, Would you mind, etc.). Construction Indirect questions always begin with an introductory phrase and unlike direct questions, they do not invert the subject. To form an indirect question,  use an introductory phrase followed by question words for information questions, and if or whether for yes/no questions. Introductory Phrase Question Word/If/Whether Subject Helping Verb Main Verb? Can you tell me where he plays tennis?I wonder if you know what time it is.Do you think she will be able to come next week?Excuse me, do you know when the next bus leaves? Introductory phrase question word (or if) positive sentence I wonder if you could help me with this problem.Do you know when the next train leaves?Would you mind if I opened the window? NOTE: If you are asking a yes-no question, use if to connect the introductory phrase with the actual question statement. Do you know if she will come to the party?I wonder if you can answer a few questions.Can you tell me if he is married? Otherwise, use a question word where, when, why, or how to connect the two phrases. Using Question Tags for Clarification Question tags turn statements into questions. Depending on the intonation of the voice, they are used to verify information that we think is correct or to ask for more information. If the voice goes up at the end of the sentence, the person is asking for more information. If the voice drops, someone is confirming information that is known. Construction We can understand question tags as having two parts separated by a comma. The first part uses the subject followed by a helping verb as used in direct questions (Has she). The second part uses the opposite form of the helping verb followed by the same subject (Hasnt she). Subject Helping verb Objects ,   Opposite Helping Verb Subject? You live in New York, dont you?She hasnt studied French, has she?Were good friends, arent we?Ive met you before, havent I? Polite Questions Quiz First, identify which type of question is asked (i.e. direct, indirect, or question tag). Next, provide a missing word to fill in the gap to complete the question. Can you tell me ______ you live?They wont attend this class, _____ they?I wonder ______ you like chocolate or not.______ me, what time does the train leave?Excuse me, _____ you help me with my homework?Do you know how long Mark _____ been working for that company?_____ I make a suggestion?Excuse me, do you know _____ the next show begins? Answers wherewillif/whetherExcuse/Pardoncould/wouldhasMaywhen / what time

Department of Homeland Security Act of 2002 Essay

Department of Homeland Security Act of 2002 - Essay Example This research will try to find out how the DHS was implemented, its strategies and objectives. In its establishment though, the department's mission were added with four more significant missions that are deemed necessary for further strengthening homeland security. The following are the four other primary mission of DHS enacted in 2002: ensure that the functions of entities transferred to the Department that are not related directly to securing the homeland are not diminished or neglected except by a specific explicit Act of Congress In reference to this definition and mission, and with its continuing battle for terrorism, the United States federal government enacted the Homeland Security Act (P.L. 107-296) which initiated a major reorganization and expansion of the federal government. It is rather recognized as the most monumental event that happened since 1947 with regards to foreign policies. (Inamete, p. 20) Along with its goal of creating an efficient and effective government structure that provides immediate response to the threats of terrorism, new government agencies were created and the old ones strengthened. Extreme efforts have been demanded from the government in order to create this new department. There were 22 federal agencies, meaning, 22 diverse organizational cultures were consolidated within 92 other already-existing federal departments to form the DHS. (Inamete, p. 20) In his Congressional Testimony in July 2002, then Gov. Tom Ridge stated that the creation of the Department of Homeland Security is the result of the most significant transformation of the US government in over a half-century. The creation of DHS would aid in developing a more focused federal agency that would provide efficient solutions to the threat on terrorism. (Ridge, para 5) Before the enactment of P.L. 107-296, homeland security responsibilities were distributed into various government agencies. There is no single department in the US government that addresses solely this major concern of the American society. Therefore, the development of DHS paved the way to a more unified and competent agency that prioritizes this most crucial problem in the society - homeland security. (Ridge, para 7) With DHS'

Various summaries from 5 Leadership articles which I submit to you Essay

Various summaries from 5 Leadership articles which I submit to you - Essay Example This is a problem because a cynical workforce can have a very damaging effect on the performance of the company as a whole. â€Å"Organizations that have been struggling with a cynical workforce increasingly note a decrease in the quality of service to internal and external stakeholders, customer satisfaction, productivity and market share† (125). What cynicism does is causes employees to be hyper-sensitive to shifting climates within the organizational structure and to view any attempts at improvement as a failure waiting to happen. This attitude almost guarantees the expected results as employees fail to ‘buy into’ the program initiatives. What Dreilinger offers in this article, though, are some very specific steps that companies can take to try to overcome some of these issues. He indicates the first step in addressing cynical employees or a cynical company atmosphere is to acknowledge that it exists. Organizations that have successfully turned around the corporate climate have done so through what Dreilinger characterizes as a five step process. â€Å"First, they make past history discussable – and learn from it. Second, they directly address the legacy of previous change efforts and do so without ‘business babble’. Third, they take steps to anticipate and address unintended and potentially adverse consequences of new changes. Fourth, they provide employees with real opportunities to participate in decisions about future changes that affect them personally, rather than those that simply benefit the company. Fifth, they communicate information by telling employees: what they know and are able to discuss; what they are unable to discuss; what they do not yet know; and by asking employees what else they want to know† (126). Within this process, it can be seen that these companies are directly addressing the two main contributors to the development of cynicism – fear and mistrust. These steps are effective in this

Focus Movie Summary Review Example | Topics and Well Written Essays - 500 words

Focus Summary - Movie Review Example The movie starts with Nicky Spurgeon acting as Will Smith going to a nightclub. Smith is seasonal con man. In the nightclub, Jess acting as Margot Robbie who is inexperienced grifter seduces Smith and pretended that her husband has caught them together. After the deception failed, Smith told them they should not lose focus when faced with compromising or unexpected situation. Jess found Smith in another nightclub and told her to be her mentor. Nicks took her to New Orleans and introduced her to his crew. Jess is trained and under goes a pick pocket test. In the training Nicky and Jess starts a romantic relationship. Nicky was told by his father that he should not start a romantic relationship in the line of duty but he could not resist Jess. In American Football Championship game, played in Miami, Jess together with Nicky coned Tse all his money by tricking him to take a wrong players number. They tricked Tse to take number 55 which was a number won by his crew member in the side of Chicago. Latter, Jess was given her share by Nicky and sent away. Jess was left heartbroken at that time (Movieclips Trailer, 2015). Nicky went to work with a motor car company and helped the owner to win car race championship. In the competition, Nicky meets Jess again and they started moving out together. Nicky gave out the component for competition to McEwen at a price of 3 million Euros and sold it to other team. As Nicky was in hotel waiting for Jess, he received message information him to leave because he was exposed.

Website Review Essay Example | Topics and Well Written Essays - 750 words - 1

Website Review - Essay Example through incorporating effective web design measures that form the main aim of the study to analyze the criteria foe effective web design and comparison of two corporate websites. There are certain characteristics that a business must have to be considered effective in terms of design to be a driving force in meeting advertising and information delivery needs of the business. These characteristics include: Professional brand driven design: a website has to have a professional look and convey the brand image ensuring clients have a very easy time understanding the business and the access to information should be easy and quick. Professional design  allows the client to have access to required information in an effective and efficient manner in the website. Usability: designing a website to ensure the presence of links that are easy to recognize, moderate visuals, and a clear structure allowing the client easy navigation on the website in the other effective web design criteria. Websites are more effective when users can easily find their way through the information and links provided than when the websites are difficult to use. Use of effective writing: the writing style on a website has to be adjusted to meet user’s browsing habits and preferences. This can be achieved through using concise and short phrases, plain and objective language to allow the users make their en decision on the purchase, and merging textual and visual elements on the website. Effective writing makes use of bullets, content categories, and multiple subheadings in a website. Simplicity: providing a simple rather than a complex website is effective in meeting the needs of the clients. Using a simple design with icons providing additional information, headers, footers, and content in a simple manner, and lack of advertising allows for a good web experience for the clients. Content: the other criteria for an effective website are provision of useful and valuable information to the users.

Why should the school day be extened Research Paper

Why should the school day be extened - Research Paper Example The report suggested that the American education system needed an improvement of time, content and expectations, in order to be effective. Different States had different opinions regarding the issue of extending the school day, with some opposing it and some supporting it (Aronson, Simmerman, & Carols, 1998). Currently, numerous research studies keep showing that America is not a world leader in educating children. Numerous reports also support these claims by showing where the country has failed. Over the decades, there has been insignificant improvement shown by the National Assessment of Education Progress. The success disparity between the white and black children is getting wider, as SAT scores keep getting worse. All these factors are majorly attributed to the fact that school days are not as long as required. This paper will discuss why the school day should be extended, giving the advantages of making such a move. The school day should be extended, so that school going childr en can be adequately prepared for the tough world of work that they will face after leaving school. According to Chmelynski (2006), the classroom can be used to make the modern work place more relevant by asssuring employers that school leavers are adequately prepared to deal with difficult work situations. ... These students are the same ones who will become workers once they leave school. If they are expected to work long hours, they need to be prepared for that from an early age, while still in school (Silva, 2007). Recently, United States President, Barrack Obama, was quoted as saying that spending more time in school could help students of this generation to compete effectively with their international peers. The President proposed that this could be achieved by extending the duration of time that American children spend in class, or lessening the amount of time spent on summer vacations. Such a move, according to the American President, would effectively prepare them for the economy of the 21st century. The short amount of time spent by American children in class puts the country at an economic disadvantage compared to other countries with longer school days. According to Silva (2007), American children were found to spend very little time in school, compared to all other regions of t he world. Japan is the country whose children spend the most number of days in school, in a year. They spend up to 243 days a year, as opposed to American children who only spend an average of 180 days a year in school. This makes the American children incapable of effectively competing with students from other countries. For this reason, the school day should be extended (Aronson, Simmerman, & Carols, 1998). With extended school days, administrators have the ability to ensure that the children are given a well-rounded education. This is in the sense that, today, as a result of short school days, many schools continually sacrifice important aspects of education such as physical education, arts and social studies,

A reflective account of the application of learning to clinical Essay

A reflective account of the application of learning to clinical practice - Essay Example Globally, Ischaemic stroke affects more people than other forms of strokes. The stroke can happen or occur in two ways; arterial thrombosis or cerebral embolism. Arterial thrombosis is when a blockage forms in the artery that supplies blood to the brain. As a consequence, blood supply to the brain is blocked (Baker, 2008). On the other hand, cerebral embolism occurs when a blood clot forms in a different part of the body (usually a large artery or the heart) and subsequently travels to the brain and blocks the blood supply. The disease is most prevalent in older adults (people over 65 years of age). In light of this, the paper will employ Gibbs’ reflective cycle model. The model is preferable since it is fairly straight forward. Additionally, the model advocates for a succinct description of the scenario, evaluation of the feelings and experience, conclusion, and a reflection based on experience of what I would do if a similar situation came up again. The condition that I am dealing with is called the ischaemic stroke. It is the clotting of the blood in the blood arteries. In his book, a Schmer (1973) stated that the brain is deprived off food and the oxygen when clotting occurs in the arteries. As a result, the brain cells die. Although some blood cells may die immediately at the onset of the stroke, some may survive longer. If the blood supply is regained, the surviving cells may live or die. The condition may occur very fast, within seconds, or the patient may experience symptoms for some hours. The patient needed to be checked for the symptoms of an ischaemic stroke. At times, the underlying problems might not be the stroke but something different (Wilbur 1997). A patient suffering from ischaemic stroke shows numbness or some weaknesses of one side of the body. This is called contractual hemiplegia. On the other hand, some may show defects of the face such as dropping eyelids, and aptosis. Still, others get visual

Website Review Essay Example | Topics and Well Written Essays - 750 words - 1

Website Review - Essay Example through incorporating effective web design measures that form the main aim of the study to analyze the criteria foe effective web design and comparison of two corporate websites. There are certain characteristics that a business must have to be considered effective in terms of design to be a driving force in meeting advertising and information delivery needs of the business. These characteristics include: Professional brand driven design: a website has to have a professional look and convey the brand image ensuring clients have a very easy time understanding the business and the access to information should be easy and quick. Professional design  allows the client to have access to required information in an effective and efficient manner in the website. Usability: designing a website to ensure the presence of links that are easy to recognize, moderate visuals, and a clear structure allowing the client easy navigation on the website in the other effective web design criteria. Websites are more effective when users can easily find their way through the information and links provided than when the websites are difficult to use. Use of effective writing: the writing style on a website has to be adjusted to meet user’s browsing habits and preferences. This can be achieved through using concise and short phrases, plain and objective language to allow the users make their en decision on the purchase, and merging textual and visual elements on the website. Effective writing makes use of bullets, content categories, and multiple subheadings in a website. Simplicity: providing a simple rather than a complex website is effective in meeting the needs of the clients. Using a simple design with icons providing additional information, headers, footers, and content in a simple manner, and lack of advertising allows for a good web experience for the clients. Content: the other criteria for an effective website are provision of useful and valuable information to the users.

A reflective account of the application of learning to clinical Essay

A reflective account of the application of learning to clinical practice - Essay Example Globally, Ischaemic stroke affects more people than other forms of strokes. The stroke can happen or occur in two ways; arterial thrombosis or cerebral embolism. Arterial thrombosis is when a blockage forms in the artery that supplies blood to the brain. As a consequence, blood supply to the brain is blocked (Baker, 2008). On the other hand, cerebral embolism occurs when a blood clot forms in a different part of the body (usually a large artery or the heart) and subsequently travels to the brain and blocks the blood supply. The disease is most prevalent in older adults (people over 65 years of age). In light of this, the paper will employ Gibbs’ reflective cycle model. The model is preferable since it is fairly straight forward. Additionally, the model advocates for a succinct description of the scenario, evaluation of the feelings and experience, conclusion, and a reflection based on experience of what I would do if a similar situation came up again. The condition that I am dealing with is called the ischaemic stroke. It is the clotting of the blood in the blood arteries. In his book, a Schmer (1973) stated that the brain is deprived off food and the oxygen when clotting occurs in the arteries. As a result, the brain cells die. Although some blood cells may die immediately at the onset of the stroke, some may survive longer. If the blood supply is regained, the surviving cells may live or die. The condition may occur very fast, within seconds, or the patient may experience symptoms for some hours. The patient needed to be checked for the symptoms of an ischaemic stroke. At times, the underlying problems might not be the stroke but something different (Wilbur 1997). A patient suffering from ischaemic stroke shows numbness or some weaknesses of one side of the body. This is called contractual hemiplegia. On the other hand, some may show defects of the face such as dropping eyelids, and aptosis. Still, others get visual

Social Sciences Essay Example for Free

Social Sciences Essay 1. Primary data are those which are collected afresh and for the first time, and thus happen to be original in character. They are gathered by the researcher for the specific purpose of addressing the research problem. Secondary data, on the other hand, are those which have already been collected by someone else and have been processed statistically. These are collected for some purpose other than the problem at hand (Polonsky Waller, 2005; Kothari, 2005). Some of the disadvantages of using a newspaper or magazine article as secondary source are doubts in the reliability, credibility and accuracy of data as sources may not be known, and the obsolescence of data as well (Summers Johnson-Morgan, 2005). Primary and secondary data alone are not sufficient. They should be both used in research because secondary data can be lacking something that only primary data can provide (Groucutt, Leadley, Forsyth, 2004). 2. Television broadcasts such as news are not totally valid as there is a tendency, especially in programs aimed at a wide public, to oversimplify data. News normally offers one set of secondary data. It would be a better practice to compare data from different sources (Walliman, 2006). The questionnaire, as a means for collecting primary data, should have minimal errors in its design in order to minimize bias in reporting and to maximize the likelihood of generating information that is reliable and valid (Amedeo, Golledge, Stimson, 2008). A systematic research design is aimed to ensure that appropriate issues are taken into account. It provides the mechanism by which research processes and practices can be assessed. The research design lays the foundation for a sound hypothesis describing the interrelationship of variables and providing the researcher with a baseline from which to work. A good research design eliminates ambiguity in concepts, thus ensuring construct validity. The actual design of the research process ensures that no other variables can affect the study, hence enhancing internal validity. The research design also provides control to unwanted variables that may arise in the conduct of the research in order to uphold its external validity. Statistical tests are used as instruments to verify the validity of the hypothesis. Hence, if statistical information is wrong, the hypothesis will be invalid (Black, 1999). References Amedeo, D. , Golledge, R. G. , Stimson, R. J. (2008). Person-Environment-Behavior Research: Investigating Activities and Experiences in Spaces and Environments. New York: Guilford Press. Black, T. R. (1999). Doing Quantitative Research in the Social Sciences: An Integrated Approach to Research Design, Measurement and Statistics. California: SAGE Publishing. Groucutt, J. , Leadley, P. , Forsyth, P. (2004). Marketing: Essential Principles, New Realities. London: Kogan Page Publishers. Kothari, C. R. (2005). Research Methodology: Methods Techniques. New Delhi: New Age Publishers. Polonsky, M. J. , Waller, D. S. (2005). Designing and Managing a Research Project: A Business Students Guide. California: SAGE Publishing. Summers, J. Johnson-Morgan, M. (2005). Sports Marketing. Ontario: Nelson Thomson Learning. Walliman, N. S. R. (2006). Social Research Methods. California: SAGE Publishing.

Cyclo-oxygenase inhibitors of human diseases

Cyclo-oxygenase inhibitors of human diseases Historical background Cyclooxygenase (COX) inhibitors are a widely prescribed group of antipyretics and analgesics worldwide and are important component in the treatment of inflammatory conditions. Although first COX inhibitor was discovered more than a decade ago their origin dates back to ancient Mediterranean descent1. Back and other body pains where treated using extracts of poplar tree bark and leaves of myrtle. Use of willow bark emerged far more lately and its first appearance was reported in England in 17631. As was later discovered, the essence of the willow bark possessing anti-inflammatory and antipyretic properties was salicin. Further modification of its structural properties allowed generation of salicylic acid that eventually was developed via Kolbe reaction using phenol1,3. In 1899 Bayer company went ahead in synthesising more susceptible derivative of it, acetylsalicylic acid and named it aspirin. Following this phenylbutazone (1949) and indomethacin (1963) came along however the mystery of mechanism of their action in the body was not yet developed. It was not known until 8 years later when an idea surrounding the synthesis of prostaglandins within body was revealed and for which a Nobel Prize in physiology and medicine was awarded (1982)1. It was proposed that first non-steroidal anti-inflammatory drug (NSAID), aspirin, acted upon inhibition of an enzyme that played role in utilising unsaturated fatty acids into biochemical molecules exerting their action in conditions such as inflammation, pain, and fever and platelet synthesis. It was accepted that during changes occurring within stimulated cells and tissues prostaglandins synthesis was taking place 1,3. Structure of COX was isolated in 1976 and its second isoform was confirmed around 14 years later by few different laboratory investigations; investigations which greatly allowed appreciating the nature of first nonselective cox inhibitors NSAIDs in the treatment of human diseases1. 1.1 The pharmacology and chemistry of cyclooxygenase enzyme Cyclooxygenase (COX aka PGG2/H2 synthase) belongs to the family of enzymes known as myeloperoxidases and it is the crucial enzyme in the synthesis of prostaglandins, prostacyclin and tromboxane A2 resullting from the conversion of arachidonic acid (AA) 2,4. This heme-containing COX enzyme is a bifunctional biocatalyst with two interconnected active sites: cyclooxygenase and peroxidase which action involves generation of hydroperoxy endoperoxide PGG2 via cyclooxygenase cycle (Fig.1.) into its reduced form of hydroxy endoperoxide (PGH2) (Fig. 2.) 2,4. Both isoforms of COX enzyme are expressed in endothelial, monocytic and renal cells with COX-2 being more profound in inflammatory and cancer tissues. Both enzymes are characterised by signal peptide, endothelium growth like factor (EGF) region, membrane in-bound domain, catalytic part, interface between monomers and N-linked polysaccharides residues2. The signal peptide in COX-1 consists of 23 residues whereas COX-2 has only 17. The EGF like region constitutes a major part of the interface and is not found in other myeloperoxidases. It is involved in Cys-Cys cross linked bridges with lack of Cys9 in COX-1 and Cys512 in COX-2. The membrane in-bound domain accounts for 33% of overall similarity and 24% of identity within membranous face. This domain is described as consisting of 4 amphipathic a helices that surround the entry to the COX site. The catalytic part is known to be the largest part of the enzyme with remained homology between other myeloperoxidases. 180Â ° rotation between subunits is preserved with chemical interaction between polar, ionic and hydrophobic moieties. Differences in residue positioning prevent heterodimerization and dissociation from facial interaction inactivates the enzymes overall catalytic activity 1,2,3,4,5. Figure 1. Mechanism of COX cycle in cyclooxygenase active site showing free radicals formation denoted by ? prior to PGH2 synthesis in POX pathway (not shown) 2. Attraction of hydrogen atom from Tyr385 by peroxyl radical of PGG2 allows for the regeneration of the steps of the reaction in the COX cycle of prostanoid biosynthesis. The coloured boxes are to indicate the origin of oxygen atoms. PLA2 phospholipase A2, S secretory, C cytoplasmic. Figure 2. A diagram summarising changes made to AA in the distinct active sites of the PGG2/H2 synthase and products formed via action of each catalytic active site 2. 1.2 The nature of cyclooxygenase inhibition in the human body Inhibition of cyclooxygenase action is desired in the treatment of human diseases. Not only because it suppresses the inflammatory production of prostaglandins in the conditions such as: dysmenorrhoea, rheumatoid arthritis, osteoarthritis but also because it prevents platelet aggregation, suppresses tumour growth and prevents cancer5. Until 1994 it was not clear by which mode, mechanism or process inhibition of COX was carried out. Just complexation studies between COX and flurbiprofen allowed insight into molecular basis of COX inhibition. The investigation led by Garavito and his colleagues proposed such model of inhibition. In his model it was suggested that the enzyme in question possesses long hydrophobic path that originates from in-membrane bound moiety up to the heart of the dimer subunit. Blocking this channel stops the endogenous substrate (AA) from binding hence possible intervention in the process of prostaglandins biosynthesis5. 1.3 The types of cyclooxygenase inhibitors in the treatment of human diseases There are several types of COX inhibitors available in the treatment of human diseases. The very first one, aspirin, is known to act through non-selective and irreversible manner. As this manner suggests aspirin binds to both types of COX enzyme by acetylating Ser530 residue upon covalent modification. Consequently effects such as risk of excessive bleeding, ulcer formation or foetal deformation limit the use of aspirin in dealing with long term diseases. Nowadays it is mainly considered as the important component in the treatment of cardiovascular conditions due to its anti-platelet activity 1,3. Other types of non-selective NSAIDs such as piroxicam, ibuprofen or diclofenac, constitute majority of therapeutic agents being prescribed however due to harmful effects they are being considered less effective in the long term treatment. The damage to the gastrointestinal (GI) system is due to inhibition of COX-1 expressed in GI mucosa which results in formation of ulcers with associated bleeding. Therefore since the main target for choosing those drugs is found to be of inflammatory nature (inhibition of COX-2) they are nowadays preferred in topical dosage forms 1,3,5. The consequence of the undesired effects caused by non-selective COX inhibitors targeted new approach towards development of more specifically acting agents. The era began on discovery of the second isoform of cyclooxygenase and introduction of first COX-2 selective agent (1999) was introduced to the market within 10 years since its discovery with celecoxib and rofecoxib for the treatment of arthritis. The discovery proposed mechanism of actions of both enzymes within the body with COX-1 possessing more constitutive effects especially in GI tract. It was therefore suggested that COX-2 was an inducible form in conditions such as inflammation and pain, symptoms desired in treatment of human diseases associated with the effects of COX-2 isozyme 1,3. 2. ASPIRIN THE ORIGINAL COX INHIBITOR (Joyce) 2.1. Pharmacology and chemistry of Aspirin Plant ingredient salicin was discovered in the willow bark and leaves in the 17th century by a greek physician (Hippocrates) who prescribed it as an analgesic and antipyretic. Further into the 17th century a crude form of salicylic acid was made by a German scientist (Charles Frederic von Gerhardt). This was followed by production of a purer form of salicylic acid by another German chemist (Karl Johann Kraut). Finally in 1897 a German chemist Felix Hoffmann, who worked for the pharmaceutical company Bayer, was assigned the task to find a better derivative of salicylic acid. He also had his own personal reasons for wanting to find a better derivative. His father had been taking salicylic acid for his arthritis pain but could no longer take it without vomiting3,7. In 1889 Hoff man then found a way of acetylating the hydroxyl group on the benzene ring of salicylic acid to form acetylsalicylic acid. Hoffman father tried the new derivative and it was pronounced effective. The name ‘ASPIRIN was given to the drug by Bayer chief pharmacologist Henrich Dreser7. Aspirin was found to have antipyretic, analgesic and anti-inflammatory effects. It does this by inhibiting cyclo-oxygenase(COX) or prostaglandin endoperoxide synthase(PGHS) enzyme irreversibly. COX is responsible for cyclizing arachidonic acid and adds the 15-hydroperoxy group to form PGG2 which is the precursor to prostaglandins. An enzyme perioxidase is responsible for reducing the hydroperoxy group of PGG2 to the hydroxyl group of PGH2.(4)(See Figure 15- prostaglandins synthesis) Prostaglandins can be described as chemical mediators that produce a variety of strong physiological effects in the body. Most importantly they are responsible for the activation of the inflammatory response, production of pain, and fever. There are three isoforms of the COX enzyme of which aspirin has an effect on two which are COX-1 and COX-2. Aspirin binds covalently modifiying COX-1 through acetylation of its Ser-530 and COX-2 through acetylation of its serine 516 residue by placing a bulky constituent (acetyl) and this directly inhibits binding of arachidonic acid. Aspirins action is more potent against COX-1 than against COX-2. This difference in inhibition of the two COX enzymes by aspirin is due to the larger volume of the COX-2 active site produced by the Val-523 substitution at the side pocket. (1,7, 9) The difference in the size of the active site has been exploited by pharmaceutical companies to develop selective COX-2 inhibitors (section 4) COX-1 is an essential enzyme expressed in majority of tissues and also in platelets. It is responsible for prostaglandin production involved in homeostatic mechanisms e.g. platelet aggregation, gastric wall protection, regulation of renal blood flow and initiation of labour in childbirth. In contrast, COX-2, is an inducible form which becomes up regulated by inflammatory mediators such as cytokine (Interleukin and tumour necrosis factor). 2.2 The problems associated with aspirin(1, 10) a. Unwanted effects GASTRIC PROBLEMS The inhibition of COX 1 can produce gastric disturbances as an unwanted effect because the prostaglandin production in the GI tract is a homeostatic mechanism to protect the gastric mucosa. It causes inherent symptoms like heartburn; dyspepsia, nausea, and abdominal pain. (1, 10)This effect can cause Aspirin users to change or discontinue its use. Some of these inherent symptoms are quite common for most NSAIDs. Secondly it can also causes gastro duodenal mucosal lesions such as erosions and asymptomatic ulcers, which may or may not heal spontaneously; and finally more serious gastro ulcers with life-threatening complications like perforation, symptomatic ulcers, and bleeding ulcers. Symptoms of this could be black, bloody, or tar like stools or vomiting/coughing up blood REYES SYNDROME Reyes syndrome is a collection of symptoms consisting of altered consciousness, convulsions, low blood glucose, and enlargement of the liver associated with fatty infiltration of the liver. It is a deadly disease, which can strike any child, teenager, or adult without warning. All body organs are normally affected, but the liver and brain are antagonised the most. In 1965 it was stipulated that Reyess syndrome can be caused by the administration of aspirin in children under 16years of age. There is no discovered mechanism for the role of salicylate in this but it is thought that aspirin enhances the release of tumour necrosis factor which induces apoptosis of cells which can cause inflammation, viral replication e.t.c. SALICYLISM This is caused by the excessive ingestion of aspirin. There are two main pathways in the metabolism of aspirin. (10)Phase 1 reaction that involves the oxidation of aspirin to salicylic acid by a cytochrome P450 monooxygenase. By addition of a reactive group (OH) to get it ready for conjugation to a soluble component and hence aid excretion. This conjugation involves the attachment of small polar molecules glycine and gluconoride to salicylic acid. This results in further deactivation of the aspirin and the production of water-soluble metabolites that will be readily excreted in the urine or bile. The pathway conjugated with glycine, is the one that is easily overloaded in cases of toxicity. Thus elimination of salicylic acid slows down and accumulation leads to a variety of side effects. Below are the pathways showing oxidation and conjugation. This excess salicylate produces toxic effects include below. Ringing in ears Hyperventilation which causes increase in CO2- respiratory alkalosis, Dehydration: increased water loss due to hyperventilation Loss of carbonic acid metabolic acidosis. This in turn will reduce the blood pH, and make aspirin return to its non-ionised form allowing free aspirin in the blood stream. Hyperthermia. These pathways overload uncouples the energy producing processes (oxidative phosphorylation) of the mitochondria thus causing production of heat rather than ATP. Fatality especially in children Interactions with other drugs Reduced effect of aspirin if given with ibuprofen and avoid concomitant use of aspirin with NSAIDS due to increased side effects. Increase risk of bleeding when aspirin is given with coumarins, SSRIs, clopidogrel, illoprost, and sibutramine, Aspirin enhances effect of Heparins, Phenytoin, Valporate, Aspirin antagonises effect of Spirolactone, Sulfinpyrazone and Probenacid Rate of excretion of aspirin is increases by some antacids. The effect of aspirin on the gastrointestinal tract may be enhanced by the intake of alcohol and corticosteroids. 3. NON STEROIDAL ANTINFLAMMATORY DRUGS NON SELECTIVE COX INHIBITORS (Christina) 3.1 Isozymes of Cyclooxygenase Cyclooxygenase has various isozymes. The main isozymes are COX-1 and COX-2, however there is now evidence of a third form- COX-3. COX, originally known as prostaglandin H synthase is responsible for the oxidation of arachadonic acid to prostaglandin G2 and prostaglandin H2. It catalyses the reaction in which the arachadonic acid substrate and two molecules of O2 are converted to prostaglandin G2 and then in the perioxidase reaction Prostaglandin G2 is reduced to PGH2 by a 2 electron reduction. The COX isozymes are heme containing enzymes that are homodimers. Each monomer contains three main domains; A membrane binding domain, a N-terminal epidermal growth factor domain and a C-terminal catalytic domain. COX-1 is made up of 602 amino acids while COX-2 is comprised of 604.3 The catalytic reaction in COX takes place in a hydrophobic channel in the core of the enzyme while the peroxidise reaction takes place in the heme containing region near the surface of the enzyme. The membrane binding domain consists of four alpha helices with one helix that fuses with the catalytic domain. These helices congregate around an opening and through these openings fatty acids and NSAIDS are considered to enter the active site. The COX-1 isozyme is considered a constitutive enzyme. It is present in high volumes in most cells and tissues i.e. renal collecting tubules, monocytes, endothelium etc. However COX-2 is hardly noticeable in most cells, it is an inducible enzyme so it becomes more abundant in cells or tissues when macrophages are activated or by any other inflammation mediators e.g. TNF-a (tumor necrosis factor-alpha) or IL-1 (interleukin-1).5 Both COX-1 and COX-2 isozymes are attatched to the endoplasmic reticulum and nuclear envelope. The COX isozymes need to be N-linked glycosylated to enable them to be folded and attatched to the endoplasmic reticulum and nuclear envelope. The COX isozymes have very similar structures for their binding site, catalytic mechanisms and produce the same biosynthetic products3 COX-3 COX-3 a third isozyme was discovered in 2002 by Simmons and co-workers. They conducted a study on dogs and this resulted in them discovering a novel COX-1 splice variant termed COX-3 that was sensitive to acetaminophen (paracetamol). It was suspected for a while that acetaminophen worked by inhibiting a different specific isozyme due to the fact that it did not directly inhibit COX-1 and COX-2 very effectively at therapeutic concentrations but it generated prostanoids in neuronal systems. 3, 15 The Simmons and co-worker group showed that acetaminophen was the actual target for COX-3, and that it acted separately from COX-1 and COX-2. 3 Canine COX-3 is a membrane bound protein consisting of 613 amino acids with a molecular weight of ~65 kDa. It has a high expression in cells and tissues like COX-1 suggesting it may be a constitutive enzyme. However the question that needs to be asked is if generalisations can truly be made on the presence of COX-3 in humans based on Canine studies, so future experiments need to be designed to clarify whether a human COX-3 actually does exist that acts independently from COX-1 and COX-2 in vivo. 14 NSAIDs are known to inhibit COX in order for them to exhibit their anti-inflammatory actions, a structural NSAID binding study was carried out. The COX-1 active site contains a long hydrophobic channel that extends from the membrane binding domain to the core of the COX monomer. The tip of the COX active site houses Tyr385 that is located near the heme iron. Ser530 is positioned just below Tyr385 and that is the site for aspirin acetylation. Glu524 and Arg120 are positioned at the mouth of the COX-1 channel. A typical NSAID such as fluobriprofen, when introduced to the COX enzyme, its carboxylate moiety is usually directed towards the mouth of the COX-1 channel in order for it to be positioned in the most ideal place that will allow it to interact with the two polar residues Glu524 and Arg120. From these studies a better insight into the binding profiles of NSAIDs were observed. Non selective NSAIDs can bind in three different ways: Reversibly (e.g. Ibuprofen) Fast, low affinity reversible binding followed by a higher affinity, time dependant slowly reversible binding (e.g. fluobriprofen) Rapid, reversible binding followed by a covalent modification of the enzyme (e.g. Aspirin) 3 Arg120, Glu524, Tyr355 and His90 form a network of hydrogen bonds at the entrance of the COX channel acting like a gate to the binding site. NSAIDs generally bind between the upper portion of the COX channel near Tyr 385 and Arg 120 which is at the mouth of the COX channel. 3 Through the use of hydrogen bonding and electrostatic interactions, the carboxyl moiety of acidic NSAIDs like fluoribiprofen interact with Arg120 in both COX isozymes. The significant differences in the structure of the binding sites for both COX isozymes has been manipulated to enable the design of selective COX-2 inhibitors. In the COX-2 active site there is an extra accessible pocket due to the presence of a smaller valine amino acid residue at position 523 and a valine substitution at position 434, unlike COX-1, this difference increases the overall volume at the COX-2 active site by about 20%. 1 This means that due to reduced steric and ionic crowding at the mouth of the channel by Arg120, non acidic selective COX-2 inhibitors can show an enhanced and specific binding to the COX-2 enzyme. Another structural difference exists at the amino acid residue 513 where COX-1 has a histidine residue and COX-2 has an arginine moiety. 1 These small differences provides flexibility in the substrates that can be utilised in the COX-2 active site. 3.2 Problems Associated With Non Selective Non Steroidal Anti-Inflammatory Drugs NSAIDs are one group of drugs that are regularly used by the worlds population to relieve pain, reduce inflammation and lower temperature. They are COX inhibitors and act to inhibit the catalysation of arachadonic acid to PGH2. COX-1 is constitutively present in most cells while COX-2 is induced by chemical mediators of inflammation and activated macrophages.13 COX-1 and COX-2 as mentioned above have 2 specific roles. The 1st role gives PGG2 and the other role is in the peroxidise reaction that gives PGH2. Both COX-1 and COX-2 inhibitors work by inhibiting the 1st and main role i.e. inhibiting the conversion of arachadonic acid to PGG2. COX-1 and COX-2 possesses hydrophobic channels within their core. The classical NSAIDs exhibit their effects by blocking these enzymes halfway down the COX channel near Tyr385 and the Arg120 which is at the mouth of the COX channel by hydrogen bonding to the Arg120 residue. This results in the prohibition of any fatty acid substrates from entering the catalytic domain of the COX enzyme.3 In COX-1, these drugs tend to inhibit the enzyme quickly yet generally the inhibition is often reversible, however in COX-2 the inhibition is time dependant and often results in irreversible inhibition. As mentioned before, the COX-1 and COX-2 isozyme differ slightly. In the COX-2 active site there is an extra accessible side pocket due to the presence of a smaller valine amino acid residue at position 523 instead of isoleucin as in COX-1. This is important for understanding why some NSAIDs are selective for the COX-2 isozyme.13 There are a number of side effects associated with traditional NSAID therapy. NSAIDs can cause renal failure, liver damage/disorders, aseptic meningitis, skin reactions and bone marrow disturbances which can interfere with bone fracture healing. However amongst them all gastrointestinal (GI) toxicities is amongst the most common. These are believed to arise from the inhibition of COX-1 in the gastric mucosa.14 GI toxicities In humans and other species it has been shown that COX-1 not COX-2 is constitutively expressed throughout the GI tract.13 COX-1 is responsible for the synthesis of prostaglandins like PGE2 and PGI2 which are responsible for protecting the GI mucosa by reducing acid secretion in the stomach by the parietal cells, increasing blood flow in the mucosa and stimulating the release of viscous mucous. This leads to conditions of ulcers, dyspepsia, diarrhoea, nausea and vomiting and can even lead to gastric bleeding in some cases. These undesirable side effects have led to the development of COX-2 selective inhibitors. These drugs are effective anti-inflammatorys and reflect good analgesic effects. They have considerable less gastric damage due to the fact they selectively inhibit COX-2 with minimal action on COX-1. Unfortunately the use of COX-2 selective drugs has been associated with increased incidence of myocardial infarction and stroke.3 Renal effects Prostaglandins especially PGE2 and PGI2 are involved in regulating renal blood flow and vascular tone. Recent studies have shown that COX-2 is constitutively expressed in the macula densa, epithelia cells lining the ascending loop of henle and medullary interstitial cells of the renal papillae, while COX-1 is constitutively expressed in the collecting ducts, loop of henle and in the vasculature. The COX-2 enzyme is associated with normal renal function and inhibition of COX-2 results in NSAID-induced sodium retention while inhibition of COX-1 results in a disease in glomerular filtration rate.3 This conclusively tells us that both COX-1 and COX-2 are involved in the physiology of the kidneys. However therapeutic doses in patients with normal renal function are at little risk of renal complications. It is mostly neonates and the elderly who are more susceptible as well as patients with heart, liver or kidney disease. 4. SELECTIVE COX 2 INHIBITORS (Nadine) 4.1 Reasoning behind selective inhibition 4.2 Benefits and risks 5. MECHANISM OF ACTION OF COX INHIBITORS IN HUMAN DISEASES 5.1 Analgesic (Joyce) Pain can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a self protection mechanism which helps of forces us to identify danger and move away from it. It is one of the main symptoms used to identify a condition in medicine. Removing pain is very essential in terms of either eliminating the disease or condition or in fact suppressing its effect. This can be done by the use of medicines called analgesics. Pain receptors also called nociceptors are present on special nerve fibres that are sensitive to noxious of harmless stimuli. The stimulation of these receptors are on A-delta and C-fibers which are located in skin, connective tissue, viscera, muscle e.t.c. COX inhibitors act by blocking transmission to peripheral nerves. Pain associated with I. Arthritis Arthritis is the inflammation of joints. The inflammation and movement of the joints cause extreme pain in the sufferer. There are two major types a. Osteoarthritis(10) This is a chronic disease that features the breakdown of the joints cartilage. Cartilage is flexible connective tissue found in between joints that cushions or protects the ends of the bones and allows easy mobility of joints. This breakdown of cartilage causes the bones to rub against each other creating friction, causing joint tension, pain and loss of mobility in the joint. There are different types of arthritis of which osteoarthritis is most common; it can also be referred to a degenerative joint disease. There are two types of osteoarthritis, primary of which is associated with old age, general wear and tear of the cartilage. And secondary where it occurs where there is a cause example obesity, trauma, or hereditary. Treatment: Paracetamol may be considered as first line therapy for Osteoarthritis patients with mild to moderate pain. If the pain does not respond to paracetamol or patient has severe symptoms then other traditional NSAIDs like Ibuprofen, diclofenac or coxibs should be used. Coxibs have shown to produce reduced GI side effects. However they have the probability of increasing cardiovascular risk because they inhibit prostacyclin production in endothelial cells but not thromboxane in platelets, hence this can increase the chance of a thrombus formation. The choice of a coxib or a specific NSAID should be based on the patient characteristics and risk factors. b. Rheumatoid arthritis(12 ) This is an autoimmune disease of unknown origin whose major characteristic is the inflammation and erosion of the synovial membrane or synovium. This membrane lines and surrounds the joint and synovial cavity. The synovium secretes a slightly viscous, clear fluid known as synovial fluid, which lubricates cavity that lies between the cartilage and joint on the bone. In Rheumatoid arthritis accumulation of the synovial fluid builds up within the joint space and causes inflammation. This makes the joint look and feel swollen. Rubor occurs do to the increased blood flow to the area because of inflammation. In conditions of long-term RA, joint degeneration can occur causing mobility to be very painful and restricted. Treatment: Aspirin used to be used to treat RA but because of its GI toxicity. The use of aspirin as first line of therapy has been superceded by other NSAIDs. There are a large number of NSAIDs that have been invented since aspirin, but have similarities in toxicities e.g. Ibuprofen, naproxen meloxicam, etodolac selective COX-2 inhibitors have been invented to control inflammation. These drugs were designed to combat the gastrointestinal risk of NSAIDS, but there are concerns of increases in cardiovascular risk. II. Cancer (11) Can be defined as an abnormal growth of cells as when a group ofcellsdisplayuncontrolled division,invasion, and sometimesmetastasis. Cells become cancer cells because of its damaging effect to the DNA of the cell. A normal cell will try to repair damaged DNA but in a cancer cell it replicates with the damaged DNA. The cancer cell continues making new cells that the body does not require. The most common cause of cancer pain is infiltration of the tumour into bone. Bone metastases occur as a consequence of different types of cancer. Another mechanism of pain apart from bone metastasis is the secretion of Prostaglandins by carcinomas. For this reason, NSAIDs should be included in any regimen to control pain associated with bone metastasis. Because NSAIDs do not activate opioid receptors, they can provide additional pain relief when combined with an opioid analgesic. Thus, combining an NSAID with an opioid analgesic may provide adequate pain control with a clinically significant reduction in opioid dose. This opioid-sparing effect of NSAID therapy allows the clinician to diminish the side effects associated with opioid therapy without sacrificing pain control. Coxibs: Another Option for Cancer Pain Management(11) The recent introduction of the coxibs, on their use in cancer patients is still being studied. Oncologists are replacing NSAIDs, with the use of coxib, because of the improved safety profile compared to traditional agents. Surgical oncologists are exploring the use of coxibs both preoperatively and during the post-operative period to reduce opioid usage in order to speed the recovery process 5.2 Anti-pyretic (Nadine) 5.3 Anti-inflammatory (Christina) To date there are over 100 inflammatory diseases- each of which causes the degeneration of connective tissue in one or more parts of the body. These include: Rheumatoid Arthritis Osteoarthritis Atherosclerosis Irritable Bowel Disease Alzheimers and many more. Inflammation is characterised by dolor, rubor, calor and tubor, its one of the bodys ways of responding to harmful stimuli, pathogens, injury or disease. These usually initiate an acute or chronic inflammatory response. Arthritis is a general term used to characterise inflammation in the joints. Rheumatoid arthritis describes arthritis that occurs on both sides of the body i.e symmetrical. These usually occur in the wrists, hands and knees. It is not known what causes this disease many theories have been put forward but it happens when the immune system begins to attack the joints. A number of anti-inflammatory drugs are available worldwide and are widely used to relieve pain, swelling and inflammation associated with soft tissue inflammation. A number of these drugs act via the inhibition of COX. When you experience pain and inflammation from arthritis, an increase in microvascular permeability occurs selectively in post-capillary venules. The endothelial cells undergo conformational change leading to vascular leakage through gaps between the adjacent endothelial cells. At the site of injury phagocytes are attracted and move into the affected tissue along with plasma. The plasma causes the associated swelling observed in inflammation and the phagocytes engulf dead cells and bacteria. Prostanoic acids are