Vol 2, Issue 1

Volume 2, Issue 1
January - March, 2014
Aims and Scope

El Mednifico Journal is an open access, quarterly, peer-reviewed journal from Pakistan that aims to publish scientifically sound research across all fields of medicine. It is the first journal from Pakistan that publishes researches as soon as they are ready, without waiting to be assigned to an issue. The journal has certain unique characteristics: EMJ is one of the first journals from Pakistan that publishes articles in provisional versions as soon as they are ready, without waiting for an issue to come out. These articles are then proofread, copyedited and arranged into four issues per volume and one volume per year EMJ is one of the few journals where students and undergraduates form an integral part of the editorial team EMJ is one of the few journals that provides incentives to students and undergraduates
EMJ is published once every 3 months by Mednifico Publishers. Editorial correspondence should be addressed to: The Editor-in-Chief, El Mednifico Journal, C2 Block R, North Nazimabad, Karachi, Sindh - 74700 - Pakistan. Tel: (92-334-2090696); Email: editorial@mednifico.com; Website: http://mednifico.com Articles should be sent to: Submissions EMJ, C2 Block R, North Nazimabad, Karachi, Sindh - 74700 - Pakistan. Email: submit@mednifico.com Want to partner with EMJ? Send your proposal to: editorial@mednifico.com Were hiring! Send your CVs to: apply@mednifico.com i
Editorial Board
Senior Editor-in-Chief
Prof. Nazeer Khan
Executive Editors
Syed Salman Ahmed, Sajid Ali
Editor-in-Chief
Asfandyar Sheikh
Managing Editor
Syed Arsalan Ali
Assistant Editor-in-Chief
Haris Sheikh
Assistant Managing Editor

Shanawer Khan
Senior Editors
Dr. Mansoor Husain, Dr. Muzaffar H Qazilbash, Dr. Tasneem Z Naqvi, Prof. Haruhiro Inoue, Dr. Athanassios Kyrgidis, Dr. Asim A Shah, Dr. Kothandam Sivakumar, Dr. Samina Abidi, Dr. Rashid Mazhar, Dr. Gautam Sikka, Dr. Mosaddiq Iqbal, Prof. Javed Akram, Prof. Abdul Bari Khan, Prof. Ashraf Ganatra, Dr. Raza Ur Rehman, Dr. Waris Qidwai, Dr. Muhammad Ishaq Ghori, Dr. Akber Agha, Dr. Adnan Mustafa Zubairi, Dr. Saqib Ansari, Dr. Mohsina Ibrahim, Dr. Qamaruddin Nizami, Dr. Samra Bashir, Dr. Nabeel Manzar, Muhammad Ashar Malik
Section Editors
Ali Sajjad, Hafiz Muhammad Aslam, Syed Askari Hasan, Muhammad Uzair Rauf, Syed Mumtaz Ali Naqvi, Manish Khazane, Smitha N Gowda, Supriya Kumar, Zeba Unnisa, Suhasis Mondal
Editors
Dr. Hussain Muhammad Abdullah, Asfandyar Khan Niazi, Muhammad Danish Saleem, Smith Giri, Iqra Ansari
Assistant Editors
Gulrayz Ahmed, Raza Mahmood Hussain, Uzair Ahmed Siddiqui, Maheen Anwer, Anum Saleem, Hira Hussain Khan, Imran Jawaid, Hina Azhar Usmani, Shayan Ali, Shoaib Bhatti, Hira Burhan, Quratulain Ghori, Bushra Iqbal, Maria Rahim
Production Editors
Muhammad Hamid Chaudhary, Bushra Mufti, Parisa Aijaz, Adnan Salim
Statistics Editors
Mehwish Hussain, Syed Ali Adnan
Layout Editor
Shahzad Anwar ii
Table of Contents
FrontPage Editorial Board Call for Papers Health Poster Table of Contents i ii iii iv v
Editorial
From freshman to sophomore
Syed Salman Ahmed
Original Articles
Framingham Risk Score for the prediction of cardiovascular risk in Saudi population
Yasmeen Hetari, Archana Iyer, Said S M Eldesouky, Nabil Alama, Saleh M Aldaqal, Taha Kumosani
Audit of prescribing patterns of doctors for the management of acute respiratory infections in children
Muhammad Irfanullah Siddiqui, Akhtar Ali Baloch, Syed Ishtiaq Ahmed, Syed Imtiaz Ahmed Jafri
Comparison of oral health knowledge, attitudes, practices and oral hygiene status of Central Reserve Police Force officials in Srinagar, Kashmir
Swapnil S Bumb, D J Bhasker, Chandan R Agali, Himanshu Punia, Vikas Singh, Safalya Kadtane
10
Review
Pharmacology, neurobiology and neurotoxicity of methamphetamine
Zia Choudhry, Azadeh A Rikani, Adnan Maqsood Choudhry, Sadaf Tariq, Fozia Zakaria, Saifal Anwar, Muhammad Harris Laghari, Kamran Haider, Afia Ansar Shafiq, Nusrat Jahan Mobassarah
15
Opinions and Debates

Health issues: The leading cause of deaths worldwide
Aqsa Sajjad
23
Essays
SNARE proteins and membrane fusion
Zia Choudhry, Azadeh A Rikani, Adnan Maqsood Choudhry, Sadaf Tariq, Fozia Zakaria, Muhammad Waheed Asghar, Muhammad Khan Sarfraz, Numan Majeed, Huma Ikram, Nusrat Jahan Mobassarah
25
Icosapent ethyl: A novel drug for hypertriglyceridemia

Atta Abbas, Farrukh R Ahmed
28
Letters to Editor
Extensive endomyocardial calcification of unknown cause: a rare manifestation of left ventricular non-compaction?
Ahmed Bashir, Richard Paul Steeds
30
Detection of multiple pseudoaneurysms of mitral-aortic intervalvular fibrosa by multislice computed tomography in a patient with aortic valve replacement
Melike Rusen Metin, Hasan Aydn, Evrim zmen, mer Faruk Ate
32
Cerebroprotein hydrolysate in traumatic brain injury

Sagar Karia, Priyanka Thukral Mahajan, Nilesh Shah, Sushma Sonavane, Avinash De Sousa
34 36
The association between type II diabetes mellitus and Parkinsons disease: A case report
Atta Abbas
Appendices
Instructions to Authors Sponsorship Information Best of Blogemia vii xi xiv
vi
Ahmed SS
Open Access
From freshman to sophomore
Syed Salman Ahmed1
Editorial
Editorial
December 17th, 2012 marks the day when a casual conversation with my associates about the persistent lack of biomedical research culture and the disinterest shown by the civil authorities throughout South Asia encouraged us to lay the foundation of El Mednifico Journal (EMJ) [1]. From the very beginning, EMJ was founded as a journal that would eventually provide biomedical and allied professionals and undergraduates from different institutes a healthy platform to utilize their potentials for research conduction and presentation, with special emphasis on recent advancements and discoveries made throughout the field of medicine. An attached blogging platform named Blogemia was also launched in order to inculcate a sense of research in biomedical students by promoting healthy writing practices that would eventually benefit them in their professional life. Throughout its first year, EMJ has emerged as a trendsetter. It has the honor of being one of the first Open Journal Systems (OJS) based medical journals from Pakistan that publishes articles in provisional ahead-of-print versions as soon as they are ready. These articles are then proofread, copyedited and arranged into four issues per volume and one volume per year. OJS is a dedicated journal system that streamlines the editorial process, and provides tools for indexation and archiving. It is also continuously being developed, which made it a perfect candidate for EMJ to be based on. The first call for papers was sent out in mid-December and the response that we received was overwhelming. We received as many as 12 submissions within the first month. The submissions were mostly from Pakistan and India, the latter being due to our partnership with The Medical Students Association of India. In the months thereafter, the breadth of the submissions in terms of countries of origin expanded. We now have submissions from more than 10 countries that include Pakistan, India, United Kingdom, Turkey, Saudi Arabia, United States, Iran, Nigeria, Nepal and Germany. All articles continue to be free and open access. No charges are requested for article submission, processing or publishing and no fees are charged for readers to access full text content. Right from the very beginning, emphasis has been laid on online submission and guidelines and instructions have been uploaded on the website. Although EMJs institutional manifesto does not limit the scope of submissions which traverses all fields and specialties in
medicine, no compromise is made on the quality of the content received. Hence, many articles are rejected either upon receipt, or after undergoing peer-review. Annual statistical reports from our submissions department show that out of the 47 submissions that were received during the year 2013, only 27 were accepted giving an acceptance rate of 57%. Our team believes in a fast and accurate editorial process. Hence, we have maintained high processing speeds for the year 2013 in order to ensure that scientifically sound work is presented to the audience as soon as it is ready, and to ensure that authors do not have to face undue delays in case their submission is rejected. Acknowledgement emails were sent to the respected author, on average, within 18 2 hours. The average time taken for editorial screening was 4 1 days, for in-house review 6 1 days and for sending out for external peer review 2 1 days. The average time taken for peer reviewers to send in reports was 34 4 days. The average time taken for the first editorial decision was 3 1 days. The authors took, on average, 16 5 days for returning a revised version. The second editorial decision was made within 2 1 days after receipt. Hence, the whole process from submission to acceptance takes 2 months on average. In just 12 months, EMJ has had the privilege of getting indexed at DOAJ, Index Copernicus, Ulrichs Web, Open-J-gate, Genamics and Google Scholar. Further efforts are underway to get the journal indexed in other indexes such as Scopus and Medline. The annual print version is also under production. All of this has been made possible by the combined efforts of the editorial team that we have at EMJ. I would like to congratulate the Editors-in-Chief, Executive Editors, Editors and Reviewers for their contribution to the cause. A special token of appreciation goes to our partners (S.O.C.H, Justuju and MSAIndia) whose support had a crucial role in the debutant year for EMJ. Lastly, I would like to thank the readers for appreciating and citing our content in their research works.
Competing interests: The author is an Executive Editor at El Mednifico Journal Received: 5 December 2013 Accepted: 7 December 2013 Published Online: 7 December 2013
References
1. Sheikh A, Ahmed SS, Ali S: El Mednifico Journal: Objectively galvanizing research culture in students. El Mednifico Journal 2012, 1(1):1.
Dow University of Health Sciences, Pakistan Correspondence: Syed Salman Ahmed Email: salman.ahmed@mednifico.com
http://www.mednifico.com/index.php/elmedj/article/view/56
Framingham Risk Score for the prediction of cardiovascular risk
Open Access
Framingham Risk Score for the prediction of cardiovascular risk in Saudi population
Yasmeen Hetari1, Archana Iyer1, Said S M Eldesouky1, Nabil Alama1, Saleh M Aldaqal1, Taha Kumosani1
Original Article
Abstract
Background: Many previous studies confirm that cardiovascular disease (CVD) development has a strong relationship with many risk factors. The Framingham Risk Score (FRS) is one of the most widely used risk assessment methods for prediction of coronary artery disease risk (CAD). The objective of this study was to study the FRS with relation to obesity in a Saudi population and associate it with risk of cardiovascular diseases. In the present study, we compare Framingham risk factors among normal weight and obese for both genders. Methods: This study was conducted on 212 unrelated individuals. 106 were non-obese (BMI = 18.5-24.9 kg/m2) while 106 were obese (BMI 30 kg/m2). Major risk factors identified by the Framingham Heart Study, including sex, age, smoking, systolic blood pressure, total cholesterol and high-density lipoprotein (HDL) were incorporated into a scoring system that identifies subjects at high (20%), intermediate (10%20%), and low (10%) risk for developing CAD over the next 10 years. Results: The results show that CVD risk factors were more prevalent among obese than normal weight subjects. In male subjects, the difference was statistically significant with regards to hypertension (p=0.000), triglycerides (p=0.033), HDL (p=0.048), fasting blood glucose (p=0.038). In female subjects, the difference was statistically significant for age (p=0.008), cholesterol (p=0.015), triglycerides (p=0.011), low density lipoprotein (p=0.017) and fasting blood glucose (p=0.000). Conclusion: These findings carry implications for clinical practice: Obese adults without clinical cardiovascular disease may already have a clustering of traditional cardiovascular risk factors. Institution of early and aggressive preventive measures in this population could delay or arrest progression to clinical cardiovascular disease. (El Med J 2:1; 2014) Keywords: Obesity, Framingham Heart Study, Cardiovascular disease
Introduction
Over the past 150 years, there have been numerous efforts to explain the complex events associated with the development of atherosclerosis. Many previous studies confirmed that the cardiovascular disease (CVD) development has a strong relationship with many risk factors; therefore the risk factors are important to prognosis and prediction of CVD development. The Framingham Risk Score (FRS) is one of the most widely used risk assessment methods for prediction of coronary artery disease (CAD) risk [1]. FRS was derived from the Framingham Heart Study (FHS) cohort and was designed to predict 10-year risk of hard coronary events, including mortality due to coronary heart disease and nonfatal myocardial infarction (MI) by considering the presence or absence of important risk factors [2]. Risk factors of CVD have been categorized in two major groups: modifiable and non-modifiable. Age, genetic family history, race, and gender for CVD have been indicated as non-modifiable risk factors of CVD among men and women. Major modifiable risk factors of CVD include high blood pressure, abnormal blood lipids (high total cholesterol, LDL-C and triglyceride levels, and low levels of HDL-C), tobacco use, physical inactivity, obesity, unhealthy diets, and diabetes mellitus [3, 4]. Several studies have documented the association between obesity and cardiovascular disease. On the basis of the FRS, the risk of CHD is categorized as high (20%), intermediate (10%20%), and low risk (10%) [5]. American Heart Association (AHA) guidelines (2002) for primary prevention of cardiovascular disease and stroke recommend that risk factor screening in adults should begin at age 20 and should be repeated at least every 5 years in the absence of risk factors and
1
every 2 years if risk factors are present [6]. The score sheets (or points systems) that enable clinicians to determine the 10-year risk of CAD are separate for men and women. To use the score sheets, a clinician simply totals the points associated with the patients age, their cholesterol and smoking status, which in turn depend on age, high density lipoprotein (HDL) and systolic blood pressure, either treated or untreated. A point total is computed by summing all the points for the risk factor profile. The 10-year coronary risk is then determined based on the point total as indicated in the table at the bottom of the score sheet (NCEP 2002) [7]. The present study has been conducted on two hundred and twelve volunteers, all of whom were Saudi nationals. The required parameters for the FHS were included and the correlation of risk of developing cardiovascular heart disease and obesity has been analyzed.
Materials and Methods

Study Population This study was approved by the ethics committee of the King Abdul Aziz University Hospital, Jeddah, Saudi Arabia for sample collection. Written informed consent was obtained from all participants prior to the study. The participants completed an investigator-developed questionnaire on health history. Various demographic variables were assessed, including age in years, marital status, education level, medication, tobacco use, physical activity and history of gastric bypass. All were classified by yes/no based self-report. Study Population The following inclusion and exclusion criteria were established to identify subjects for this investigation.
King Abdul Aziz University, Kingdom of Saudi Arabia. Correspondence: Archana Iyer Email: arch729@gmail.com
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Hetari Y, Iyer A, Eldesouky SSM et al
3 Biochemical Analysis After 10-12 hours overnight fasting, five millilitres of blood was drawn from each participant by using standard venipuncture technique in plain vacutainer tubes for serum separation. The serum was separated by centrifugation at 2000 rpm for 10 minutes in a Hettich centrifuge, USA. The serum was separated into eppendorf tubes and stored at -80C for further analysis. Quantitative determination of total cholesterol, HDL and LDL concentration in human serum was measured spectrophotometrically by a time-endpoint method [8].
Inclusion Criteria

Self-identity as Saudis. 20-70 years of age. Body mass index (BMI) of 18.5 to 24.9 kg/m2 for the normal weight category or a BMI 30 kg/m2 for the obese category. Pregnancy and/or currently breastfeeding. Chronic diseases (cancer, chronic renal disease, heart disease and stroke). Use of hormone replacement therapy, steroids, and/or cholesterol lowering medications such as statins.
Exclusion Criteria

Results
The FRS was calculated from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) algorithm, based on six coronary risk factors: gender, age, total cholesterol, HDL-cholesterol (HDL-c), systolic blood pressure (BP) and smoking habit. Blood pressure was categorized according to Joint National Committee (JNC VII) criteria. Cholesterol, triglycerides, HDL-c and LDL-c levels were categorized according to ATP III guidelines. Participants were classified in two groups: non-smokers (never smoked or ex-smokers) and smokers (current smokers). Finally, the corresponding point was assigned to each individual and the total score was used as the individuals CHD risk level. On the basis of the FRS, the risk of CHD is categorized as high (20%), intermediate (10%20%), and low (10%) risk. Results of Framingham CVD risk scores are shown in table 2. Analysis of these scores revealed that about 96.4% of non-obese males had low risk while 1.8% had intermediate risk and 1.8% had high risk score. In obese males, 84.3% had low risk, 5.9% were categorized as intermediate risk and 9.8% as high risk. In non-obese female subjects, 98.0% were scored as high risk, while 2.0% had intermediate risk and none had >20% risk. In obese female subjects, 90.9% were in the low risk category and 9.1% were categorized as high risk. Table 2: Cardiovascular risk for all subjects based on Framingham risk score Framingham NonGender 10 year risk* Obese obese LR (<10%) 54 (96.4%) 43 (84.3%) Males IR (10%-20%) 1 (1.8%) 3 (5.9%) HR (>20%) 1 (1.8%) 5 (9.8%) LR (<10%) 49 (98.0%) 50 (90.9%) Females IR (10%-20%) 1 (2.0%) 0 (0.0%) HR (>20%) 0 (0.0%) 5 (9.1%)
*LR = Low Risk; IR = Intermediate Risk; HR = High Risk
Study Design This study was conducted on two hundred and twelve unrelated individuals. One hundred and six were non obese (BMI = 18.5 to 24.9 kg/m2) while one hundred and six were obese (BMI 30 kg/m2). The subjects were recruited to the study from November, 2011 to June, 2012 at King Fahd Medical Research Center (KFMRC), Madaen AlFahad Medical Center and medical administration for males at King Abdulaziz University. Morbidly obese individuals were recruited from the obesity clinic at the Department of General Surgery, King Abdul Aziz University Hospital. Figure 1 gives the study population chart.
Study Population (N=212)
Non-obese (N=106)
Obese (N=106)
Male (N=56)
Female (N=50)
Male (N=51)
Female (N=55)
Figure 1: Study Population Anthropometric Assessment Height and weight measurements were obtained from each participant by the same investigator. Subjects were required to remove shoes and heavy outer garments before the measurements of height and weight. Body Mass Index (BMI) Body Mass Index (BMI) was calculated by the equation: BMI = Weight in kg/(height in m)2 Using BMI the subjects were graded for obesity using Quetelet's index (Garrow and Webster, 1985) and nomogram of WHO (1995). Table 1: BMI Classification Subjects Normal Obesity Grade I Obesity Grade II Obesity Grade III BMI 18.5-24.9 30.0-34.9 35.0-39.9 40
P-value 0.121
0.039
In males subjects, the difference was statistically significant with regards to blood hypertension (P=0.000), triglycerides (P=0.033), HDL (P=0.048). In females subjects, the difference was statistically significant with regards to age (P=0.008), cholesterol (P=0.015), triglycerides (P=0.011) and LDL (P=0.017). The distribution of cigarettes smoking as risk factor was 36.4% for males and 18.1% for females. 33.9% of non-obese males were smokers, while 39.2% of obese males were smokers. 14.0% of non-obese females were smokers and 21.8% of obese females were smokers.
Framingham Risk Score for the prediction of cardiovascular risk
Discussion
The Framingham Heart Study introduced the concept of risk factors for coronary heart disease (CHD) and has served as the standard for risk assessment over the years [6, 9]. Our results show that cardiovascular disease risk factors were more prevalent among obese than normal weight subjects. These findings are similar to the results of the Multi-Ethnic Study of Atherosclerosis, which examined the relation of obesity in older individuals 45 to 84 years old [10]. In our study, Saudi women had a high prevalence of cardiovascular disease risk factors. Our result is coincident with several studies [11, 12]. These studies have further reported that African Americans who are obese have a greater chance of having high blood pressure, diabetes, and high blood levels of triglycerides and cholesterol than those who are not obese, and these conditions increase the risk of developing cardiovascular disease. The distribution of males and females in our study was (50.5% and 49.5%). Similar results were observed in Qazvin population (50.2% and 49.8%), but not in a Jordanian study (78.3% and 21.7%) [13, 14]. Our results showed the prevalence of smoking among obese people is more than reported in US. The proportion of adults who smoke and are obese in the US is relatively low: the total number being 9 million (4.7%). Overall, 5.3% of men and 4.2% of women who smoke are obese [15]. Previous studies of Saudi smoking behavior have investigated the prevalence of smoking among adults in Saudi Arabia. The prevalence of current smoking among adults in Saudi Arabia range from 11.6-52.3%. Only one study investigated the prevalence of current smoking among elderly people (50-89 years) and found that 25% of them were current smoker. The prevalence of current smoking in males ranges from 13-38%, while in females it ranges from 1-16% [16-18]. Other studies in the Kingdom and in other Arab countries have reported similar findings [19, 20]. This differs from Western societies, where female smoking is more common [21, 22]. Our result agreed with the result of another study, in which the authors reported that Arab women were less involved in active smoking, but suffered more from passive smoking [23]. Hypertension has been identified as the most common risk factor for coronary heart disease events [24]. Obesity and weight gain have been identified as the most important determinants of hypertension [25, 26]. The association between obesity and hypertension forms part of a broader relationship between body weight and blood pressure (BP). Our results in general revealed that most of Saudi population was classified as pre-hypertensive. A higher percentage of the obese male group compared with non-obese group was found to exhibit stage 1 hypertension. In female population, a higher percentage of obese groups compared with non-obese group was found to exhibit pre-hypertension and stage 1 hypertension. Furthermore, it was found that obesity had the strongest association with pre-hypertension and hypertension. This finding is in line with the published data from Iran [27]. However, social and cultural differences, the subjects characteristics, the age span as well as the methodology used, may account for the observed discrepancies among the previous studies. Nonetheless, although direct comparisons with other studies are not possible, it is rather self-evident that the prevalence of pre-hypertension is high in
Vol 2, No 1
both developed and developing countries, and in eastern and western populations. It, therefore, needs further in-depth clarification. Previous studies on the prevalence of hypertension in KSA have demonstrated persistently increasing figures [28]. Several reasons such as lifestyle change in KSA towards urbanization and adopting new dietary habits, are likely to result in hypertension and increasing prevalence of obesity.
Conclusion
These findings carry implications for clinical practice: Obese adults without clinical cardiovascular disease may already have a clustering of traditional cardiovascular risk factors. Institution of early and aggressive preventive measures in this population could delay or arrest progression to clinical cardiovascular disease.
Competing interests: The authors declare that no competing interests exist. This study is a part of a doctoral thesis and the experiments were performed at the King Fahd Medical Research Centre, Jeddah, Kingdom of Saudi Arabia. Received: 25 November 2013 Accepted: 2 January 2014 Published Online: 2 January 2014
References
1. Stocker R, Keaney JF, Jr.: Role of oxidative modifications in atherosclerosis. Physiological reviews 2004, 84(4):1381-1478. 2. Lee GK, Lee LC, Liu CW, Lim SL, Shi LM, Ong HY, Lim YT, Yeo TC: Framingham risk score inadequately predicts cardiac risk in young patients presenting with a first myocardial infarction. Annals of the Academy of Medicine, Singapore 2010, 39(3):163-167. 3. Appel SJ, Harrell JS, Deng S: Racial and socioeconomic differences in risk factors for cardiovascular disease among Southern rural women. Nursing research 2002, 51(3):140-147. 4. Grundy SM, Pasternak R, Greenland P, Smith S, Jr., Fuster V: Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 1999, 100(13):1481-1492. 5. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB: Prediction of coronary heart disease using risk factor categories. Circulation 1998, 97(18):1837-1847. 6. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, Franklin BA, Goldstein LB, Greenland P, Grundy SM et al: AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 Update: Consensus Panel Guide to Comprehensive Risk Reduction for Adult Patients Without Coronary or Other Atherosclerotic Vascular Diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002, 106(3):388-391. 7. Sullivan LM, Massaro JM, D'Agostino RB, Sr.: Presentation of multivariate data for clinical use: The Framingham Study risk score functions. Statistics in medicine 2004, 23(10):1631-1660. 8. Roeschlau P, Bernt E, Gruber W: Enzymatic determination of total cholesterol in serum. Zeitschrift fur klinische Chemie und klinische Biochemie 1974, 12(5):226. 9. Anderson KM, Wilson PW, Odell PM, Kannel WB: An updated coronary risk profile. A statement for health professionals. Circulation 1991, 83(1):356-362. 10. Bild DE, Detrano R, Peterson D, Guerci A, Liu K, Shahar E, Ouyang P, Jackson S, Saad MF: Ethnic differences in coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2005, 111(10):1313-1320. 11. Diez-Roux AV, Northridge ME, Morabia A, Bassett MT, Shea S: Prevalence and social correlates of cardiovascular disease risk factors in Harlem. American journal of public health 1999, 89(3):302-307. 12. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and trends in obesity among US adults, 1999-2000. JAMA : the journal of the American Medical Association 2002, 288(14):1723-1727. 13. Fakhrzadeh H, Bandarian F, Adibi H, Samavat T, Malekafzali H, Hodjatzadeh E, Larijani B: Coronary heart disease and associated risk factors in Qazvin: a population-based study. Eastern Mediterranean health journal = La revue de
Hetari Y, Iyer A, Eldesouky SSM et al
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21. Felimban F: The smoking practices and attitudes towards smoking of female university students in Riyadh. Saudi medical journal 1993, 14(3):220-224. 22. WHO: Guidelines for controlling and monitoring the tobacco epidemic,. Geneva; 1996. 23. Jabara R, Namouz S, Kark JD, Lotan C: Risk characteristics of Arab and Jewish women with coronary heart disease in Jerusalem. The Israel Medical Association journal : IMAJ 2007, 9(4):316-320. 24. Greenland P, Knoll MD, Stamler J, Neaton JD, Dyer AR, Garside DB, Wilson PW: Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA : the journal of the American Medical Association 2003, 290(7):891-897. 25. Oliveria SA, Lapuerta P, McCarthy BD, L'Italien GJ, Berlowitz DR, Asch SM: Physician-related barriers to the effective management of uncontrolled hypertension. Archives of internal medicine 2002, 162(4):413-420. 26. Ahmed A, Mahmoud M: The prevalence of hypertension in Saudi Arabia. Saudi medical journal 1992, 13(6):548-551. 27. Rahmanian K, Shojaie M: The prevalence of pre-hypertension and its association to established cardiovascular risk factors in south of Iran. BMC research notes 2012, 5:386. 28. Al-Nozha MM, Ali MS, Osman AK: Arterial hypertension in Saudi Arabia. Annals of Saudi medicine 1997, 17(2):170-174.
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sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq almutawassit 2008, 14(1):33-41. Hammoudeh AJ, Izraiq M, Al-Mousa E, Al-Tarawneh H, Elharassis A, Mahadeen Z, Badran N, Haddad J: Serum lipid profiles with and without CAD: Jordan Hyperlipidaemia and Related Targets Study (JoHARTS-1). Eastern Mediterranean health journal = La revue de sante de la Mediterranee orientale = al-Majallah al-sihhiyah li-sharq al-mutawassit 2008, 14(1):24-32. Healton CG, Vallone D, McCausland KL, Xiao H, Green MP: Smoking, obesity, and their co-occurrence in the United States: cross sectional analysis. BMJ (Clinical research ed) 2006, 333(7557):25-26. Abdalla AM, Al-Kaabba AF, Saeed AA, Abdulrahman BM, Raat H: Gender differences in smoking behavior among adolescents in Saudi Arabia. Saudi medical journal 2007, 28(7):1102-1108. Almas K, Al-Hawish A, Al-Khamis W: Oral hygiene practices, smoking habit, and self-perceived oral malodor among dental students. The journal of contemporary dental practice 2003, 4(4):77-90. Hasim TJ: Smoking habits of students in College of Applied Medical Science, Saudi Arabia. Saudi medical journal 2000, 21(1):76-80. Hamadeh RR: Smoking habits of medical students in Bahrain. J Smoking Related Dis 1994, 5:189-195. Awidi AS: Patterns of cigarette smoking in Jordan: A study of greater Amman area. Annals of Saudi medicine 1991, 11(2):144-147.
Management of acute respiratory infections in children
Open Access
Muhammad Irfanullah Siddiqui1, Akhtar Ali Baloch2, Syed Ishtiaq Ahmed3, Syed Imtiaz Ahmed Jafri4
Original Article
Audit of prescribing patterns of doctors for the management of acute respiratory infections in children
Abstract
Background: Acute respiratory infections (ARI) account for 80% of all children reporting to outpatient departments (OPD). In most of the cases the cause of morbidity is a viral infection that does not require antibiotic treatment, but in spite of this, antibiotics are used much too frequently. The guidelines for the management of ARI have been developed by World Health Organization (WHO), but generally, the physicians do not follow the recommended guidelines. This study was conducted to audit the prescriptions of general practitioners, to determine their practices regarding ARI management and to provide recommendations to improve their practices in the area of identified needs. Methods: Practitioners working in District Bulleda (Turbat), Balochistan were surveyed and five of them were selected randomly using simple random sampling technique for this cross sectional study. They were informed about the objectives of the study and consent was obtained. Their prescriptions of cases of ARI management for one month were obtained. Results: The results of the study show that a total of 202 patients of ARI were seen by the 5 selected physicians of the district. It was seen that in 60% cases the chief complaints were recorded. Temperature was recorded in 48% case. Respiratory rate was recorded in 33% cases. The diagnosis was noted down in 44% cases. In 97% cases, antibiotics were prescribed and in 37.5% cases the dose was not according to recommendation. Conclusion: It is concluded that most physicians in Bulleda are not following the WHO recommended protocol of ARI management. Refresher courses and training programs for physicians are recommended. Use of electronic media may be helpful in increasing awareness both in the health care provider and health care recipient. (El Med J 2:1; 2014) Keywords: Acute respiratory infections, WHO Guidelines, Audit
Introduction
Acute respiratory infections (ARI) are considered as one of the major public health problems and are the leading cause of morbidity and mortality in many developing countries. They have been estimated to cause 18% to 33% of all deaths of children under five years. Pneumonia kills more children than any other illness, more than HIV, malaria and measles combined. Effective interventions to reduce pneumonia deaths are available but reach too few children. More than a million lives could be saved if prevention and treatment interventions were implemented universally. Preventing children under five from developing pneumonia in the first place is key [1-4]. In Pakistan, 80% of morbidity and mortality is due to lower respiratory infection [5, 6]. ARI are responsible for 33% of death among children and most of the cases are treated by general practitioners (GPs) [7, 8]. This large number of deaths is due to the reason that management of ARI is not appropriate and many deaths can be prevented by appropriate intervention [9]. World Health Organization (WHO) has developed a protocol for the management of ARI especially for developing countries like Pakistan [10]. However, it is rarely followed by GPs, resulting in large number of deaths among children [11]. This study was conducted to audit the prescriptions of GPs, to determine their practices regarding ARI management and compliance to WHO protocols, and to provide recommendations to improve their practices in the area of identified needs [12].
of the city of Turbat. Turbat is the second largest city of Balochistan province. It is a subdivision and has a population of 45,000 with very few basic facilities. Most of the people are illiterate and have very little information regarding health issues. Study Design This was a cross-sectional study conducted from October, 1 to October, 31 for a period of one month. Sampling Procedure The sampling technique used was two-stage random sampling, to select registered general practitioner during first phase and later, to select their prescriptions. Randomly selected general practitioners, practicing in Bulleda were visited and their prescriptions for the month were randomly selected (thereby forming the sample size) after obtaining consent. A total of five such practitioners were selected. The sample size was estimated using 95% confidence interval and keeping 5% level of significance [13]. A total of 202 prescriptions were obtained and then compared with WHO protocol to observe whether they were consistent with the recommendations. Collected prescriptions were analyzed using the standard ARI case management guidelines of WHO [10]. All the GPs were assured of confidentiality and the data collected was kept confidential and entered into the computer to be analyzed in EPI Info software version 6, developed by Center for Disease Control Atlanta, USA. The variables included were gender, weight, chief complaints, temperature, pulse rate, respiratory rate, provisional diagnosis and the type of antibiotic prescribed.
4
Methods
Study Setting Bulleda, situated in District Turbat (Balochistan), is small village cum town surrounded by date trees. It is about 75 km towards the north
Umm Al-Qura University, Saudi Arabia Medical Officer, Turbat, Pakistan 3Hamdard University, Pakistan
1 2
Baqai University, Pakistan Correspondence: Muhammad Irfanullah Siddiqui Email: irfan7255@yahoo.com
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7 Among the combination drugs, Gentamicin was the first choice of the physicians in 7 (36.8%) cases. Table 2: Distribution of the recording of various variables required to help diagnosis Features Recorded Yes No 70 132 Weight 121 81 Chief Complaints 96 106 Temperature 25 177 Pulse 67 135 Respiratory Rate 90 112 Provisional Diagnosis
Results
A total of 202 prescriptions were collected from the 5 GPs during one month of the survey. The number of ARI prescriptions ranged from 24 to 56 with a mean of 40.4 per physician (Table 1). A total of 57 (28.2%) children were under 1 year and 168 (83.2%) were less than 5 years of age. Only 8 children were over 10 years of age. 112 (55.4%) patients were males. Table 1: Distribution of the number of ARI cases seen by each physician Physician Number Frequency Percentage 56 27.7 D1 49 24.2 D2 24 11.9 D3 48 23.8 D4 25 12.4 D5 202 100.0 Total Seventy (34.7%) patients were weighed during their visit. Only 121 (59.9%) prescriptions had an entry of the chief complaints. 84 (69.4%) of the complaints were of fever and cough combined, followed by 21 (17.4%) of only fever (Figure 1). Temperature was recorded for only 96 (47.5%) children and 10 (10.4%) of them were afebrile. The pulse was recorded only in 25 (12.4%) cases and ranged from 78 to 120. The respiratory rate was recorded only for 67 (33.2%) patients and in 43 (64.2%) cases it was above 40 per minute.
Distribution of the diagnosis of the children

6% 21%
Severe Pneumonia Pneumonia Common Cold / Cough
73%
Distribution of the chief complaints of the children

100 80 60 40 20 0 Frequency
Figure 2: Distribution of the diagnosis of the children coming to OPD Antipyretic drugs were used in 163 (80.7%) cases and in 154 (94.5%) cases, only one antipyretic was prescribed. In 86 (52.8%) cases, the drugs of choice were different brands of Paracetamol. Combination of antipyretics was used in 9 (5.5%) cases. 58 (28.7%) cases were prescribed cough syrup and among the prescriptions, Sancos (36.2%) and Benatus (32.8%) were the most prescribed cough syrups. It was observed that in 74 (37.8%) cases, the dose of antibiotic prescribed was not according to the recommendation. It was observed that only 3 out of the 5 doctors recorded weights of the children at least once during the month. One physician did not record chief complaints at all, whereas another one recorded chief complaints of only three patients. Only 3 physicians recorded respiratory rate. Each doctor on the average prescribed correct dosage according to the recommendation of WHO in 63% of cases (p=0.2934).
Chief Complaints
Figure 1: Distribution of the chief complaints of the children coming to OPD The diagnosis was noted down in 90 (44.6%) patients (Table 2). In 5 (5.6%) cases the diagnosis was severe pneumonia (Figure 2). 196 (97.0%) patients were prescribed antibiotics. In 177 (90.3%) cases, only one antibiotic was prescribed and in 18 (9.2%) cases, 2 antibiotics were prescribed. It was seen that different brands of amoxicillin were prescribed most frequently (21.4%), followed by first generation cephalosporins (19.9%). Co-trimaxazole (14.3%) was the third most prescribed drug. Ceftriaxone was prescribed in 12 (6.1%) cases (Figure 3). Combination of antibiotics were used in 19 (9.7%) cases.
Discussion
The present study was conducted to audit the prescribing practices of GPs regarding management of ARI, and then to make recommendations to improve the practices so that unnecessary deaths among the children, which are as high as 80,000 deaths annually, can be avoided [14]. Previously, a number of studies have been conducted with the aim of determining the knowledge, attitude and practices of mothers regarding management of ARI in children [15-18]. However, data regarding the practices of healthcare providers via prescription auditing is scarce [19].
Management of acute respiratory infections in children
Distribution of the chief complaints of the children

25 20 Frequency 15 10 5 0 Amoxil Ampicillin Ampiclox Arbanine Augmentin Bactrim Ceclor Cefizox Cefspan Ceporex Chloromycin Claforan Cloxacillin Erythrocin Fortum Fosfomycin Gentacin Keflex Nebcin Nicotrim Ospamox Penbritin Penicillin Princimox Rocephen Septran Standacillin Taxim Velosef Wymox Zinnat Antibiotics
Figure 1: Distribution of the chief complaints of the children coming to OPD Our results show that 28.5% children were under one year and 83% were under five years. A study conducted by Sarfaraz observed the occurrence of ARI as 91% among under-five children [20]. The presenting complaint was fever and cough in 69.4% of the prescriptions and fever alone in 17.4%. A study conducted at Multan found the chief complaints of cough and fever in 95% and 83% respectively [21]. Diagnosis was noted down in only 44.6% of cases and in 94% cases it was lower respiratory tract infection (LRTI). In the study conducted by Sarfaraz, LRTI constituted 28% of the total cases [20]. In our study 97% of the patients were prescribed at least one antibiotic while the study conducted by Imran found antibiotic prescription rate as 83%. The study conducted by Tambe et al found that a substantial number of episodes (27.3%) did not receive any treatment [16]. The drug of choice was amoxicillin in 21% of the cases, followed by first generation cephalosporins (20%). Cotrimoxizole was the third most prescribed drug. According to WHO recommendations co-trimaxazole and ampicillin should be given as the first choice drugs [10]. The study conducted by Tanveer found prescription rate of antibiotics as high as 73%. None of the physician in our study prescribed doses according to recommendations. should visit different geographical areas and conduct training programs in collaboration with local authorities and NGOs. Rational use of antibiotics should be emphasized in the training programs. Refresher courses should be conducted by the district health officer for already trained health care providers. Media should be involved effectively and management programs of ARI should be broadcasted on TV and radio to increase awareness, not only in the community, but also among health care providers.
Competing interests: The authors declare that no competing interests exist. Received: 29 November 2013 Accepted: 4 January 2014 Published Online: 4 January 2014
References
1. UNICEF | The State of World Children 2013 [http://www.unicef.org/sowc2013/] 2. Yousuf TK, Khaliq BA: Epidemiology of acute respiratory infections among children under 5 years old attending Tikrit General Teaching Hospital. 2006;14(3). Middle East Journal of Family Medicine 2006, 4(3):4-23. 3. Pneumonia: the forgotten killer of children [http://www.unicef.org/sowc08/docs/sowc08_panel_1_5.pdf] 4. Bryce J, Boschi-Pinto C, Shibuya K, Black RE: WHO estimates of the causes of death in children. Lancet 2005, 365(9465):1147-1152. 5. Pio A, Leowski J, ten Dam HG: The magnitude of the problems of acute respiratory infection in ARI in childhood. Proceeding of an international workshop, Sydney, 1984. 6. Mughal MJ: Health seeking behavior of mother belonging to different Ethic groups regarding home management / Remedies of acute respiratory infections. Dissertation submitted for MPH requirement. Baqai Medical University Karachi (1996). 7. Grant JP: The state of worlds children. New York, Oxford University Press, 1993. 8. Ilyas M: Community Medicine. 7th ed., Karachi, Time Publishers, 2008:553. 9. Myat KKS, Kyi S, Lwin TT: Indoor Air Pollution: Impact of Intervention on Acute Respiratory Infection (ARI) in Under-five Children. Regional Health Forum 2005, 9(1):30. 10. WHO. Acute Respiratory infection in children, case management in small hospital in developing countries. Federal ARI cell 1993. 11. Lawn JE, Wilczynska-Ketende K, Cousens SN: Estimating the causes of 4 million neonatal deaths in the year 2000. International journal of epidemiology 2006, 35(3):706-718.
Conclusion
The results of the study indicate that the practices of physicians working in Bulleda show great deviation from the WHO recommended protocol for ARI management. This is resulting in increased morbidity and mortality among the children of this underdeveloped area of Pakistan. Comparative results show that antibiotic prescriptions are more frequent among GPs of Bulleda, compared to other parts of Pakistan. The diagnosis is not made in most of the cases, and if made, is not on justified grounds.
Recommendations
It is recommended that this study should be taken as pilot study and a multicenter study should be conducted in other parts of Pakistan. If the results are similar, a team of trainers should be prepared who
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17. Oyejide CO, Oke EA: An ethnographic study of acute respiratory infections in four local government areas of Nigeria. African journal of medicine and medical sciences 1995, 24(1):85-91. 18. Formento Tirado JA, Prieto Esteban I, Celemin Colomina I, Alvarez Rodriguez F, Crespo Llorden A, Arenas Abad A: [Analysis of prescriptions of antibiotics for acute respiratory infections at a health center]. Atencion primaria / Sociedad Espanola de Medicina de Familia y Comunitaria 1995, 16(5):281-284. 19. Sarfaraz T: Acute respiratory infection in children. Pak Armed Forces Med J 1996, 46(2):28-32. 20. Iqbal I, Pervaiz S, Baig S: Management of the children with Acute Respiratory Infection (ARI) by General Practitioners in Multan. An Observational study. JPMA The Journal of the Pakistan Medical Association 1997, 47(1):24-28.
12. Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wolff M, Chastre J, Tubach F et al: Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Evidence-based child health : a Cochrane review journal 2013, 8(4):1297-1371. 13. Huley SB: Designing clinical research. William and Wilkins, Baltimore; 1998:220. 14. David RM, Haq IU, Qureshi AF: Childhood ARI in Pakistan. J Pak Med Assoc 1993, 43:14-20 15. Tambe MP, Shivaram C, Chandrashekhar Y: Acute respiratory infection in children: a survey in the rural community. Indian journal of medical sciences 1999, 53(6):249-253. 16. Khan AJ, Khan JA, Akbar M, Addiss DG: Acute respiratory infections in children: a case management intervention in Abbottabad District, Pakistan. Bull World Health Organ 1990, 68(5):577-585.
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Oral health of Central Reserve Police Force officials
Open Access
Swapnil S Bumb1, D J Bhaskar1, Chandan R Agali1, Himashu Punia1, Vikas Singh1, Safalya Kadtane1
Original Article
Comparison of oral health knowledge, attitudes, practices and oral hygiene status of Central Reserve Police Force officials in Srinagar, Kashmir
Abstract
Background: Central Reserve Police Force (CRPF) police officials are at constant risk of uncertainty and tension, leading to stress, anxiety, depression and alcoholism. All the above factors may have an effect on oral health. Literature regarding the oral health situation of CRPF officials is scarce. This study was, therefore, conducted to determine the oral health knowledge, attitudes, practices and oral hygiene status of CRPF officials. Methods: A cross sectional questionnaire survey was conducted among 321 CRPF officials who voluntarily participated. A questionnaire consisting of 21 questions was used to determine the knowledge, attitudes and practices. Clinical examination was done to assess oral hygiene status. Results: Out of 321 officials, only 57.6% were aware of the fact that tooth brushing helps in preventing caries and gum diseases. Only 26.5% were aware of the role of fluoridated toothpaste in the prevention of caries. 80.4% were of the view that regular visit to a dentist is necessary. 84.4% used toothpaste with toothbrush for cleaning of teeth, 5.0% used toothpowder with fingers and 10.6% used toothpowder with brush. 27.7% had never visited a dentist in their lives. Conclusion: Deficiencies were found in the CRPF officials knowledge about gum diseases, use of fluoridated toothpaste and oral hygiene aids. Among the officials interviewed, 82% had poor and 18% had fair oral hygiene status. None of them had good oral hygiene status. Most of CRPF officials did not have knowledge about the causes and prevention of dental diseases. (El Med J 2:1; 2014) Keywords: Central Reserve Police Force, Oral Hygiene, Caries, Oral Health, India
Introduction
Health is a theme in most cultures and is fundamental human right without distinction of race, religion and political belief, economic and social condition [1]. The work environment constitutes an important part of mans total environment, so health to a large extent is affected by working conditions. Although several types of environments exist, it is the physical environment that renders an important effect on health [2]. Oral health is an integral part of general health and is one of the determinants of quality of life. Oral health and general health are determined by various factors such as lifestyle, dietary habits, socioeconomic conditions, occupational environment etc [3]. Oral health is the standard of health of oral and related tissues that enables an individual to eat, speak and socialize without active disease, discomfort or embarrassment and contributes to general wellbeing. It is concerned with maintaining the health of the craniofacial complex, the teeth and gums as well as the tissue of face and head that surrounds the mouth. Loss of teeth and deterioration of oral tissue substantially reduces the quality of life [1]. As military defends the country from external threats, the role of police is for the maintenance of internal law and order [4]. Police personnel are law enforces with busy work schedule. The nature of the job is such that they are subjected to physical, mental and emotional stress. The irregular shifts in their work schedule leads to neglecting of their regular diet and indulging in regular, often detrimental habits. The work shifts also deprive them of their routine sleeping pattern and social activities [5]. The target population on which we conducted this study were police of Central Reserve Police Force (CRPF), Srinagar, Kashmir. CRPF is the largest of India's central armed police forces. It functions under the
1
aegis of Ministry of Home Affairs of the Government of India. The CRPF's primary role lies in assisting the State/Union territories in police operations to maintain law and order and contain insurgency. It came into existence as the Crown Representative's Police on 27 July 1939. After Indian Independence, it became the CRPF on enactment of the CRPF Act on 28 December 1949 [6]. The rigors of physical, mental and social discipline insisted upon the military personnel is also applicable on the police. One of the aims of the military training given to soldiers is to achieve the required physical and mental fitness for the mission to be carried out. This requires sufficient general and oral health for training and taking part in exercises, maneuvers and deployments [7]. For years, the police profession has been ranked among the top five of most stressful occupations. The constant risk of uncertainty and tension which are inherent in law enforcement and the vast amounts of human suffering and violence can lead susceptible individuals to stress, anxiety, depression and alcoholism. Many studies have shown relationship of stress factors to periodontal diseases [8]. All the above factors might have an effect on general as well as oral health. It is, therefore, the responsibility of society to safeguard the health of their defenders. Literature regarding oral health status of these officials is not available. A clear picture of oral diseases will help us in organizing preventive and curative programs for containment of oral disease [9]. This information is very important for establishing priority and determining the type and quantity of prevention and treatment services required, as well as the type of personnel needed to provide the same. This study was, therefore, conducted to determine the oral health knowledge, attitudes, practices and oral hygiene status of CRPF officials in Srinagar, Kashmir.
Teerthanker Mahaveer Dental College and Research Centre, India Correspondence: Swapnil S Bumb Email: drswapnilbumb@gmail.com
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11 No of permanent teeth 16 20 24 32 Dont Know Clean bright teeth Reducing the cost of dental care Prevention of tooth decay and gum disease Prevention of oral cancers Dont know 1-3 months 4-6 months 7-12 months More than 1 year Dont know Soft deposit teeth Hard deposit on teeth Discoloration of teeth White patches on teeth Dont know Staining of teeth Oral ulcers Oral ulcers Tooth decay and gum disease White patches on teeth Dont know Healthy gum Tooth infection Calcium deficiency in body Gum disease (inflammation) Dont know Calcium deficiency Excess sweet Eating Gum disease due to improper brushing Tooth infection Dont know Tobacco chewing Worms Improper brushing Vit C deficiency Dont know Yes No Dont know 9 (2.8%) 3 (0.9%) 34 (10.6%) 240 (74.8%) 35 (10.9%) 88 (27.4%) 30 (9.4%) 185 (57.6%) 10 (3.1%) 8 (2.5%) 199 (62.0%) 83 (25.9%) 29 (9.0%) 3 (0.9%) 7 (2.2%) 106 (33.0%) 10 (3.1%) 69 (21.5%) 26 (8.1%) 110 (34.3%) 72 (22.4%) 34 (10.6%) 78 (24.3%) 31 (9.7%) 106 (33.0%) 69 (21.5%) 44 (13.7%) 59 (18.4%) 136 (42.4%) 13 (4.1%) 53 (16.5%) 33 (10.3%) 195 (60.8%) 31 (9.7%) 9 (2.8%) 122 (38.0%) 28 (8.7%) 125 (38.9%) 28 (8.7%) 18 (5.6%) 186 (57.9%) 65 (20.2%) 70 (20.9%)
Materials and Methods

The present study was conducted on 321 CRPF officials who voluntarily participated. The subjects were in the age group of 20-60 years. Ethical clearance was obtained from Institutional Review Board of Teerthanker Mahaveer University. Permission to conduct the study was obtained from commanding officer as well as medical officer of CRPF Srinagar unit. Convenience sampling was used to collect the sample based on subjects present during the conduction of study. A cross-sectional questionnaire-based survey was conducted. The questionnaire consisted of 21 questions. Clinical examination was done to assess the oral hygiene status (via Simplified Oral Hygiene Index). Sufficient number of instruments were taken to avoid any interruption during examinations. Following instruments were used to conduct clinical examination: plane mouth mirror, explorer, tweezers, kidney trays, chip blowers, cotton holders, disposable mouth masks, disposable gloves, sterilized cotton and gauze pieces, towels and soaps. A single trained examiner who was expert in the department conducted all the examinations. A well-trained assistant was taken for recording the data. A schedule was prepared for data collection. The questionnaires were distributed and were required to be completed within half an hour. Knowledge, attitude and practice scores were calculated separately. The significance value was set at p<0.05. Statistical analysis was performed using the Statistical Package for Social Sciences software version 18 and MS Excel. Mean, Frequency and percentage were calculated. Inclusion Criteria Subjects who were present on the day of examination and were willing to give Informed consent. Exclusion Criteria Subjects who did not give informed consent.
Purpose of tooth brushing
Interval for change of tooth brush Plaque means
Dental plaque leads to
Gum bleeding means
Results
Oral health knowledge and opinions (Table 1) Majority of the officials (57.6%) were aware of the fact that tooth brushing helps in preventing caries and gum diseases. Only 26.5% were aware about the role of fluorides and fluoridated tooth paste in prevention of dental caries. 54.8% were aware that tobacco consumption leads to oral cancer. Table 1: Oral health knowledge and opinions* Questions Options Sets of dentitions One Two Three Four Dont Know 10 No of milk teeth 16 20 32 Dont Know N (%) 80 (24.9%) 210 (65.4%) 12 (3.7%) 10 (3.1%) 9 (2.8%) 7 (2.2%) 49 (15.3%) 161 (50.2%) 60 (18.7%) 44 (13.7%)
Reasons for gum bleeding
Reason of tooth decay
Fizzy soft drinks affect the teeth adversely
12 Table 1 (Continued) Questions Methods to prevent bleeding from gums Options Regular tooth brushing and flossing Calcium supplements Reduction in sweet consumption Eat soft food Dont know Mobility of teeth Yellowish staining of teeth Leads to tooth decay Leads to bleeding of gums Dont know Avoid tobacco chewing Vit C supplements Regular brushing with fluoridated toothpaste Calcium supplements Dont know Gives clean bright teeth Prevents tooth decay Prevents mobility of teeth Prevents gum disease Dont know Improper brushing Tobacco chewing or smoking Vit C deficiency Excess sweet eating Dont know Gums disease Tooth decay Old age Reduced dietary intake Dont know Yes No Dont know Yes No Dont know Yes No Dont know N (%) 188 (58.6%) 41 (12.8%) 62 (19.3%) 23 (7.2%) 7 (2.2%) 75 (23.4%) 45 (13.0%) 153 (47.7%) 30 (9.4%) 18 (5.6%) 107 (33.3%) 18 (5.6%) 166 (51.7%) 19 (5.9%) 11 (3.4%) 59 (18.4%) 73 (22.7%) 85 (26.5%) 57 (17.8%) 47 (14.6%) 96 (29.9%) 176 (54.8%) 36 (11.2%) 7 (2.2%) 6 (1.9%) 197 (61.4%) 42 (13.1%) 71 (22.1%) 8 (2.5%) 3 (0.9%) 226 (70.4%) 50 (15.6%) 45 (14.0%) 300 (93.5%) 10 (3.1%) 11 (3.4%) 274 (85.4%) 13 (4.1%) 34 (10.6%)
Loss of teeth can interfere with speech
Yes No Dont know
272 (84.7%) 14 (4.4%) 35 (10.9%)
*Options marked in bold are correct answers
Oral health attitudes (Table 2) 80.4% of officials were of the view that regular visits to the dentist are necessary. 54.8% opined that immediate replacement of missing natural teeth is necessary. 90.3% agreed that gutkha chewing and smoking is a bad habit. Table 2: Oral health attitudes Questions Options Yes Regular visit to No dentist is Dont know necessary Yes Immediate No replacement of Dont know missing natural teeth by artificial teeth is necessary Guthka chewing / Yes smoking is a bad No Dont know habit Dentists care only Yes No about treatment & not prevention Dont know Yes Treatment of No toothache is as important as any Dont know other organ in body N (%) 258 (80.4%) 30 (9.3%) 33 (10.3%) 176 (54.8%) 21 (6.5%) 124 (38.6%) 290 (90.3%) 26 (8.1%) 5 (1.6%) 251 (78.2%) 43 (13.4%) 27 (8.4%) 227 (70.7%) 28 (8.7%) 66 (20.6%)
Effect of sweet retention on dentition
Methods to prevent tooth decay
Effect of fluorides on dentition
Reason for development of oral cancer
Reasons of tooth loss in old age
Oral health behavior (Table 3) 52.3% of the officials reported brushing once a day, whereas 44.9% brushed twice a day. 84.4% used toothpaste with toothbrush for cleaning of teeth, 5.0% used toothpowder with fingers and 10.6% used toothpowder with brush. 62.6% reported changing their brush due to fraying of bristles. Table 3: Oral health behavior Questions Options How many times Once Twice in day do you brush your teeth? Thrice or more In morning When do you brush your teeth? In morning & before going to bed In morning, before going to bed & after sweet eating/meals Yes Use fluoridated No toothpaste Dont know N (%) 168 (52.3%) 144 (44.9%) 9 (2.8%) 167 (52.0%) 135 (42.1%) 19 (5.9%) 125 (38.9%) 38 (11.8%) 158 (49.2%)
Decayed teeth can affect the appearance of the person Health of mouth and dentition impact the health of body Is it possible to move irregularly placed teeth in correct position?
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13 N (%) 271 (84.4%) 16 (5.0%) 34 (10.6%) 201 (62.6%) 61 (19.0%) 59 (18.4%) 164 (51.1%) 157 (48.9%) 62 (19.3%) 77 (24.0%) 182 (56.7%) 76 (23.7%) 62 (19.3%) 94 (29.3%) 89 (27.7%) 244 (76.0%) 36 (11.2%) 41 (12.8%) 229 (71.3%) 92 (28.7%) 222 (69.2%) 99 (30.1%) Table 5: Oral hygiene index - Simplified group Frequency 264 Poor 57 Fair 321 Total Percentage 82.2% 17.8% 100%
Table 3 (Continued) Questions Material you use for brushing your teeth Reason to change the toothbrush Do you clean your tongue? Do you use any oral hygiene aid? Have you ever visited a dentist, what was the driving factor? How many times in a day you eat sweets? Do you take care of your teeth as much as other part of body? Any habits like pan chewing, guthka chewing, cigarette smoking
Options Toothpaste with brush Toothpowder or others with finger Toothpowder with brush Fraying of bristles New toothbrush design in market After breakage Yes No Dental floss Mouthwash No Routine checkup Severe dental pain Treatment of common dental diseases Never visited dentist 1-3 times 4-6 times Not at all Yes No Yes No
officials of Srinagar, Kashmir and to measure oral hygiene status. CRPF officials knowledge about gum diseases and use of fluoridated dentifrices was found to be low, dental visits were frequent and consumption of sweets was found to be very high. Officials must be provided with oral health education at such settings along with physical and general health education. In the present study, majority of officials were not aware of whether they used fluoride containing dentrifices, similar to findings of Abhinav Singh who conducted a study to assess the oral health knowledge, attitude & practice among NCC cadets in South India [10]. Majority of officials did not know that dental floss helps in preventing dental caries and gum disease. But most of the officials were aware of the fact that tooth brushing prevents caries. Lack of knowledge regarding dental floss and gum diseases can be attributed to low level of dental education of CRPF officials. About 58% of the officials considered soft drinks to be harmful to teeth. Peterson et al, in study conducted among 12 year old urban and rural school children in southern Thailand, reported that consumption of sweets is an important predicator of high caries experience [11]. In the present study, 76% of officials reported consumption of sweets 1-3 times a day, 12% consumed 4-6 times a day and only 13% did not consume sweets at all. Similar findings were reported in Singh among NCC cadets in South India in which 49% of cadets reported consumption of sweets very often and 14.4% reported its consumption all the time [10]. Our findings indicate that most of the officials lacked knowledge about the causes and prevention of dental disease. Findings similar to the present study regarding oral health knowledge and attitudes were reported by Al-Hussaini et al, Christensen et al and El-Qaderi and Taani [12-14]. The results of the present study showed that officials appeared to be interested in receiving more information on a substantial number of different dental issues. A significant number of officials wanted further information, so it can be safely concluded that officials had a positive attitude towards oral health.
Descriptive statistics Table 4 provides an overview of the descriptive statistics for the officials examined. Table 4: Descriptive Statistics Age Debris Index 20 0.83 Minimum 59 3.00 Maximum 36.2741 1.9910 Mean 9.3307 0.4734 Standard Deviation Standard Error 0.5208 0.0264 of Mean Calculus Index 0.66 3.00 1.8388 0.5122 0.0286 OHI-S 1.49 5.83 3.8298 0.8943 0.0499
Conclusion
Therefore, the study suggests and recommends that proper oral health education is required to improve attitude and behaviors of CRPF officials. Health authorities should implement oral disease prevention and health programs for CRPF officials. Prevention of oral disease is considered to be the most effective, acceptable and efficient method implicated to pave the way to oral health. Ideally, adults should be educated to prevent the initiation and progression of the spectrum of dental disease they are likely to encounter throughout life.
Clinical examination Table 5 provides an overview of the clinical examination based on the Simplified Oral Hygiene Index.
Discussion
The present study was aimed in gathering epidemiology data regarding oral health knowledge, attitude and behavior among CRPF
14
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experimentally induced periodontal inflammation in mice. European journal of oral sciences 2009, 117(3):238-247. Naveen N, Reddy C: Oral health status and treatment needs of police personnel in Mysore city, Karnataka. SRM University Journal of Dental Sciences 2010, 1(2):156-160. Singh A: Oral health knowledge, attitude and practice among NCC Navy Cadets and their correlation with oral hygiene in south India. Oral health & preventive dentistry 2009, 7(4):363. Petersen PE, Hoerup N, Poomviset N, Prommajan J, Watanapa A: Oral health status and oral health behaviour of urban and rural schoolchildren in Southern Thailand. International Dental Journal 2001, 51(2):95-102. Al-Hussaini R, Al-Kandari M, Hamadi T, Al-Mutawa A, Honkala S, Memon A: Dental health knowledge, attitudes and behaviour among students at the Kuwait University Health Sciences Centre. Medical Principles and Practice 2003, 12(4):260-265. Christensen LB, Petersen PE, Bhambal A: Oral health and oral health behaviour among 11-13-year-olds in Bhopal, India. Community dental health 2003, 20(3):153-158. El-Qaderi SS, Taani DQ: Oral health knowledge and dental health practices among schoolchildren in Jerash district/Jordan. International journal of dental hygiene 2004, 2(2):78-85.
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Choudhry Z, Rikani AA, Choudhry AM et al
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Open Access
Pharmacology, neurobiology and neurotoxicity of methamphetamine
Review
Zia Choudhry1,2,3*, Azadeh A Rikani1,2*, Adnan Maqsood Choudhry3, Sadaf Tariq4, Fozia Zakaria5,6, Saifal Anwar7, Muhammad Harris Laghari7, Kamran Haider8, Afia Ansar Shafiq9, Nusrat Jahan Mobassarah10
Abstract
Methamphetamine (MA) is a synthetic, powerfully addictive central nervous system stimulant drug, derived from amphetamine. It is used for both medicinal and illegal recreational proposes. MA causes an increase in activity, decrease in appetite, and a strong feeling of euphoria. MA exerts powerful effects on several neurochemical systems throughout the brainincluding dopamine, GABA and GLU. MA is highly lipophilic, which allows rapid and efficient transport across the blood-brain barrier and results in increased CNS penetration. It causes massive release of newly synthesized catecholamines, and blocks their reuptake from the synapse in several areas of the brain, including the nucleus accumbens, the prefrontal cortex and the striatum. This review presents: (i) an overview of the neurochemical and pharmacological effects of MA administration, (ii) a summary of the clinical effects of MA administration and (iii) evidence of MAs neurotoxic effects. Due to its toxic potential, It is very important to develop research strategies towards prospective designs looking at large cohorts of young people belonging to a risk group for recreational drug use. (El Med J 2:1; 2014) Keywords: Methamphetamine, Crystal Meth, Pharmacology, Neurobiology, Neurotoxicity
Introduction
Methamphetamine (MA) is a synthetic, powerfully addictive central nervous system (CNS) stimulant drug, derived from amphetamine (AMP) having a similar chemical structure [1]. It is used for both medicinal and illegal recreational proposes. MA causes an increase in activity, decrease in appetite, and a strong feeling of euphoria, also referred to as high or rush [1-3]. MA is a schedule II stimulant, i.e. a drug with high potential of abuse available only through a prescription that cannot be refilled. It has been used, for the treatment of: (1) narcolepsy, (2) attention deficit disorder and (3) obesity (short-term use), but this use is limited [3]. Medicinal MA or Desoxyn is available in pure 5-10mg tablet form. Illegal MA or speed is available on the street and is normally presented as a white, odorless, bitter-tasting crystalline powder that easily dissolves in water or alcohol. It can be in pure or adulterated form, which may be diluted with non-psychoactive /psychoactive drugs. In 1995 the DEA reported street MA to be 54% pure at gram/and ounce level [2-5]. Epidemiological studies reports 34 million global MA users [6]. The US 2000 Substance Abuse and Mental Health Services Administration (SAMSHA) National Household Survey on Drug Abuse showed: (i) 4% of people had some lifetime MA use, (ii) 1.1% had used it in the past year and (iii) 0.5% had used in the past month [7]. In 2002, 5.3% had used MA in their lifetime, 0.7% in the last year [8]. The frequency of emergency room visits due to acute MA intoxication data has shown a dramatic increase in the past few years [7]. MA is highly abused by different age groups [5]. Greatest use is among men between the ages of 19 and 40 years, especially college students and young professionals involved in the club scene or attending rave parties [3-5, 8-11]. Use of MA by gay and bisexual males is very high
[12]. MA dependence studies have shown that in certain populations, 50% to 75% of individuals with multiple AMP exposure develop dependence [13]. MA holds allure because it is cheap, easy to use and easily accessible. It has the potential to induce an abuse epidemic and become the most abused drug. This review will present: (i) an overview of the neurochemical and pharmacological effects of MA administration, (ii) a summary of the clinical effects of MA administration and (iii) evidence of MAs neurotoxic effects.
Neurochemical and Pharmacological effects

MA exerts powerful effects on several neurochemical systems throughout the brain. These include dopamine, GABA and GLU [14]. MA is highly lipophilic. This allows rapid and efficient transport across the blood-brain barrier and results in increased CNS penetration [1, 2, 15-18]. MA causes massive release of newly synthesized catecholamines (dopamine (DA), norepinephrine (NE) and serotonin (5HT)) and blocks their reuptake from the synapse in several areas of the brain, including the nucleus accumbens (NAc.), the prefrontal cortex (PFC) and the striatum [1, 9, 10, 19-24]. Studies with transgenic knockout mice have shown that AMP targets the dopamine transporter (DAT) which is critical for the reuptake of dopamine at the synapse and regulation of dopaminergic transmission [1, 2, 20, 21]. MA/ AMP: (i) act on DAT and block DA reuptake, (ii) reverse the direction of DA transport through the channel, (iii) displace DA from vesicular stores by occupying vesicular monoamine transporter (VMAT2), leading to increased DA release (iv) and also potently inhibit monoamine oxidase (MAO) [1, 2, 20, 25-27]. Collectively these effects increase the catecholamine concentration in the synapse and the brain. Studies have shown that alpha-methyl-tyrosine (AMT) attenuates, whereas reserpine potentiates the releasing action of AMP [27, 28]. Acute and prolonged MA exposure can elevate postsynaptic
Medicentres, Canada Jinnah Post Graduate Medical Centre, Pakistan 10 Institute of Integrated Cell-Material Science, Japan *Equal Contributors Correspondence: Adnan Maqsood Choudhry Email: am.choudhry@live.com
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Douglas Hospital Research Centre, Canada McGill University, Montreal, Canada 3International Maternal and Child Health Foundation, Canada 4Clifton Hospital, Pakistan 5Millbourne Mall Medical Centre, Primary Care Network, Canada 6Meadowbrook Medical Clinic, Primary Care Network, Canada 7University of Alberta, Canada
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16 nigrostriatal DA [14, 22]. Acute MA administration can result in increased dopamine turnover in the caudate nucleus, and changes in monoamines and peptides in the basal ganglia [14, 29, 30]. Acute administration of high and repeated doses of MA/AMP in monkeys, results in a transitory decline in DA in various brain regions. This might be due to temporary inhibition of tyrosine hydroxylase activity [28, 31-33] In rats, repeated administration of low dose AMP results in a reduction in the number of DA receptors, but chronic administration of AMP in young guinea pigs results in behavioral supersensitivity [34, 35]. Inconsistencies in rodent data can be explained by the observation that chronic AMP treatment induces persistent changes in dopamine receptor sensitivity. This yields increased striatal DA receptor sensitivity and decreased response of dopamine receptors in the NAc [36]. Pharmacological effects of MA depend on the dose and pattern of administration. In animal studies, different effects are observed in rodents with (i) administration of a single dose, (ii) repeated administration of low doses at long intervals, (iii) repeated administration of high doses at short intervals and (iv) high-dose runs superimposed on chronic low-dose administration [37]. In humans, MA is usually ingested, smoked, snorted, or injected intravenously. The amount administered at every dose varies depending on factors such as; (i) route of administration, (ii) individual tolerance and (iii) purity. However, smoked or injected MA results in immediate and intense euphoria which lasts for several minutes and Ingested or snorted MA results in a less immediate, less intense, but longer lasting high. Intranasal and oral users experience euphoria after 3-5 minutes and 15-20 min of administration, respectively. This high may last 812 hours. AMP has a longer duration of action than cocaine (813 hours versus 13 hours) and thus has higher addiction potential [1-3]. Nearly 45% of MA is metabolized to amphetamine, and both are excreted by the kidneys [1].
Pharmacology of methamphetamine
sional parasitosis. Psychiatric complaints are usually observed during (i) intoxication, (ii) withdrawal and (iii) long-term abstinence as residual symptoms. These can be exacerbated by reuse or by psychological stress in chronic users [39-42]. Abrupt cessation in chronic MA users results in withdrawal symptoms: (i) depression, (ii) dysphoria leading to lethal suicidal ideation, (iii) irritability and (iv) agitation [1, 43]. These last for days. Their increased severity and duration is believed to be the clinical manifestations of residual neurotoxicity from chronic MA abuse [44]. Most studies of neurotoxicity, however, have been performed in animal models [2].
Neurotoxicity of Methamphetamine
Neurotoxicity is commonly recognized as: (i) cell death, (ii) loss of presynaptic nerve terminals, and (iii) an increase in the expression of glial fibrillary acidic protein (GFAP), a marker of gliosis. MA neurotoxicity, as defined in this paper does not require (i) permanency of lesion, (ii) permanent loss of cell bodies and/or (iii) functional consequences. It refers to the potential of MA/AMP to produce long lasting reductions in the brain markers of DA and/or 5-HT axon terminals (i.e. a distal axotomy) which cannot be explained by MAs acute pharmacological effects or the neuroadaptive response to these pharmacological effects. The neurotoxic potential of MA towards brain DA was first reported in monkeys and rats. Repeated administration of high systemic doses of MA produced persistent reductions in brain markers of DA axons and axon terminals [45, 46]. Further studies research showed that: (i) MA damages brain 5-HT axons and axon terminals and (ii) MA and its analogs have the potential to damage DA and/or 5-HT axon terminals [44, 47, 48]. Miller et al showed that toxic doses of MA increase the expression of GFAP in the striatum of the C57BL/6J mice [49]. Similar effects were seen in other brain regions including cerebellum and hippocampus [14, 50]. Prolonged MA exposure causes neurotoxicity by apoptotic and neurotoxic mechanisms in striatal cells [10, 51]. This neurotoxicity is associated with a marked decrease in tyrosine hydroxylase (TH) activity, DA, and DAT binding sites in the striatum [45, 52]. MA use leads to neurotoxicity to both the DAT and SERT systems across a wide variety of mammalian species [2]. Studies have also shown that repeated doses of MA for several weeks show losses of the 5HT transporter (SERT), 5HT depletion, depletion of the major 5HT metabolite, 5-hydoxyindole acetic acid, and reductions in tryptophan hydroxylase (TPH) [47, 53]. Animal studies show that, MA treated animals develop long-lasting reductions in vesicular monoamine (VMAT) transporters [54-56]. Silver staining studies have shown that MA treatment results in axon terminal degeneration in the striatum [49]. Seen collectively, all the data mentioned above strongly suggest that MA produces a distal chemical axotomy of brain DA and 5-HT neurons. Evidence for Neurotoxicity
Animal studies
Clinical Effects
In human clinical studies, MA nave users show heightened alertness, attentiveness, and energy at low doses due to excessive stimulation of the sympathetic nervous system. Higher dose intoxication results in a sense of well-being, euphoria, and enhanced self-esteem that can approach hypomania and grandiosity [1]. Sexual activity and pleasure is increased with initial use, this decreases with time and use. Longer use is associated with impaired sexual functioning in males, a phenomenon known as "crystal dick" [12]. Adverse effects include restlessness, insomnia, bruxism and excessive weight loss due to appetite suppression [11, 38]. Fetal studies show that MA crosses the placenta and concentrates in fetal tissue. Further studies have shown decreases in: (i) visual recognition memory, (ii) IQ, (iii) mathematical and language skills, (iv) poor social adjustment, and (v) aggressive behavior in children with prenatal stimulant exposure [2]. Chronic use of MA results in catecholamine depletion, and leads to crash (almost lifeless state lasting 1-3 days). Marked psychiatric complaints such as psychotic and anxiety disorder-like states are associated with chronic MA abuse [39-42]. Obsession with minute details progressing to compulsive repetitious behaviors is also observed. Skin picking is very common and is accompanied by delu-
Since the 1970s, it has been observed that repeated administration of high doses of AMP/MA in animals leads to long-lasting depletions of central monoamine levels. These depletions are accompanied by changes in other neurochemical markers suggesting permanent neuron damage induced by AMP. Initially researchers investigated effects of MA administration in rhesus monkeys. The monkeys were
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17 More recent rat studies have shown degeneration of DA nerve fibers, loss of tyrosine hydroxylase, DA transporter, tryptophan hydroxylase, and loss of 5-HT-immunoreactive axons and axon terminals following a high dose of MA [10, 63, 64] Many studies have shown that MA use results in damaged striatal DA nerve terminals and DA cell bodies in substantia nigra (SN), pars compacta, and ventral tegmental area (VTA) [64]. These finding provided neuroanatomical evidence of neurotoxic effects of MA. Studies profiling duration of neurotoxicity in animals have shown long term neurotoxicity following administration of high doses MA, which spans from months in rats to years in monkeys [32]. The extent of dopaminergic and serotonergic neurotoxicity caused by AMP analogs depends on several factors including: (a) specific amphetamine analogs, (b) animal species, (c) mouse strain, (d) dosage and frequency of drug administration and (e) the ambient temperature of drug administration and the thermoregulatory effect of the drug [22, 49, 65]. Rats administered with 10 to 15 mg/kg MA every 6 hours for 5 doses, showed decreased TH activity and DA content in the neostriatum within 18 hours after the first dose [66, 67]. Administration of 5 mg/kg of MA, every 3 hours to Swiss Webster mice caused selective depletion of striatal DA, DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and DAT binding sites, with no evidence of 5-HT depletion [23]. MA induced neurochemical deficits persist for extended periods of time even after the drug is discontinued in rats and monkeys (4 years) [68, 69]. Thus, from the above mentioned data we can conclude that MA/AMP exert toxic effects in a variety of animal species and the MA-induced changes appear to be long-lasting and in some cases, may be permanent. Further experiments across species are necessary to elucidate the functional consequences of MA induced neurotoxicity.
Human studies
given low dose MA eight times per day. This dose was increased as they became tolerant to the debilitating effects of the drug. They were receiving a total dose of 52 mg/kg per day for a period of four to six months. They were sacrificed after six months and regional brain assay of transmitter levels was conducted. It was observed that MA treated monkeys had significantly reduced regional DA and NE levels with respect to control monkeys. This experiment clearly showed that the repeated administration of MA caused permanent neuron changes [22, 46, 57]. Further studies exploring species differences to MA administration showed, a marked decrease in nigral and striatal TH activity of rats following repeated doses of methamphetamine [45]. MA metabolism studies showed that rhesus monkeys, guinea pigs and humans metabolize MA through oxidative deamination, while rats metabolize the compound primarily through parahydroxylation [58]. In another study, Wagner et al administered high doses of MA to groups of rats and guinea pigs for a period of 30 days. The total daily dose of 50 mg/kg was divided into two subcutaneous injections spaced twelve hours apart. The animals were sacrificed two weeks following the last injection and regional brain assays were performed. Results showed that: (i) striatal DA levels of drug-treated subjects were depleted to about 50% of control values and (ii) these depletions appeared to be dose dependent [59]. These findings collectively showed that repeated administration of MA caused long-lasting depletions of central DA lasting six months in rhesus monkeys and two weeks in rodents. Wagner et al in the same experiment administered high doses of MA to another sub group of rats for 30 days. The rats were sacrificed 2, 4, or 8 weeks after the last injection and regional brain assay was done. Results showed significant depletion of striatal DA after all three waiting periods. No recovery was observed over the 8-week waiting period, and depletion was the same even after 6 months of the last injection [60, 61]. In another study, groups of rats received different daily doses of MA (12.5, 25, or 50 mg/kg per day) for 40, 20, or 10 days, respectively, such that each rat received the same total dose of MA. After 2 weeks from the last injection they were sacrificed. The results showed significant striatal DA depletions in rats receiving two higher doses of MA. In a counterpart to this study, groups of rats received 12.5, 25, 50, or 100 mg/kg per day for four days; all other parameters were the same. Similarly, rats receiving two larger daily doses of MA showed DA depletions [60]. These findings suggest that low clinical dose of MA even for prolonged periods resulted in minimal brain dysfunction and might not be associated with neuronal damage in humans. Further exploration in primates showed higher sensitivity to AMP compared to rodents. In recent studies researchers administered 2.0 mg/kg of AMP or MA to vervet monkeys in two IM injections, 4-hours apart. They observed substantial and long-lasting depletion of striatal DA after one month, but reported a partial recovery by three months [31, 62]. The 2.0 mg/kg dose used in these studies was considerably lower than those used in earlier rodent studies, but the magnitude of the DA depletion was quite comparable. This finding indicates that primates have higher AMP neurotoxicity sensitivity than rats. DA recovery was observed in monkeys, but not in the rodents, nor in the monkeys treated with the higher doses of MA. This might be because the MA doses administered to the vervet monkeys were comparatively low doses administered in just a few injections via a different route as compared to earlier rhesus monkey and rodent studies.
In 1990s researchers started looking at the effects of AMP/MA in humans. Wilson et al in 1996 conducted post-mortem analyses of brain tissue from humans who had abused AMP long before they had died and controls. They reported that, AMP abusers had deficits in DA, TH activity, and the DAT in the NAc, caudate, and putamen indicating that AMP abuse damaged the striatal DA system [70]. These findings might explain the rationale for the dose escalation and dysphoria that are frequently found in MA abusers, and also help us better understand persistent psychosis and paranoia reported by MA abusers [41, 70]. Neuropsychological studies in MA abusers have shown an association between severity of AMP dependence and poorer performance on measures of memory, attention and concentration [71, 72]. Preliminary neuroimaging studies in MA abusers suggest that MA may be neurotoxic. Magnetic resonance imaging (MRI) has showed cerebral infarcts and hemorrhage in some individuals who develop neurological complications after MA use [73, 74]. Two qualitative SPECT ([99mTc]-HMPAO) studies demonstrated multiple perfusion defects in both active users and in abstinent METH users [75, 76]. Recent PET studies have shown that there are long-lasting reductions in striatal DAT in previous MA or methcathinone abusers [48]. Lower DAT density in NAc, PFC, and the caudate/putamen of MA users is seen compared to controls. MA users also exhibited psychiatric symptoms, the severity of which was significantly correlated with the duration of MA use [77]. Volkow et al, showed significant
18 reduction in the DAT density of MA abusers in the caudate (28%) and putamen (21%), which was associated with motor slowing and memory impairment [78]. Chang et al, in 20 abstinent MA abusers, found deficits in working memory tasks compared to matched controls Perfusion magnetic resonance imaging (pMRI) studies of these subjects showed an increase in regional cerebral blood flow (rCBF) in several parietal regions and a decrease in rCBF in putamen regions. These changes indicate possible neuronal damage [79]. Using FDG-PET, Volkow et al showed decreased glucose metabolism in the thalamus and striatum, but increased metabolism in the parietal cortex of abstinent MA users [80]. Ernst et al, using Proton MR spectroscopy (1H MRS), reported decreased concentrations of N-acetyl (NAA) compounds in the frontal white matter and the basal ganglia, and increased choline (Cho) and myoinositol in the frontal cortex of abstinent MA abusers. These results suggest neuronal damage of frontal white matter and the basal ganglia; and gliosis of frontal cortex [19]. Other MRS studies have found: (i) evidence of abnormally low normalized NAA (i.e., NAA/Cr) levels and higher normalized Cho (i.e., Cho/Cr) levels in the anterior cingulum (ACC), with no evidence of such findings in the primary visual cortex in recently abstinent MA subjects, and (ii) evidence of low NAA in the anterior cingulum and a trend toward a low NAA value for the basal ganglia [1, 81]. These MRS findings are interpreted as consistent with neural damage to the frontostriatal regions. A functional MRI study of 10 METH users reported decreased prefrontal activation and elevated parietal activation during tasks that involved decision-making [82]. The imaging findings show that chronic MA abuse causes alterations in brain structure and function. Moszczynska et al, in a recent post mortem study compared dopamine levels in autopsied brain tissue of chronic MA users with those in patients with Parkinsons disease and in a control group. They reported reductions in mean dopamine levels in the MA users more in the caudate (61%) than in the putamen (50%) [83]. This finding of reduction in the caudate explains cognitive disturbances in chronic MA users. Chang et al, in a structural MRI study, recently reported both striatal and pallidal enlargement in abstinent MA abusers. MA abusers showed larger globus pallidus (9.6%) and putamen (9.9%) volumes compared to age and gender comparable controls. Chang has suggested structural enlargement might be due to inflammation and reactive gliosis induced by striatal injury caused by long term MA abuse [84]. Studies profiling duration of MA neurotoxicity in humans have been mixed, with conflicting findings. McCann et al in a PET study showed reduced striatal DAT density in chronic MA abusers after three years of abstinence. This suggests that chronic MA abuse leads to destruction of DA nerve terminals or cell bodies [48]. In a recent PET study, Volkow et al reported DAT normalization, but no change in cognitive deficits following DAT normalization in a paired study of five subjects that were initially examined in early abstinence and then in late abstinence (1.5 to 2 years). Volkow et al have suggested that DAT recovery might be due to increased arborisation or transporter protein up regulation on surviving DA terminals. This could lead to normalized ligand binding in imaging studies, but it may not be sufficient to fully restore the dopaminergic neurotransmission that subjects need in order to resume baseline neuropsychological functioning
[85]. This finding suggests that chronic exposure to methamphetamine does not necessarily cause permanent deficits or damage to the DA system in human users. Autopsy studies in MA abusers have shown marked decreases in striatal TH, DAT, and DA, but preservation of the presynaptic DA markers VMAT and DOPA decarboxylase without any signs of pigmented cell loss in the substantia nigra [70, 83]. Collectively, these findings suggest that MA-induced neurotoxicity leads to selective destruction/down-regulation of particular DA synthetic and functional proteins rather than to general destruction of DA terminals or cell bodies [70]. Thus, findings from neuroanatomical, neurochemical, neuropsychological, imaging and postmortem data support the conclusion that methamphetamine abuse causes damage to multiple transmitter systems that are distributed throughout the brain. Whether the ensuing damage is permanent or reversible over time has not yet been determined, but additional studies are needed to address this important issue. Mechanisms of Neurotoxicity The mechanisms involved in MA induced neurotoxicity are still unclear. Studies have implicated reactive oxygen species and the resultant oxidative stress. Studies investing the role of DA in inducing MA neurotoxic response, showed that pre-treatment with DA synthesis inhibitors, such as alpha-methyl-p-tyrosine (AMT) provide protection against MA induced neurotoxicity to both DA and 5HT systems. Similarly, treatment with L-DOPA restored the capability of MA to induce neurotoxicity. These findings provide evidence indicating that endogenous DA is required for MA induced neurotoxicity [44, 53, 86]. In addition, Seiden et al in a rat study showed that following a single injection of MA (100 mg/kg), 6-hydroxydopamine (0.39 +/0.31 nanograms/mg of tissue at 2 hr) was formed in the caudate nucleus. They also showed a 50% depletion of caudate dopamine at 2 weeks post MA administration. This suggest that MA treatment leads to the formation of 6-hydroxydopamine from endogenous dopamine which is responsible for the MA induced neurotoxicity to dopamine terminals [87]. Severity of MA-induced neurotoxicity studies showed that MA induced neurotoxic insult is influenced by the levels of: (i) reducing enzyme super-oxide dismutase (SOD), (ii) ROS-producing enzyme neuronal nitrous oxide synthase (nNOS), and (iii) antioxidant ascorbic acid [23, 65, 88]. Studies of VMAT-2 knockout mice showed, increased damage to DA system after MA treatment. This finding suggests that MA might redistribute DA from the synaptic vesicle (reducing environment) into the neurons cytoplasm (oxidizing environment). This redistribution would result is the generation of free radicals and reactive metabolites that likely lead to protein and cell membrane destruction [21]. Limitations of Methamphetamine Neurotoxicity Research
Animal studies
Animal research advocates have claimed animal models to be reliable models of human conditions as they are conducted in controlled laboratory environments. Considerable work has been done with regards to MA neurotoxicity in animals. These studies have reported consistent positive findings, showing that MA administration results in neurotoxicity. However, there are concerns with regards to the clinical relevance of these studies. These are: (i) interspecies differences in anatomy and physiology, (ii) differences in cause and course of MA neurotoxicity between human and animal, and (ii)
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19 reporting MA induced deficits lack sample size and/or both genders. These factors decrease the significance of their results and its application to the general MA user population. Inaccuracy in clinical history and history of drug use by the subjects is a serious limitation in interpreting human MA neurotoxicity results. Most of the studies are retrospective, relying on participants self-report. This makes it difficult to ascertain the amount and type of drug used by the participants, thus reducing the reliability of the findings. Retrospective studies also lack in their ability to determine differences between control and user groups prior to MA use. Control groups are important in assessing the extent of neurotoxicity caused by MA. Many studies have used poorly matched control groups that include nonusers, and poly-drug users with overall moderate use patterns than the poly-drug MA users. Studies have shown illegal/street MA to be impure as it is diluted /cut with other psychoactive active substances (ketamine, dextromethorphan, AMP, MDMA, ephedrine and salicylates), which makes it very difficult to confirm whether the neurotoxic effects exhibited by MA abuser are MA specific or are the cumulative effects of other psychoactive substances. Recently, brain imaging studies have provided much needed insight in the structural and functional aspects of the brains of living MA abusers. These studies provide important information on how MA changes the structure and functioning of specific brain regions. However, limitations of this technique in humans make it difficult to determine conclusively that brain cells are damaged or destroyed as result of MA abuse. Another important limitation observed in some brain imaging studies was that neuropsychological and cognitive testing was performed in MA abusers and not in controls. Thus, it is not possible to determine the extent to which MA abusers differed from controls. Thus, human MA neurotoxicity research has a number of significant limitations which impair our understanding of the extent of MA induced neurotoxicity. At present, we are unable to completely rule out the influence of comorbid factors. More methodologically sound research is required to fully understand the extent and duration of neurotoxicity induced by MA. Remaining challenges Since 1976, significant progress has been made in elucidating the neurobiology of MA/AMP, but still a number of challenges are remaining. The exact mechanism of MA induced neurotoxicity is very elusive. Studies have shown the possible involvement of transporter and temperature in the expression of MA induced toxicity of the DA and 5HT neurons [49]. However, studies in this area havent explored the resistance of NE neurons to this toxic effect. NE neurons exhibit similar properties as DA and 5HT neurons, with the exception of resisting MA/AMP induced neurotoxicity. Studies exploring differences between DA and NE neurons may help in identifying features of DA neurons that predispose them to MA/AMP neurotoxicity. Studies have shown that DA and 5HT cell bodies are spared from MA /AMP neurotoxicity, even in the worst case of MA administration. Research in the area of neuron vitality should explore factors vital to the health of the axons and axon terminals. This would help in identifying candidate processes involved in AMP-induced injury. If candidate genes important to axonal integrity are identified, focused and testable hypotheses regarding mechanisms underlying neurotoxicity could be generated using present advances in genomics and proteomics.
stress (due to caging, social disruption, restraint, transport, and repeated handling) experienced by animals in laboratories. These factors can invariably alter research results. Many MA neurotoxicity studies have shown disparity across different species with regards to (i) MA exposure, (ii) severity of MA induced insult, (iii) duration to which toxic effects are observed, and (iv) pattern of recovery from MA induced neurotoxic insult. Most rodent studies have used an acute regimen of a high dose of MA/AMP given within 8-72 hours. This is in complete contrast to the human pattern of MA abuse which extends over a period of weeks, months and years. Scientist involved in rodent studies have advocated the use of acute model claiming its relevance to the final outcome i.e. MA induced neurotoxicity. Skeptics of this model are of the opinion that patterns of abuse influence the degree of neurotoxic damage. Explanation given by animal researchers to this concern is that acute dosing model in rodents may resemble the binge pattern of drug abuse in humans. The issue of sensitivity differences to psychoactive drugs is another important concern in MA animal model research. It has been observed that sensitivity differences do exist in rodents and humans: the dosage of AMPs given to rodents exceeds the dosage abused by humans. These dose differences are explained by difference in diverse pharmacokinetics and pharmacodynamics of the drug in rodents and humans. Animal model studies are not good predictors of clinical symptoms/behavioral effects due to AMP/MA neurotoxicity, as animals cannot reveal subjective effects (headache or psychological effects) post MA administration. Thus, animal studies have limited functional significance in their ability to predict MA neurotoxicity in humans.
Human studies
Since the 1990s researchers have been looking at the effects of AMP/MA in humans. Many studies have been conducted looking at the neuroanatomical, neurochemical, neuropsychological, imaging and postmortem changes associated with MA abuse. They have shown that MA abuse causes damage to multiple transmitter systems, distributed throughout the brain. Although these studies showed positive findings, they have significant methodological limitations. Earlier studies have failed to capture vital data on: (i) the parallel use of other drugs, (ii) length of abstinence periods. Drug specificity is an important parameter in assessing neurotoxicity. Polydrug abuse (alcohol, cannabis, cocaine) in human MA abusers makes it difficult to delineate the specific neurotoxic effects of MA. Thus data from studies, utilizing poly-drug abusers and reporting neurotoxic effects of AMP/MA is not very credible, as it does not show the specific effects of MA on human subjects. Data from studies examining the effects of low prescribed MA doses (for minimal brain dysfunction or reduction in food intake) can help in understanding specific deleterious effects on the dopaminergic system caused by MA. Length of abstinence periods is important in assessing duration of MA induced neurotoxicity and recovery. Failure to capture this data impairs our ability to interpret the long-term effects of MA. Recent studies also exhibit methodological weaknesses without an obvious solution to date, i.e. (i) inadequate MA dependent group, (ii) questionable reliability of statements/histories by the subjects themselves on their current and earlier drug abuse habits, (iii) difficulties recruiting adequate control groups, (iv) uncertainties related to the precise chemical composition of cut MA. Robust sample size is important in elucidating clinical neurotoxic effects of MA. Many studies
20 Different species respond differently to MA insults. Murine research has shown increased DA toxicity (possible vulnerability) and no or little 5-HT toxicity (possible resistance) following MA/AMP administration. Further analysis of a possible selective response mechanism could help in: (i) predicting the effects of AMP in other animal species, and (ii) may also help in understanding the mechanisms of AMP toxicity. Primates exhibit long-lasting toxicity, whereas rodents tend to recover from AMP analogue neurotoxicity over time. Similarly, Volkow et al (2001) have shown DAT recovery in human MA abusers with protracted abstinence [85]. Exploration of factors involved in the duration of toxic injury across different species, could help in devising methods for reversing injury. Studies exploring possible neuronal recovery factors would have great implications for a variety of neurodegenerative conditions. These studies should also define possible recovery characteristics if it occurs (reinstatement of original, normal neuronal pathways/aberrant re-innervation) and its consequences. Functional consequences are integral to MA neurotoxicity research. Animal studies have discussed abnormal dopamine-mediated behaviors following MA/AMP -induced DA and 5-HT neurotoxicity [89]. Functional research in this area could provide potential clues to: (i) similar damage in humans, and (ii) further findings in the role of DA and 5-HT in normal behaviors. Many researchers have shown evidence of MA-induced DA neurotoxicity in humans [48, 77, 85]. There are still grey areas in this field with regards to the (i) doses and drug regimens needed to produce neurotoxicity in humans, (ii) the functional consequences of neurotoxicity, and (iii) potential long-term clinical implications of MA toxicity (vulnerable to Parkinsons disease with advanced age). Furthermore, epidemiological studies focusing on the prevalence of a variety of neurologic and psychiatric conditions (e.g. movement disorders, depression, anxiety disorders, sleep disorders) in individuals exposed to these drugs relative to the general population are in order.
course and features of recovery and (iii) MAs involvement in neurodegenerative diseases (Parkinsons disease). It is very important to develop research strategies towards prospective designs, looking at large cohorts of young people (not MA users) belonging to a risk group for recreational drug use (attendants of rave parties/ bisexual and gays). Following-up on them over years and re-examining them, recording drug histories using psychometric instruments and carrying out neuropsychological tests. These efforts, could help in better understanding of (i) relation between drug use and sub-clinical psychological symptoms or neuro-cognitive failures and, (ii) questions regarding progression, persistency and reversibility (if any) of the MA induced alterations. There will always be debate about ethical aspects of such studies, but they are definitely needed to determine the answers to the important questions around possible long-lasting adverse effects of MA on the human brain.
Competing interests: The authors declare that no competing interests exist. Received: 8 October 2013 Accepted: 12 January 2014 Published Online: 12 January 2014
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Conclusions & Future directions

MA exerts powerful effects on several neurochemical systems throughout the brain including dopamine, GABA and GLU. It causes a strong feeling of euphoria, which creates a potential for addiction and abuse. Epidemiological data suggests a progressive increase in the MA epidemic all over the world, with its use highest in younger male cohorts. MA has a longer half-life: this may produce exceptionally long-lasting toxic effects. Abrupt cessation results in depression, dysphoria, suicidal ideation, irritability, and agitation. Neuro-cognitive impairments that affect information processing, verbal memory and other domains of cognition are commonly seen in MA abusers. MA neurotoxicity research has shown a number of factors influencing the nature and degree of toxicity. These include (i) dose, (ii) dosing interval, (iii) route of administration, and (iv) temperature. Up-todate neurotoxicity research shows that MA abuse causes: (i) serious cognitive impairments in humans, and (ii) DA and 5HT neurons damage in rodents. Focused research elucidating functional consequences of MA induced toxicity in animals and humans is needed. Concentrated efforts should focus on (i) mechanisms by which MA leads to selective DA and/or 5-HT damage, (ii) mechanisms, time
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Vol 2, No 1
Sajjad A
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Open Access
Aqsa Sajjad1
Opinion and Debate
Abstract
The World Health Organization (WHO) defines health as a state of complete physical, mental and social wellbeing and not merely the absence of disease and infirmity. Health issues are higher on the international work list and getting better health of people is a central issue in development. They are especially relevant for the developing world, where they have a higher mortality rate due to limited access to healthcare and social protection. The importance of these basic causes of health must, therefore, be composed into development policies. (El Med J 2:1; 2014) Keywords: Health Issues
Introduction
Health is a state of being free from physical and psychological disease, illness or malfunction. The World Health Organization (WHO) defines health as a state of complete physical, mental and social wellbeing and not merely the absence of disease and infirmity. Generally, it is increasingly observed that health is maintained and improved not only through the application and advancement of health sciences, but also through the struggle and the lifestyle of the individuals and society. The main elements of health, such as the social, economic and physical environment, and the persons individual characteristics and behavior help to build up and promote the quality of life and health status [1]. Health issues are higher on the international work list and getting better health of people is a central issue in development. They are especially relevant for the developing world, where they have a higher mortality rate due to limited access to healthcare and social protection. The importance of these basic causes of health must, therefore, be composed into development policies.
With 9.4 million new cases, tuberculosis kills 1.7 million people each year [2]. 225 million acute illnesses are caused by malaria and over 780,000 deaths annually are attributed to the disease [2]. In 2008, 164,000 people, mostly children under the age of 5, died from measles even though effective immunization costs less than 1 US dollar and has been available for more than 40 years [2]. Every year, 1.6 million people still die from pneumococcal diseases, making it the number one vaccine preventable cause of deaths worldwide. Most of the victims are children [2]
Factors
Poverty is a major problem. Although health facilities have improved in developing countries, this has created a health divide between those who can afford them and those who cannot. In addition, a huge number of people does not have access to these facilities. This leads to a vicious cycle: poverty aggravates poor health which in turn makes it difficult to overcome of poverty. Most of the worlds health care systems depend on the most inequitable methods for financing health care services. Over 100 million people around the world are pushed into poverty each year due to catastrophic health care expenditure [3]. Food and nutrition are also fastidious factors that influence the health of poor people. Almost 800 million people in developing countries are chronically undernourished. This in turn affects the immune system, increase the severity of diseases and thereby leading to child mortality [4]. Lifestyle changes such as tobacco and alcohol use along with injuries now contribute an increasing share of deaths. NCDs, such as cancer, circulatory systems aliments, psychiatric disorders, infectious disease and child malnutrition are major contributors to the global disease burden. Other risk factors such as tobacco, insufficient physical activity, unhealthy diet, raised blood pressure, obesity, raised cholesterol, cancer-associated infections also contribute significantly. An analysis of existing data on mental illness reveals that depression, epilepsy, schizophrenia and substance abuse are responsible for ris-
Global Health Issues

Although there have been improvements in health since 1950, many challenges still remain that require urgent attention:

1 billion people lack access to health care systems [2]. 36 million deaths each year are caused by non-communicable diseases (NCDs) such as cancer, diabetes, cardiovascular diseases and chronic heart diseases. Over 56 million deaths occur each year worldwide [2]. Cardiovascular diseases (CVDs) are the most common condition causing death globally. An estimated 17.5 million people died from CVDs in 2005, representing 30% of all global deaths. Over 80% of CVDs deaths occur in low and middle income countries [2]. Over 7.5 million children under the age of 5 die from malnutrition and mostly preventable disease each year [2]. 6.7 million people died as a result of infectious diseases in 2008 [2]. AIDS/HIV has spread rapidly, UNAIDS estimates 33.4 million living with HIV, 2.7 million new infections of HIV and 2 million deaths from AIDS [2].
Ziauddin Medical University, Pakistan Correspondence: Aqsa Sajjad Email: aqsasajjad23@live.com

24 ing suicide rates in many parts of the world. Due to this, mental illness has been frequently attributed to the upsurge of poverty, political instability, violence, unemployment and other social evils.
Conclusion
To conclude, we need to focus on overcoming structural barriers of health. Inadequate medical diagnosis and inept treatment squander many resources that lead to additional suffering and mortality. Preventive intervention that achieves health equity for all people worldwide is needed. Although there is a decrease in mortality and a consequent increase in life expectancy, strong plans need to be made to overcome current and future challenges.
Competing interests: The authors declare that no competing interests exist. Received: 2 December 2013 Accepted: 5 December 2013 Published Online: 9 December 2013
Approaches

To promote growth, budget should be governed by social policies in areas such as education, labor, and primary health care. Investing in education (universal primary education) helps to diminish health inequalities and furnishes people to obtain health literacy, better jobs, preventive health care measures and avoid risky health behavior. To promote primary and essential health care, the slogan of health for all should be strictly followed. Non-governmental organization should work in conjunction with the government to deliver health services through different segments of society. Mobilizing community resources is the modern way to upgrade the health of people. Approaches include comprehensive training of community-based health workers, involvement of traditional leaders and local development of health services [3]. Establishing health financing approaches through appropriate taxation or insurance helps in promoting roper utilization of health care services.
References
1. Report of the Consultative Forum Subgroup on Population Health/Health Promotion [http://www.dohc.ie/issues/health_strategy/reppop.pdf?direct=1] 2. Global Health Issues [http://www.globalissues.org/issue/587/health-issues] 3. Primary Health Care, Now More Than Ever | WHO World Report 2008 [http://www.who.int/whr/2008/whr08_en.pdf] 4. Poverty and Health in Developing Countries: key actions [http://www.oecd.org/development/povertyreduction/33965811.pdf]
Vol 2, No 1
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Open Access
Essay
Zia Choudhry1,2,3*, Azadeh A. Rikani1,2*, Adnan Maqsood Choudhry3, Sadaf Tariq4, Fozia Zakaria5,6, Muhammad Waheed Asghar7, Muhammad Khan Sarfraz8, Numan Majeed8, Huma Ikram9, Nusrat Jahan Mobassarah10
Abstract
Diverse proteins catalyze membrane fusion reactions. These mediate recognition of the membranes for fusion and pull the membranes close together to destabilize the lipid/water interface and to initiate mixing of the lipids. In the nervous system, membrane fusion is vital for neuroexocytosis, neuro transmitter release and chemical synaptic transmission. Three neuronal soluble NSF (N-ethyl-maleimide-sensitive fusion protein) attachment receptor (SNARE) proteins exist, namely: (i) vesicle associated membrane protein (VAMP-2), also called synaptobrevin; (ii) 25 kDa synaptosome-associated protein (SNAP-25); and (iii) syntaxin 1A (STX1). The SNAREs are involved in the neuronal membrane fusion process. (El Med J 2:1; 2014) Keywords: SNARE Proteins, Membrane fusion, Nervous system
Introduction
Diverse proteins catalyze membrane fusion reactions. These mediate recognition of the membranes for fusion and pull the membranes close together to destabilize the lipid/water interface and to initiate mixing of the lipids [1]. In the nervous system, membrane fusion is vital for neuro-exocytosis, neurotransmitter release and chemical synaptic transmission [2, 3]. Three neuronal soluble NSF (N-ethyl-maleimide-sensitive fusion protein) attachment receptor (SNARE) proteins exist, namely: (i) vesicle associated membrane protein (VAMP2), also called synaptobrevin; (ii) 25 kDa synaptosome-associated protein (SNAP-25); (iii) and syntaxin 1A (STX1). The SNAREs are involved in the neuronal membrane fusion process [4, 5]. VAMP-2 is a v-SNARE (v stands for vesicle) and STX1 is a t-SNARE (t stands for target). Both of these are single-pass transmembrane proteins in the vesicular and plasma membrane. SNAP-25 is a t-SNARE and contains two SNARE domains flanking a region of palmitolyated cysteines which associates it with the plasma membrane [4, 5]. SNAREs contain conserved heptad repeat sequences that form coiled-coil structure and are thought to promote synaptic vesicle exocytosis via SNARE complex formation [6, 7]. In this brief review the literature supporting the following hypotheses will be presented: (i) SNARE proteins are necessary for membrane fusion; (ii) SNARE pairing is sufficient for in vitro membrane fusion. Furthermore, the application of the SNARE mediated membrane fusion model to membrane fusion in vivo will also be discussed.
(i) a simple vesicle docking mechanism between vesicle and target exists; (ii) NSF and SNAPs are components of a vesicle fusion apparatus; (iii) SNARE proteins provide vesicle-to-target specificity thus help in membrane fusion [8]. Experimental data form numerous in vitro neurotoxin studies conducted to assess neuro-exocytosis clearly provides evidence supporting a direct correlation between SNARE protein proteolysis and inhibition of neurotransmitter release. Clostridium neurotoxins (CNT) selectively cleave SNARE proteins and abolish synaptic transmission. Tetanus neurotoxin (TeNT) and botulinum neurotoxin (BoNT)-A, B, C are zinc endoproteases which cleave VAMP, syntaxin and SNAP-25 respectively [9-11]. Many researchers observed cells intoxicated with TeNT or BoNT in which SNARE proteins were cleaved in synaptosomes. This resulted in a corresponding inhibition in neuro-exocytosis [12, 13]. This finding supports the notion that SNARE proteins are necessary in the membrane fusion process. This suggests that SNARE proteins inhibited by CNTs results in the negative regulation of neurotransmitter release. In accordance with this study, peptides present at the cleavage site of VAMP inhibited TeNT and BoNT/B in Aplysia and squid neurons [14, 15]. Furthermore, VAMP-specific antibody inhibits TeNT and BoNT/B, thereby preventing cleavage of SNAREs and inhibition of neurotransmitter release in Aplysia neurons [16]. All these experimental findings suggest that SNAREs are responsible for membrane fusion and neurotransmitter release. Drosophila lacking VAMP or syntaxin showed normal docking of vesicles at active zones and a complete block of synaptic transmission. Broadie et al investigated the level of this blockade. Ultra-structural analyses revealed that docked vesicles were mature and functional without VAMP; this may be due to spontaneous vesicle fusion. Vesicle fusion triggered in the absence of syntaxin may be due to hyperosmotic saline. Schulze et al demonstrated that drosophila mutants of syntaxin-1A gene had an alteration in morphology and secretion.
Are SNARE proteins necessary for membrane fusion?

Sollner et al. developed a cell free assay system for Golgi membrane fusion. They used an affinity purification procedure utilizing NSF and SNAP proteins to isolate SNAREs from bovine brain. Four principal proteins were isolated, one in the vesicle and another in the plasma membrane. This finding suggests:
Douglas Hospital Research Centre, Canada McGill University, Canada 3International Maternal and Child Health Foundation, Canada 4Clifton Hospital, Pakistan 5Millbourne Mall Medical Centre, Primary Care Network, Canada 6Meadowbrook Medical Clinic, Primary Care Network, Canada 7University of Alberta, Canada
1 2
Services for Public Health and Research, Pakistan Jinnah Postgraduate Medical Centre, Pakistan 10 Kyoto University, Japan *Contributed equally to this work Correspondence: Adnan Maqsood Choudhry Email: am.choudhry@live.com
8 9
26 Electrophysiological recordings in partial loss-of-function mutants indicated lack of endogenous synaptic transmission at the neuromuscular junction and an 80% reduction of evoked transmission. In complete absence of syntaxin-1A gene, subtle morphological defects in the nervous system were observed and this affected secretory events, resulting in complete inhibition of neurotransmitter release. These combined results provide evidence that syntaxin and VAMP play key roles in non-neuronal secretion, membrane fusion and neurotransmitter release, and that syntaxin is absolutely required for evoked neurotransmission [17, 18]. Nickel et al used a novel complementary oligonucleotide assay system to demonstrate membrane bilayer fusion, mediated by vSNAREs and t-SNAREs. These were initially present in separate populations of liposomes but when mixed, they fused with high efficiency at a physiologically meaningful rate. This showed that SNARE proteins are sufficient to mediate complete membrane fusion accompanied by mixing of luminal content. The experiment also revealed that SNARE-mediated membrane fusion did not compromise the integrity of liposomes [19]. Thus SNAREs in an isolated system can fuse membranes.
concluded that SNARE proteins are topologically restricted by design to function either as a v-SNARE or as part of a t-SNARE complex [24, 27].
Is SNARE pairing/complex sufficient for membrane fusion in vivo?

Washbourne et al generated a mouse model lacking the SNAP-25 gene. This resulted in embryonic lethality of the mutant mice (death at E17.5-18.5). SNAP-25 null embryos had abolished evoked synaptic exocytosis/transmission at neuromuscular junctions and central synapses. These results show that SNAP 25 is enough for Ca++ evoked synaptic transmission and neurotransmitter release [23]. Furthermore, Schoch et al showed that VAMP2 homozygous knockout mice died immediately after birth, and spontaneous synaptic vesicle fusion was decreased by 10-fold, but fast Ca++ triggered fusion by 100fold. Thus, VAMP2 is suggested to function in catalyzing fusion reactions and stabilizing fusion intermediates but is not absolutely required for synaptic fusion [28]. In a recent study by Deak, et al it was suggested that VAMP2 is a crucial factor in fast recycling of synaptic vesicles. After depletion of the readily releasable vesicle pool, replenishment of the pool is delayed in VAMP2-null mice. This is because the shape and size of vesicles are altered in the absence of VAMP2. Finally, mouse gene Syn4 (syn1 in humans), which is a widely expressed t-SNARE, is essential for early embryonic development since Syn4-null embryos die before E7.5. As observed in the gene knockout studies in mice, SNARE proteins and SNARE complex play an integral role in membrane fusion, neurotransmitter release and consequently, synaptic activity. Absence of SNAREs results in embryonic lethality and the inability to exert individual or collective effects of SNARE proteins. These results are in accordance with the experimental outcomes of the aforementioned in vitro studies performed on SNARE proteins and the SNARE complex.
Is SNARE pairing/complex sufficient for membrane fusion in vitro?

The SNARE complex consists of four helices, in which one is from the v-SNARE, VAMP and three are from the t-SNAREs, SNAP-25 and syntaxin [20, 21]. Rothman and coworkers used an in vitro method to study vesicle fusion by measuring lipid content mixing from two separate liposomal vesicles, each one reconstituted with v-SNARE and tSNAREs, respectively. They observed the v-SNARE and t-SNARE proteins reconstituted into separate lipid bilayer vesicles assembled into SNARE pins/SNARE complexes linking two membranes. This linkage led to spontaneous fusion of the docked membranes at physiological temperature. This data implied that SNARE pins/SNARE complexes are the most integral machinery for cellular membrane fusion and promotes fusion between lipid vesicles [22-24]. McNew et al used an in vitro method to test v-SNAREs encoded in the yeast genome for their ability to trigger fusion by partnering with t-SNAREs that marked the Golgi, the vacuole and the plasma membrane. It was observed that the pattern of cellular membrane flow is encoded and recapitulated by its isolated SNARE proteins. This finding proposes that vesicles dock specifically to target membranes when cognate SNAREs link-up, and that the assembly of these SNARE complexes initiates the mechanism of bilayer fusion [24, 25]. In yeast there are 4 proteins orthologous to the SNARE proteins, namely: Sed5, Bos1, Sec22 and Bet1 [26]. Parlati F et al in an in vitro study explored the effects of anchoring arrangement of the four helices of the yeast SNARE complex and their ability to mediate fusion. Two populations of phospholipid bilayer vesicles were reconstituted, with the individual SNARE proteins distributed in all possible combinations between them. Interestingly, one out of the eight non-redundant permutations of four subunits distributed over two vesicle populations, resulted in membrane fusion. Fusion only occurred when the v-SNARE Bet1 was on one membrane and the syntaxin heavy chain Sed5 and its two light chains, Bos1 and Sec22, were on the other where they constituted a functional t-SNARE. Thus, it was
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Conclusion
Current research has provided a more progressive more logical molecular model of SNARE-mediated membrane fusion. This recent outburst of knowledge with regards to the SNAREs, the SNARE model and the SNARE mediated membrane fusion is due to new research both in vitro as well as in vivo. However, till now many things about this model remain mysterious. More research is required to ascertain the principle of membrane fusion utilized by the SNAREs. This new research would have far reaching effects as it can help us better understand the phenomenon of membrane fusion. SNARE proteins can be used to develop artificial fusion systems which can be used for drug delivery in vivo. In addition to a greater understanding of the mechanistic of SNARE proteins and their effects lipid membranes, we need to explore the key regulatory mechanisms of in vitro membrane fusion, such as Ca++ and Rab-GTPase. More in vivo studies are required in mammalian knockouts to better understand this mechanism in a living model.
Competing interests: The authors declare that no competing interests exist. Received: 1 November 2013 Accepted: 7 December 2013 Published Online: 7 December 2013
27
16. Poulain B, Rossetto O, Deloye F, Schiavo G, Tauc L, Montecucco C: Antibodies against rat brain vesicle-associated membrane protein (synaptobrevin) prevent inhibition of acetylcholine release by tetanus toxin or botulinum neurotoxin type B. Journal of neurochemistry 1993, 61(3):1175-1178. 17. Broadie K, Prokop A, Bellen HJ, O'Kane CJ, Schulze KL, Sweeney ST: Syntaxin and synaptobrevin function downstream of vesicle docking in Drosophila. Neuron 1995, 15(3):663-673. 18. Schulze KL, Broadie K, Perin MS, Bellen HJ: Genetic and electrophysiological studies of Drosophila syntaxin-1A demonstrate its role in nonneuronal secretion and neurotransmission. Cell 1995, 80(2):311-320. 19. Nickel W, Weber T, McNew JA, Parlati F, Sollner TH, Rothman JE: Content mixing and membrane integrity during membrane fusion driven by pairing of isolated v-SNAREs and t-SNAREs. Proceedings of the National Academy of Sciences of the United States of America 1999, 96(22):12571-12576. 20. Sutton RB, Fasshauer D, Jahn R, Brunger AT: Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution. Nature 1998, 395(6700):347-353. 21. Lonart G, Sudhof TC: Assembly of SNARE core complexes prior to neurotransmitter release sets the readily releasable pool of synaptic vesicles. The Journal of biological chemistry 2000, 275(36):27703-27707. 22. Weber T, Zemelman BV, McNew JA, Westermann B, Gmachl M, Parlati F, Sollner TH, Rothman JE: SNAREpins: minimal machinery for membrane fusion. Cell 1998, 92(6):759-772. 23. Washbourne P, Thompson PM, Carta M, Costa ET, Mathews JR, Lopez-Bendito G, Molnar Z, Becher MW, Valenzuela CF, Partridge LD et al: Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nature neuroscience 2002, 5(1):19-26. 24. Xue M, Zhang B: Do SNARE proteins confer specificity for vesicle fusion? Proceedings of the National Academy of Sciences of the United States of America 2002, 99(21):13359-13361. 25. McNew JA, Weber T, Parlati F, Johnston RJ, Melia TJ, Sollner TH, Rothman JE: Close is not enough: SNARE-dependent membrane fusion requires an active mechanism that transduces force to membrane anchors. The Journal of cell biology 2000, 150(1):105-117. 26. Novick P, Field C, Schekman R: Identification of 23 complementation groups required for post-translational events in the yeast secretory pathway. Cell 1980, 21(1):205-215. 27. Parlati F, McNew JA, Fukuda R, Miller R, Sollner TH, Rothman JE: Topological restriction of SNARE-dependent membrane fusion. Nature 2000, 407(6801):194-198. 28. Schoch S, Deak F, Konigstorfer A, Mozhayeva M, Sara Y, Sudhof TC, Kavalali ET: SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science (New York, NY) 2001, 294(5544):1117-1122.
References
1. Jahn R, Lang T, Sudhof TC: Membrane fusion. Cell 2003, 112(4):519-533. 2. Lledo PM, Zhang X, Sudhof TC, Malenka RC, Nicoll RA: Postsynaptic membrane fusion and long-term potentiation. Science (New York, NY) 1998, 279(5349):399-403. 3. Chen YA, Scheller RH: SNARE-mediated membrane fusion. Nature reviews Molecular cell biology 2001, 2(2):98-106. 4. Lin RC, Scheller RH: Mechanisms of synaptic vesicle exocytosis. Annual review of cell and developmental biology 2000, 16:19-49. 5. Duman JG, Forte JG: What is the role of SNARE proteins in membrane fusion? American journal of physiology Cell physiology 2003, 285(2):C237-249. 6. Rossi V, Banfield DK, Vacca M, Dietrich LE, Ungermann C, D'Esposito M, Galli T, Filippini F: Longins and their longin domains: regulated SNAREs and multifunctional SNARE regulators. Trends in biochemical sciences 2004, 29(12):682-688. 7. Weimbs T, Mostov K, Low SH, Hofmann K: A model for structural similarity between different SNARE complexes based on sequence relationships. Trends in cell biology 1998, 8(7):260-262. 8. Sollner T, Whiteheart SW, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE: SNAP receptors implicated in vesicle targeting and fusion. Nature 1993, 362(6418):318-324. 9. Banerjee A, Kowalchyk JA, DasGupta BR, Martin TF: SNAP-25 is required for a late postdocking step in Ca2+-dependent exocytosis. The Journal of biological chemistry 1996, 271(34):20227-20230. 10. Lawrence GW, Foran P, Mohammed N, DasGupta BR, Dolly JO: Importance of two adjacent C-terminal sequences of SNAP-25 in exocytosis from intact and permeabilized chromaffin cells revealed by inhibition with botulinum neurotoxins A and E. Biochemistry 1997, 36(11):3061-3067. 11. Xu T, Binz T, Niemann H, Neher E: Multiple kinetic components of exocytosis distinguished by neurotoxin sensitivity. Nature neuroscience 1998, 1(3):192200. 12. Blasi J, Chapman ER, Yamasaki S, Binz T, Niemann H, Jahn R: Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC1/syntaxin. The EMBO journal 1993, 12(12):4821-4828. 13. Capogna M, McKinney RA, O'Connor V, Gahwiler BH, Thompson SM: Ca2+ or Sr2+ partially rescues synaptic transmission in hippocampal cultures treated with botulinum toxin A and C, but not tetanus toxin. The Journal of neuroscience : the official journal of the Society for Neuroscience 1997, 17(19):7190-7202. 14. Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, Montecucco C: Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc. The EMBO journal 1992, 11(10):3577-3583. 15. Hunt JM, Bommert K, Charlton MP, Kistner A, Habermann E, Augustine GJ, Betz H: A post-docking role for synaptobrevin in synaptic vesicle fusion. Neuron 1994, 12(6):1269-1279.
28
Open Access
Atta Abbas1, Farrukh R Ahmed2
Essay
Abstract
Icosapent ethyl is a lipid regulating drug which was recently given a green signal from FDA. It is used as an adjunct drug along with diet control to lower triglycerides in those patients who present with very high levels. It lowers the production and/or secretion of very low-density lipoprotein triglycerides (VLDL-TG) in liver and augments triglyceride clearance from VLDL particles. (El Med J 2:1; 2014) Keywords: Icosapent ethyl, Hypertriglyceridemia, Very low-density lipoproteins
Introduction
Icosapent ethyl (IE) is a lipid regulating drug which was recently given a green signal from FDA. It is used as an adjunct drug along with diet control to decrease triglycerides (TG) in those patients who present with very high levels. It lowers the production and/or secretion of very low-density lipoprotein triglycerides (VLDL-TG) in liver and augments TG clearance from VLDL particles. The exact mechanism is still unknown. However, probable mechanisms consist of inhibition of acyl-CoA and 1,2-diacylglycerol acyltransferase (DGAT); increased -oxidation, decreased hepatic lipogenesis and increasing the activity of plasma lipoprotein lipase. The drug is de-esterified throughout its journey after oral administration and the active metabolite eicosapantaenoic acid (EPA) is absorbed by means of the thoracic duct lymphatic system. It takes approximately 5 hours for EPA to reach its peak plasma concentration following an oral dose. EPA has a mean volume of distribution of approximately 88 liters at steady-state and the bulk of EPA that circulates in plasma is normally integrated in triglycerides, cholesteryl esters, phospholipids and less than 1% is in the form of free un-esterified fatty acid. Hence, more than 99% of EPA in un-esterified form is bound with plasma proteins. Metabolism of EPA is carried out by the liver passing mainly through -oxidation pathway analogous to dietary fatty acids. It splits the long carbon chain of EPA into acetyl coenzyme A, which is then used to release energy via Krebs cycle. However, EPA is also metabolized and eliminated through cytochrome P450-mediated pathway to a very little extent. The plasma elimination half-life (t1/2) of EPA at steady state is approximately 89 hours and it does not go through the renal pathway of excretion [1-4]. The drug has been studied at 4g/day dose in conjunction with omeprazole 40mg, rosiglitazone 4mg, atorvastatin 80mg/day and warfarin 25mg which are typical substrates of cytochrome P450 enzymes, and no drug-drug interactions were observed. The drug, however, does interact with anti-coagulants. In addition, a study conducted on the efficacy and safety of IE on adults having very high levels of fasting triglycerides concluded that the drug had remarkably reduced lipoproteins and undesired lipids in the target population. IE has also been subjected to a 2-year rat carcinogenicity study and a 6-month transgenic mice carcinogenicity study and both have
1 2
reported no drug related neoplasm. It has also been subjected to in vivo mouse micronucleus assay and has not been found to be mutagenic. In lactating rats, the drug is excreted in the milk, reaching levels that are 6-14 times those in plasma. However, in rat fertility test, increased anogenital distance in female pups and increase cervical ribs in males have been observed by exposure to the highest strength of the dose which is seven times the human systemic exposure. The most common adverse effect of IE is arthralgia, which has an occurrence rate of greater than 2%. The drug may also prolong bleeding time. Periodic monitoring is required in patients receiving anti-platelet therapy as well as in patients having hepatic impairment. The drug is contraindicated in patients who have a history of hypersensitivity to fish and/or shellfish [5-8]. The daily dose of IE is 4g and can be in the form of two capsules twice daily along with food. The capsule should be swallowed, but not chewed, crushed or broken [9].
Discussion
The safety and efficacy of IE is a case of ambiguity for nursing mothers, since the drug is excreted in breast milk and the effect of that is still undetermined; therefore, the patient should exercise caution especially those having borderline high triglyceride levels. Additional studies of the drug are required to ascertain the risk of pancreatitis and to establish cardiovascular mortality and morbidity. The pharmacokinetics of the drug in patients with renal and hepatic impairment is not yet known. However, it is advised that the ALT and AST levels be monitored regularly during the therapy as the drug is eliminated through hepatic route. Recently, an FDA approved study (REDUCE-IT) was initiated to evaluate the drugs ability to reduce cardiovascular events in high-risk patients having elevated triglyceride levels and who were already on statins. The study will end in November, 2016. As of September 2013 over 6000 patients have been enrolled in the study at 400 trials sites/centers spanned in over 11 countries.
Conclusion
In short, although a host of studies have been carried out on IE which has given it an approved status for populations having high triglyceride levels, but it has yet to undergo major trials in order to ensure the safety of the drug in all segments of the patient population having various manifestations of dyslipidemia.
University of Sunderland, England, United Kingdom Ziauddin University, Pakistan Correspondence: Atta Abbas Email: bg33bd@student.sunderland.ac.uk
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Abbas A, Ahmed FR
29
5. Bays HE, Braeckman RA, Ballantyne CM, Kastelein JJ, Otvos JD, Stirtan WG, Soni PN: Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). Journal of clinical lipidology 2012, 6(6):565-572. 6. Wood SJ, Cocchi L, Proffitt TM, McConchie M, Jackson GD, Takahashi T, Pantelis C, McGorry PD, Berger GE: Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: a longitudinal T2 relaxometry pilot study. Psychiatry research 2010, 182(2):180-182. 7. Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, Braeckman RA, Soni PN: Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). The American journal of cardiology 2012, 110(7):984-992. 8. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman RA, Soni PN: Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with an open-label Extension [MARINE] trial). The American journal of cardiology 2011, 108(5):682-690. 9. Prescribing information for Vascepa TM. Amarin Pharma Inc; 2011. [http://cerealkiller.it/wp-content/uploads/ICOSAPENT ETHYL_label.pdf]
Competing interests: The authors declare that no competing interests exist. Received: 29 October 2013 Accepted: 9 December 2013 Published Online: 9 December 2013
References
1. Amarin Announces FDA Approval of Vascepa(TM) (icosapent ethyl) [http://files.shareholder.com/downloads/AMRN/0x0x586350/7f7dbe6f-10f4477a-98a2-1439493b53b5/AMRN_News_2012_7_26_General_Releases.pdf] 2. Highlights of prescribing information: VASCEPA (icosapent ethyl) [http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202057S000lbl. pdf] 3. Food and drug authority. FDA; 2012. Monthly Approvals [http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseactio n=Reports.MonthlyApprovalsAll] 4. Icosapent ethyl capsules (Vascepa) approved in US as adjunct to diet to reduce triglyceride levels in patients with severe hypertriglyceridaemia [http://www.nelm.nhs.uk/en/NeLM-Area/News/2012---July/30/Icosapentethyl-capsules-Icosapentethyl approved-in-US-as-adjunct-to-diet-to-reducetriglyceride-levels-in-patients-with-severe hypertriglyceridaemia-/]
30
Extensive endomyocardial calcification of unknown cause
Open Access
Ahmed Bashir1, Richard Paul Steeds1
Letter to Editor
Extensive endomyocardial calcification of unknown cause: a rare manifestation of left ventricular noncompaction?
Abstract
We present a case of a 44 year old female who presented with a second episode of embolic stroke. She was noted to have extensive endomyocardial calcification on computed tomography. Cardiac MRI (CMR) showed myocardial thinning with hypertrabeculation of the left ventricular apex and extensive signal voids due to calcification attached to the distal end of the trabeculation. She was extensively investigated to find out the etiology of endomyocardial calcification but no cause of either metastatic or dystrophic calcification was found. We believe this may reflect a variant of left ventricular non-compaction (LVNC) in view of the CMR findings. Association between extensive endomyocardial calcification and left ventricular non-compaction has not been reported in literature before. (El Med J 2:1; 2014) Keywords: Endomyocardial Calcification, Ventricular Non-compaction
Case Description
A 44 year old female complained of severe headache associated with sudden onset of a visual field defect, confirmed by ophthalmology to be due to an embolic infarct within the superotemporal circulation of the right eye. At the age of 18, the patient had suffered a nondisabling stroke soon after starting an oral contraceptive. She went on to have three children by normal vaginal delivery without complications, although all pregnancies were covered by subcutaneous heparin. Following her final pregnancy over 15 years ago, she was incidentally found to have extensive endomyocardial calcification on CT, which was performed to investigate single episode of hemoptysis. She remained under follow-up on an annual basis without further clinical event until her current presentation when she was started on warfarin and lisinopril. The patient reported taking citalopram, but has not received any other pharmacotherapy in the intervening years. She has no other past medical history of note, no history of major trauma and has no risk factors for coronary artery disease. There is no history of family illness or inherited disease. She has never used recreational drugs or been exposed to industrial dust or toxins. Her husband works in property management and the patient has been a housewife living in a rural environment all her adult life. Clinical examination was unremarkable. Her resting 12-lead ECG showed sinus rhythm with left axis deviation and left bundle branch block. Investigations on this admission included normal full blood count, clotting (including pro-thrombotic screen), serum electrolytes, liver function tests, serum calcium, magnesium and phosphate, serum immunoglobulins and protein electrophoresis, 25-hydroxyvitamin D, 24-hour urine calcium excretion, ACE levels, thyroid function tests, negative autoimmune profile (ANA, ENA, ANCA, complement titers, RA latex and anticardiolipin antibodies for IgG and IgM), negative Bence Jones urinalysis and negative HIV test. Her total cholesterol was 5.9 mol/L and CRP was 42 mg/L. Coronary angiography was normal. Transthoracic and transesophageal echocardiography confirmed a bicuspid aortic valve with fused left and right coronary cusps with
1
no aortic stenosis and mild aortic regurgitation. The left ventricle was normal in size with gross calcification throughout the endocardium (Figure 1), combined with extensive mobile and sessile thrombus. The right heart was normal. Cardiac MRI (CMR) confirmed normal left ventricular size with mild reduction in systolic function and normal left ventricular mass. There was marked myocardial thinning with hypertrabeculation of the left ventricular apex and extensive signal voids due to calcification attached to the distal end of the trabeculation (Figure 2). There was no evidence of late enhancement on gadolinium imaging. A whole body CT confirmed multiple foci of calcification within the left ventricular endomyocardium (Figure 3) but there was no evidence of ectopic calcification anywhere else outside the heart. This extensive endomyocardial calcification was also demonstrated on fluoroscopy (Figure 4). Her three children had normal 12-lead ECGs and normal transthoracic echocardiography.
Figure 1: Mid-esophageal 4 chamber Figure 2: CT scan chest showing view showing gross intracavity multiple foci of calcification related to calcification and multiple mobile the LV endo-myocardium extending masses, consistent with partly calcified into the left AV groove where some of thrombus (arrow). this is also epicardial.
Figure 3: Cardiac MRI vertical long axis Figure 4: Fluoroscopy showing view showing marked myocardial extensive endomyocardial calcification thinning with hyper trabeculation of the left ventricle and extensive calcification attached to the distal ends of the this trabeculation.
Queen Elizabeth Hospital, Birmingham, United Kingdom Correspondence: Ahmed Bashir Email: drahmedbashir@doctors.org.uk
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Bashir A, Steeds R
31 tion (LVNC) in view of the CMR findings, although an association with extensive endomyocardial calcification has not been reported in literature before.
Discussion and Conclusion

Endomyocardial calcification may be either of metastatic or endocrine origin, due to significant disturbances in calcium and phosphate metabolism, or more commonly dystrophic, which is secondary to direct myocardial damage [1]. Metastatic or endocrine calcification that involves the heart is characterized by deposits elsewhere. Dystrophic calcification is usually secondary to ischemic damage, although in this case, the patient had no relevant history, a normal coronary angiogram and no evidence of late enhancement on CMR [2]. Less common causes of dystrophic calcification include infection (usually tuberculosis), endomyocardial fibro-elastosis, or local tumor infiltration which are unlikely given the general well-being of the patient and the longevity of the documented calcification. One hypothesis is that this may reflect a variant of left ventricular non-compac-
References
1. van Kruijsdijk RC, van der Heijden JJ, Uijlings R, Otterspoor LC: Sepsis-related myocardial calcification. Circulation Heart failure 2011, 4(5):e16-18. 2. El-Bialy A, Shenoda M, Saleh J, Tilkian A: Myocardial calcification as a rare cause of congestive heart failure: a case report. Journal of cardiovascular pharmacology and therapeutics 2005, 10(2):137-143.
32
Pseudoaneurysms of mitral-aortic intervalvular fibrosa
Open Access
Melike Rusen Metin1, Hasan Aydn2, Evrim zmen1, mer Faruk Ate1
Letter to Editor
Detection of multiple pseudoaneurysms of mitral-aortic intervalvular fibrosa by multislice computed tomography in a patient with aortic valve replacement
Abstract
Mitral-aortic intervalvular fibrosa pseudoaneurysms are a rare entity that may complicate mitral valve surgery and the management of infective endocarditis and thoracic trauma. They may result in fistulisation, valve dysfunction, pericardial rupture and mass effect to the adjacent organs. Here we present a patient of aortic insufficiency with aortic valve replacement and multiple pseudoaneurysms, detected by 64 slices CT. (El Med J 2:1; 2014) Keywords: Multislice Computerized Tomography, Pseudoaneurysm, Aortic Valve Replacement
Introduction
Mitral-aortic intervalvular fibrosa (MAIF) pseudoaneurysms are a rare entity that may complicate mitral valve surgery and management of infective endocarditis and thorax trauma [1, 2]. Anginal symptoms caused by direct compression to left coronary artery may be the initial manifestation in such patients. They may also be seen as a pulsatile cavity enlarging during systole in echocardiography or can be incidentally detected during cardiac computerized tomography (CT) angiography. MAIF pseudoaneurysms may result in disastrous consequences including fistulisation, valve dysfunction, pericardial rupture and mass effect to the adjacent organs [3, 4]. To the best of our knowledge, detection of multiple pseudoaneurysms by using multislice CT (MSCT) has not yet been documented. Here we present the first reported case of multiple pseudoaneurysms detected by 64 slices CT.
mostly solitary, multiple lesions may occur depending upon the site and severity of the injury.
Figure 1 (a)
Figure 1 (b)
Case Presentation and Technique

Due to severe aortic insufficiency, a 40-year old male underwent aortic valve replacement therapy and postoperative follow-up was performed in our clinic. One year after the procedure, he complained of shortness of breath with increased exertion for two months when he visited our clinic for routine MSCT angiography. Total calcium score was 0, no coronary artery pathology was detected. Posterior descending artery and posterolateral artery originated from right coronary artery and normal interventricular septum thickness was observed during MSCT angiography. Metallic aortic valve implant was seen at aortic valve level. At this level as well as inferior and superior adjacent levels, numerous pseudodiverticuli were seen, with a maximum diameter of 10 mm (figures). Multi-planar reconstruction (MPR) method was performed with MSCT to demonstrate pseudodiverticuli (figures) and they were evaluated dynamically. Dynamic evaluation failed to show significant change in size of those diverticuli, but this is thought to be caused by the milimetric dimensions
Figure 2 (a) Figure 2 (b)
Figure 3
Discussion and Conclusion

MAIF pseudoaneurysm is a rare but life threatening condition that is believed to be caused by secondary injury at the fibrous tissue extending between mitral and aortic valves [5]. Therefore, although
1 2
Figure 4 (a)
Figure 4 (b)
These pseudoaneurysms are mostly detected as cavities having pseudolumens and expanding during systole often spotted during
Ankara Ataturk Education and Research Hospital, Turkey Dkap Yldrm Beyazt Education and Research Hospital, Turkey Correspondence: Hasan Aydn Email: dr.hasanaydin@hotmail.com
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transesophageal and transthoracic echocardiography. Several authors have reported that echocardiography has 90% sensitivity in detecting these lesions, but localization, size and quantity is essential in diagnosis and small pseudoaneurysms may be ignored when echocardiography is performed. MSCT with simultaneous electrocardiography is a practical method in diagnosis and detection of site and size of the lesions. It has several advantages including high spatial resolution, ability to observe pulsatility with showing dynamic cardiac cycle and post-processing 3-D evaluation. It is also suggested that MCST may be helpful in follow-up of patient with valve replacement.
References
1. David TE, Kuo J, Armstrong S: Aortic and mitral valve replacement with reconstruction of the intervalvular fibrous body. The Journal of thoracic and cardiovascular surgery 1997, 114(5):766-771; discussion 771-762. 2. Espinosa-Caliani JS, Montijano A, Melero JM, Montiel A: Pseudoaneurysm in the mitral-aortic intervalvular fibrosa. A cause of mitral regurgitation. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2000, 17(6):757-759. 3. Sousa L, Branco L, Abreu J, Rasteiro R, Salomao S, Antunes AM: [A pseudoaneurysm of the mitral-aortic intervalvular fibrosis after aortic valve replacement]. Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology 1999, 18(2):177-178. 4. Delgado C, Barturen F: [Pseudoaneurysm of the mitral-aortic fibrosa secondary to the partial detachment of a mechanical aortic prosthesis]. Revista espanola de cardiologia 1999, 52(5):348-350. 5. Grimaldi A, Ho SY, Pozzoli A, Sora N, Taramasso M, Benussi S, La Canna G, Alfieri O: Pseudoaneurysm of mitral-aortic intervalvular fibrosa. Interactive cardiovascular and thoracic surgery 2011, 13(2):142-147.
34
Open Access
Sagar Karia1, Priyanka Thukral Mahajan1, Nilesh Shah1, Sushma Sonavane1, Avinash De Sousa1
Letter to Editor
Abstract
Introduction: Traumatic brain injury (TBI) is the most common cause of death and disability worldwide, especially in young people. Cerebroprotein hydrolysate (CH) exhibits complex neuroprotective and neurotrophic actions and is thus useful in patients of TBI. Here we report a case of TBI, where CH was found helpful in improving the patients condition. Case Presentation: A 50 year old male had a road traffic accident and suffered from head injury. Computed tomography of the brain showed right temporal intra parenchymal hemorrhage, right frontal hemorrhagic contusion, subarachnoid hemorrhage in right temporoparietal region and an undisplaced linear fracture of right squamous temporal bone. After gaining consciousness the patient did not remember anything, and suffered cognitive deficits. Anterograde amnesia secondary to contusional injury was diagnosed, and patient observation for spontaneous recovery of memory was recommended. Even after 20 days post-accident, there was not much improvement in the patients condition. Relatives were given an option of trying out injectable CH, which they agreed. CH was started and the patient started showing signs of improvement. On the night prior to the day of discharge, he suffered from right sided hemiplegia whose cause could not be ascertained. Conclusion: Cerebroprotein hydrolysate is a medication that acts at the brain level and provides us with an effective tool for improving levels of activities of daily living in patients of head injury, thereby decreasing their dependence on caregivers. However, further randomized, controlled trials involving large populations are required. (El Med J 2:1; 2014) Keywords: Cerebroprotein hydrolysate, Traumatic brain injury
Introduction
Traumatic brain injuries (TBI) are a steadily increasing and major cause of morbidity, mortality, and loss of productivity in resourcelimited settings, particularly among younger age groups [1]. CNS injuries are divided into two main categories: primary, which occur (mainly) at the moment of a trauma, and secondary, that develop after the initial injury. The secondary injury process involves excessive synthesis of nitric oxide and oxidative stress, microglia activation, local inflammation, disturbance of microcirculation, blood-brain barrier dysfunction and the most recently acknowledged delayed mechanisms of cell death. This leads to disastrous consequences of neuronal necrosis, neuronal apoptosis, scar and/or cyst hygroma formation, with further pathogenic effects on CNS tissue such as demyelination and disruption of morpho-functional nerve pathways [2]. Secondary brain injury is the leading cause of hospital deaths after TBI [3]. Thus, minimizing the secondary damage cascade may result in maximizing post-injury favorable evolution/recovery, including more rapid and consistent neuro-rehabilitative outcomes [3]. Cerebroprotein hydrolysate (CH) is a unique neurotrophic peptidergic mixture produced by standardized enzymatic breakdown of lipidfree porcine brain proteins [4]. It has unique neurotrophic activity that enhances neurogenesis, neuronal survival, provides neuromodulatory action, increases neuronal plasticity and neuronal repair and has neuro-immunotrophic actions [5]. It has been found in animal studies that early intervention with cerebrolysin reduces permeability changes in blood-brain and blood-cerebrospinal fluid barriers, attenuates brain pathology and brain edema, and mitigates functional deficits caused by TBI [6]. It has been found useful in improving outcomes in patients of moderate and severe head injury [7]. It improves brain bioelectrical activity i.e. reduced EEG ratio by increasing fast frequencies and reducing slow activities and also enhanced cog1
nitive performance in tasks evaluating attention and memory functions in post-acute TBI patients [8]. Here we report a case of traumatic brain injury where CH was found helpful in improvement of patients condition.
Case Presentation
A 50 year old male had a road traffic accident and suffered from head injury. He did not have any other bone fractures or other serious injuries. Computed tomography of the brain showed right temporal intraparenchymal hemorrhage, right frontal hemorrhagic contusion, subarachnoid hemorrhage in right temporo-parietal region and an undisplaced linear fracture of right squamous temporal bone. After gaining consciousness, the patient did not remember anything about the events that had transpired. He would complain of headache in frontal and right temporal regions. He started having difficulty in remembering names and would forget about recent events. He also had difficulty in walking and standing by himself and difficulty in maintaining balance. He started having difficulty in taking self-care as he had to be told to brush and bathe, and had to be taken to the bathroom. On mental status examination, the patient had impairments in immediate and recent memory but remote memory was intact. Confabulation was present as he would make up things to fill the gaps in memory and would tell wrongly what he had eaten previous night and who had come to meet him etc. MiniMental Status Examination (MMSE) score was 12/30. He was diagnosed as having neurocognitive deficits post-head injury. All his routine investigations were within normal limits. A neuro-medicine opinion was sought and they gave a diagnosis of anterograde amnesia secondary to contusional injury, while recommending to observe the patient for recovery of memory spontaneously. Neurosurgery opinion was also taken and they too advised to observe for further improvement or deterioration. He was receiving
Lokmanya Tilak Municipal Medical College, India Correspondence: Avinash De Sousa Email: avinashdes999@yahoo.co.uk
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35 level and provides us with an effective tool for improving levels of activities of daily living in patients of head injury and decreasing their dependence on caregivers though further trials in large populations and clinical trials is warranted.
Competing interests: The authors declare that no competing interests exist. Received: 3 November 2013 Accepted: 7 December 2013 Published Online: 7 December 2013
Tab. Eptoin (100mg) thrice a day and Tab. Citicholine (500mg) + Tab. Piracetam (800mg) combination thrice a day in the ward. Even after 20 days post-accident, there was not much improvement in the patients condition. Relatives were given an option of trying out injectable CH which they agreed to. CH was started at a dose of 60mg intravenous slowly over 1hr. After 11th consecutive injection he started receiving 30mg intramuscular of cerebroprotein as an intramuscular preparation which was available in the market. His MMSE score improved to 21/30 after 7th injection and to 26/30 after 20th injection. He also started showing improvements clinically. He started feeding by himself, taking self-care, would be able to stand and walk on his own. He started conversing normally. On the night prior to the day of discharge, he suffered from right sided hemiplegia and got transferred to medicine ward. Cause of the same could not be ascertained.
References
1. Gururaj G: Epidemiology of traumatic brain injuries: Indian scenario. Neurol Res 2002;24(1):24-8. 2. Onose G, Mureanu DF, Ciurea AV, Daia Chendreanu C, Mihaescu AS, et al: Neuroprotective and consequent neurorehabilitative clinical outcomes, in patients treated with the pleiotropic drug cerebrolysin. J Med Life 2009;2(4):35060. 3. Marshall LF, Gautille T, Klauber MR, et al: The outcome of severe closed head injury. J Neurosurg 1991;75:S2836. 4. Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M: Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Transm 2001;108(4):59-73. 5. Cerebrolysin - A Unique Treatment Option for Alzheimers Disease. [http://www.touchbriefings.com/pdf/28/gh031_t_Ebewe.pdf] 6. Sharma HS, Zimmermann-Meinzingen S, Johanson CE: Cerebrolysin reduces blood-cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat. Ann N Y Acad Sci 2010;1199:125-37. 7. Wong GK, Zhu XL, Poon WS: Beneficial effect of cerebrolysin on moderate and severe head injury patients: result of a cohort study. Acta Neurochir Suppl 2005;95:59-60. 8. Alvarez XA, Sampedro C, Prez P, Laredo M, Couceiro V, Hernndez A, et al: Positive effects of cerebrolysin on electroencephalogram slowing, cognition and clinical outcome in patients with postacute traumatic brain injury: an exploratory study. Int Clin Psychopharmacol 2003;18(5):271-8. 9. Selianina NV, Karakulova IV: [The effect of neurotrophic treatment on the activation of reparative processes in patients with acute traumatic brain injury.] Zh Nevrol Psikhiatr Im S S Korsakova. 2012;112(5):46-9. 10. Chen CC, Wei ST, Tsaia SC, Chen XX, Cho DY: Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: double-blind, placebocontrolled, randomized study. Br J Neurosurg 2013 [Epub ahead of print].
Discussion
Traumatic brain injury causes functional disability in the patient and only a handful of medications are available for its management. As such, CH may prove to be beneficial in such patients. A complex study of cognitive and emotional status, levels of serum serotonin and brain-derived neurotrophic factor performed in 72 patients with acute TBI, with a special focus on middle brain injuries, treated with cerebrolysin found that it promotes activation of neurotrophic processes and improves outcomes of closed craniocerebral injury [9]. A double-blind, placebo-controlled, randomized study showed that cerebrolysin improves the cognitive function of patients with mild TBI at 3rd month after injury, especially for long-term memory and drawing function tested on MMSE and Cognitive Abilities Screening Instrument (CASI) scores [10].
Conclusion
Cerebroprotein hydrolysate is a medication that acts at the brain
36
Type II diabetes mellitus and Parkinsons disease
Open Access
Atta Abbas1
Letter to Editor
The association between type II diabetes mellitus and Parkinsons disease: A case report
Abstract
Introduction: Diabetes mellitus (DM), if uncontrolled, can lead to deteriorating health consequences. One of the manifestations of DM is related to the brain; high blood sugar levels can damage the brain and lead to depression. Recently, it was reported that it can also lead to Parkinsons disease (PD). However, no study has reported the actual association during practice in a clinical setting. The present case study is based on a patient of type II DM who was diagnosed with PD in a hospital in England. Case Presentation: The case report is based on a male patient of 65 years suffering from DM for the last 7 years. The pharmaceutical care was focused on the management of DM. The main goal of management was to lower the blood glucose and bring it as close as possible to the recommended target range, and to prevent microvascular and macrovascular complications associated with the disease. Later, PD was diagnosed and the goal of management was to control motor and non-motor signs and symptoms of the disease and to minimize the adverse events associated with drug therapy. Conclusion: This report presents a case with an association between DM and PD. By following the guidelines, the risk of morbidity caused by PD can be lowered in patients who are diagnosed with DM. (El Med J 2:1; 2014) Keywords: Metabolic disorders, Diabetes mellitus, Parkinsons disease
Introduction
Diabetes mellitus (DM), if uncontrolled, can lead to deteriorating health consequences. One of the manifestations of DM is related to the brain: high blood sugar levels can damage the brain and lead to depression [1, 2]. Previous studies have pointed towards a link between DM and Parkinsons disease (PD). For example, a study reported that patients who suffered from DM were diagnosed with PD at a later stage in their life, with a rate of diagnosis of PD with DM being 3.6 as opposed to 2.1 without DM [3]. Other studies have further elaborated the link [4]. The present case study is based on a patient of type II DM who was diagnosed with PD recently.
Case Presentation
This case report is based on a male patient of 65 years suffering from DM over the last 7 years. The patient was a smoker and also consumed alcohol. He had a positive family history of DM. In terms of medication adherence, it was observed that the patient did not comply with the medications and therefore had uncontrolled type II DM. Apart from DM, the patient did not have any major co-morbidity, but he did complained of depressed mood. The records revealed that the patients medication therapy was altered in the beginning and the dose of metformin was adjusted according to the blood glucose targets. Type II DM is a known risk factor for cerebrovascular and cardiovascular complications which warrants effective management from the physician and the patient. Management The main goal of management was to lower the blood glucose and bring it in the recommended target range, or as close as possible. The NICE guidelines recommend a target blood glucose range of 90130mg/dl or HBA1c<7% for patients with DM [5]. Secondly, focus is placed on the prevention of microvascular and macrovascular complications associated with the disease. Calculation of cardiovascular risk has also been recommended [5]. The medication regimen for our patient included a 2nd generation sulphonyl urea, Glicazide 80mg
1
tablet BD, initially. Later, after the diagnosis of PD, a biguanide Metformin 1000mg OD modified release tablet was added to the therapy and the dose of Glicazide was reduced to 40mg BD. The EASD and NICE guidelines recommend the use of metformin as first-line treatment, or combination of metformin + 2nd generation sulphonyl urea for management of type II DM [5]. Metformin is also reported to reduce the risk of PD in patients who are diagnosed with DM [6]. The goal of management of Parkinsons disease was to control the motor and non-motor signs and symptoms of the disease for maximum time and to minimize the adverse events associated with drug therapy. Although the disease is lifelong and tends to worsen over time, pharmacological intervention can ameliorate the stiffness of the body and improve motor functions and mobility. Increasing disease acceptance by patient and treating associated illnesses such as depression may cause improvement in the overall quality of life [7]. Parkinsons therapy consisting of Co-careldopa 62.5mg OD was initiated and continued without any alteration in therapy. This drug is a combination of Carbidopa and Levodopa and is a gold standard in treatment of Parkinsonism and has also been recommended by AAN guidelines for the treatment of non-motor symptoms of Parkinsonism [7]. Co-careldopa is associated with many adverse effects such as depression, GI tract disturbances and, rarely, orthostatic hypotension [7, 8]. Renal function was regularly checked for our patient, and symptoms of hypoglycemia such as lethargy and general body weakness were monitored.
Discussion
The care plan for type II DM is prepared using an empirical approach to the disease. The NICE and EASD guidelines recommend a set of approaches in devising a care plan for the management of the disease. By setting individualized targets and glucose lowering therapies, help can be provided in devising a treatment strategy which will be individualized and sensitive to that particular patient. Dietary modifications are must for patients with DM, such as reducing the
University of Sunderland, England, United Kingdom. Correspondence: Atta Abbas Email: bg33bd@student.sunderland.ac.uk
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carbohydrates intake along with saturated fats. It is highly recommended to ensure incorporation of exercises such as jogging and walking in daily routine as these activities have been shown to effectively lower down cholesterol and blood glucose. Since this is a case of DM which has an established link with cardiovascular and metabolic complications, reduction in cardiovascular and thromboembolism risks are very important. Special emphasis should be placed on monitoring blood glucose and blood cholesterol regularly and routine follow up with a GP must be ensured. Routine checkup of feet and eyes is also recommended. The counseling points for patient include education about the disease and its management and social aspects such as limiting alcohol consumption and smoking cessation [5, 6]. For PD, the care plan contains pharmacological and social approach to effectively managing the disease. The drug therapy should be continued with strict compliance and routine follow up to review the improvements in signs and symptoms, and the therapy should be modified accordingly. The patient should be encouraged to work with an occupational therapist to improve/manage any difficulty in movements. Over the course of the disease, it is very important to take the patients caregivers on board in order to educate and give the patient moral support and confidence and also to educate them on managing the patient at home. The failure of prior assessment of Parkinsons disease in this case has exposed a loop hole in the health care strategies and therefore needs revision. The inclusion of metformin in the therapy of the patient should have been done initially to get a double impact on managing DM and PD, but this again resulted from not following the guidelines. In this case, patient education, medication and non-pharmacological therapy and lifestyle modifications, coupled with regular assessment, can lead to better control of the medical condition as a whole and may improve the quality of life in the long run.
Conclusion
This report presents a case with an association between DM and PD. By following the guidelines, the risk of morbidity caused by PD can be lowered in patients who are diagnosed with DM.
Consent: Prior to recording the information, an informed, written consent was obtained from the patient. Competing interests: The author declares that no competing interests exist. Received: 18 October 2013 Accepted: 30 November 2013 Published Online: 30 November 2013
References
1. Cereda E, Barichella M, Pedrolli C, Klersy C, Cassani E, Caccialanza R, Pezzoli G: Diabetes and risk of Parkinson's disease: a systematic review and metaanalysis. Diabetes care 2011, 34(12):2614-2623. 2. Sandyk R: The relationship between diabetes mellitus and Parkinson's disease. The International journal of neuroscience 1993, 69(1-4):125-130. 3. Sun Y, Chang YH, Chen HF, Su YH, Su HF, Li CY: Risk of Parkinson disease onset in patients with diabetes: a 9-year population-based cohort study with age and sex stratifications. Diabetes care 2012, 35(5):1047-1049. 4. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J: Type 2 diabetes and the risk of Parkinson's disease. Diabetes care 2007, 30(4):842-847. 5. TYPE 2 DIABETES | National clinical guideline for management in primary and secondary care (update) [http://www.nice.org.uk/nicemedia/live/11983/40803/40803.pdf] 6. Wahlqvist ML, Lee MS, Hsu CC, Chuang SY, Lee JT, Tsai HN: Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism & related disorders 2012, 18(6):753-758. 7. Parkinson Disease [http://emedicine.medscape.com/article/1831191-overview] 8. Co-Careldopa | Side effects [http://www.nhs.uk/medicineguides/pages/medicinesideeffects.aspx?condition=parkinson%60s+disease& medicine=co-careldopa&preparation=cocareldopa+50mg%2f200mg+modified-release+tablets]
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Company Profile
Mednifico Publishers, which started as an entity run by medical students, has now evolved into an organization that has a target audience that traverses a wide range of health professionals. The organization is responsible for publishing El Mednifico Journal (EMJ). It also has to its credit, Blogemia and Pakistan Research Evolution Scientific Society (PRESS). The main target audience for these products, as previously mentioned, is students. The word "students" encompasses medical, pharmaceutical, dental, nursing and allied students, residents, fellows, professors and beyond. This notion is consistent with the fact that health professionals never leave the learning curve during their lifetime.
El Mednifico Journal
http://www.mednifico.com/index.php/elmedj El Mednifico Journal (ISSN: 2307-7301) is an open access, quarterly, peer-reviewed journal from Pakistan that aims to publish scientifically sound research across all fields of medicine. It is the first journal from Pakistan that publishes researches as soon as they are ready, without waiting to be assigned to an issue. The journal has certain unique characteristics: EMJ is one of the first journals from Pakistan that publishes articles in provisional versions as soon as they are ready, without waiting for an issue to come out. These articles are then proofread, copyedited and arranged into four issues per volume and one volume per year EMJ is one of the very few OJS based journals from Pakistan EMJ is one of the few journals that provides incentives to students and undergraduates
Blogemia
http://blogemia.com/ Blogemia deals with providing proper exposure and spreading awareness among medical-related individuals, by keeping them updated regarding the latest interventions and techniques being currently deployed in health related activities around the world. Niches include, but are not limited to medical education, public health and technological advancements.
Pakistan Research Evolution Scientific Society

http://press.net.pk/ Pakistan Research Evolution Scientific Society (PRESS) is a venture undertaken to inculcate a sense of research in Pakistani medical and allied students and professionals, by promoting active indulgement in healthy investigative practices. We at PRESS firmly believe that a true research culture cannot be guaranteed in the absence of active involvement. In Pakistan, research is more of an insignificant formality and is placed lower down in the list of priorities. PRESS has, therefore, been established to shun this very mentality. PRESS has published a number of manuscripts recently in peer-reviewed and Pubmed-indexed journals throughout the world.
El Mednifico Journal C2 Block R, North Nazimabad, Karachi 74700, Sindh, Pakistan editorial@mednifico.com submit@mednifico.com apply@mednifico.com http://www.mednifico.com/index.php/elmedj http://www.linkedin.com/profile/view?id=222294632 https://www.facebook.com/elmednifico
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We are currently looking for sponsors for El Mednifico Journal. Pharmaceutical companies, publishers, representatives and retailers are welcome to apply. We also accept advertisements on both the website and the print version. Expected print audience ~ 1000; Current online audience ~ 15,000/month from Pakistan, India, Saudi Arabia, Iran, Turkey, Bangladesh, Nepal, Sri Lanka, UAE, Egypt, Germany, UK, USA, China and other countries. We have flexible options for advertisement and sponsorship. Advertisements are placed on both the website and the print version. Sponsorship results in the placement of the sponsors logo on both the website and the print version. Sponsors automatically get free advertisement placements on the websites and print versions. Send your proposals at editorial@mednifico.com.
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Best of Blogemia
Clearing Misconceptions About Psoriasis Sobia Anees
http://blogemia.com/clearingmisconceptions-about-psoriasis/ The term psoriasis is derived from Greek language, Psora means itch and sis means condition, making psoriasis literally mean itch condition.It affects 10% of the total world population.It is an autoimmune condition with strong hereditary link. However, some people believe that psoriasis is caused by bacteria or virus but the fact is that it is a skin condition in which bodys own T cells see the skin cells as foreign bodies and attack them. Another common misconception is to think psoriasis as being a form of cancer or leprosy. Because of rapid skin turnover, it may appear similar in appearance and give a false warning sign but intact, it is neither malignant nor contagious as leprosy. It was a common belief in olden times that psoriasis spread via skin contact and it affects people with poor standards of hygiene because of which such patients were victimized by the negative attitude of the society,.But the truth is, being hygienic has nothing to do with its cause which lies in the bodys immune system. Jerry Mathers was the spokesperson for the National Psoriasis Foundations awareness campaign entitled Step into my skin. When asked about the effect the disease had on his life Mathers stated, Living with psoriasis is no picnic. When youre covered with flaky, scaly, unsightly skin its difficult to live comfortably. People think it is contagious and they shun you, which can be humiliating. Patients with psoriasis frequently undergoes remissions. The disease pattern goes through cycles, sometimes better and other times worst, but it can never be fully eradicated. There is no total cure for psoriasis and it responds slowly to treatment. Not all treatment methods have the same effects on each patient, but its signs and symptoms can be managed and treated to minimize the severity of flare ups. Although there are
some well-recognized triggering factors that bring in an increased severity of signs and symptoms, but not every person with psoriasis have same triggering factors making it quite difficult to treat. Psoriasis is a complex disease with variable presentation and types. The first sign and symptom usually appears between 10-35 years of age. The most common sites of psoriasis are scalp, elbows and knees. Symptoms include itchy dry flaky skin covered with white plaques, joint pain, genital sores in males. There are five forms of psoriasis: Plaque psoriasis: The most common form, characterized by inflamed skin lesions topped with white scales Guttate: Characterized by small dot-like lesions Pustular: Characterized by pus-filled, blisterlike lesions and intense scaling Inverse: Characterized by intense inflammation in the folds of the skin Erythrodermic: Characterized by intense shedding and redness of the skin. Psoriasis is not just a skin problem. It is a chronic systemic disorder that can affect other systems aside skin. Approximately 10 percent to 30 percent of people with psoriasis will develop psoriatic arthritis. This form of arthritis is similar to rheumatoid arthritis. It can develop at any time, but for most people it appears between the ages of 30 and 50. In psoriatic arthritis, the joints and the soft tissue around them become inflamed and stiff. Psoriatic arthritis can affect the fingers and toes and may involve the neck, lower back, knees and ankles. Having psoriasis does not guarantee that all of the patients will eventually develop psoriatic arthritis. Psoriatic patients may be at the risk of other chronic conditions like depression, heart disease, obesity, high blood pressure, diabetes, cancer etc however the risk varies from one individual to another depending on other factors as well.
Treatment options for psoriasis can be broadly divided into topical, systemic and phototherapy. Topical medications include topical corticosteroids, vitamin D analogue creams like calcitriol, topical retinoids, moisturizers, topical immunomodulators, coal tar, anthralin, and others. The best treatment is individually determined by the treating physician and depends, in part, on the type of disease, the severity, and the total body area involved. Phototherapy in the form of sunlight has long been used effectively for treatment. Wavelengths of 311313 nm are most effective and special lamps have been developed for this application. The three main traditional systemic treatments are methotrexate, cyclosporine and retinoids. Methotrexate and cyclosporine are immuno-suppressant drugs; retinoids are synthetic forms of vitamin A. Apart from the above mentioned treatment options, home remedies can also be used to control psoriasis.Following are some skin care tips and home remedies for psoriasis: Dietary supplements such as fish oil, milk, evening primrose oil. Creams or lotions, baths, or soaks to keep skin moist. Avoid soaps and perfumes as they can irritate the skin. Avoid red meat and fatty foods. Apply olive or vegetable oil to troublesome plaques as it helps loosen them. Lukewarm bath with Epsom salt, mineral oil, milk, or olive oil can soothe the itching and infiltrate scales and plaques. Try short exposure to sunlight or ultraviolet (UV) light. Gently soften and remove psoriasis crusts by putting cream on the crusts and then peeling the loose crusts off. There is no known way to prevent psoriasis.Using some of the tips mentioned above, as well as using other treatment options one can custom-tailor their daily routine to keep problem itching and flaking to a minimum.
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Psychological Effects Of Acne Ambreen Fatima

http://blogemia.com/physiological-effectsof-acne/ Acne can have profound social and psychological effects. These are not necessarily related to its clinical severity. Even mild acne can be significantly disabling. Acne can affect people of all ages but it predominantly occurs during the teenage years, approximately 85% of people between the ages of 12 and 25 develop acne. What problems does it cause? The psychological and social impacts of acne are a huge concern especially because it affects adolescents at a time they are developing their personalities. During this time, peer acceptance is very important to the teenager and unfortunately it has been found that physical appearance and attractiveness is highly linked with peer status. In recent years, open discussions between patients and medical professionals have revealed the impact acne has on ones psyche. The following are some of the problems that patients with acne may face. Self esteem and body image o Some embarrassed acne patients avoid eye contact. o Some acne sufferers grow their hair long to cover the face. Girls tend to wear heavy make-up to disguise the pimples, even though they know this sometimes aggravates the condition. Boys often comment, acne is not such a problem for girls because they can wear make-up. o Truncal acne can reduce participation in sport such as swimming e.t.c Social withdrawal/relationship building o Acne, especially when it affects the face, provokes cruel taunts from other teenagers. o At a time when teenagers are learning to form relationships, those with acne may lack the self-confidence to go out and make these bonds. They become shy and even reclusive. The main concern is a fear of
negative appraisal by others. in extreme cases a social phobia can develop. Education/work o Some refuse to go school leading to poor academic performance and possibly future unemployment. o Some take sick days from work, risking their jobs or livelihood. o Acne may reduce career choices, ruling out occupations such as modelling that depend upon personal appearance. o Acne patients are less successful in job applications; their lack of confidence being as important as the potential employers reaction to their spotty skin. o More people who have acne are unemployed than people who do not have acne are. Does acne cause depression? In some patients the distress of acne may result in depression. This must be recognised and managed. Signs of depression include: loss of appetite lethargy mood disturbance behavioral problems wakefulness spontaneous crying feelings of unworthiness. In teenagers depression may manifest as social withdrawal (retreat to the bedroom or avoidance of peers) or impaired school performance (lower grades or missed assignments). Worse still, severe depression from acne has resulted in attempted suicide and, unfortunately, successful suicide. Worrying statements include I dont want to wake up in the morning; Id be better off dead; Im worthless; Youd be better off without me. Parents, friends and school counsellors need to take heed when they start to hear these types of comments.
Rarely, depression can be associated with acne treatment, particularly isotretinoin. There is much controversy about whether the drug causes depression. However, it is clear that depression does result from the acne and psychological disturbances described above. Regardless of the cause, depression must be recognised and managed early. If you think you may be depressed, contact your dermatologist or family doctor urgently for advice. What is dysmorphophobic acne? Some patients with only minor acne suffer from disturbed body image. Even in the absence of lesions, they consider they have severe acne and may suffer many of the psychological and social symptoms described above. They are said to have dysmorphophobic acne. If this is their only abnormal behavioural symptom, they respond well to oral isotretinoin therapy. A low dose of this may be required long term as even slight recurrence of oily skin may unduly concern the patient. Some severe cases of dysmorphophobia have a more global mental disorder similar to anorexia nervosa. They require expert dermatological and psychiatric assistance. Where do I go for help? If your acne is interfering significantly with your life, particularly if it is resulting in any of the problems described above, seek help promptly from your family physician or dermatologist. Suitable treatments may include: Antidepressant medication. Psychological treatments to overcome the negative thinking, anxiety and avoidance that often accompany depression. Counselling to help build confidence and rebuild self-esteem. Group therapy. It is important that a teenagers anxiety over their acne is managed appropriately.
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General principles of treatment Acne can be effectively treated, although response may sometimes be slow. Where possible, avoid excessively humid conditions such as a sauna, working in an unventilated kitchen or tropical vacations. Follow a low-glycaemic (avoid sugars), low-protein and low-dairy diet. Avoid protein or amino acid supplements, particularly if they contain leucine. Eat plenty of fresh fruit and vegetables. If you smoke, stop. Nicotine increases sebum retention and increased scale within the follicles, forming comedones (blackheads and whiteheads). Minimise the application of oils and cosmetics to the affected skin. Abrasive skin treatments can aggravate both comedones and inflammatory lesions. Try not to scratch or pick the spots. Exposure to sunlight filtered through window glass can help To avoid sunburn, protect your skin outdoors using a sunscreen and protective clothing. Wash affected areas twice daily with a mild cleanser and water or an antiseptic wash.
infection, belongs to the family of Flavivirus and is transmitted to humans by the bite of female Aedes mosquito. Its four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) can be distinguished. Mosquitoes become infected while feeding on the blood of an infected person, and spread infection to other individuals they bite. An infected mosquito transmits the infection for rest of the life when it bites another person. It multiplies inside the blood of an infected person and an infected person is a source of virus for uninfected mosquitoes. Aedes is a day biting mosquito with increased biting 2 hours after sunrise and 2 hours before sunset. Signs n symptoms start to appear 4 days after the bite of an infected mosquito. The typical symptoms include: High grade, severe , step ladder pattern fever up to 106 F Frontal headache Lumber (backache) ache There may be pain in retro-orbital region (eye pain) Nausea and vomiting Rashes may also occur throughout the body
IgM ELISA or paired serology during recovery phase of dengue fever. SOME OF THE REASONS OF LOW PLATELETS COUNT IN DENGUE FEVER: Dengue virus induces bone marrow suppression. Bone marrow is a manufacturing centre of blood cells and its suppression cause deficiency of blood cells leading to low platelet count Dengue virus can even bind to platelets of human blood in presence of virus-specific antibody. Even the antiplatelet antibodies that are produced after the infection of dengue virus can contribute to destruction of platelets. When vascular endothelial cell that are infected with dengue virus get combined with platelets they tend to destroy platelets, leading to low platelet count. Low platelet count in dengue fever leads to life threatening condition that is, hemorrhagic dengue fever that is categorized by spontaneous bleeding tendency and shock. Typical dengue usually does not result in death. The acute phase of the illness with fever, myalgias and the rest of the symptoms lasts for about one to two weeks. Convalescence is accompanied by a feeling of weakness. However, full recovery often takes several weeks. Treated DHF/DSS is associated with a 3% mortality rate. Untreated DHF/DSS is associated with a 50% mortality rate. There is no specific treatment for dengue fever, doctors may suggest intake of lots of water to prevent dehydration due to high fever and vomiting. Pain and fever can be treated with acetaminophens. Severe cases of dengue fever may require hospitalization which include supportive care, blood pressure monitoring , blood transfusion and intravenous administration of fluids and electrolyte.
Dengue Fever: A Growing Problem Saima Fahim

http://blogemia.com/dengue-fever-agrowing-problem/ Dengue has been a great problem for physicians and patients worldwide. Throughout the world it has been affecting great number of people. WHO currently estimates there may be 50100 million dengue infections worldwide every year. More than 10,000 cases of the fatal disease have been reported in various parts of Pakistan in year 2013. However, the illness is more prominent in Southeast Asia and the western Pacific islands. The infection may be clinically asymptomatic or give rise to undifferentiated fever, dengue fever, dengue hemorrhagic fever or dengue shock syndrome.Dengue is a mosquito borne viral
Minor bleeding from nose and gums may be noticed The Common Laboratory investigations show: Drop in platelets count (thrombocytopenia) Low level of white blood cells ( leucopenia Decrease HB level Elevated level of the enzyme serum aminotransferases. Diagnosis of dengue fever is usually confirmed in laboratory by serologic tests on blood samples from patients This is done by: Antigen-detection ELISA or PR-PCR during acute phase of disease
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The best way for prevention of dengue virus is avoid contact from mosquitoes. The peak biting time is early morning and evening so avoid going out at this time. Use of mosqui-
tos repellants and sprays are also suggested.Vaccine against dengue virus is still currently on its developing stage. It is hoped and expected that with all the researches
and vigorous efforts being made in this regard, mankind will soon defeat this viral infection and relieve the globe of this menace.
We require avid bloggers and medical writers to lead our sister blog, Blogemia. We are looking for section heads, editors and contributors. Those hired will be responsible for submitting at least five blogs (>500 words) per month. Individuals working in any of the aforementioned capacities will receive a share of the advertisement revenue. To apply, send your CVs along with samples at: apply@mednifico.com
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We accept Original Articles, Review Articles, Case Reports, Opinions and Debates, Essays, Letters to the Editor. There are no paper submission charges. Submit your articles via the online system or send as an email to: submit@mednifico.com We require editors, programmers, layout designers and proofreaders for our editorial staff. We also require avid medical bloggers for our sister website, http://blogemia.com. We are also looking for journal representatives from different medical schools. To apply, send your CV to: apply@mednifico.com El Mednifico Journal, Address: C2 Block R, North Nazimabad, Karachi 74700 Pakistan. Email: editorial@mednifico.com. Phone: (92-334)2090696.

Vol 2, Issue 1

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Vol 2, Issue 1

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Volume 2, Issue 1

January - March, 2014

Aims and Scope

Assistant Managing Editor

Opinions and Debates

Icosapent ethyl: A novel drug for hypertriglyceridemia

Cerebroprotein hydrolysate in traumatic brain injury

Framingham Risk Score for the prediction of cardiovascular risk

Materials and Methods

Hetari Y, Iyer A, Eldesouky SSM et al

Framingham Risk Score for the prediction of cardiovascular risk

Hetari Y, Iyer A, Eldesouky SSM et al

15. 16. 17. 18. 19. 20.

Management of acute respiratory infections in children

Baqai University, Pakistan Correspondence: Muhammad Irfanullah Siddiqui Email: irfan7255@yahoo.com

Siddiqui MI, Baloch AA, Ahmed SI et al

Distribution of the diagnosis of the children

Severe Pneumonia Pneumonia Common Cold / Cough

Distribution of the chief complaints of the children

Management of acute respiratory infections in children

Distribution of the chief complaints of the children

Siddiqui MI, Baloch AA, Ahmed SI et al

Oral health of Central Reserve Police Force officials

Bumb SS, Bhaskar DJ, Agali CR et al

Materials and Methods

Purpose of tooth brushing

Interval for change of tooth brush Plaque means

Dental plaque leads to

Gum bleeding means

Reasons for gum bleeding

Reason of tooth decay

Fizzy soft drinks affect the teeth adversely

Oral health of Central Reserve Police Force officials

Loss of teeth can interfere with speech

Yes No Dont know

272 (84.7%) 14 (4.4%) 35 (10.9%)

*Options marked in bold are correct answers

Effect of sweet retention on dentition

Methods to prevent tooth decay

Effect of fluorides on dentition

Reason for development of oral cancer

Reasons of tooth loss in old age

Bumb SS, Bhaskar DJ, Agali CR et al

Oral health of Central Reserve Police Force officials

Choudhry Z, Rikani AA, Choudhry AM et al

Neurochemical and Pharmacological effects

Choudhry Z, Rikani AA, Choudhry AM et al

Choudhry Z, Rikani AA, Choudhry AM et al

Conclusions & Future directions

Choudhry Z, Rikani AA, Choudhry AM et al

18. 19. 20. 21.

22. 23. 24. 25. 26. 27.

32. 33. 34. 35. 36. 37.

Opinion and Debate

Global Health Issues

Ziauddin Medical University, Pakistan Correspondence: Aqsa Sajjad Email: aqsasajjad23@live.com

Health issues: The leading cause of deaths worldwide

Choudhry Z, Rikani AA, Choudhry AM et al

Are SNARE proteins necessary for membrane fusion?

SNARE proteins and membrane fusion

Is SNARE pairing/complex sufficient for membrane fusion in vivo?

Is SNARE pairing/complex sufficient for membrane fusion in vitro?

Choudhry Z, Rikani AA, Choudhry AM et al

Icosapent ethyl: A novel drug for hypertriglyceridemia