KLE Health Sc. Jr. 2008; 1(1):1 KLE UniversityвЂ™s Health Science Journal An Official Peer-reviewed, Bi-annual Journal of Health Sciences of KLE University, Belgaum, Karnataka, India Aims and Scope: KLE UniversityвЂ™s Health Science Journal publishes Editorials, Original Papers, Review articles, Case reports, Short communications etc on all aspects of Health Sciences including Health Science Education. Patrons Hon. Chancellor Dr. Prabhakar B. Kore Hon. Vice -Chancellor Dr. Chandrakant Kokate Editors Chief Editor Dr. P. S. Shankar Executive Editor Dr. P. F. Kotur Editorial Board Members Dr. H.B. Rajashekhar Dr. B.S.Kodkany Dr. F.V.Manvi Dr.Prakash V Patil Dr.M.V.Jali Dr. R.S.Mudhol Mr.R.S.Hooli Dr. Subhash Khatri Dr. S.S.Goudar Dr.V.D.Patil Dr.K.R.Indushekhar Dr.M.D.Dixit Dr.R.B.Nerli Prof. A D Taranalli Dr. (Mrs.) N.S. Mahantshetti Dr. Alka Kale Editorial Incharge Dr. S R Pattan Published biannually for the KLE University in January and July Editorial and Business Office : Communications, articles and books for reviews are to be addressed to: Executive Editor, Editiorial Office, KLE University, JNMC Campus Nehru Nagar, Belgaum-590010, Karnataka, INDIA Phone: 0831-2472777 / 2493779 Fax: 0831-2493777 Web: http:/www.kleuniversity.edu.in; e-mail: [email protected] THE STATEMENTS AND OPINIONS EXPRESSED IN THIS JOURNAL ARE THE RESPONSIBILITY OF THE CONCERNED AUTHORS AND DO NOT NECESSARILY REFLECT THE OPINIONS OF THE EDITORIAL BOARD. THE EDITORIAL BOARD IS NOT RESPONSIBLE FOR WHATSOEVER FOR THE CONSEQUENCES OF ANY INACCURATE OR MISLEADING DATA, OPINION OR STATEMENT PUBLISHED HERE IN. Prior permission of the editorial board is required for reproduction of the contents of the journal in full or in part in any form. Printed by : Dr. P. F. Kotur at the Yarbal Offset Printers, Belgaum Published by : Dr. P.F. Kotur, Registrar, KLE University, Belgaum-590010. behalf of KLE University. Karnataka,India, on 2 KLE Health Sc. Jr. 2008; 1(1):2-3 EDITORIAL I A NEW JOURNAL IS BORN KLE University ever since its birth in April 2006 has not wasted any time in realizing its responsibility of promoting research with the same force as that used for imparting quality education. Thanks for the vision of our HonвЂ™ble Chancellor Dr. Prabhakar Kore and the apt encouragement of our beloved Hon Vice-Chancellor Dr. C. K. Kokate. All the findings of a sound and scientific research need to be disseminated and translated into practice so as to reach the final beneficiary. Scientific articles are the only tools to accomplish this objective. Thus was conceived the need of having a Health Science Journal, - KLE UniversityвЂ™s peer reviewed official publication. There are already enough number of journals available in any speciaity and the newer ones like this one are also being born every day. The estimated world total of journals today exceeds 1,26000 and authors are confused as where to submit their scientific articles, so also the readers as to which journal they should choose to read. How the quality of a journal is evaluated? While assessing the quality of a journal the properties those need to be considered include total circulations; readership numbers and surveys; quality of editorial board, staff and peer reviewers; number of manuscripts, percentage accepted and turnaround; Science Citation Index, RAW numbers, Immediacy factor and Impact factor; number of paid subscribers; advertising revenue; listing on Medline; international distribution; cost to the reader; page or peer review charge to the author. 1 Objective assessment of the quality of a journal is very difficult to perform and perhaps it is impossible to define the same numerically. Quality measures are useful to publishers, advertisers, librarians, editors and authors alike. Impact factor (IF), which has been defined as the вЂњfrequency with which the average article in a journal has been cited in a particular yearвЂќ is the most common bibliometric quantitative parameter or criterion in use today and has mostly replaced subjective criteria used in the past to define journal quality and prestige. It is thus a dynamic parameter and an indicator of the editorial quality of a journal. It has also been considered as putative index of the scientific production of a single author. However, since among the numerous variables which may influence the IF there are such parameters as, the average number of bibliographical references in a single article, self citations, salami publications, the IF seems on the contrary to be inadequate to evaluate accurately the quality of a single author, paper and research group. Further more a limited number of papers, all focused on the so called вЂњHot TopicsвЂќ, may contribute to increase the IF of a single Journal.2 The IF reflects the average citation rate of the average article in journal and not a specific article. Many parameters influence the citation rate of a particular journals articles and therefore its IF.These include the visibility and size of the circulation of the journal, including the availability of electronic formats and options for online search and retrieval. Other things to consider are editorial standards especially rapid and effective peer reviewing and a short time lag between acceptance and appearance in print. The number of self citations and citation density (the ratio of references to articles) and also the inclusion of many review articles containing hundreds of references to recently published articles will boost IF.3 It has been suggested that term вЂњIFвЂќ be abolished and that this measure be renamed in keeping with its actual role, that merely of a time specific вЂњcitation rate indexвЂќ and nothing more. Like all measures the use of IF has to be tempered with knowledge of its limitations and common sense.4 There is absolutely nothing incorrect with the calculation of the ratio itself. However IF is misnamed and misleading. Being misnamed and misleading, the IF has been misused. It is being held out as a measure of the importance of a specific journal article and the journal in which article appeared. By extension IF is also being misused to gauge the relative importance of individual researchers, research programs and even the institution hosting research.5 Status of Indian authors, articles and journals: The institute for Scientific Information (ISI) http:// www.isinet.com though was founded in 1971 and though has been publishing Science Citation Index (SCI) and indirectly IF for many years, has been able to cover only about 3500 journals of the estimated world total exceeding 1,30,000 as it is not feasible to code individually about 15 million references processed each year. Majority of the Indian Health Science Journals are not indexed with Medline (NLM, USA) or Science Direct (Elsevier) (the two giant electronic data bases in the world) for obvious valid and invalid reasons. This has resulted in the non availability of Indian articles or research, readily to any subsequent author for citation. Hence there has existed KLE HEALTH SCIENCE JOURNAL, JULY 2008 3 a gap or deficit in citing any Indian work by the next author anywhere in the world. However in the past one decade, ever since the establishment of Indian electronic Biomedical/ Science Data base (www.IndMED.org and www.medIND.org the scenario has changed. Free Full texts of almost 100 Indian Science Journals from the year 2000 are available online free of cost. Now the issues raised about IF and its use to assess the quality of an article and journal will start appearing in our Indian context. Having been aware of all the pros and cons of these controversial issues we are always at an advantage of overcoming these problems before they are born6. Authors should submit their articles to journals that are easily available to all and are read by the most interested audience/end users so that the benefits of their research reaches the right persons rather than paying attention to journal indexing or IF 6. Dr. P.F.Kotur Executive Editor References: 1. George Lundberg Editorials The вЂњOmnipotentвЂќ Science Citation Index Impact Factor MJA 2003 178 (6): 253-54. 2. Gensini GF, Conti AA. The impact factor: a factor of impact or the impact of a (sole) factor? The limits of a bibliometric in dicator as a candidate for an instrument to evaluate scientific production, Ann Ital Med Int. 1999;14(2):130-33 3. Jones AW Impact factors of forensic science and toxicology journals: what do the numbers really mean? Forensic Sci Int. 2003 Apr 23; 133(1-2):1-8 4. Magnavita N. Fifty years of impact factor: pros and cons Med Lav.2005 Sep-Oct;96(5):383-90 5. Hecht F, Hecht BK, Sandberg AA. The Journal вЂњImpact factorвЂќ. A misnamed, misleading, misused measure. Cancer Genet Cytogenet. 1998 Jul 15; 104(2):77-81 6. Kotur PF. Editorial, Impact Factor A misused measure of Scientific Literature. Indian J Anaesth. 2006;50(4):246-48. Advt Tariff KLE Health Sc. Jr. 2008; 1(1):4-6 4 EDITORIAL II INDIAN HEALTH INFORMATION NETWORK Advances in information and communication technology (ICT) have provided lots of new opportunities to enhance the efficacy of public health care delivery all over the world. The things that were inconceivable a decade ago have become a reality due to health information technology (HIT). It has the capacity to lead us to health care perfection with good quality and efficiency. This has shown the potentiality transforming the delivery of health care to a new design with a change in the practice of medicine and the relationship between the physician and the patient (1). HIT consists of a variety of technologies that enable the transmission of health information of the patients that has been stored and processed to the persons involved in health and health care. Among different types of HIT, electronic (e) health is of significance.. eHealth refers to the use of information and communication technologies for health. It represents a commitment for networked global thinking to improve health care locally, regionally and worldwide by using ICT (2). In this context our country has to develop a comprehensive web-based network, connecting all health care establishments, in both public and private sector. When they are fully developed and become operational, it is possible to record all health care transactions electronically. Such data in the health vault can be made available to all authorized users when needed. Man has practiced telemedicine since ancient times. A patient who is too sick to travel to a healer, his/her symptoms was described to the healer by an intermediary and the recommended therapy was carried back. Such an approach to telemedicine exists even today in remote, inaccessible areas of the country. This approach got an impetus when Kenneth Bird created a two-way audiovisual microwave circuit. It facilitated physician at Massachusetts General Hospital (MGH) in Boston to offer medical care to patients three miles away (3). Today the integration of different media into a single system around computers with telecommunication, videoconferencing and real-time data transfer has brought about startling changes in telemedicine. Internet facility gave an impetus to the new technology. An e-mail message in April 1995 seeking international help for a Chinese student, Zhu Lingling suffering from a serious neurological disorder enabled to make the first recorded diagnosis of Guillain-Barre syndrome. Today it is possible to send routinely the clinical history, and imaging studies through the internet and carry out live demonstrations and remote consultations through videoconferencing (3). It has opened a new chapter in health care delivery. The patient need not be transported to a place where the medical expert is based. Instead the knowledge of the expert is transported to the patient. Telemedicine is an application of ICT to deliver medical expertise from one place to another inside or outside the country, offering supportive health care at a distance, thus health care on line. The transfer of medical information, images, text and sounds by using telephone and computerвЂ™s network and software has been possible at an astonishingly rapid rate. Telemedicine refers to the use of ICT to link health care specialists with hospitals, clinics, primary care physicians and patients in order to provide remote diagnosis, treatment, consultation and continuing education. Telecommunication infrastructure offers the technology to pass the information electronically cutting across the institutional and geographic barriers to far off places linked to electronic networks. The telemedicine infrastructure consists of the equipment and mechanisms used to obtain and present clinical information, and to store and retrieve data. They include data digitizing and display, text processors and image processors and teleconferencing (4). Electronic health record (EHR) system supplies patientвЂ™s entire medical history, physical examination findings, investigations and treatment carried out from birth to death. It is possible to treat a person in a far-off place by a physician in another part of the country or continent through the use of telemedicine. Such a record makes all patient information immediately accessible and easily transferable. eHealth innovations such as electronic health records, computerassisted prescription systems and clinical databases are transforming health today. All the data collected at one place is accessible at a single key stroke. These developments are holding greater promise for the future, and are likely to bring about changes in the daily work of physician and other health care providers. This has replaced paper by the computer screen with rapid access to an organized information. Online transmission of these records can be made. Online repositories will allow patients to store, retrieve, manage and share their health data. EHR is a system capable of performing eight functions electronically (functionalities). Of them the core functions are four and remaining are other functionalities (5). KLE HEALTH SCIENCE JOURNAL, JULY 2008 5 1. Core functions : Health information and data, Results management Order entry and support Decision support 2. Other functionalities: Electronic communication and connectivity Patient support Administrative support Reporting and population health management Thus EHR is able electronically to collect and store data about patients, supply that information to providers on request, permit physician to enter and provide health professionals with advice for making health care decisions about individual patients (1). E-Health is a global phenomenon. The development of eHealth provides a global view, to identify health trends, opportunity and emerging challenges to health. World Health Organization (WHO) has prepared the global baseline data on the existing state of eHealth. The complete profile of eHealth of the country can be accessed. It supports clinical care, provides information to the general public, scientific information to professionals and provides a platform for publishing, disseminating health alerts. WHO on eHealth focuses on strengthening health systems in countries, fostering public-private partnerships in ICT, research and development for health supporting capacity building for eHealth and development and the use of norms and standards. ICT is gradually getting integrated into health systems and service in the country. WHO has taken the lead to strengthen health systems in countries fostering publicprivate participation in ICT The Global Observatory for eHealth will develop a set of tools and guidelines on e-Health policy (4). WHO has planned to provide member states with strategic information and guidance on effective practices and standards on eHealth. The objectives of the Global observatory for eHealth are to i) provide relevant, timely and high-quality evidence and information to support national governments and international bodies in improving policy, practice of management of eHealth, ii) increase awareness and commitment of governments and the private sector to invest in promote and advance eHealth, and iii) generate knowledge that contributes to improve health through the use of ICT, and iv) disseminate research finding through publications. Choudhry et al in a review on impact of HIT including HER, on quality, efficiency and costs of medical care, have observed that implementation of a multifunctional HER system could increase the delivery of care that would adhere to guidelines and protocols, enhance the capacity of the providers of health care to perform surveillance and monitoring for disease conditions and care delivery, decrease rates of medication errors and lower utilization of care (6). However the results on the efficiency of care and productivity of physicians were equivocal. In India more than one hundred projects in telemedicine have been created, and it has led to a significant increase in experience of expertise in the sphere of telemedicine. There is a necessity to establish e-Health governance bodies. Our country has to draw up a long-term strategic plan for the development and implementation of e-Health service. The application of e-Health includes the following domains: 1. Public services: information services provided to the citizens usually via internet in a digital format 2. Knowledge services: electronic information and education services aimed at health care professionals in training and practice. International and National electronic journals published in electronic format, and National open archives in which the authors deposit their works in digital format for dissemination of scientific information. A health professional can upgrade his knowledge and skills through e-Learning by staying his place. eLearning is successfully utilized for education and training of students of health and medical sciences. It has brought about improvement in quality of education; and has increased accessibility to geographically isolated students. It has helped students with poor local learning facilities. It offers a cost-effective delivery of courses to large number of people throughout the world. 3. Provider services: eHealth tools and services used in the provision of health care to citizens. WHO in collaboration with public and private sector partners proposes to facilitate i) the development of general eHealth tools to monitor and evaluate eHealth services, ii) accessibility to exiting tools, and iii) knowledge exchange, and iv) professional education (7). Together we must work to build a healthier world-a world where information and communication technologies help support and enhance health care services and are available to all. The findings of the global survey for eHealth SHANKAR: EDITORIAL:INDIAN HEALTH INFORMATION NETWORK confirm that the use of ICT is steadily being integrated into health systems and services worldwide. The survey has found that there has been strong growth since 2000 in many areas assessed. eLearning can effectively improve the quality of education. The National Knowledge Commission (NKC) has proposed to develop a knowledge network with gigabit capabilities on which the health information network of a вЂ�hub and spoke modelвЂ™ take a foothold (8). In this model all the health care establishments in a district will be connected to a central data repository at the district head-quarters, which in turn will be connected to a state-level data bank. The information from different states will ultimately get connected with a central data bank. This network becomes successful only when there is an active involvement of public and private health sectors. The information provided by such a network will be of great benefit to public health planning, medical education, cost control, medical research, drug development, prevention of fraud, disaster management and improved patient care (8). In order to make the health information network a successful project, National Knowledge Commission has formulated the following steps of action: 1. 2. 3. 4. Establishment of National standards for clinical terminology and health informatics: The web-based national grid should have a common clinical nomenclature to be interoperable. The common terminology used in electronic transactions will make it possible for all entities distributed far and wide in the country to communicate in one language understood by all. It will facilitate collection and transmission of data. The ehealth informatics of the country should have a national standard. Creation of a common EHR: It is necessary to document the hospital records of a patient including the laboratory investigations and treatment electronically. Such a data which is stored can be used subsequently. The EHR should be based on common clinical and IT standards so as to be applicable throughout the country. Promotion of use of IT in health care: The Government plays a pivotal role in the use of IT in health care needs of the country, and use effectively electronic format in all transactions in health care in the country within a time-frame of 7-10 years. Creation of a policy frame-work to protect health care data: It is necessary to maintain the confidentiality 6 and security of all personal health data of citizens. There should not be any room for its misuse. In order to sensitize and train the medical students about HIT, a ell-structured health informatics curriculum should incorporated in the medical education at various levels of study. All the Medical Colleges in the country should have good quality access to internet and e-Journals. Education-related portals can be effectively utilized to impart training. There is an urgent need to set up institutional body with appropriate professionals with domain experts to implement the recommendations of NKC in the coming years. It will go a long way in improving the health care delivery in India. We must be prepared to use this powerful tool in the way that is best for patient care. P.S. Shankar Chief Editor References 1. Blumenthal D, Glaser JP. Information technology comes to Medicine. N Engl J Med. 2007: 356; 2527-37 2. Eysenbach G. Editorial. What is eHealth? Jour Med Internat Res. 2001: 3; e20 3. Building Foundation for eHealth. Progress of Member States. Report of the WHO Global Observatory for eHealth. Geneva, World Health Organization, 2006 4. Shankar PS. Telemedicine Technology in Recent advances in Medicine-2. Mumbai, National Book Depot. 2003:101-104 5. Waegemann CP. Closer to reality personal health records health care IT system and accessibility on patient data. Health Manag Technol 2005: 26; 16-18 6. Choudhry B. Wong J, Wu S, et al. Systematic review: Impact of helath information technology on quality efficiency and costs of medical care. Ann Intern Med. 2006: 144; 742-52 7. WHO Global Observatory for eHealth. eHealth tools and services-need of the member states. Geneva, World Health Organization. 2006 8. Pitroda S. Recommendations on health information network, Delhi, National Knowledge Commission. 2007. KLE Health Sc. Jr. 2008; 1(1):7-11 7 ORIGINAL ARTICLE How to Write a Scientic Article for a Health Science Journal? Dr. P.F.Kotur* вЂњNot all who look at a journal are going to read even one article in it; Writers must know therefore what turns a looker in to a readerвЂќ J.W.Howie1 Research is essential for the growth and development of any medical science. Only through sound, scientific and educational research can new and old ideas get tested, thus guarding against stagnation and dogmatism, In order to achieve its goal of becoming useful to the community, the research has to be translated and applied to the patients in the day today clinical practice. The challenge faced by the practising physician today is to provide up to date medical care to his patients by incorporating the valid, new information 2. The role played by the scientific articles in the translation of research into clinical practice need not to be emphasized as it is the only available path for the up date of any specialty. There has been a dramatic increase in the numbers of medical journals published in the last one decade and there has been an increasing demand for the scientific articles. Every year 6 million scientific medical articles get published. Despite this gargantuan volume of medical literature, less than 15% all articles published on a particular topic are useful3. Even articles published in the most prestigious journals are far from perfect. Analyses of clinical trials published in a wide variety of journals have described large deficiencies in the design, analysis and reporting. Although improving with time, average quality score of clinical trials during the past 2 decades is less than 50%. 4,5,6 The researches thus, must take the personal responsibility of providing a valid, readable, scientific material. Conveying oneвЂ™s research findings is an exciting moment because it represents the out comes and recognition of an arduous process. Clarity in reporting how the research was con- ducted and what results were obtained is paramount both for the research community and for the medical practitioners. Only through clear and thorough writing can the clinicians transfer the benefit of the research to the patients and to fellow researchers eventually to explore the topic one step further. It is through the correctly written * MD (Anaesth), Sr.Prof. of Anaesthesia Editor, SAARC Journal of Anaesthesia Ex-Editor, Indian Journal of Anaesthesia Prof. of Anaesth. J.N.M.C Registrar, KLE University, Belgaum, (Karnataka) INDIA article that the clinicians appreciate the concepts being developed and judge the extent to which results can be applied in their setting. The results serve as basis on which clinical actions can be planned and implemented. Thus, a healthy and productive cycle is created between theory and clinical practice: theory-practice-theory7. Another potent stimulus, rather a compulsion for any body to write a scientific paper is an albeit, misplaced, universal emphasis on вЂ�publicationsвЂ™ as a criteria of determining competence and suitability for academic positions. Papers written solely for this purpose contribute significantly for the low quality publications. The common deficits found in the articles written in our county are due to poorly planned and conducted research and poorly presented research. A poorly designed and conducted research can never yield a worthwhile paper and therefore due attention must be given to this aspect at the conception stage. It is beyond the scope of this lecture to discuss about how to conduct a good research. Let us assume that a scientifically valid research has been conducted and the aim of this lecture is to highlight the art of presentation of a well-conducted study, so that it will not be rejected by any journal. Before going on further discussion on the art of writing, I want all the authors to realize before hand вЂ�What generally happens to manuscripts submitted to a journalвЂ™? For both editorial staff and authors the selection of articles for journal publication is, a key quality issue8. Authors (and readers also) will find it helpful to know how journal articles are selected for publication. Manuscripts submitted to a journal enter a two-stage review process. Initially they are read by the editor and assessed for quality, relevance and style. One or more of the associate editors may also read manuscripts as they are received. A small number of articles may be rejected at this stage. Having passed this first scrutiny, manuscripts enter the second phase вЂ“ peer review. These are the experts who have knowledge, experience and interest in the manuscript topic. The process of editorial review and peer review is 8 KLE HEALTH SCIENCE JOURNAL, JULY 2008 confidential and reviewers are reminded of both this and other responsibilities, each time they receive an article. After completion of these stages, manuscripts may be returned to authors with suggestions for improvement through amendment or rejected. Many manuscripts are accepted for publication subject to appropriate amendment. Occasionally papers are returned to authors with a request for revision that does not necessarily guarantee acceptance. Such papers are reassessed before final decisions are made. It is useful for prospective authors to be aware of these steps in the publication cycle, especially those relating to reviewers comments and subsequent amendments. Adhering to the вЂ�Guide lines for AuthorsвЂ™ greatly speeds up the decision making process. This is a part of the quality assurance cycle of journal publication and usually results in a stronger, more easily read, better-organised and better-structured paper. i) What is the best format of presentation of the research done? e.g.: as original article, review, case report, or correspondence,? Because format is different for different type of articles. Purcell, Donovan and Davidoff (1998) recently reviewed changes made to papers submitted to a leading North American medical journal. They found five types of problems; too much information, too little information, inaccurate information and problems of structure or of organization4. Changes were requested most often because of missing information, particularly in the introduction or conclusions to the paper. In addition to the above problems, as an editor of a medical journal, I find most of the times that the articles written by Indian researchers are deficient both in grammatically correct language, and adequate references in support of the statements made in the article. The latter problem is getting sorted out slowly with easy availability of a fast, low cost access to the electronic medical literature database through electronic mail and Internet. The decision to accept for publication or otherwise of an article is based upon twin criteria of importance and quality. Other factors those may influence the decision are the page length of an article or recent publication of similar articles. Prologue: вЂ�A well begun is half doneвЂ™ Author must think before hand, about вЂњHow to write?вЂќ вЂњWhat to write?вЂќ and вЂњWhere to submit?вЂќ Having affirmed all of the above, with the data of a well conducted and concluded research project in hand, author must think of a вЂњclear messageвЂќ intended to be given through his write up. A good measure of success is the conclusions drawn from the study, if can be written in one meaningful sentence. The others considerations to be decided priorly are ii) Target audience for the publication and which journal? Aspiring authors will improve their chance of acceptance if they choose an appropriate journal for their topic and adhere to conventional rules. The reason why this decision must be taken in the early phases is that from the first draft, the paper must be written in the style and format of the specific, journal targeting particular group of audience. iii) A thorough literature search is quite essential: a) to identify the knowledge gaps in the existing information and the proposed paper may be aimed to fill them up. b) to avoid duplication if the same message or project has been published already. Most journals do not wish to consider for publication a paper or work that has already been reported in a published paper. iv) Other matters related to authorship, ethical, and statistical clearance may be obtained well in advance. Useful Hints for Good Writing. Editors and reviewers look for brevity, clarity, and validity when reviewing manuscripts. Good and bad papers generally identify themselves. One of the key developments in scientific publication since 1950, has been the wide spread adoption of the IMRAD structure. It is set around four distinct sections: 1) The Introduction (Why did we start). 2) Methods (What did we do?). 3) Results (What did we find?). 4) Discussion (What does it all mean?). Apart from this, article also includes Title, Abstract, Keywords, Acknowledgements, and References, which again may be remembered by acronym. TAKAR. Ever since the publishing of вЂњUniform requirements for manuscripts submitted to Biomedical journalsвЂќ in the year 1979, by the International committee of Medical Journal Editors, (ICMJE), (which is periodically revised by the committee) more than 500 journals have accepted and adopted them9 They have agreed to receive manuscripts in accordance with the requirements. It is important to emphasize what these requirements imply and what they donвЂ™t; They are available on line www.icmje.org. In addition, the journalвЂ™s instructions to contributors are likely to contain other requirements, unique to that journal, KOTUR:EDITORIAL:HOW TO WRITE A SCIENTIFIC ARTICLE FOR A MEDICAL JOURNAL such as: number of copies of manuscripts, acceptable languages, length of articles and approved abbreviations. In spite of all these facilitations, writing a journal article is a demanding exercise and for those whose first language is not English, it is much more difficult. Georges B in the year (1989) presented some 40 factors, which he classified under nine headings, which follow the usual order of presentations in any journal article, to facilitate the task of preparing a paper for publication7.viz 1)Title 2) Author 3) Abstract 4) Introduction and Review of literature.5) Material and Method 6) Results 7) Discussion and conclusion 8) References and 9) General considerations. How I want to proceed further in my lecture is to discuss these 40 factors sequentially under the guidelines of ICJME requirements with special references to Indian scenario. I) Title. 1. Title should correctly represent the content and breadth of the study reported and should not be misleading. For example вЂњComparative evaluation of Propofol вЂ“ Ketamine and Propofol-Fentanyl in minor SurgeryвЂќ. On reading the title, we cannot know the content and breadth of the study ; whether dosage, duration, efficiency, and sequalae, of two group are studied or not whether they are studied as only induction agents or as sole anaesthetic agents; what group of patients?. None of the information can be had from this title. 2) It should be clear, concise, and informative. It should contain keywords that capture attention of the reader. No abbreviations are used in the title. The decision to read an article often rests on the appeal of its title. A More appropriate title could be вЂ“вЂќComparative evaluation of Efficiency of Propofol вЂ“ Ketamine and Propofol вЂ“ Fentanyl combinations as sole anaesthetic agents, in patients undergoing minor Ambulatory Gynecological operationsвЂќ. II) Author: 3) Designation, degree, affiliation and address of authors are to be clearly indicated, with additional details like telephone number, email address of the corresponding author. 9 III) Abstract & Keywords. 4) Abstract should cover each and every component of, the study in 150 words for вЂ�unstructuredвЂ™ abstracts and 250 words for вЂ�structuredвЂ™ abstracts. It should state the purpose of the study or investigation, basic procedures, (selection of study subjects, methodology, main findings, statistical significance), the principal conclusion and implications. 5) The abstract should contain precise information and should not contain abbreviations. 6) The implications and benefits should commensurate with the results obtained, and are to be highlighted. 7) Key words (or short phrases) 3 to 10 should be listed covering all the aspects of the study. Use preferably the terms listed as Medical subject headings (MESH) in Index Medicus (Medline) IV) Introduction and Review of Literature: 8) The goal or purpose of the study is clearly stated. The introduction should contain detailed information about the problem being studied, and about the specific research question/hypothesis. 9) Four or five pertinent publications related to the problem should be presented and critiqued. No data or conclusions are to be reported. 10) Do not review the literature extensively. 11) The pertinence of the study is presented, in relation to the current theories and methods associated with the problem. The existing gaps in the knowledge or conflicting data is to be highlighted. 12) A general overview of the study is presented. Over view serves as organiser for the sections to follow to the reader. V) Material and Method: 13) The selection of the subjects for the study has to be described clearly. Inclusion and exclusion criteria are to be mentioned with method of allocation to groups. 14) The research design is to be described in detail. Research design is the plan that is chosen to answer the research question. The methods, apparatus and procedures are to be identified in sufficient detail to allow other workers to reproduce the results, if necessary. 15) Give references of all the methods used in the study including statistical methods. 10 KLE HEALTH SCIENCE JOURNAL, JULY 2008 16) Identify precisely all drugs and chemicals used, including generic names, doses and routes of administration. 17) Methods of elimination of errors viz blinding, introduction of control group and placebo, randomization etc are to be mentioned distinctly. 18) The measurement instrument including its psychometric qualities is described clearly. The psychometric qualities include validity, reliability, objectivity and precision. An example of the instrument should be given in the text or in an appendix. For example in the above mentioned study, if вЂ�home readinessвЂ™ is intended to be studied, the вЂ�Post Anaesthetic Discharge scoring systemвЂ™ (PADS) utilised in the study has to be a reliable, and an accepted one for its objectivity and precision. 19) The data collection procedure is to be clearly described. 20) The setting in which the study took place is described. This information is useful to the reader in deciding whether results can be applied to his/her setting. 21) The data analysis procedures are stated in precise terms. VI) Results. 22) Present your results in logical sequence in the text, tables and illustrations. Do not repeat in the text all the data, in the tables or illustrations. 23) Emphasize or summarize important observations. Results section should contain only actuals, and no opinions. 24) All the patients included in the study should be accounted for. There should not be any hesitation in reporting any negative or unexpected result. VII) Discussion & Conclusion. 25) The discussion should cover all the debatable aspects of the study. The discussion can go beyond the results obtained and can cover methodological and the critical issues. The discussion should not be misused as a platform to state opinions. Readers should not be side tracked in to another topic. 26) Relate the observations to the other relevant studies. Bring out similarities and conflicts. 27) The new and important aspects of the study and the conclusions drawn are to be emphasized. The implications of the findings and their limitations are to be discussed. For example if you find that Propofol вЂ“ Ketamine combination fared well except that there was вЂ�excitatory phenomenonвЂ™ of Ketamine observed in these group of patients, this limitation has to be mentioned without fail. 28) Scope and need for future additional research is to be discussed. 29) Link conclusions with goals of the study but avoid unqualified statements and conclusions not supported by your data. 30) State new hypothesis when warranted. Recommendations when appropriate may be included. For eg. Propofol does not have any effect on excitatory phenomenon associated with Ketamine. 31) The conclusions and practical outcomes of the study should commensurate with the design used and results obtained. The conclusions and recommendations made should not go beyond the limits of the study conducted i.e. should not over generalize the design and sample used. Suppose the haemodynamics were stable in KetaminePropofol group as compared to Propofol вЂ“ Fentanyl group, one should not generative that the combination is recommended for patients with cardiovascular diseases. VIII) REFERENCES. 32) This is the most disturbing aspect amongst the Indian publications. It is a wrong notion amongst Indian authors that, providing a long list of references increases the validity (of their article) which is wrong. References are to be written correctly with due care. Correct abbreviated, accepted names, of the journals to be mentioned. The number of references should be reasonable (neither too many nor too few); Some journals specify the number of references to be included in a particular type of study. 33) Avoid using вЂ�abstractsвЂ™ as references. The author must verify the references against the original documents. 34) The references are presented according to standard rules of publication as specified by a particular journal. for e.g., whether Vancouver style or Harvard style is followed. KOTUR:EDITORIAL:HOW TO WRITE A SCIENTIFIC ARTICLE FOR A MEDICAL JOURNAL General Considerations. 35) The various sections of the paper are clearly identifiable and appropriate. The content of each section should correspond to the subtitle used; for instance, there is no вЂ�DiscussionвЂ™ in the вЂ�ResultsвЂ™ section. The transition from one section to next should be easy to follow. 36) The terminology has to be uniform through out the paper. For e.g. abbreviations should be consistent and units of measurements should be the same in the text as in tables. 37) The writing style has to be clear and pleasant. There should not be spelling mistakes. Special care is needed in following British Vs American spellings. Text is, generally written in passive voice. Uniform вЂ�tenseвЂ™ has to be used. 38) Follow the instructions of the journal, for which you are writing, regarding tables, graphs illustrations, the text matter, type of manuscripts etc. to be used in the article. 39) Follow the ethical guidelines strictly as specified by ICMJE. If there is confusion as what is ethical and what is non-ethical and there is no ethical committee to guide, вЂ�a self testвЂ™ may be employed. Ask yourself whether you will be conducting the similar study on your kith and kin. If yes, go ahead with your study. 40) All the direct and indirect help in the study has to be acknowledged, without fail. Editors and referees вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦вЂ¦. but are busy people whose humanitarian instincts should not be abused; and it is better for all concerned if authors try to submit papers that are in good working order5 . Plagiarized from OвЂ™ Connor M, Woodford F P References: 11 3) Lock .S. Does Editorial peer review work? Ann.Intern Med 1994; 121:60-1. 4) Sonis J, Joines J. The quality of clinical trials published in the Journal of family practice, 1974-1991. J Fam pract 1994, 39:225-35 5) Beggc. Cho M, Eastwood s, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of RCT. The consort statement JAMA 1996; 276:637-9 6) Altman D G. The scandal of poor medical research: we need less search, better research, and research done for eight reasons. BMJ 1994; 308: 283-4 7) Bordage Georges, Considerations on preparing a paper for publication.Teaching and Learning in Medicine 1989; 1 (1) 47-52 8) What happens to manuscripts submitted to the journal? Editorial. Medical Education 1998, 32, 167-70. 9) International Committee of Medical Journal Editors. Uniform Requirements for Manuscripts submitted to Bio medical journals. Ann. Intern.Med. 1997; 126: 36-37. (Updated;November,2007) Suggested reading: 1)How to write and publish a scientific paper by Day RA Phoenix, Arizona, Oryx press 1988. 2)Writing Scientific papers in English by OвЂ™ Connor M. Woodford F P. Pitman medical. First Edition 1986 3)How to write and publish papers in medical sciences 2nd edition Williams and Williams Baltimore 1990. 4)How to write a paper. Edited by George M Hall. 3rd Edition. Byword Publishers Pvt Ltd (BMJ Publishing Group) 2004. 1) Howie. JW, Writing and Speaking in Medicine BMJ, 1976,3,1113-25. 5)How to Read a paper. by Trisha Greenhalgh. BMJ Books. 2nd edition.2003. 2) Miser William F ,Critical Appraisal of the Literature. JABFP 1999; 12(4), 35-33. 6)Scientific Writing; Easy when you know how. By Jennifer Peat, Elizabeth Elliott, Louise Baur and Victoria Keena. Byword Viva Publishers First Indian Edition 2004. KLE Health Sc. Jr. 2008; 1(1): 12-16 12 ORIGINAL ARTICLE INFLAMMATION : A NOVEL RISK FACTOR FOR CORONARY ARTERY DISEASE Kothiwale V. A.1, Madhav Prabhu 2 ABSTRACT Traditional risk factors for myocardial infarction (MI) are diabetes, hypertension, hyperlipidaemia, and smoking. In a considerable number of patients however no risk factor can be established. This study aims to assess HsCRP as an independent risk factor for MI and establish relationship of risk factors with HsCRP 100 consecutive patients of coronary artery disease (CAD) were studied and risk factors analysed. HsCRP (C-reactive protein) was done for patients and. next patients who had no risk factors were identified and their HsCRP values were obtained. HsCRP showed consistent association with hypertension (p=.010) and diabetes (p=.040) but not with smoking (p=.237). HsCRP was consistently higher in patients with MI who had no other risk factors. Dyslipidaemia was mainly seen in association with diabetes. Increased values of HsCRP correlates well with traditional risk factors for CAD HsCRP is high in patients with no other risk factor and is thus an independent risk factor for MI Key words-Atherosclerosis, HsCRP, Coronary Artery Disease Introduction Coronary Artery Disease prevalence has now reached pandemic proportion .CAD kills more patients than most diseases combined. Sedentary lifestyles, altered dietary habits and lack of physical activity contribute to the increase in CAD. CAD has always been believed to be the culminating event of complex processes involving various risk factor interactions contributing to atherosclerosis. Several risk factors have been implicated in the development of CAD like age, male sex, menopause, diabetes, hypertension and smoking. Although these conventional risk factors have for long been known to the development of CAD the exact mechanism of how they do this is subject of intense debate. There is also no common denominator which can assess the amount of risk that these risk factors expose an individual to. Another issue that complicates this matter further is the fact that a sizeable number of patients come to us with absence of all conventional risk factors. This has now forced us to explore newer risk factors for CAD, the most often studied now being inflammation. Inflammation now has firmly established itself as a risk factor for CAD .Initially thought to play only a minor role, it is now known to be critical in all the steps of atherosclerosis. Inflammation is also a factor where the risk can be easily 1. Prof. & Head Dept of Medicine 2. Assistant Professor Department- of Internal Medicine, Jawaharlal Nehru Medical College Belgaum [email protected] quantified, in this aspect several markers have been devised including HsCRP, IL-6, Myeloperoxidase etc. HsCRP however has now established itself as the most consistent, credible and economic amongst these factors. CRP is a widely known acute phase protein, produced by the liver in response to proinflammatory cytokines, and especially (interleukin,(IL)-6, tumor necrosis factor (TNF)ГЎ and IL-1b.1 Although CRP is a non-specific inflammatory marker, it appears to be a stronger predictor of cardiovascular risk compared to most of the other known circulating inflammatory molecules.2 CRP is the most reliable marker of inflammation. It is a 1, 35,000 Dalton non-immunoglobin protein, having five identical subunit. The name of the Creactive protein derives from the fact that it reacts with capsular polysaccharide of Streptococcus pneumoniae which was first noticed in 1930.3 CRP specifically recognizes phosphocholine, the hydrophilic part of phosphatidylcholine of the cell membranes, complexion of CRP to the cell wall activates complement via classical pathway thus stimulate macrophages and other cells to undergo phagocytosis. Recent studies have proved that, quantification of C reactive protein is superior than cytokine measurement (like IL-6, IL-Гџ1,TNFs) for detecting the presence of inflammation in intensive care patients. CRP is now the fore runner in the hunt for inflammatory markers and is subject to intensive research in numerous studies world wide. CRP is easily and inexpensively measured, and standardized high sensitivity assays are commercially available. Because CRP levels are stable over long periods of time, are not affected by food intake, and KLE HEALTH SCIENCE JOURNAL, JULY 2008 13 demonstrate almost no circadian variation, there is no need to obtain fasting blood samples for CRP assessment. This makes measuring CRP more convenient. With this background in mind we conducted this study to evaluate the association of traditional risk factor for HsCRP and to evaluate HsCRP and thus inflammation as an independent risk factor to CAD. Materials and Methods The study material consisted of 100 patients coming to KLE Hospital Belgaum with a history of coronary artery disease including chronic stable angina (SA), Unstable Angina(USA) and myocardial infarction. Patients were interviewed at admission according to a predetermined questionnaire after an informed written consent. Diagnosis was established based on history, electrophysiology and serum enzymes in accordance with standard diagnostic criteria. History of hypertension, diabetes, smoking, alcohol and other risk factors was taken. Past and current history of smoking was considered, those who smoked at least one cigarette per day during the preceding year were classified as current smokers and their status was reported as smokers and non smokers. Patients who consumed at least 50 g alcohol per week were considered as current drinkers and status was reported as drinkers and non drinkers. All patients with renal or hepatic diseases, autoimmune disorders and chronic inflammatory diseases were excluded as these conditions could influence HsCRP levels and give false values. Patients with fever and history of surgery in the past three months were also excluded. Laboratory assessment-once consent was taken patients blood sample was collected for cardiac enzymes, HsCRP and other biochemical parameters. Samples for HsCRP were collected and sent to laboratory as soon as possible .PatientвЂ™s serum HsCRP was measured by Particle Enhanced Turbidimetric Immunoanalysis (PETIA) method using Dade Behring UK kit. HsCRP values were reported in mg/L. The assay had sensitivity to detect as low as 0.5 mg/liter of CRP. Undetectable CRP values were recorded as 0.015 mg/liter. Levels greater than 1 were considered significant. Statistical methods-statistical analysis was done using standard statistical methods. Student t test was employed to assess the statistical significance of HsCRP in various risk factors. Other statistical methods were employed wherever necessary. Results There were totally 100 patients of whom 81 were males and 19 females. Of the 81 males there were 33 with stable angina, 19 with unstable angina and 29 with myocardial infarction. Of the 19 females there were 2 patients of stable angina, 6 with unstable angina and 11 with myocardial infarction. The proportion of males coming with stable disease was higher whereas in females those with unstable disease were higher. In our study maximum patients were in age group of 56-75 (45), maximum females were also in this age group. The mean HsCRP in males was 5.29 mg/lt and that in females was 7.58 mg/lt. In females the HsCRP was significantly higher in the peri-and immediate post-menopausal age group (36-55) (p=0.033) compared to the males. There was no significant association between age and HsCRP. In our study there were 39 patients who had diabetes, 33 had hypertension, 20 were smokers, 18 consumed alcohol and 37 had no habits. A significant number of patients had multiple risk factors (29). There were total of 39 diabetics and 61 non diabetics in the study .The mean HsCRP in diabetics was 7.23 mg/lt and that in non-diabetics was 5.61 mg/lt. The difference in the mean HsCRP values was quiet significant with p=0.040. In our study there were 33 hypertensives. The mean HsCRP in hypertensives was 7.65 mg/lt when compared KOTHIWALE, PRABHU: INFLAMMATION A NOVEL RISK FACTOR to non-hypertensives which was 5.54 mg/lt, this was statistically significant p=0.010. In this study there were 20 smokers the mean HsCRP in smokers was very high 7.16 mg/ lt but this was not significant when compared to non smokers that is 6.01 mg/lt with p=0.237. In our study 18 patients consumed alcohol and 82 did not. The mean HsCRP in those who consumed alcohol was 5.46 mg/lt which was less than that who did not 6.41mg/lt. This was however not significant p=0.348. Table 1- Showing Inflammation in Different Risk factors and their Statistical significance Risk Present HsCRP in mg/lt Absent HsCRP in mg/lt p= 7.23 sd 3.84 5.61 sd 3.78 .040 Hypertension 7.65 sd 4.09 5.54 sd 3.58 .010 Smoking 7.16 sd 3.99 6.01 sd 3.82 .237 Alcohol 5.46 sd 3.82 6.41 sd 3.87 .348 Diabetes When we analyzed patients who only had alcohol without smoking the statistical significance was much higher with mean HsCRP in the only alcohol group being 4.36mg/lt. Diagram 3-showing decrease in HsCRP with Alcohol In the study we also analyzed patients with no risk factors. There were 37 such patients 11 of whom had myocardial infarction, 19 had unstable angina and 7 had stable angina. Hs-CRP was independently higher in patients with myocardial infarction 9.39 mg/lt when compared to other groups. This difference was statistically significant (p=0.000). Discussion 100 cases of ischemic heart disease who were admitted during 2006-2007. The patients were interviewed at admission 14 for history, and thorough physical examination was then done. Relevant investigations were done like ECG, cardiac enzymes and ECHO, stress test and diagnosis established. Serum HsCRP was done once diagnosis was established to evaluate the inflammatory burden. Of the 100 patients that were studied 35 had stable angina, 25 had unstable angina and 40 had myocardial infarction. Of the total 100 patients there were 81 males and 19 females .33 males had stable angina 19 had unstable angina and 29 had myocardial infarction, of the females 2 had stable angina, 6 had unstable angina while 11 had myocardial infarction. Most females came with myocardial infarction while most males came with stable angina .The higher percentage of women coming with myocardial infarction could be explained by the fact that most female patients in this study were in the perimenopausal or postmenopausal age group (36-55) which is the age group at increased risk of unstable coronary disease .The mean HsCRP levels were also slightly higher in females than in males. This was however statistically insignificant. The higher HsCRP and thus higher inflammation could explain the vulnerability of postmenopausal women to unstable coronary lesions. Similar findings had been found in the WomenвЂ™s Health Study, 4 in which 57 healthy postmenopausal women who were in the highest CRP quartile (> 0.73mg/dL) had a fivefold higher risk for any vascular event and a sevenfold higher risk for MI or stroke compared with those in the lowest CRP quartile. This conclusion in our study could however be biased by the relatively less number of females included in the study. In a study4,5 for analysis of apparently healthy American men and women showed that overall, for each quintile increase in HsCRP, the adjusted relative risk of suffering a future cardiovascular event increased 26% for men (95% CI 11% to 44%; P<0.005) and 33% for women (95% CI 13% to 56%; P<0.001). In our study too males and females with higher HsCRP had more unstable lesions. Thus risk for coronary artery disease has a linear and directly proportional relation with serum hs-CRP. Women in post menopausal age are at increased risk with higher inflammation. The clinical significance of CRP is not genderspecific. However, women appear to have higher plasma CRP levels than men do. In the WomenвЂ™s Health Study, 4 women who subsequently had a cardiac event had a median CRP level of 0.42 mg/dL, compared with 0.28 mg/dL in those who remained event-free. In contrast, in the Physicians Health Study,6 the median CRP in men with cardiac events was 0.15 mg/dL, vs 0.11 in those who were event free. Such major difference was not observed in our study because of less number of female patients. In agreement however with the 15 above studies hs-CRP values were higher in women in our study when compared to males although this was not statistically significant. We had 39 patients who were diabetics, 33 had hypertension, 20 were smokers and 18 consumed alcohol. 37 patients had no traditional established risk factors for atherosclerosis.29 patients had multiple risk factors and thus could confound the inflammatory burden associated with any one risk factor. In our study HsCRP was found to be significantly higher in diabetics than in non-diabetic patients. Diabetics in our study had a mean HsCRP value of 7.23 mg/lt when compared to non-diabetics 5.61 mg/lt, this difference was statistically significant (p=0.040). This could be explained by increased oxidized lipids and glycation end products associated with vascular damage. Several studies have demonstrated strong links between diabetes and inflammation.7,8 The results of our study are in strong agreement with these studies. In one study in people with diabetes, CRP levels in the highest tertile (> 0.28 mg/dL) were associated with a twofold increase in cardiovascular mortality after adjusting for age, sex, and glucose tolerance status.9 King et al. 10 recently suggested an association between glycemic control and systemic inflammation, i.e., between HbA1c levels and HsCRP, based on data from 1,018 participants in the Third National Health and Nutrition Examination Survey. These studies prove that poor glycemic control is associated with increased inflammation and thus is an important risk factor for coronary vascular disease. The results of our study are in excellent agreement with these studies. In our study HsCRP was found to be significantly higher in hypertensives 7.65 mg/lt than non-hypertensives 5.54 mg/lt. Hypertension increases the shearing stress across the vascular endothelium, and is often associated with insulin resistance. This contributes to increased microvascular inflammation. Several studies have demonstrated strong association between hypertension and inflammation, which are in agreement with our study. In one study consisting of 424 non-diabetic patients at least 45-years-old who were being treated for hypertension, the HsCRP level was independently associated with arterial stiffness (p=0.001) after controlling for age, body mass index, systolic blood pressure (BP), heart rate, gender, HDL-cholesterol, triglyceride, glucose level and medications.11 In another study Systolic blood pressure increased 1.17 mmHg [95% confidence interval (CI), 0.60вЂ“ 1.74] and diastolic blood pressure 1.04 mmHg (95% CI, 0.64вЂ“ 1.45) from one CRP quintile to the next. After adjustment for sex, obesity, race, serum insulin level and family history of KLE HEALTH SCIENCE JOURNAL, JULY 2008 coronary heart disease, odds ratios for hypertension increased progressively across CRP quintiles. Participants in the highest CRP quintile were 2.35 times more likely to have hypertension than those in the lowest quintile (P=0.03, trend test P=0.04).81 Our study has also found significant association of hypertension with serum HsCRP. In our study smokers were found to have a slightly higher HsCRP (7.16 mg/lt) when compared to non-smokers (6.01 mg/lt). This difference was however not found to be statistically significant. This could be due to the fact that most smokers who were part of the study were only occasional smokers and also due to the fact that some of these patients (n=8) also consumed alcohol which could decrease the hsCRP levels. Several studies have demonstrated higher inflammation and thus increased risk for CAD in smokers, our study though demonstrating this finding could not find the association significant. The Multiple Risk Factor Intervention Trial (MRFIT) 12 reported a nearly threefold increase in cardiac mortality among healthy men (primarily smokers) in the highest quartile of CRP. It was also found that smokers had a much higher hs-CRP level when compared to non smokers. Although smokers in our study had high serum HsCRP levels we could not demonstrate their statistical significance. In our study we found a slight reduction in the levels of HsCRP in those who consumed alcohol (5.46 mg/lt) than in those who did not (6.41 mg/lt). This finding was however not found to be statistically significant. The presence of associated smoking may have increased the HsCRP values because when we analyzed patients who consumed alcohol but did not smoke, we found that HsCRP was significantly low (4.36 mg/lt) when compared to non alcoholics (6.4 mg/lt). However the number of such patients was considerably less(n=8) and thus could not be held statistically significant. A Sierksma et al 13 in their study demonstrated that plasma Creactive protein levels were decreased by 35% (p=0.02) and 12.4% (p=0.001), respectively, after 3 weeks consumption of alcohol, as compared to no-alcohol consumption. This study concluded that moderate alcohol consumption significantly decreased plasma C-reactive protein. Whether alcohol is cardioprotective needs to be established. Although our study showed slight reduction in hs-CRP levels in those who consumed alcohol statistical significance was not observed. In patients who consumed alcohol but did not smoke the HsCRP levels were much lower than those who both smoked and consumed alcohol, and this was in turn lower in those who only smoked this could mean that alcohol had a protective effect as it could bring down the atherosclerotic burden. KOTHIWALE, PRABHU: INFLAMMATION A NOVEL RISK FACTOR In patients with no other risk factors it was noticed that patients with myocardial infarction had significantly higher HsCRP levels. This difference was statistically significant. This could mean that hs-CRP could independently predict the myocardial infarction and thus it would act as an independent risk factor for myocardial infarction. Similar observation was also noticed in the WomenвЂ™s Health Study.4Several other studies have now also verified the capacity of HsCRP to independently predict the risk for myocardial infarction. This observation however needs further investigation as limited data is available in this regards. The AHA/CDC statement also recommends that in patients with stable coronary disease or acute coronary syndromes, hsCRP measurement may be useful as an independent marker of prognosis for recurrent events, including death, myocardial infarction.14 reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836вЂ“843. 5. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study.Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996;144:537вЂ“547. 6. Ridker PM, Cushman M, Stampler MJ. Inflammation, aspirin and the risk of cardiovascular disease in apparently heathy men. N Engl J Med. 1997;336:973979. 7. Rodriguez-Moran M, Guerrero-Romero F. Increased levels of C-reactive protein in noncontrolled type II diabetic subjects. J Diabetes Complications. 1999;13:211-215. 8. Crook MA, Tutt P, Simpson H. Serum sialic acid and acute phase proteins in type 1 and type 2 diabetes mellitus. Clin Chim Acta. 1993;219:131-138. 9. Jager A, van Hinsbergh VW, Kostense PJ. von Willebrand factor, Creactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoom Study. Arterioscler Thromb Vasc Biol 1999; 19:3071вЂ“3078. 10. King DE, Mainous AG, Buchanan TA, Pearson WS: Creactive protein and glycemic control in adults with diabetes. Diabetes Care 26:1535вЂ“1539, 2003 11. J. Kim, T. Kang, J. Kim, H. Seo; Significant association of C-reactive protein with arterial stiffness in treated non-diabetic hypertensive patients. Atherosclerosis,2007: 192; 401-406 12. Bautista LE, Atwood JE, OвЂ™Malley PG & Taylor AJ. Association between C-reactive protein and hypertension in healthy middle-aged men and women. Coronary Artery Dis 2004; 15: 331"336. 13. A Sierksma, MS van der Gaag, C Kluft and HFJ Hendriks: Moderate alcohol consumption reduces plasma C-reactive protein and fibrinogen levels; a randomized, diet-controlled intervention study. European Journal of Clinical Nutrition 2002:56, 1130вЂ“ 1136. 14. AHA/CDC scientific statement on markers of inflammation and cardiovascular disease. Circulation. 2003;107:499-511. Conclusion The present study was done to evaluate the relation of HsCRP and thus inflammation with traditional risk factors and to evaluate the independence of HsCRP as an independent risk factor for coronary artery disease. In the study inflammatory burden was higher in women when compared to males; this was significant as most women were in peri and immediate post menopausal age group. Females had more inflammatory burden and thus also more unstable lesions compared to males. Hs-CRP was found to correlate well with conventional established risk factors for coronary artery disease. Hs-CRP and thus inflammation was significantly higher in diabetics and hypertensives when compared to those who were non diabetics and non hypertensives. Hs-CRP was slightly higher in smokers than in non smokers and was slightly lower in those who consumed alcohol than in those who did not. In patients with myocardial infarction serum HsCRP was found to be an independent risk factor for even in those patients who had no established risk factors like diabetes, hypertension or smoking. References 1. Yeh ET, Anderson HV, Pasceri V. C-reactive protein: linking inflammation to cardiovascular complications. Circulation 2001;104:974вЂ“5 2. Blake GJ,Ridker PM. Inflammatory bio-markers and cardiovascular risk prediction. J Intern Med 2002;252:283вЂ“94. 3. Theodore Abernerthy, Thomas Francis, Study of the somatic C polysaccharide of pneumococcus . Journal of Experimental Medicine July 21 2007 4. Ridker PM, Hennekens CH, Buring JE, Rifai N. C- 16 KLE Health Sc. Jr. 2008; 1(1): 17-24 17 ORIGINAL ARTICLE SPERM RETRIEVAL RATE IN VARIOUS TESTICULAR HISTOLOGY USING NEEDLE ASPIRATION BIOPSY (NAB) R B Nerli1, Ravish I R2, Ashish Koura3, Nandeshwar Patil4 ABSTRACT The goals of surgical sperm retrieval are to obtain the best quality sperms possible, to retrieve adequate sperms both for immediate use and for cryo-preservation and at the same time to minimize damage to the reproductive tract so as not to jeopardize future attempts at sperm retrieval or surgical reconstruction. 40 patients undergoing testicular biopsy for evaluation of infertility formed the study group. Needle aspiration biopsy (NAB) of testis was done under local scrotal block . 18 G scalp vein needle was used to aspirate the seminiferous tubule. Histopathological examination showed hypospermatogenesis in 15%, Maturation arrest in 77.5%, Sertoli cell only in 3.75 % and atropic testis in 3.75%. The sperm retrieval rate was 84%, 64%, 24% and 0% respectively. Needle aspiration biopsy of testis is a safe, cheap and minimally invasive procedure. The sperm retrieval rates are similar to other surgical sperm retrieval procedures. Key Words : sperm retrieval , male infertility , needle aspiration biopsy during hydrocele surgery , with marked adhesions and Introduction the anatomy is totally distorted or during hernia The indications for obtaining a testicular biopsy have surgery the vas is injured leading to extensive injury expanded significantly over the last several following and damage, and tuberculous obstruction, affecting intracytoplasmic sperm injection (ICSI). The testicular biopsy multiple sites that cannot be corrected by surgery now has new and important diagnostic and therapeutic 2. obstructive azoospermia if reconstruction has failed implications for the infertile male. finding. Most patients with clinically apparent testicular failure may harbor sperms within 3. obstructive azoospermia if the couple chooses ICSI the testis. A testicular biopsy should be offered to these men rather than reconstruction if ICSI is an acceptable alternative for the couple. Before introduction of ICSI, the patient with testicular failure used to 4. non-obstructive azoospermia such as Sertoli cell be told that adoption and the use of donor sperm were the syndrome and Maturation arrest. only options available. The finding of mature sperm in the (Sperms may be found in the testes of 20% of men testicular biopsy of 30% of such men demonstrates that even with Sertoli cell syndrome and in 50% of men with men with severe disorders are potentially capable of fathering maturation arrest) 2. children with ICSI 1. 5. Failure to ejaculate during an assisted reproduction Surgical sperm retrieval is indicated in a variety of therapy (ART) cycle clinical conditions: 1. Obstructive azoospermia when reconstruction is not possible such as congenital bilateral vas aplasia, iatrogenic obstruction due to epididymal damage 1. Professor and Head 2. Assistant Professor M.ch 3. Post Graduate Student M.ch Department of Urology, KLES Kidney Foundation and Assisted Reproduction Centre, KLES Hospital, Nehrunagar, Belgaum, Karnataka, INDIA-590 010 Correspond to: e-mail:[email protected] 6. Total astheno/necrozoospermia. Use of testicular sperm is preferred on the assumption that even if they are immotile they may probably be viable 2. The method of sperm retrieval is dependent on presence of obstructive or non-obstructive azoospermia.. When testicular failure is due to non-obstructive azoospermia, the testis is the site of choice for retrieval. Epididymal Sperm retrieval techniques includes procedures such as 1. Microsurgical Epididymal Sperm Aspiration (MESA) 2. Open Fine Needle Aspiration (OFNA), and 3. Percutaneous Epididymal Sperm Aspiration (PESA) Testicular Sperm retrieval techniques include Testicular 18 KLE HEALTH SCIENCE JOURNAL, JULY 2008 Sperm Aspiration (TESA), and Needle Aspiration Biopsy (NAB)) Fig.2 Showing Seminiferrous tubule being extracted Needle Biopsy: using truecut needle or biopty gun. Conventional open Testicular Biopsy Microbiopsy techniques consist of Single Seminiferous Tubule biopsy or Microsurgical selective biopsy technique . While multiple techniques are available, it is preferable to choose the simplest and the least invasive procedure that procures sufficient sperms for ICSI. Needle Aspiration Biopsy (NAB) is a simple and safe procedure for procuring testicular sperm. NAB can retrieve enough sperms in case of obstructive azoospermia. A prospective study of patients with primary infertility undergoing testicular biopsy was undertaken and in whom, the sperm retrieval rate using NAB was assessed in different testicular histology. Materials and Methods Patients undergoing testicular biopsy for evaluation of infertility formed the study group. Testicular biopsy was done under local anaesthesia. Needle Aspiration Biopsy was done using an 18 G scalp vein needle. It was introduced into the testis, and suction applied using a 10 ml syringe .The needle was pushed in up to its hub, then pulled partly out (staying within the tunica) and then pushed in again. The needle was rotated 180Вє (to cut the tissue) and in and out motion of the needle was repeated. The tubing of the scalp vein set was then clamped and the needle withdrawn slowly Fig. 1 Showing needle biopsy being done with the help of 18 guage SV set and carefully. As the needle emerged from the scrotal skin, a strand of testicular tissue which was pulled out was grasped and pulled out till it snapped or a sufficient length of the tubule was obtained. An additional length of testicular tubule present within the lumen of the needle was flushed out gently. This specimen was placed in tissue media and sent to the Assisted Reproduction Center for processing. The specimen was divided into two parts, for sperm retrieval and for histopathological examination. Needle aspiration biopsy was carried out on both the testes and at 2 вЂ“4 sites on each side. The patient was observed for complications following biopsy. Results During the study period (2004) a total of 40 patients underwent testicular biopsy by the needle aspiration biopsy technique (NAB). The age of the patients ranged from 24 years to 41 years., with mean age of 33 years. All 40 patients approached us for primary infertility. The duration of infertility ranged from 1 year to 11 years. The mean testicular volume was 17 ml. 18 (45%) patients had an associated varicocele . 34 (85%) patients were azoospermic whereas the remaining six (15%) had severe oligoasthenospermia . The serum FSH values were raised in six (15%), whereas the serum LH values were raised in four (10%) patients. 240 biopsy specimens were obtained from the study group. The histopathological examination revealed hypospermatogenesis in 36 (15%) patients, Maturation arrest was noted in 186 (77.5%), Sertoli cell only (3.75%) and atropic hyalinization (3.75%) were other abnormalities. The sperm retrieval rate was 84 % in hypospermatogenesis, 64% in maturation arrest, 24% in Sertoli cell only and none in atropic histological states. NERLI, RAVISH, KOURA, PATIL: NEEDLE ASPIRATION BIOPSY None of the patients had evidence of bleeding, ecchymosis and infection at the site of biopsy. None of the patients required analgesics after 24 hours. Discussion The introduction of ICSI has offered the opportunity partially to alleviate male factor infertility due to nonobstructive azoospermia. The fantastic possibility of achieving a pregnancy with even only one available sperm led to the evolution of a number of methods aiming to obtain sperm from testicular tissue. However, studies have shown that independently of the method used, patients with hypospermatogenesis have an invariably high recovery rate, whereas in patients with maturation arrest, Sertoli cell only, or tubular hyalinization, recovery rates range from 11 вЂ“ 70% 2,3,4,5 . The goals of surgical sperm retrieval are 1) to obtain the best quality sperm possible, 2) to retrieve an adequate number of sperms for both immediate use and for cryopreservation , and 3) to minimize damage to the reproductive tract so as not to jeopardize future attempts at sperm retrieval or surgical reconstruction . The multiple open testicular biopsy technique initially described by Devroey provides good retrieval rates despite the need for multiple incisions in the tunica albuginea 6.This technique may create a potential devascularization problems, because of a limited blood supply underneath the tunica albuginea of the testis before its penetration into the testicular parenchyma. Removal of a large volumes of testicular tissue through a single incision has resulted in a similar retrieval rates with less risk to the testicular blood supply but might result in a greater loss of testicular tissue volumes 7. Testicular sperm extraction (TESE) is an effective method for sperm retrieval from men with non-obstructive azoospermia for ICSI. However, the conventional TESE technique requires multiple blind testis biopsies, with excision of large volumes (> 700mg) of testicular tissue and risks of permanent damage to the testis. Using optical magnification, a relatively avascular region of the testis can be located for an incision. The testicular blood supply can be easily identified under 20 to 25X magnification. The testicle can be inspected for the presence of a spermatogenically active region of normal seminiferous tubules, which contain many developing germ cells. Those tubules are usually larger and more opaque than tubules without sperm production 8. The efficacy of sperm retrieval, by sequential excision of microdissected testicular tubules (10mg or 2mm in length 19 of seminiferous tubule) has been shown by comparing results achieved using conventional techniques of TESE, or biopsies from adjacent areas of testicular tissue. Schlegal has shown that microdissection improved sperm retrieval rates from 45% to 63% in a sequential series of TESE attempts. Microdissected samples yielded on an average of 160,000 spermatozoa per sample in only 9.4 mg of tissue, whereas only 64,000 sperms were found in conventional biopsy samples that averaged 720 mg in volume 8. Using microdissection TESE technique for men with non-obstructive azoospermia, sufficient sperms can be retrieved with minimal excision of testicular tissue. 81% of men had sperm retrieval when the histopathology showed hypospermatogenesis, 42% in maturation arrest and 24% in Sertoli cell only histologic pattern 8. The disadvantage of Microdissection TESE is the need for a surgeon trained in microsurgery and the procedure being invasive. Minimally invasive techniques to obtain testicular sperm have been described. The testicular fine needle aspiration (TEFNA) approach may enable the operator to reach more testicular sites, without causing extensive testicular damage and consequently with lesser side effects. Sperm retrieval rates were 46.4% in patients with maturation arrest, 48.3% in patients with Sertoli cell only, and 66.6% in patients with tubular hyalinization. No major side effects, such as haematoma or infection were recorded 9. The advantages of percutaneous aspiration are that they can be performed with local anaesthesia , without open scrotal exploration and its attendant postoperative discomfort , and without microsurgical expertise . Percutaneous needle biopsy has also been used to procure testicular tissue for histopathological assessment as well as sperm retrieval. Cutting needles of varying gauges have been utilized to procure testicular tissue. This is a simple and relatively cost-effective procedure. Conclusion In our study Needle aspiration of testis was found to be a safe, minimally invasive procedure, which can be done under local anaesthesia, with minimal or no complications. The specimen obtained by NAB is sufficient to give a histopathological opinion as well as procure enough sperms for assisted reproduction techniques. The sperm retrieval rates are on par with other techniques used for sperm retrieval. Referencess 1. Kim ED, Gilbaugh JH III , Patel VP, et al. Testis biopsies frequently demonstrate sperm in azoospermic men with KLE HEALTH SCIENCE JOURNAL, JULY 2008 20 reovered by testicular fine needle aspiration in case of hypergonadotrophic azoospermia due to maturation arrest . Hum Reprod 1996:11; 769-771 significantly elevated follicle-stimulating hormone levels . J Urol 1997:157l; 44 2. Tournaye H, Liu J , Nagy Z et al: Correlation between testicular histology and outcome after intracytoplasmic sperm injection using testicular sperm . Hum Reprod 1996:11;127-132 3. Friedler S, Raziel A, Strassburger D . Testicular sperm retrieval by percutaneous fine needle aspiration compared with testicular sperm extraction by open biopsy in men with non-obstructive azoospermia. Hum Reprod 1997:12; 1488 вЂ“ 1493 4. 5. Ezeh UIO , Moore HDM , Cooke ID . Correlation of testicular sperm extraction with morphological , biophysical and endocrine profiles in men with azoospermia due to primary gonadal failure . Hum Reprod 1998:13; 3066 вЂ“ 3074 Lewin A , Weiss DB , Friedler S . Delivery following intracytoplasmic injection of mature sperm cells 6. Devroey P , Liu J , Nagy Z , Goossens A . Pregnancies after testicular sperm extraction and intracytoplasmic sperm injection (ICSI) in non-obstructive azoospermia. Hum Reprod 1995:10; 1457-1460 7. Schlegel PN , Palermo GD , Goldstein M . Testicular sperm extraction with ICSI for non-obstructive azoospermia . Urology 1997: 8. Schlegel PN. Testicular sperm extraction : microdissection improves sperm yield with minimal tissue excision . Hum Reprod 1999:14; 131-135 9. Lewin A, Reubinoff B, Porat-Katz A, Weiss D, Eisenberg V, Arbel R, Bar-el H and Safran A. Testicular fine needle aspiration :the alternative method for sperm retrieval in non-obstructive azoospermia . Hum Reprod 1999:14; 1785. KLE Health Sc. Jr. 2008; 1(1): 23-26 21 ORIGINAL ARTICLE GASTROINTESTINAL STROMAL TUMORS вЂ“ AN ANALYSIS OF 35 CASES Prakash R. Malur1, Punitha S2, Hema B Bannur3, Vijaalaxmi V. Suranagi4 Ranjit P. P. Kangle5, Ashok S. Godhi6 ABSTRACT Primary mesenchymal tumors of the Gastrointestinal tract(GIT) were originally classified as leiomyomas or leiomyosarcomas if they had a spindle cell morphology or leiomyoblastomas or leiomyosarcomas if they were of the epitheloid type.This was to indicate that they were of smooth muscle cell origin. But, recently debatable discussions on the histogenesis of these tumors are aplently. The term вЂњGastrointestinal Stromal TumorsвЂќ or GIST was coined as a histogenetically neutral term to aptly describe these lesions. They are believed to originate from the Interstitial Cells of Cajal(ICC) or related stem cells. In the present study, we have analysed 35 GI stromal tumors of which 16(45.71%) were of mesentery and retroperitoneum, 10 cases(28.57%) arising from the small intestine, 6(14.29%) from stomach and 4(11.43%) from colon. Histologically, 65.71% of the tumors were of spindle cell variety, 22.86% epitheloid and the remaining (11.43%) of mixed pattern.Additionally, 11 of the selected cases representing each of the locations were subjected to immunohistochemical stains of CD34, Vimentin, SMA and S-100. CD34 was expressed in 45.46% of the tumors, SMA in 72.73% ,Vimentin in 54.55% and 18.18% for S-100. Key words : GIST, stomach, small intestine, colon, mesentry, retroperitoneum Introduction Gastrointestinal stromal tumors represent a distinct and the most important subset of mesenchymal tumors of the GIT. These tumors are both phenotypically and genotypically different from true leiomyoma and usually express CD34, a haematopoietic progenitor cell antigen. CD117 is expressed in both benign and malignant GISTs, and in spindle and epitheloid subtypes in all locations2. The estimated incidence of GISTs in the United States is atleast 1000 new cases per year, and the actual incidence is probably much higher if very small (< 1 cm) lesion found incidentally during laparotomy for other conditions are included3. The age range at diagnosis is generally 40-80 years(median 58 years) and the incidence is slightly higher in men than in women3.GISTs may arise anywhere in the tubular GIT. In addition, identical lesions also occur in extra GI locations, principally mesentry, omentum and retroperitoneum 1,4-5.. 1. Professor & Head, Dept of Pathology 2. Post Graduate Student 3. Professor 4. Assistant Professor 5. Assistant Professor 6. Professor & Head of Surgery Department of Pathology, J.N.Medical College and KLE Dr. Prabhakar KoreвЂ™s Hospital, Belgaum 590 010 Correspondence to: E-mail: [email protected] Gastrointestinal stromal tumor is a well established entity. However we would be sharing our experiences with these tumors at J. N. Medical College & KLEвЂ™s Prabhakar Kore Hospital and Research Center. Material and Methods The present study comprised of 35 cases of GISTs . The most common complaint was pain in the abdomen(43.33%), followed by mass per abdomen(40%). Other non-specific symptoms included altered bowel habits(20%), abdominal fullness and loss of appetite(6.67% each). The tissue was processed and paraffin sections were stained by Haematoxylin and Eosin(H&E) stains.The tumors were assessed for cellularity, growth pattern, cell type, nuclear pleomorphism, mitotic figures, mucosal infiltration, skenoid fibres (extracellular eosinophilic collagen globules) and necrosis. The tumors were evaluated according to their sizes and mitotic counts(mitotic figures from 50 High Power Fields counted) and assessed for risk behaviour according to criteria laid down by Fletcher CDM et al6 into very low, low, intermediate or high risk categories. Additionally, Immunohistochemical stains were done on selected 11 cases representing all the sites. The panel of antigens detected were CD34, Vimentin, SMA and S-100. Cytoplasmic staining pattern was considered as positive for Vimentin, SMA and CD34 and both nuclear and cytoplasmic staining for S-100. KLE HEALTH SCIENCE JOURNAL, JULY 2008 22 Results Ages of the patients ranged from 1-85 years, and maximum number (70%) of cases were in patients above 30 years of age. Males were more affected than females. Maximum number of cases included tumors arising from the mesentery and retroperitoneum(16cases,45.72%). Ten cases(28.57%) were from the small intestine, 5(14.29%) from stomach and 4(11.43%) from the colon. The tumor size varied remarkably, the largest arising from the mesentery measured 30 cms in diameter. Twenty-two tumors (62.86%) were more than 5cms in size. Grossly, the tumors varied from grayishwhite, slightly pinkish to yellowish in colour. Twelve tumors had areas of haemorrhage, 8 had gross necrosis, 4 showed areas of cystic degeneration.(Fig-1). Only 1 case showed calcification. Fig 1: Mucosal infiltration was not evident in any of the tumors. Ten cases(28.57%) showed presence of skeinoid fibres. Two cases of GISTs from the stomach and 3 from mesentery and retroperitoneum had mitotic count of <5/50 HPF and 3 cases from stomach , 2 each of small intestine and colon and13 from retroperitoneum and mesentery had mitotic counts >5/50 HPF.. Table I : Categorization of tumors into different risk behaviour. Site Very Low Risk Low Risk Intermediate Risk High Risk Stomach 2 _ _ 3 Small Intestine 2 2 2 4 Colon _ 1 2 1 Retroperitoneum _ _ 4 12 Total 4 3 8 20 Mesentry and Table I shows the tumors categorized into different risk behaviour. Table II : Immunohistochemical analysis of 11 cases. Site CD34 SMA S-100 Vimentin Fig-1: A-Mass from the ileum- Cut surface shows irregular lobulated mass with haemorrhage and necrosis B-Mass from the mesentery- Cut surface shows variegated appearance with areas of haemorrhage and necrosis. Microscopically, 23 tumors(65.71%) showed spindle cell pattern, 8(22.86%) epitheloid and remaining 4 cases(11.43%) ,a mixed pattern(Fig-2). Fig-2: Stomach 2/2 2/2 0/2 2/2 Small Intestine 0/1 0/1 1/1 0/1 Colon 2/3 2/3 0/3 1/3 Mesentry and Retroperitoneum 1/5 4/5 1/5 3/5 Immumohistochemical analysis of the selected 11 cases is shown in Table II. Fig-3: MALLUR, PUNITA, BANNUR, SURANAGI, KANGLE, GODHI:GASTROINTESTINAL STROMAL TUMORS Fig-3: A-CD34 staining-Tumor cells showing cytoplasmic positivity (X200;IHC for CD34). B-SMA staining showing cytoplasmic positivity (X200;IHC for SMA) C-S-100 protein positivity of the spindle cells(X400;IHC for S-100) D- Vimentin positivity within the cytoplasm of the spindle cells(X200;IHC for vimentin) Discussion Intra-abdominal spindle cell lesions are uncommon and often present a diagnostic challenge. An important group of such lesions are the GISTs. Other spindle cell lesions include fibromatosis, various sarcomas such as leiomyosarcoma, liposarcoma and malignant peripheral nerve sheath tumor and in women, endometrial stromal sarcoma7. GISTs form a distinctive group of mesenchymal neoplasms showing differentiation towards the interstitial cells of Cajal8. Older adults are most at risk for GIST, very rarely they occur in children and young adults (sometimes connected with CarneyвЂ™s triad) or on a familial basis9. Stomach accounts for 60%, small intestine 35%, rectum, esophagus, omentum and mesentery for less than 5% of cases10. Familial GISTs occur in patients with inheritable germ line KIT or Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) mutations 10. Morphologically GISTs vary from cellular spindle cell tumors to epitheloid or mixed epitheloid and spindle cell variants8.Most GISTs express Kit (CD117)(95%),CD34(70%) aend heavy Caldesmon(80%), whereas 25% are positive for SMA, 10% for S-100 protein and less than 5% for desmin. Tumor size and mitotic activity are best predictive prognostic features; small intestinal tumors behave more aggressively than gastric tumors with similar parameters. Mutations in kit juxtramembrane domain (exon 11) are the most common GISTs of all sites, whereas rare kit extracellular domain (exon 9) Ala 502-Tyr 503 duplication is specific for intestinal GISTs 10. In our study, 45.46% of tumors expressed CD34, 54.55% vimentin, 18.2% S-100 and 72.73% SMA. Miettinen et al 11 used CD34 to identify GIST from leiomyoma and Schwannommas. Features associated with an adverse outcome includes tumor size eвЂќ 7 cms, high cellularity, mucosal invasion, high nuclear grade, mitotic counts eвЂќ 5/50 HPF, mixed cell type and presence of a myxoid background and/or absence of stromal hyalinization. Surgical wide excision without lymphnode dissection remains surgery of non-metastatic GISTs. Imatinib mesylate, a вЂњTyrosine kinaseвЂќ inhibitor given in a dose of 400-600 mg/ 23 day has shown a response rate of 40-70% as a targeted therapy when administered before surgery 12. Type of mutations that affect the response to Imatinib includes GISTs expressing missence exon 11 show 89% response whereas others show a response of 40%. Compound 11248 (Sunitinib) targeting multiple tyrosine kinases (KIT, PDGFRA, FLT3 and VEGF-R) are showing better response in nonresponders, recurrences and irresectable masses. Radiotherapy and chemotherapy are not helpful 14. Conclusion GISTs include most tumors previously diagnosed as leiomyoma, leiomyoblastoma and leiomyosarcoma. They are composed of spindle or epitheloid cells. Tumor size and mitotic count indicate their risk status. Categorising stromal tumors of the GIT is important since newer modalities like Imatinib are available as specific targeted therapy. The cell of origin is not fully understood, but resemblance to the ICC, expression of some smooth muscle markers and occurrence outside the GIT suggest the origin from multipotential cells that can differentiate into Cajal and smooth muscle cells. References 1. Miettinen M, Monihan J M, Sarlomo-Rikala M et al. Gastrointestinal stromal tumors/ smooth muscle tumors (GISTs). Primary in the omentum and mesentry : Clinicopathologic and Immunohistochemical stydy of 26 cases. Am J Surg Pathol 1999;23:1109-1118. 2. Sarlomo-Rikala M, Kovatich A J, Barusevicius M, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 1998 Aug;11(8):728-734. 3. Dematteo R P, Heinrich M C, W AвЂ™ el M, El-Rifai, Demetri G. Clinical management of gastrointestinal stromal tumors: Before and After STI-571. Human Pathol 2002;33:466-477. 4. Reith J D, Goldblum J R, Lytes R H et al. Extragastrointestinal stromal tumors: An analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol 2000;13:577-585. 5. Weiss S W, Goldblum J R (Eds): Extragastrointestinal stromal tumors. in Weiss S W, Goldblum J R (Eds) Enzinger and WeissвЂ™s Soft Tissue Tumors. 4th Edn, St. Louis, Mosby, 2001:750-768. 6. Joss J R. Tumors of the Intestine and Anus. In Christopher D M FletcherвЂ™s Diagnostic Histopathology of Tumors. 2nd Edn. Edinburgh: KLE HEALTH SCIENCE JOURNAL, JULY 2008 24 7. 8. 9. 10. 11. Harcourt, 2000:395-391. 12. Al-Nafussi A and Wong NA CS. Intraabdominal spindle cell lesions : A review and practical aids to diagnosis. Histopathol 2001 38;387-391. Van Oosterom A T, Judson J, Verneij J et al. Safety and efficacy of Imatinib in metastatic gastrointestinal tumors. A Phase I study. Lancet 2001:358;1421-1423. 13. Pisters PWT, Bramwell VHC,Rubin BR, Sullivan B OвЂ™. Sarcomas of soft tissue In Abeloff MD,Armitage JO, Niederhuber JE, Kastan MB, McKenna GW (eds).Clinical Oncology. 3rd Edn, Philadelphia, Pennsylvania : Elsevier Churchill Livingstone, 2004:2608-2609. 14. Devita V, Hellman S, Rosenbera S. Principles and Practice of Oncology. 7th Edition Lippincott 2005 14501060. Wasag B, Dubiec-Rychter M, Pauwels P, Stul M, Vranckx H, VanOosterom A, Hagemeijer A, Sciot R. Differential expression of KIT/PDGFRA mutant isoforms in epitheloid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site. Modern Pathology 2004;17:889-894. Miettinen M, Majidi M, Lasota J. Pathology and diagnostic criteria of GISTs: a review. Eur J Cancer 2002 : 385 supp5;39-51. Miettinen M, Lasota J. GISTs:review on morphology molecular pathology, prognosis and differential diagnosis. Arch Pathol Lab Med. 2006 :130;1466-1478. Miettinen M, Virolainen M, Sarlomo-Rikala M. GISTsvalue of CD34 antigen in their identification and separation from true leiomyoma and Schwannomas. Am J Surg Pathol 1995;19(2):207-216. Acknowledgements: We acknowledge Dr.Reena Bharadwaj for helping us to undertake the immunohistochemistry in this study. We also acknowledge the Principal, JNMC and the Medical Director and CEO, K L EвЂ™s Prabhakar Kore Hospital and Medical Research Center for allowing us to publish this article. KLE Health Sc. Jr. 2008; 1(1): 25-30 25 ORIGINAL ARTICLE STUDY OF PROSTATIC INTRAEPITHELIAL NEOPLASIA AND ITS ASSOCIATION WITH BPH AND CARCINOMA PROSTATE Sunita Y. Patil1, Meena N. Jadhav2, S. B. Patil3, B. R. Yelikar4 ABSTRACT The search for the precursors of prostatic adenocarcinoma has focused on two lesions, prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH). The present study aimed to identify PIN and to study its association with benign prostatic hyperplasia (BPH) and adenocarcinoma . It also focused on different architectural patterns of high grade (HG)PIN. A total of 200 specimens of prostate in the form of biopsy, whole prostatectomy and transurethral resection were studied. The tissue was routinely processed and stained. PIN was seen in 36.6% of cases of BPH and 82.6% of cases of adenocarcinoma. LG PIN was more commonly associated with BPH (27.3%) and HGPIN with adenocarcinoma (66.6%). HGPIN is a most likely precursor of adenocarcinoma The most commonly observed pattern of HGPIN was tufting (40%). Pattern of PIN has no prognostic significance. Key Words : Premalignant lesions, PIN, BPH, Prostatic carcinoma. Introduction Premalignant lesions have been well documented in a number of organs including uterine cervix, endometrium, gastrointestinal tract, and respiratory tract. In case of prostate it is a recent development. The search for the precursors of prostatic adenocarcinoma has focused on two lesions, prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (AAH).1 The term prostatic intraepithelial neoplasia is characterized by severe cytologic changes within the preexisting ducts and acini, and atypical adenomatous hyperplasia (AAH) is characterized by architectural changes, with the proliferation of small glands but without significant cytologic atypia.2 PIN represents the putative precancerous end of the 1. Assistant Prof, Dept of Pathology, J.N.Medical College, Belgaum-590010. 2. Professor, BLDEAвЂ™s Shri B.M.Patil Medical College, Bijapur. 3. Professor & Head Department of Urology, BLDEвЂ™S SBMDMC 4. Professor & Head Department of Pathology, BLDEвЂ™S SBMP, Bijapur Correspond to: Dr. Sunita Y. Patil, Email вЂ“ [email protected] morphologic continuum of cellular proliferation, within the ducts, ductules and acini. The lesion was first described by Mc Neal in 1965 and was more precisely characterized in 1986 by Mc Neal and Bostwick, at which time the entity was called, вЂ�Intraductal dysplasia.вЂ™ The term PIN was endorsed by consensus at 1989 International Conference. This consensus also proposed that PIN be divided into two grades (low grade and high grade), to replace the previous three grade system. ( PIN 1 is considered Low grade and PIN 2 & PIN 3 are considered High grade).3 PIN 1 consists of an architecturally benign prostatic acini, ducts, or ductules, lined by cytologically atypical cells. PIN 1 is characterized by increased nuclear size with increased variability of nucleolar size, along with irregular, focal crowding and multilayering. In PIN 2 there are similar features of PIN 1 with the additional finding of hyperchromatism and occasional small prominent nucleoli. The hallmark of PIN 3 is the finding of numerous large prominent nucleoli. The distinction between low and high grade PIN is the finding of prominent nucleoli in high grade PIN.4. A few studies have shown that PIN is the most likely precursor of prostatic adenocarcinoma than AAH. Foci of low grade PIN were seen in a significant number of cases of nodular hyperplasia and high grade PIN mostly in cases of prostatic adenocarcinoma1,3. The other lesion of AAH has shown weaker association with carcinoma1. PIN displays various architectural patterns5, but there 26 KLE HEALTH SCIENCE JOURNAL, JULY 2008 are very few reports on the architectural patterns of PIN. Hence this study was conducted to identify PIN and to study its association with nodular hyperplasia and carcinoma prostate The specimens were extensively studied for the presence and association of PIN with nodular hyperplasia and carcinoma prostate. GleasonвЂ™s grading system was used for carcinoma prostate. Set criteria were used for the diagnosis of PIN Materials & Methods Results The present study consisted of 200 prostate specimens, received in the Department of Pathology, B.L.D.E.AвЂ™s Shri B.M Patil Medical College, Hospital & Research Centre Bijapur, during the period from August 2001 to July 2006 for histopathological evaluation. Patients who underwent biopsy, transurethral resection of prostate (TURP) or whole Prostatectomy for BPH and Carcinoma, were included in the study and specimens with a diagnosis of acute prostatitis and prostatic abscess were excluded from the present study. Detailed clinical history was obtained and the findings of clinical examinations were noted in each case. In a prospective study the specimen were examined for gross details and then embedded. The tissue was routinely processed and stained by Hematoxylin and Eosin (H & E). Special stains like PAS & reticulin stain were performed whenever required. In the retrospective study, blocks and slides were collected for evaluation and studied similarly. 200 prostate specimens received in the Department of Pathology were taken up for the study and were placed into either of the following categories. Category I : Nodular hyperplasia Category II : Adenocarcinoma Category III : Nodular hyperplasia with adenocarcinoma together. All the cases were thoroughly examined for the presence of foci of PIN and belonged to the following categories: Category I 179 cases (89.5%) Category II 11 cases (5.5%) Category III 10 cases (5%) Prostatic intraepithelial neoplasia (PIN): Diagnostic criteria.3 Features Low grade PIN (Formerly PIN 1) High grade PIN (Formerly PIN 2 and PIN 3) Architecture Epithelial cell crowding and stratification, with irregular spacing. Similar to low grade PIN; more crowding and stratification; 4 patterns; tufting, micropapillary, cribriform and flat. Nuclei Enlarged with considerable size variation. Enlarged; some size and shape variation. Chromatin Normal Increased density and clumping. Nucleoli Rarely prominent. Occasionally to frequently large and prominent, similar to invasive carcinomas, sometimes multiple. Basal cell layer Intact. May show some disruption. Basement membrane Intact Intact. High grade PIN displays four architectural patterns; tufting, micropapillary, cribriform and flat 5 PATIL, JADHAV, PATIL, YELIKAR: STUDY OF PROSTATIC INTRAEPITHELIAL NEOPLASIA AND CP 27 Fig 1. A microphotograph of LGPIN showing stratification, nucleomegaly and variation in nuclear size.(H & E x 400) Fig 2. A microphotograph of HGPIN showing tufting pattern, nucleomegaly and prominent nucleoli(arrow). (H &E x 400) 84 cases (42%) showed the presence of foci of PIN. In category I, 65 cases (36.3%) showed presence of PIN where as category II revealed PIN in 9 out of 11 cases (81.8%). In Category III, Foci of PIN were observed in all 10 cases (100%) (Table 1). Table 1 Frequency of PIN in various categories Category FIG 3. A microphotograph of HGPIN showing flat pattern. (H & E x 200) Total No PIN cases No of +ve cases % P. value 1 179 65 36.3% 2 11 9 81.8% 3 10 10 100% Total 200 84 42% <0.001 PIN was found to be more closely associated with carcinoma. Statistically the association of PIN with carcinoma was found to be highly significant (P < 0.001). The grades of PIN in nodular hyperplasia and adenocarcinoma in diffierent categories is shown in table 2. Table 2 Low grade PIN was more commonly associated with Grades of PIN in cases of nodular hyperplasia and adenocarcinoma, placed in various categories Category Total LGPIN No cases No of +ve cases % I 179 49 27.3% II 11 3 27.2% III 10 2 20% Total 200 54 27% HGPIN P. value >0.05 No of +ve cases % 16 8.9% 6 54.5% 8 80% 30 15% P. Values <0.001 KLE HEALTH SCIENCE JOURNAL, JULY 2008 28 nodular hyperplasia and high-grade PIN with carcinoma. High grade PIN revealed 4 morphological patterns, i.e tufting, micropapillary, cribriform and flat, all with nucleomegaly and prominent nucleoli.(Table 3) Table 3 Architectural patters of High grade PIN Category Tufting Micropapillary Cribriform Flat No of cases % No of cases % No of cases % No of cases % 1  6 37.5% 5 31.25% 1 6.25% 4 25% 2  3 50% 1 16.6% 0 0% 2 33.3% 3  3 37.5% 2 25% 1 12.5% 2 25% 30 12 40% 8 26.6% 2 6.8% 8 26.6% These patterns merged with each other from gland to gland although fields with one single pattern were observed occasionally. Tufting was the commonest pattern observed (40%), second commonest patterns were micropapillary and flat (26.6%) and the least was cribriform (6.8%). Various other lesions were also identified with some normal anatomical structures that constituted as a differential diagnosis for PIN. These included portions of seminal vesicles, basal cell hyperplasia, atrophy associated hyperplasia, cribriform hyperplasia, squamous metaplasia, transitional metaplasia etc. Out of these, foci of basal cell hyperplasia was most commonly observed lesion. It was seen in 73 cases (40.7%) in category I and 2 (20%) in category III. Discussion Early diagnosis of prostate cancer is an important issue among urologists and pathologists. A multidisciplinary approach using digital rectal examination (DRE), transrectal ultrasound and prostate specific antigen (PSA) assay has been adopted for early detection of prostate cancer. Despite these efforts, 33% of the patients still present with advanced stage of the disease.1 Identification of premalignant lesions assume importance in this context. Lately, PIN and AAH have been recognized as putative premalignant lesions of prostate. However the supportive evidence for PIN is much greater than AAH, with High grade PIN being the most likely precursor, arising in the peripheral zone6. Association of PIN with BPH & Adenocarcinoma : A wide variation in the incidence and prevalence of PIN in nodular hyperplasia has been reported in the world literature, ranging from 12.8% to 43%,7,8. The association of PIN with adenocarcinoma has always been observed to be higher, as is evident from earlier studies, where it was observed to be 76-100%1,8. Our study revealed an intermediate frequency of PIN in BPH cases (36.3%), between the lowest and highest observed results. Earlier studies9 have reported low grades of PIN in 1481% cases of nodular hyperplasia and higher grades of PIN in carcinomatous prostates. In the present study, low grade PIN was the most commonly observed grade in cases of nodular hyperplasia. This was consistent with other studies The present study also showed higher grades of PIN in cases of adenocarcinoma of the prostate reflecting the greater possibly of high grade PIN as a precursor lesion to carcinoma prostate. The percentage of HGPIN in carcinoma in the present study could be compared to other studies. However in 2 cases, carcinoma was diagnosed on biopsy specimen where foci PIN could not be identified. Rekhi et al 1 observed a significant association (88.2%) of HGPIN with cases of nodular hyperplasia and adenocarcinoma. The present study also revealed a similar association of HGPIN with cases of nodular hyperplasia and carcinoma (Category III). High grade PIN has a high predictive value as a marker for adenocarcinoma and its identification in biopsy specimens warrants a further search for concurrent invasive carcinoma. Davidson et al 10 found adenocarcinoma in 35% of subsequent biopsies from patient with previous diagnosis of PIN, compared with 13% in a control group without PIN. HGPIN, patients age and serum prostate specific antigen (PSA) concentration are all highly significant predictors of cancer, but PIN alone increases the risk 15 fold above those patients PATIL, JADHAV, PATIL, YELIKAR: STUDY OF PROSTATIC INTRAEPITHELIAL NEOPLASIA AND CP without PIN and provides a highest risk ratio. Others have reported a high predictive value of PIN for cancer ranging from 38-100%. These data underscore the strong association of PIN and adenocarcinoma and indicate that, diagnostic follow up is needed31. Architectural patterns of high grade PIN; PIN exhibits a variety of architectural patterns, although four patterns arecommon; Tufting, Micropapillary, Cribriform and Flat are common. In studies by Bostwick et al 5 and Qian et al12, tufting was the commonest pattern and flat and cribriform pattern were least common types respectively. In the present study, tufting pattern was the commonest (40%) and cribriform was the least common type, which was consistent with the above two studies. However in studies by Wilkox et al 13 and Rekhi et al1, cribriform pattern was the most common type and they also found another pattern ie, comedo pattern alone (10% Rekhi et al) or in combination with solid pattern (7% or cribriform / comedo 4% Wilcox et al). Comedo-necrosis was more commonly seen in cases of HGPIN with higher GleasonвЂ™s grading and this pattern is considered to represent cancer13. However in other studies 1,5,12 GleasonвЂ™s grade of tumour did not correlate with the pattern of high grade PIN, suggesting that currently there are no recognized prognostic differences between the architectural patterns of HGPIN and their recognition appears to be only for diagnostic utility 12. In the present study also GleasonвЂ™s grade of the tumour did not correlate with the pattern of HGPIN. Other associated lesions: Basal cell hyperplasia: Several other associated lesions and normal anatomical structures entered as a differential diagnoses, like a portion of seminal vesicle, foci of basal cell hyperplasia, squamous and transitional metaplasia etc. According to Rekhi et al 1, the two common associated lesions were, basal cell hyperplasia and chronic prostatitis. In the present study also, basal cell hyperplasia was the commonest associated lesion. Bostwick and Srigley have given a detailed account of such lesions. They also stated that, basal cell hyperplasia commonly merges with areas of nodular hyperplasia 14. However according to Grizzle basal cell hyperplasia could have a role as a precursor of adenocarcinoma, on the basis of sequential changes15. Other studies also share the idea of considering basal cell hyperplasia as an important precursor lesion to prostate carcinoma of basaloid type 16. Basal cell hyperplasia as the commonest other lesion in the present study and it implies 29 that, it could have a role as a precursor to adenocarcinoma, as it can be explained on the basis of sequential changes of basal cell hyperplasia вЂ™! low grade PIN вЂ™! High grade PIN вЂ™! Cancer1. Biopsy remains the only definitive method for detecting PIN and early invasive cancer. If all procedures fail to identify co-existent carcinoma, close surveillance and follow up are indicated. However identification of PIN in the prostate should not influence or dictate therapeutic decisions 11. Conclusion PIN is seen both in cases of BPH and adenocarcinoma. Low grade PIN is more commonly seen in cases of nodular hyperplasia. High grade PIN is more commonly seen in cases of adenocarcinoma of prostate. HGPIN may be a precursor of prostatic carcinoma and HGPIN has high predictive value for adenocarcinoma. Pattern of PIN has no prognostic significance. Basal cell hyperplasia could have a role as a precursor to adenocarcinoma. The presence of HGPIN in biopsy specimens warrants a further search for the concurrent invasive carcinoma and patients need a close follow up observations and investigations to rule out existence of carcinoma especially in the peripheral zone. Acknowledgement We acknowledge the Principal, BLDEA Shri B.M. Patil Medical College and Research Centre for allowing us to carry out the work and publish this article, References 1) Rekhi B, Jaswal TS, Arora B. Premalignant lesions of the prostate and their association with nodular hyperplasia and carcinoma prostate. Ind J Cancer 2004:41;60-62. 2) Bostwick DG, Amin MB. Prostate and seminal vesicles. in:Linder J, Damjanov I. Eds. AndersonвЂ™s Pathology. Vol 2. 10th edition. Missouri, Mosby; 1996:2207-2215. 3) Drago JR, Mastifi FK, Lee F. Introductory remarks and workshop summary. Urology 1989: 6; 2-3. 4) Bostwick DG, Brawer MK. Prostatic Intraepithelial neoplasia and early invasion in prostate cancer. Cancer 1987:59; 788-794. 5) Moore CK, Karikehalli S, Nazeer T, Fisher HAG, Kaufman RP and Mian BM. Prognostic significance of high grade neoplasia and atypical small proliferation KLE HEALTH SCIENCE JOURNAL, JULY 2008 30 in the contemporary era. J Urol 2005:173; 70-72 6) Jones EC, Young RH. The differential diagnosis of prostatic carcinoma: Its distinction from premalignant lesions of the prostate gland. Am J Surg Pathol 1994:101; 48-64. Atypical adenomatous hyperplasia. Cancer 1996:78; 330-336. 12) Srigley J Toth P, Hardwick RWJ, Atypical histological patterns in cases of benign prostatic hyperplasia. Lab Invest 1989:60;90A. 7) Sakr WA, Haus GP, Cassin BJ, Pontes JE and Crissman JD. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993: 150; 379. 13) Wilcox G, Sob S, Chakraborty S, Scardino RT, and Wheeler TM. Patterns of high grade prostatic intraepithelial neoplasia with clinically aggressive prostate cancer. Hum Pathol 1998:29; 1119-1123. 8) Mc Neal JE, Bostwick DG. Intraductal dysplasia: A premalignant lesion of the prostate. Hum Pathol 1986:17; 64-71. 14) 9) Brawer MK. Prostatic intraepithelial neoplasia: A premalignant lesion. Hum Pathol 1992: 23 ;242-248. Srigley JR, Bostwick DG. Premalignant lesions in Bostwick DG, Roth LM, Editor. Contemporory issues in surgical pathology No 15, Pathology of the Prostate. London: Churchill Livingstone. 1990 :37-59. 15) Grizzle W. Prostatic intraepithelial neoplasia: Will it help doctors pin-point prostate cancer? J Natl Cancer Inst 1996: 88;1023-1024. 16) Bankoff H, Stein V, Romberger K. Multidirectional differentiation in the normal, hyperplastic and neoplastic human prostate: Simultaneous demonstration of cell specific epithelial markers. Hum Pathol 1994:25; 42-46. 10) 11) Hausser O, Epstein JI, Amin B, Heitz PU and Hailemariam S. Cell proliferation, apoptosis, oncogene and tumour suppressor gene status in adenosis with comparison to Benign prostatic hyperplasia, prostatic intraepithelial neoplasia and cancer. Hum Pathol 1999:30; 1077-1086. Bostwick DG. Prospective origins of prostate carcinoma: Prostatic intraepithelial neoplasia and KLE Health Sc. Jr. 2008; 1(1): 31-34 31 ORIGINAL ARTICLE A HOSPITAL BASED PROSPECTIVE STUDY OF CASES OF ENDONASAL DACRYOCYSTORHINOSTOMY (EnDCR) Anil S. Harugop1, R. S. Mudhol2, M. Maheswaran3 ABSTRACT The objectives of this study are to report the results of Endonasal Dacryocystorhinostomy (EnDCR) and the role of silicon intubation in EnDCR in Indian population. Patients aged from 2-72 years underwent EnDCR- 240 without silicon intubation and 50 with silicon intubation. Patients were followed up for average 18.6 months in first group and 5.2 months in second group. Outcome was evaluated subjectively and objectively. There was symptomatic imporvement in 93.3% cases in those who had EnDCR without silicon intubation.The procedure was successful in 96% of cases with silicon intubation. EnDCR is safe and has potential advantages in Dacryocystitis cases. The use of silicon intubation in nasolacrimal pathway helps in maintaining the pathway of rhinostomy with better results. Key words вЂ“ Endoscopic dacryocystorhinostomy , silicone intubation. Introduction DCR is an operation that has been used for more than past 100 years. Toti originally described the traditional external approach in 1904. The original intranasal approach was described by Caldwell in 1883 and it was modified later by West and Halle in 1914, using microscope for visualization1. In last two decades, with the introduction of high-resolution endoscopes for paranasal surgery, EnDCR has begun to gain popularity. McDonogh and Meiring described the first modern endonasal DCR procedure in 19892. Since this description, a number of modifications using laser have also been described as a useful tool in EnDCR4. In addition to avoiding a skin incision and without disrupting the medial canthal anatomy and function, EnDCR enables the surgeon to identify and correct common intranasal causes of DCR failures, such as adhesions, an enlarged middle turbinate, or an infected ethmoid sinus. EnDCR has definitive role in failed ExtDCR cases and revision cases. Most of the studies have showed good result and excellent patient acceptability. Hence in this study we report the results of En DCR and role of silicon intubation in Indian population. 1. 2. 3. Asso Prof Prof & Unit Head Resident Dept. of ENT & Head and Neck Surgery, K.L.E.вЂ™s University, Jawaharlal Nehru Medical College, Belgaum. Correspond to: E-mail: Materials and Methods Patient selection A Prospective study was conducted on 290 patients diagnosed to have chronic dacryocystitis between Jan 2002 to July 2007 in KLESH & MRC and DH, Belgaum. The cases with presaccal block, previous lacrimal trauma, were excluded from the study. Patients who required other nasal procedures like septoplasty, release of adhesion, and clearance of agar nasi were included in the study. Revision surgery was done in 13 patients- 8 patients were subjected to revision surgery after external DCR, and 5 after endonasal DCR. Silicon stenting was performed in randomly chosen 50 cases. The data regarding the patientвЂ™s age, sex, addition procedures, type of surgery, (with or without silicon intubations) side of operation and follow up were depicted in Table-1. Table 1. Descriptive characteristics Sex Male Female Age (y) Mean Range Laterality B/L Right Left Additional Procedure Septoplasty Release of adhesion Follow up (months) avg Without Silicon Stent With Silicon Stent 66(22.8%) 174(60%) 18(6.2%) 32(11%) 40.5 2-72 45.46 19-73 42(17.5%) 107(44.6%) 91(37.9%) 8(16%) 22(44%) 20(40%) 17 - 3 2 18.6 5.2 KLE HEALTH SCIENCE JOURNAL, JULY 2008 32 Diagnosis The diagnosis was made by the patientвЂ™s historyrecurrent infections of the lacrimal sac and intermittent or permanent epiphora were the most frequent symptoms. Diagnostic procedures include catheterization and irrigation of the lacrimal duct. In selected cases, Jones dye test and dacryocystogram were done for confirmation the NLD obstruction. The preoperative rhinologic examination consisted of inspection and palpation of the medical canthus, nasal cavity to note, anatomical deformities and nasal diseases. Methods Age of the patients ranged from 2-72 years. (Fig.1& fig.2) Out of 290 cases, 287 cases were operated under local anesthesia with Premedication (Pentazocine, Atropine, Promethazine) and packing of nasal cavity with pledgets soaked in 4% lignocaine with 1:30,000 adrenaline half an hour before the start of the procedure. This helps in vasoconstriction, gives mucosal anesthesia and bloodless field. General anaeshesia was used in 3 paediatric patients2yrs, 5yrs and 11yrs. The 4mm 30- degree endoscope with camera was used for the procedure, except when a septoplasty was required. The average time required was 30-45minutes in Plain EnDCR as well as EnDCR with stenting cases. Most of the cases bleeding was minimal and nose was packed with medicated ribbon gauge for 24 hrs. The patients were discharged the following day and postoperatively antibiotic, antiinflammatory, local decongestant, antibiotic steroid eye drop, saline nasal douching & gentle digital massaging of sac region were advised. Fig.2: 72yrs man externally failed case Surgical Technique The mucosa of the lateral nasal wall in the region of the maxillary line was infiltrated with 2% lignocaine and adrenaline (1 in 100,000). The incision was made in lateral wall of nose with help of sickle knife or 12no blade, starting just anterior to the axilla of middle turbinate make horizontal incision 0.8cm then vertically 1cm to complete the square window. Mucosa was resected. Under endoscopic control, the entire medial bony covering of the sac could be removed using 2mm Kerrisons punch. A sickle knife was used to open the sac. Kerrisons punch was used to remove the lateral half of the sac. Stenting was performed in randomly chosen 50 cases. A silicon tube was inserted through upper and lower puncta and both ends were taken out from the nasal cavity and tied with several knots (4-6 knots) (Fig, 3,4). Nasal packing was place for 24-hours. The tubes were usually left in place for 3 months. Endoscopic suction clearance was done weekly for one month, then monthly for 6 months to prevent crusting / adhesions. Fig. 3: Stent in situ- externally. Fig.1: Child of 2yrs with bilateral disease HARUGUP, MUDHOL, MAHESWARAN: A HOSPITAL BASED PROSPECTIVE STUDY OF (EnDCR) 33 Eight patients (16%) presented with bilateral disease, among them three patient underwent bilateral surgery. 22 (44%) patients presented with right sided and 20(40%) patients presented with left sided disease. 5 patients had a mucocele. Three patient required septoplasty and in two case adhesion band was released. We are able to analyse all patients three month postoperatively with average follow up for 5.2 months. (Fig. 5,6). Fig. 4 :Stent in situ-internally(after3wks). Results The surgical outcome was evaluated both subjectively and objectively. In the subjective assessment the patients were asked to grade the degree of epiphora relief on a 5-point scale: symptom free, significantly improved, slightly improved, no improvement, and worsening. They were asked whether they were disturbed by silicon stent. Any declaration of improvement by the patient was considered as success. The procedure was successful in 48 (96%) patients in 3months follow up (Table-2). Premature stent extrusion (due to foreign body sensation and granuloma) was noted in two patients and the procedure is unsuccessful in same patient. Minimal granulation tissue was observed in 5 cases but resolved with local steroid and antibiotic. Three patients, who developed postoperative dacryocystitis, was successfully treated with IV antibiotics and showed symptomatic improvement without any premature stent removal. Complications of surgery were not encountered in any of the cases. The objective assessment examined the visibility of rhinostomy opening, the presence of granulation tissue at the rhinostomy opening, presence of synechiae, and whether methylene blue was observed in the nasal cavity after instillation to the eye, either spontaneously or after pressure was applied over lacrimal sac, or no flow. EnDCR without intubation: 240 EnDCR procedures were performed without lacrimal intubation. Of these, 174 were female and 66 were male, with a ratio of m: f = 1:2.6.There ages ranged from 2yrs to 72 yrs, with a mean age of 40.5 years. Forty two (17.5%) patients presented with bilateral disease among them twenty six patients underwent bilateral surgery.107 (44.6%) patients presented with right sided and 91 (37.9%) patients presented with left sided disease. 36 patients had a mucocele. 17(14.11%) patients required septoplasty to gain access to the area of the lacrimal sac and duct. We were able to analyse all patientвЂ™s 3months postoperatively with average follow up for 18.6 months. At three months follow up there was symptomatic cure in 224 (93.3%) patients (Table-2), all of whom reported a dry, comfortable eye. EnDCR with intubation: 50 EnDCR procedures were performed with lacrimal intubation. Of these, 32 were female and 18 were male, with a ratio of M: F = 1:1:78.There ages ranged from 19 to 73 years, with a mean age of 45.46 years. Fig. 5 :Rhinostomy after 2months of stent removal. Fig. 6 Rhinostomy after 6 months of stent removal Table 2. Outcomes of surgery. No.of Patients Successful Failure Without Silicon Stent 240 224(93.3%) 16(6.7%) With Silicon Stent 50 48(96%) 2(4%) Discussion In the present study most of the patients were in 30 to 50 years of age, youngest was 2 years old and oldest was 73 yrs old. M: F ratio was found to be 1:2.5 (84:206) and our data correlate well with studies of Heike (1994), Young & Hardman (1998). KLE HEALTH SCIENCE JOURNAL, JULY 2008 34 A 93.3% success rate in cases of EnDCR without intubation and 96% success rate in cases of EnDCR with intubation were recorded in this series when the patients were reviewed three months after the procedure. Review of literature shows an 82 to 95% success rate with EnDCR. The success rates depend upon providing a wide intranasal stoma with removal of adequate bone around the stomal area reducing the chances of postoperative stenosis and adhesions. A septoplasty may sometimes be required to gain access. Inadequate bony removal is the commonest cause of postoperative stomal stenosis. Conculsion Silicon stenting was used in 50 cases. Granulation tissue was observed in 5 cases and acute dacryocystitis observed in three case. All of them were managed by application of local steroid and or antibiotics, except in one case in which, there was premature stent extrusion due to excessive granuloma and complaints of foreign body sensation, failure of surgery was observed. Bousch observed a strong relationship between stent retention and success rate. In this present series patients were accessed both subjectively and objectively. 1. West and Halle, Intranasalen operation am tranen sack. Arch Laryngolrhinol 1914: 28; 256-66. 2. Mc Donogh M, Meiring JH. Endoscopic transnasal dacryocystorhinostomy. J Laryngol Otol 1989:103;585-7 3. Massaro BM, Gonnesing RS. Harris GJ. Endonasal laser dacryostorhinostomy. A new approach to nasolacrimal duct obstruction. Arach Ophthalmol 1990: 108;1172-6. 4. Metson R Endoscopic surgery for lacrimal obstruction Otolaryngol Head Neck Sug 1991: 104;473-9. 5. Zhou W, Zhou M, Li Z, Wang Endoscopic Intranasal DCR in forty five patients Clinical Medical Journal (Engl) 1996: 109 ;747 -8. 6. Halis Unlu H, Asim Aslan, Baris Toprak Comparison of surgical outcomes in primary Endoscopic dacryocystorhinostomy with and without silicone intubation. Ann Otol Rhinol Laryngol 2002: 111; 704-9. 7. Mangal singh, Vimal Jain, S.C. Gupta, S.P. Singh (2004): Intranasal Endoscopic DCR (END-DCR) in cases of dacryocystitis. Indian journal of otolaryngology and Head and Neck surgery 2004: 56; 177-183. The advent of endoscope has made EnDCR a preferred method. A good knowledge of the anatomy and variations in the lateral nasal wall is essential. Good functional results of endoscopic DCR can be explained by the fact that pumping action of orbicularis oculi muscle remains intact. Silicon tubing has been proposed to maintain the patency of the fistula by impending fibrous closure during the postoperative healing period. It also has been shown that patients adequately retained silicon tubes performed better than patients who failed to retain silicon tube after EnDCR. EnDCR has potential advantages over the standard external DCR in case of chronic dacryocystitis with nasolacrimal duct obstruction like avoiding external scar, better cosmetic acceptibility, maintains pumping action and easy in revision cases. In addition, the use of silicon stenting in nasolacrimal pathway helps in maintaining the pathway of rhinostomy and also better results. Regular follow up is important. References KLE Health Sc. Jr. 2008; 1(1): 35-37 35 SHORT COMMUNICATION SEPIAPTERIN REDUCTASE DEFICIENCY MASQUERADING AS HYPOTINIC CEREBRAL PALSY ( Report of two cases from India) Gurusidheswar M. Wali1, Nenad Blau2, Thony Beat3 ABSTRACT Sepiapterin reductase def iciency (SRD) is a recently described rare, treatable disorder of tetrahydrobiopterin metabolism with cognitive delay and L-dopa responsive movement disorder. We describe the first two biochemically confirmed cases of SRD from India. Both patients had global hypotonia as the dominant symptom and were initially diagnosed as cases of hypotonic cerebral palsy as the dominant symptom and were initially diagnosed as cases of hypotonic cerebral palsy/ Response to Ldopa therapy was striking and persistent. We suggest that patients either children or adults presenting as вЂ�cerebral palsyвЂ™ shuld be evaluated for possible dopa responsive motor disorder especially when neuroimaging is normal. Key words: Sepiapterin reductase deficiency, Dopa responsive dystonia, hypotonic cerebral palsy Introduction Sepiapterin reductase (SR) deficiency is an under recognized potentially treatable disorder of tetrahydrobiopterin (BH)-4 metabolism without hyperphenylalaninemia (1). OIt presents as an autosomal recessive type of dopa-responsive dystonia. Additional imporatant clinical findings include mental retardation, hypotonia, hypertonia, hypersomnia, and oculogyric crisis. It may be misdiagnosed as cerebral palsy and remain untreated unless clinically suspected, and appropriate CSF studies are to be carried out. The disorder has been described recently and only twenty cases have been reported from all over the world till date (2). The purpose of this report is to describe the first two confirmed cases of sepiapterin reductase deficiency from India. These cases were initially considered as cases of hypotonic cerebral palsy and did not receive any specific therapy. Patient 1: The patient aged 10 years were the eldest of 3 sibs born to consanguineous parents. His younger sister was normal while the youngest one was affected similary and reported below as patient 2. He was born of full term normal delivery and had no history of birth injury or asphyxia. He had mild psychomotor delay; head holding was achieved at 8 1. Prof of Neurology, J.N. Medical, Belgaum. 2 & 3 Laboratory of clinical chemistry & Prichemistry University........ Correspond to: Dr. G. M. Wali, e-mail:[email protected] months while sitting was possible at 2 years of age. During this period he was noticed to be floppy and weak. He attempted walking at 4 years, but fell frequently due to postural instability and poor muscle tone. He had fidgety and tremulous movements of the limbs and the peri-oral region along with dysarthria. Additional observations by the parents included the presence of frequent oculogyric crisis and hypersomnia. All his symptoms showed diurnal fluctuation and sleep benefit. He suffered a single generalized convulsion at the age of 7 years. At the time of clinical examination his psychological assessment revealed a global IQ of 36%. Attention deficit was present. he was almost chair bound with global hypotonia an weakness and needed help to move a few steps. The cumulative effect of his physical and psychological deficits hindered his regular schooling. MRI scan of the brain was normal, while EEG showed frequent spike waves discharges arising from the right temporoparietal region. Treatment with L-dopa was tried considering the possibility of atypical dopa responsive dystonia. Levo-dopa/ carbidopa (25 mg/2.5 mg) administered twice daily produced a dramatic improvement in his motor condition within a day. He was able to stand erect and move around without help. Disturbing choreiform movemetns appeared following initiation of therapy requiring down titration of the dose. At the end of one year he maintains a persistent good motor activity enabling him to attend school by himself. Patient 2: The patient was youngest sister of patient 1, and was examined at the age of 11 months. She was born of full term uneventful delivery and cried soon after birth. Head holding and sitting was delayed. She was noted to be floppy and unable to take turns. She head hypersomnia and slept 14- KLE HEALTH SCIENCE JOURNAL, JULY 2008 36 16 hours a day. She manifested oculogyric crisis. Mild sleep benefit was present. There was no historyof seizures. MRI scan of the brain was normal. EEG showed evidence of occasional low voltage spikes arising from the right parietal region. Treatment with low dose levo-dopa/carbidopa (12.5 mg/1.25 mg) administered twice daily produced dramatic improvemtn in her motor funtion. She was able to sit erect by hersilf and the hypersomnia reduced significantly. The oculogyric crisis stopped completely. However she developed dyskinesia in the form of repeated tongue protrusion which however did not affect her swallowing. At one year of followup she was able to walk around freely and has attained good cognition. CSF biochemical analysis: Considering the features of dopa-responsive motor disorder occurring as an autosomal recessive condition, suggested the diagnosis of Sepiaperin reductase deficiency. The values of the various parameters are shown in the table 1. Table 1 : Biogenic amines and Pterins in CSF Patient 1 (10 years) Patient 2 (<1 year) Test value (nM) Ref. range value (nM) Ref. range 5 HIAA 6 88-178 12 114-336 HVA 103 144-801 189 295-932 HVA/5HIAA 17 1.5-3.5 16 1.5-3.5 Bio 36 10-30 45 15-40 5 HIAA: 5 Hydroxyindoleacetic acid; HVA: Homovanilic acid; Bio: Biopterin DNA mutation analysis: Analysis of genomic DNA for the SPR gene including sequence analysis of all three exons and adjacent regions for the patients and of exon two and adjacent regions for the relatives was performed. The analysis revealed the mutation p VI38D which was found in the homozygous state in the two patients and in the heterozygous state in the parents. It was absent in the healthy sibling. The SR mutant allele v138D has not been described previously and may be responsible for the reduced enzyme activity. Discussion SR deficiency is a recently described example of paediatric neurotransmitter disease (PND). This group of diseases comprises of genetic disorders that affect the synthesis, metablism and catabolism of neurotransmitters in children and persist into adulthood. These inborn errors of metabolism affect the central nervous system in children and if lect untreated can lead to severely compromised neurological function. Dopa-responsive dystonias (DRD) comprise a subgroup of PND-related to tetrahydrobiopterin-4 metabolism. The well recognized examples of autosomal dominant dopa-responsive dystonia (Segawa disease) and the recently described rare autosomal recessive SR deficiency are examples of BH-4 metabolism disorder presenting without hyperphenylalaninaemia and thus cannot be detected by neonatal screening tests for phenylketonuria (PKU). These diseases are eminently treatable with supplementation of dopamine. Due to lack of awareness and lack of screening tests, they are quite often misdiagnosed as cases of cerebral palsy and remain untreated. The major clinical features of SR deficiency as observed in few reported cases (3-7) include developmental motor delaym cognitive impairment, hypotonia, hypertonia, dystonia, bulbar weakness, oculogyric crisis and excessive salivation. Diurnal fluctuation and sleep benefit of the motor symptoms is often present. All cases show good and eprsistent motor response to low dose of levo-dopa/carbidopa therapy. The cognitive changes may improve partially. Appearance of unwanted choreic movements with levodopa/carbidopa therapy is common requiring dose titraion. Biochemical diagnosis of SR deficiency requires elaborate analysis of the CSF which is performed in a few selected laboratories. CSF of patients with SR deficiency shows elevation of total biopterin dihydrobiopterin and oxidized biopterin while neopterin is normal (1). Enzymatic dignosis of SR deficiency is only possible with skin fibroblast cultrue. The chromosomal localization of SRD is on 2p14.p12. Mutations in the SPR gene are detected in all reported patients and their family members. Only than mutations from a single founder, most are homozygous, unique mutations (5). Our patients are the first two cases of SR deficiency to be reported from India. Interestingly both the sibs were initially diagnosed as cases of hypotonic cerebral palsy and received no specific therapy. Both the patients presented with global hypotonia as the dominant symptom without significant dystonia. Diurnal fluctuations, sleep benefit, oculogyric crisis, hypersomnia, and good response to levodopa trial revealed that the positive effect of levo-dopa/ carbidopa was persistent and that further cognitive impairment was prevented. DNA analysis revealed a new hitherto WALI, BLAU, BEAT:SEPIAPTERIN REDUCTASE DEFICIENCY 37 undescribed, mutation in the SRP gene. 4. As a corollary to the clinical observations made in these two cases, a trial of levo-dopa/carbidopa is justified in patients who are considered to have hypotnic cerebral palsy especialy when diurnal variation, sleep benefit, oculogyric crisis and hypersomnia coexist and brain scans are normal. The subset of cases responsive to levo-dopa/carbidopa therapy can be considered for CSF biochemical analsysis and DNA mutation studies. Elzaouk L, Osmani H, Romstad A, Friedman J, Maccolin M, Thony B, Blau N. Sepiapterin reductase deficiency: molecular analysis in a new case presenting with neurotransmitter deficiency without hyperphenylalaninemia in Milstein S, Kapatos G, Levine RA, Shane B (eds) Chemistry and bBiology of Pteridines and folates. Norwell, Kluwer Acdemic Publishers 2002: 277-284 5. Neville BG, Parscandalo R, Ferrugia R, Felice A. Sepiapterin reductase deficiency: a congenital doparesponsive motor and cognitive disorder Brain 2005: 128; 2291-2296 6. Abeling NG, Duran M, Dakker HD, Stroomer L, Thony B, Blau N, Booij J. The TP sepiapterin reductase deficiency: an autosomal recessive DOPA responsive dystonia. Mol Genet Metabol 2006: 89; 116-120 7. Friedman J, Hyland K, Blau N, MacCollin M. Doparesponsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency. Neurol 2006: 67; 2032-35. References 1. Blau N, Bonafe L, Thony B. Tetrahydrobiopterin deficiencies without hyperphenylalaninemia. Diagnosis and genetics of Dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 2001: 74; 172-185 2. BIODEF (International database of tetrahydrobiopterin deficiencies ) at www.bh4.org 3. Bonafe L, Thony B, Penzien JM, Czarneck B, Blau N. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin dependent monoamine neurotransmitter deficiency without hyperphenylalaninemia Am HJ Hum Genet 2001: 69; 269-277 KLE Health Sc. Jr. 2008; 1(1): 38-48 38 REVIEW ARTICLE PREDIABETES : EARLY DETECTION AND INTERVENTIONS Mallikarjun V. Jali ABSTRACT Prediabetes is a precursor condtion to type-2 diabetes mellitus and is characterised by higher normal blood glucose levels. Most individuals with prediabetic state eventually develop diabetes. Early recognition is extremely important to initiate early itnerventions to stop the onset of diabetes and related complications. Intensive lifestyle changes are effective and are to be encouraged. Key words: Prediabetes, type-2 diabetes, impaired glucose tolerence, impaired fasting glucose Introduction Diabetes is a global epidemic and it has been posing a biggest threat ever witnessed with devastating human, social and economic consequences. The disease claims as many lives per year as HIV/AIDS and places a severe burden on healthcare systems and economies everywhere with heaviest burden falling on low- and middle-income countries.1 Diabetes Mellitus (DM) is a metabolic disorder of multiple etiologies that is characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism resulting from the defects of insulin secretion, insulin action, or a combination of both.2 Type-1 diabetes is due to a virtually complete lack of endogenous pancreatic insulin production, whereas in type 2 diabetes, the rising blood glucose results due to a combination of genetic predisposition, unhealthy diet, physical inactivity, and increasing weight with a central distribution of abdominal adiposity resulting in complex patho-physiological processes under the shadow of environmental factors. DM is associated with the development of specific long-term organ damage due to micro-vascular related diabetic complications. Patients with diabetes are also at a particularly high risk for cardiovascular, cerebrovascular, and peripheral artery disease3. It is estimated that 246 million people worldwide have diabetes 1, 2, 4, representing roughly 6% of the adult population (20-79 age group) and the number is expected to reach some 380 million by 2025, representing 7.1% of adult population (International Diabetes Federation-IDF). Perhaps, even greater concern is the simultaneous dramatic increase in the Dr. M. V. Jali Chief Consultant Diabetologist, Director, Diabetes Centre; Medical Director & CEO K.L.E.S. Prabhakar Kore Hospital & Medical Research Centre, K.L.E.University Belgaum 590010, India. E-mail: numbers with Prediabetes. This is occurring not only in adults but, in poorly quantified number, of children and adolescents, which is a great concern. Prediabetes 3 is also called impaired glucose tolerance (IGT), or impaired fasting glucose (IFG), depending on the test used to diagnose it. Prediabetes is a precursor condition to type 2 diabetes, and it is characterized by higher normal blood glucose levels. The transition from the early metabolic abnormalities that precede diabetes impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), to diabetes may take many years. However, current estimates indicate that most individuals (perhaps up to 70%) with these pre-diabetic states eventually develop diabetes 4, 5. At some stage in the pre-diabetic state, the risk of a cardiovascular disease (CVD) event is modestly increased.6 Between 1997 and 2006, eight major clinical trials examined whether lifestyle or pharmacologic interventions7 would prevent or delay the development of diabetes in populations at high risk by virtue of having IFG and/or IGT. The study populations often had other recognized risk factors for diabetes including obesity, a prior history of gestational diabetes, or a positive family history of diabetes 8. All of these trials demonstrated reductions in the development of diabetes of 25 to 60% over the period of follow-up. The largest reductions (60%) were accomplished with lifestyle interventions aimed at weight loss and increasing physical activity and with thiazolidinediones. 9, 10 Lesser degrees of reduction (25 to 30%) have been achieved with other drugs.11 The availability of intervention3 that have been shown to decrease the development of diabetes has enthused consideration, whether such interventions should be recommended and implemented, in whom, and under what circumstances. History Although the exact origin of the term вЂ�PrediabetesвЂ™ is imprecise, the earliest known mention was made by Maranon12 in the early 1940вЂ™s, later in humans by Camerini-Davalos13 in KLE HEALTH SCIENCE JOURNAL, JULY 2008 39 1951 in relation to pregnancy. In the 1960вЂ™s, вЂ�PrediabetesвЂ™ was more familiarly used to describe patients with no glycosuria and a usually normal fasting blood sugar level, but having a diabetic abnormality in standard glucose tolerance tests. In contrast and around the same time, the British Diabetic Association recommended that вЂ�PrediabetesвЂ™ should only be used retrospectively to describe the life of a diabetic before their diagnosis was confirmed. The World Health Organization (WHO) replaced the term вЂ�PrediabetesвЂ™ in the 1980вЂ™s with statistical risk classes. The term impaired glucose tolerance (IGT) was developed in 1979-1980 (WHO) 4, and it was only later in 1997 and 1999 (American Diabetes Association (ADA) and WHO 4, 14 the term impaired fasting glucose (IFG) was brought into use. вЂ�PrediabetesвЂ™ 14, as it is currently known, owe its rebirth to Tommy G Thompson, the US Secretary of State for Health, in 2002. It was basically used to describe people with either IGT or IFG, in an attempt to warn Americans of their high future risk of developing diabetes. This modern use of вЂ�PrediabetesвЂ™ solely relates to people with IGT and IFG. Some people have both IFG and IGT. IFG is a condition in which the blood sugar level is high (100 to 125 milligrams per deciliter or mg/dL) after an overnight fast but not high enough to be classified as diabetes. The former definition of IFG was 110 mg/dl to 125 mg/dl. IGT is a condition in which the blood sugar level is high (140 to 199 mg/dL) after a 2-hour oral glucose tolerance test, but is not high enough to be classified as diabetes 15. вЂњPrediabetesвЂќ вЂ” WhatвЂ™s in a Name? The term Prediabetes (which embraces impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]) has had a make sure history, as Professor George Alberti described in the opening lecture of the 1st International Congress on Prediabetes and the Metabolic Syndrome 16, held in Berlin in 2005. On one hand, it may be inappropriate to use the term Prediabetes when there is only a 50% chance of developing diabetes in the next 10 years following diagnosis. Moreover, the definition of Prediabetes does not include some people at risk of developing diabetes, such as those with a family history of diabetes or other normoglycemic risk groups of certain ethnic origins. On the other hand, the American Diabetes Association (ADA) 17, and other national organizations recognize the difficulty of communicating to the general public the concept of a high-risk situation, and the term Prediabetes is certainly easier to promote than IGT and/or IFG. Prediabetes is a relatively new clinical diagnosis and the new term 15 when introduced in 2002 by the Department of Health and Human Services (DHHS) and ADA, the sole reasons for renaming Prediabetes from its former clinical name of impaired glucose tolerance was to highlight the seriousness of the condition and to motivate people to get appropriate treatment. Revised definition means millions more have вЂњPreDiabetesвЂќ. вЂњPre-diabetesвЂќ is a condition that raises a personвЂ™s risk of developing type 2 diabetes, heart disease, and stroke 7 17 . The U.S. Department of Health and Human Services (DHHS) and the ADA estimated that 41 million Americans between the ages of 40 and 74 years are living with Prediabetes, and most remain unaware of their condition. Without intervention and appropriate treatment, people with Prediabetes are at risk for developing type 2 diabetes within 10 years. 16 вЂњPrediabetesвЂќ and the Metabolic Syndrome are extremely prevalent and persons with вЂњPrediabetes and the Metabolic SyndromeвЂќ 16 are at high risk for diabetes and CVD and they are the ideal target population for prevention or intervention programmes. In 2005,вЂ™ PrediabetesвЂ™ was given a global overview 14, in terms of isolated impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), or a combination of the two, and highlighted the necessity to conduct an oral glucose test before diagnosing IGT. Prevalence data from a number of countries has generally found that IGT is more prevalent than IFG. The epidemiology of Prediabetes On a global level,2 the type 2 diabetes epidemic in 2025 will comprise of 97 million known cases, and an equivalent number of unknown cases, with around 314 million people having IGT. By 2025, it is estimated that IOT will rise to approximately 500 million people raising concerns about a potential cardiovascular epidemic. (Table 1) Table 1 JALI:EARLY DETECTION AND INTERVENTIONS 40 TABLE 1 : 3rd edition, (IDF-Diabetes Atlas, International Diabetes Federation, 2006) From global projections14 the major changes will occur in Eastern European states, the Middle East and India. Between 10% and 25% of Western populations may already have IGT. For example, Australian Diabetes, Obesity and Lifestyle Study published in 2000, 18 the overall prevalence of diabetes was 7.4%, but the combined prevalence of IFG and IGT was more than twice as high, at 16.4%. These glucoseintolerant, but non-diabetic, individuals represent a reservoir of potential new diabetes cases. Approximately 4 to 9% of individuals with impaired glucose tolerance go on to develop type 2 diabetes each year. Declining levels of physical activity, increasing caloric intake and consequent rises in the rate of obesity are leading to increase in the number of people with IGT from most ethnic and cultural backgrounds.16 Countries in the Middle East and Gulf States 16 too have a high prevalence of IGT, as do India and China 19 (Table 2) . Table 2 : South East Asia вЂ“ diabetes prevalence and future projections 1 2003 2005 Total Adult Population (millions) 705 1081 No. with Diabetes (millions) 39.3 81.6 Diabetes Prevalence (%) 5.6 7.5 No. with IGT (millions) 93.4 146.3 IGT Prevalence (%) 13.2 13.5 Table 2: 3 rd edition, (IDF-Diabetes Atlas, International Diabetes Federation, 2006) More than 50% of people with diabetes will come from Asia over the next decade 14. In developed countries, the major increase in the number of people with diabetes will be among the young and middle-aged. However, additional data from SГ¶derberg and Ramachandran from Sweden and India, respectively, suggest that the вЂ�PrediabetesвЂ™ epidemic of IGT / IFG may be reaching a plateau in certain countries 16. In addition, gender differences are evident between IGT and IFG with women generally having a higher prevalence rate of IGT whilst men have a higher prevalence of IFG. On the contrary, the prevalence of IGT is higher in women than men in all age groups except over the age of 60 in Asian populations and over the age of 80 in the European groups 18, 19. The unabated rise in the prevalence of childhood obesity has been accompanied by the appearance of a new paediatric disease, type 2 diabetes. Little is known about IGT in paediatrics.41 In adding up to differences in the overall prevalence between IGT and IFG, there are now clear evidence of differences in phenotype between the two categories. Genetic marker studies in South Indians showed the complex nature of genetic pathology in type 2 diabetes. Certain mutations of candidate genes related to insulin secretion and insulin action such as Calpain 10, Vitamin D, Insulin receptor substrate-1, UCP2, UCP3, Apo-lipoprotein D gene are associated with the disorder. However; the nature of the major gene(s) responsible for the disease remains elusive. 20 IGT and IFG are not equivalent metabolically, and it is therefore not surprising that there are differences in their prevalence and in the people categorized as having one or the other. In most populations, IGT is considerably more prevalent than IFG 16, 19. Furthermore, there is limited overlap between the categories - the majority of people with IGT do not have IFG, and the majorities with IFG do not have IGT. Hence, the terminology of вЂ�isolated IGTвЂ™ and вЂ�isolated IFGвЂ™ has been given 3. Thus, IFG and IGT identify substantially different segments of the population with impaired glucose regulation (Table 3). The mechanisms of IGT and IFG are likely to be different; IFG is thought to be associated with a defect in insulin secretion whilst IGT is thought to be associated with hyperinsulinaemia or insulin resistance. Thus вЂ�PrediabetesвЂ™ may encompass two different mechanisms of disease, necessitating the need for further research into both the mechanism and outcome of these two states. Table 3: Classification of Glucose Tolerance States 3,23 State FPG level (mg/dl) 2-h plasma ucose in OGTT (mg/dl)* IFG 100 to 125 <200 100 to 125 <140 <126 140 to 199 <100 140 to 199 Combined IFG/IGT 100 to 125 140 to 199 NGT <100 <140 Isolated IFG IGT Isolated IGT *Standard 75-g OG Significance of IFG and IGT in Indians One of the earliest studies in India21 during 1986-87, in an urban population in a township in south India, found the prevalence of 5% diabetes and 14 had impaired glucose KLE HEALTH SCIENCE JOURNAL, JULY 2008 41 tolerance. A family history of diabetes was present in 16 of the 34 subjects with diabetes and nine of the 15 with impaired glucose tolerance. India has the highest number of IGT, prevalence of IGT and IFG are also high in India and southeast Asia in general 16, 19.which is expected to increase from 85.6 million (2003) to 132 million by 2025. Table 3: Diagnostic Blood Sugar Values Table 4 : South East Asia вЂ“ diabetes prevalence and future projections 1 2003 2005 Total Adult Population (millions) 705 1081 No. with Diabetes (millions) 39.3 81.6 Diabetes Prevalence (%) 5.6 7.5 No. with IGT (millions) 93.4 146.3 IGT Prevalence (%) 13.2 13.5 Prediabetes: Early recognition, its clinical significance and risks Early stages of glucose intolerance (Prediabetes) are not only forerunners of diabetes but also carry high risk for cardiovascular diseases. Indians have high insulin resistance background in adding together to the presence of all other cardiovascular risk factors. IGT occurs at a much younger age in Indians 19 and they are predisposed to get diabetes more or less a decade prior as compared to the rest of the high risk population worldwide. Early recognition is of extreme importance in initiating early interventions to stop the onset of diabetes related complications. Prediabetes is diagnosed with one of two blood testsвЂ”a fasting plasma glucose test or a two-hour oral glucose tolerance test (OGTT). The fasting plasma glucose test requires an eight-hour fast (no food or drink except water), after which is blood drawn. It is usually done in the morning. For an oral glucose tolerance test, a patient is given a drink of 75 grams of glucose, and blood is taken two hours later. The following laboratory values are the ADA practice guidelines for the diagnosis of Prediabetes and Diabetes. 17, (Table 3 & 4) Table 4. Classification of Glucose Tolerance States3 State FPG level (mg/dl) 2-h plasma glucose in OGTT (mg/dl)* IFG 100 to 125 <200 100 to 125 <140 <126 140 to 199 <100 140 to 199 Combined IFG/IGT 100 to 125 140 to 199 NGT <100 <140 Isolated IFG IGT Isolated IGT *Standard 75-g OGTT. 1. An oral glucose tolerance test plasma glucose value between 140 to 199 mg/dl (7.78 - 11.06 mmol/l) at 2 hours post-glucose load (indicating impaired glucose tolerance). 2. The ADA recommends that men and women aged 45 and older, especially those that are overweight (i.e., BMI of 25 or higher), be screened for Prediabetes. 3. Screening should also be considered in individuals younger than 45 if they are overweight and have one or more additional risk factors. JALI:EARLY DETECTION AND INTERVENTIONS 4. If testing is positive for Prediabetes, a follow up test should be performed on a subsequent day to confirm the diagnosis. 5. People diagnosed Prediabetes should receive regular retesting every one to two years to monitor for type-2 diabetes. Individuals with a normal screening result can be retested every three years. Criteria for the Diagnosis of Diabetes*. (Normoglycemia, IFG or IGT Diabetes)17 пЃ® FPG <100 mg/dl (5.6mmol/L) = Normal fasting glucose; пЃ® FPG <100 -125 mg/dl (5.6-6.9mmol/L) = (IFGimpaired fasting glucose); пЃ® FPG eвЂќ126 mg/dl (7.0mmol/L) = Provisional diagnosis of Diabetes (the diagnosis must be confirmed, as described below). пЃ® 2-h PGвЂ <140 mg/dl 2-h + Normal glucose tolerance test пЃ® 2-PG 140 -199 mg/dl (7.8-11.1 mmol/L) = Impaired Glucose Tolerance (IGT) пЃ® 2-h PG >200 mg/dl (11.1 mmol/L) = Provisional diagnosis of Diabetes (the diagnosis must be confirmed, as below). Symptoms of diabetes and casual plasma glucose concentration eвЂќ200 mg/dl *In the absence of unequivocal hyperglycemia, a diagnosis of diabetes must be confirmed, on a subsequent day, by measurement of FPG, 2-h PG, or random plasma glucose (if symptoms are present). The FPG test is greatly preferred because of ease of administration, convenience, acceptability to patients, and lower cost. Fasting is defined as no caloric intake for at least 8 h. вЂ This test requires the use of a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. 2-h PG, 2-h post load glucose. Patients with IFG and/or IGT are now referred to as having вЂњpre-diabetesвЂќ 17 indicate a relatively high risk for development of diabetes. In the absence of pregnancy, IFG and IGT are not clinical entities in their own right but rather risk factors for future diabetes as well as cardiovascular disease. They can be observed as intermediate stages in any of the disease processes. IFG and IGT are associated with the metabolic syndrome, which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high- 42 triglyceride and low/or low-HDL type, and hypertension. It is worth mentioning that medical nutrition therapy aimed at producing 5-10% loss of body weight; exercise, and certain pharmacological agents have variably demonstrated to prevent or delay the development of diabetes in people with IGT, the potential impact of such interventions to reduce cardiovascular risk has not been examined to date. It should be noted that many individuals with IGT are euglycemic in their daily lives. Individuals with IFG or IGT may have normal or near normal glycated haemoglobin levels. Individuals with IGT often manifest hyperglycemia only when challenged with the oral glucose load used in the standard OGTT. Preclinical Natural History 22, 33 Insulin Resistance, Insulin Secretion and the Balance between Alpha (Гњ ) vs. Beta Cells (Гў) : Insulin resistance tends to be the вЂњbackboneвЂќ of type 2 diabetes; 80% to 85% of patients with type 2 diabetes have some degree of insulin resistance. Two things that influence its development: genetic predisposition for insulin resistance, which some persons probably will inherit if family members have diabetes, and lifestyle and diet. If one is obese and sedentary, it contributes to the development of insulin resistance. If a person is inherited the genetic potential, one need not be obese to have insulin resistance. In fact, about 20% of patients who have a normal weight or who are even underweight have insulin resistance, and about 20% of overweight patients who are clearly overweight or obese do not have insulin resistance. Obesity is important as a promoter of insulin resistance, but it is not required to develop insulin resistance. Typically, someone with genetic potential may also have a sedentary lifestyle, eat a diet that is hypercaloric, and gain weight. However, someone with a genetic predisposition for abnormal beta-cell function can lose beta cells as time passes, without necessarily having insulin resistance. Finally, a person can eat a diet associated with weight gain, have a sedentary lifestyle and yet not have insulin resistance, and even maintain normal beta-cell function. So being overweight and sedentary does not necessarily mean that a person has insulin resistance, and conversely, a person does not need to have a genetic predisposition for insulin resistance in order to have abnormal beta-cell function. But assuming that a patient has insulin resistance, the susceptible individual can take one of the two pathways: patient either has genetically-programmed normal beta cells, or has genetically-programmed abnormal beta cells. If patient has normal beta cell function the person will go through life compensating for his hyperinsulinaemia but person will always remain normoglycemic. KLE HEALTH SCIENCE JOURNAL, JULY 2008 43 Those patients who have the metabolic syndrome, which is a Prediabetes stage never develop elevated blood glucose because their beta cells are able to compensate for their insulin resistance. At this point is to do glucose challenge test has to be done. A lot of these patients do not have normal blood glucose; they have IGT. But if the patientвЂ™s beta cells are programmed to function abnormally, they will not be able to compensate for their insulin resistance. They will have relative insulin deficiency, develop hyperglycemia, and eventually, type 2 diabetes. Interestingly, only about 20% to 25% of patients at risk for diabetes, who have normal betacell function will deteriorate into abnormal beta-cell function. This means that about 80% of at-risk population is walking around with normal blood glucose. The problem is that insulin resistance, IGT, compensatory hyperinsulinaemia, and diabetes all accelerate atherogenesis. Just because the glucose is not elevated does not mean that there is no problem. There is a huge problem. The cardiovascular complication rate in IGT or metabolic syndrome is not quite what it is in overt diabetes, but it is still quite a bit higher than in a normal individual. How far a patient goes on this continuum is determined by how healthy their beta cells are, and elevated blood glucose is the last stage of this evolution. Regulation of Insulin Secretion : 22 There are many things that affect the regulation of insulin secretion. The sulfonylurea drugs and the Dphenylalanine drugs attach themselves to the beta cell and do their work through transporters, etc. That is a complicated mechanism, but the purpose of this illustration is to show that drugs, neurotransmitters, nutrients, and hormones all affect insulin release from the beta cells of the pancreas. Nutrients are often underappreciated. For example, that glucose affects insulin release. If an individual has a healthy pancreas, the higher the blood glucose, the more insulin is released. Amino acids do that too; they are pretty effective stimulators of insulin secretion. What is sometimes not appreciated is the role of free fatty acids, which are really powerful. When they are elevated, as in obesity, there is actually a shutdown of insulin production вЂ”called lipotoxicityвЂ”just as in glucose elevation. When glucose is elevated chronically, there is a shutdown of insulin production called gluco-toxicity. Many patients have gluco- and lipotoxicity. All these factors can affect insulin secretion. The newest players are the hormones: glucagon-like peptide-1 (GLP-1) principally, and the next one is gastric inhibitory polypeptide (GIP). Islet Alpha- and Beta-cell Hormones Regulate Glucose Homeostasis 18, 22 The normal healthy subject has many beta cells in the islets that secrete insulin, and much fewer alpha cells in the islets that secrete glucagon. In type 2 diabetes it is a different situation. The number of beta cells is reduced, and they do not secrete as much insulin. The alpha cells do not decrease in numberвЂ”the glucagon-producing cells remain about the sameвЂ”but they become dysfunctional. They start secreting glucagon, when glucagon should be suppressed. When there is type 2 diabetes, there is inappropriate secretion of glucagon from pancreatic alpha cells. There are mechanisms that are responsible for changes in beta-cell function. A normal beta cell adapts to insulin resistance by increasing secretion from each cell and increasing the number of cells (beta-cell mass). But when there is impaired beta-cell adaptation, and the inherited beta-cell weakness component, the susceptible person is destined to have impaired beta cells with decreased insulin secretion from each cell as well as reduced beta-cell mass. Changes in Beta-Cell function over time: United Kingdom Prospective Diabetes Study (UKPDS) Data 33 From the UKPDS, that it has been shown that over a very long 12- to 14-year study, beta-cell function failed progressively. By the time diabetes was diagnosed, with fasting blood glucose greater than 126 mg/dL, at least 50% of the functioning beta-cell population has been lost and maybe even 75% or 80%. (Figure 1). FIGURE 1: Source 33 Lebovitz H. Changes in beta-cell function over time: UKPDS data, Diabetes Rev. 1999:7, 139-53 The process begins 10 or 12 years before diagnosis 22. The blood glucose rises and the beta-cell mass begins to decrease. There is a very straight line that continues until, eventually, persons with type 2 diabetes, if they live long enough, will have almost no insulin production from their beta cells. Most type 2 diabetics need insulin eventually, JALI:EARLY DETECTION AND INTERVENTIONS because all the agents that are available today that are so effective in managing type 2 diabetes depend on the ability of pancreas to produce some insulin in order for these agents like Metformin, Sulfonylurea to work. With too little or no physiologic insulin production, exogenous insulin will then need to be administered. This is an important concept. Most type 2 diabetics, if they live long enough, will eventually need insulin either as supplemental or total therapy because their beta cells will continue to fail. Beta-Cell Mass in Normal Patients and Patients with Diabetes and Prediabetes. 22 In fact, autopsy studies have shown that people with diabetes, whether they are lean or obese, have much reduced beta-cell mass. In the mid-1970s and early 1980, islet cell auto antibodies (ICA), insulin auto antibodies (IAA), and recently, a 64-kd protein were found to be present in the serum of the majority of patients with type 1 diabetes at the time of diagnosis. This form of diabetes, which accounts for only 5вЂ“ 10% of those with diabetes, previously encompassed by the terms insulin-dependent diabetes, type-1 diabetes, or juvenileonset diabetes, results from a cell-mediated autoimmune destruction of the Гџ-cells of the pancreas. Markers of the immune destruction of the Гџ-cell include islet cell autoantibodies, auto-antibodies to insulin, auto-antibodies to glutamic acid decarboxylase (GAD65), and auto-antibodies to the tyrosine phosphatase IA-2 and IA-2Гџ. One and usually more of these auto-antibodies are present in 85вЂ“90% of individuals when fasting hyperglycemia (IFG) is initially detected. Also, the disease has strong HLA associations, with linkage to the DQA and DQB genes, and it is influenced by the DRB genes. These HLA-DR/DQ alleles can be either predisposing or protective. Source 42 Lebovitz H. Changes in beta-cell function over time: UKPDS data, Diabetes Rev. 1999:7, 139-53 44 In this form of diabetes, the rate of Гџ-cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Immunemediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the 8th and 9th decades of life known as вЂњLatent Onset of Diabetes in AdultsвЂќ (LADA) 22, 23, 33. Autoimmune destruction of Гџ-cells has multiple genetic predispositions and is also related to environmental factors that are still poorly defined. Although patients are rarely obese when they present with this type of diabetes, the presence of obesity is not incompatible with the diagnosis. These patients are also prone to other autoimmune disorders such as GravesвЂ™ disease, HashimotoвЂ™s thyroiditis, AddisonвЂ™s disease, vitiligo, celiac disease, sprue, autoimmune hepatitis, myasthenia gravis, and pernicious anemia. Theoretically, it can be fairly predicted that immune markers are reasonably useful in early detection of type 1 diabetes as early as few years too that will help in designing early interventions and prevent Type 1 diabetes. Insulin Patterns in Diabetes 22: Abnormal acute insulin response to intravenous glucose in Type 2 Diabetes is seen in some of patientsвЂ™ cousins, uncles, aunts, and grandparents and some of these relatives will have blunted first-phase insulin release. Their blood glucose levels may be normal but the first-phase insulin release may be blunted. A very strong marker of genetically transmitted diabetes is the loss of first-phase insulin release. Clinical significance of Prediabetes and Diabetes risk: Prediabetes as a model of the metabolic syndrome There has been in recent times confusion about definitions of Prediabetes. Traditionally, Prediabetes referred to studies in which subjects were followed longitudinally and one could actually identify which subjects would later develop diabetes. In 2003, the ADA suggested that certain high-risk groups such as individuals with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) should be identified as having Prediabetes. This is an unfortunate choice of a name, since many or most IGT and particularly IFG subjects will never develop diabetes23. Given the natural history of Prediabetes, about 3%вЂ“10% of people per year with Prediabetes develop diabetes. Data are particularly well substantiated for IGT. In the Diabetes Prevention Programme24 with subjects who had IGT, with or without IFG, there was about a 10% annual rate of progression to diabetes in the control group. Overall, Prediabetes confers about a six fold increased risk of diabetes compared with normal glucose KLE HEALTH SCIENCE JOURNAL, JULY 2008 45 tolerance. In most populations studied, the rates of conversion from IFG and IGT to diabetes are similar, with IGT having greater sensitivity but less specificity than IFG in predicting diabetes risk 25. In an 11-year follow-up study among adults with IGT in Mauritius, 46% developed diabetes, 28% remained unchanged in category, 4% developed IFG, and glucose levels normalized in 24%. Thus, many people with Prediabetes (a quarter or more) may revert in long term to having normal glucose tolerance, and after a protracted follow-up, only about 50% of people with IGT or IFG will develop diabetes. Cardiovascular disease risk In comparison with adults who have normal glucose tolerance, people with Prediabetes have an increased risk of developing cardiovascular disease (CVD) and cardiovascular and all-cause mortality.26 There is a two- to three-fold increased prospective risk of cardiovascular events, which is most marked in younger adults with Prediabetes. Prediabetes is associated with increased rates of the cardiovascular risk factors found in people with type 2 diabetes. Some data indicates that people with IGT and normal levels of fasting plasma glucose have a greater risk of CVD than those with IFG. In addition, when other known CVD risk factors, such as hypertension and lipid abnormalities, are adjusted statistically, IGT, but possibly not IFG, remains an independent CVD risk factor. An increasing plasma glucose level in IGT is associated with a greater risk from cardiovascular deaths. Associations with the metabolic syndrome The metabolic syndrome (MetS) refers to a clustering in an individual of CVD risk factors and diabetes susceptibility.26 People with MetS have about a twofold increased risk of developing diabetes and cardiovascular disease, compared with those without the syndrome. Several MetS definitions exist, with two being widely used. Recently, a third definition has been adopted by the International Diabetes Federation.27 Each definition has impairment of glucose metabolism as an optional criterion, although some consider only IFG. Most adults who have Prediabetes will also have MetS. Whether Prediabetes or MetS best defines diabetes and cardiovascular risk remains to be determined. However, it is not clear whether MetS and Prediabetes represent the same or different clinical entities28. The data demonstrated by Diamantopoulos et al28 showed that MetS and Prediabetes have an overlapping pattern. MetS appears to have a more pronounced effect on early renal dysfunction and increased inflammatory activation, while Prediabetes tends to be associated with early carotid structural changes. These findings may be due to a different patho-physiologic substrate of these clinical phenotypes in terms of insulin resistance and secretion, as well as to the varying prevalence of cardiovascular risk factors. IGT also accounts for a highly heterogeneous Japanese population29, with the condition varying from individual to individual. In this study, findings suggest that IGT subjects with high insulin response and those with low insulin response vary greatly in regard to the number of atherosclerotic risk factors and the frequency with which they are associated with the metabolic syndrome. It is also shown in middle-aged Japanese males that of the two forms of IGT, IGT with high insulin response is more closely linked to the pathogenesis of atherosclerotic cardiovascular disease. Impaired glucose tolerance (IGT) represents a Prediabetic state positioned somewhere between normal glucose tolerance and diabetes, which is also assumed to make individuals in this state highly susceptible to atherosclerotic disease. 29 An observation by Sahib et al30 suggested that insulin resistance may be associated with essential hypertension. There are some thoughts to favour the argument that insulin resistant Individuals are at a higher risk to develop hypertension as compared to insulin sensitive individuals. Interventions to prevent Prediabetes 3: Just as there are different potential definitions of the natural history of IFG and IGT, there are different ways in which the natural history can be altered. The progression to diabetes is a time-dependent phenomenon; one possible alteration is simply to вЂњreset the clockвЂќ without changing the rate of the deterioration. It is possible that some interventions will lower glycaemia initially but do nothing to change the subsequent rate of rise of glycaemia. This mechanism will delay crossing the glycaemia threshold that defines diabetes. Prediabetes is a condition that does not fall squarely into the primary or secondary prevention domain, and therefore tends to be inadequately addressed by interventions in either health promotion or disease management. There is substantial evidence to suggest that even at these blood glucose levels, significant risk exists for both micro and, macro vascular complications. Biuso et al31 have introduces a conceptual framework of care for Prediabetes that includes both screening and the provision of up-to-date clinical therapies in conjunction with an evidence-based health coaching intervention. In combination, these modalities represent the most effective means for delaying or even preventing the onset of diabetes in a Prediabetes population. Research studies have found that lifestyle changes3,31,34 can prevent or delay the onset of type 2 diabetes among high-risk adults. The three components of lifestyle JALI:EARLY DETECTION AND INTERVENTIONS modification are diet, exercise, and behavior therapy (Table 5 & FIGURE 3), Table 5. Treatment Recommendation for Individuals with IFG, IGT, or Both 3 Population Treatment IFG or IGT Lifestyle modification (i.e., 5 to 10% weight loss and moderate intensity physical activity > 30 min/day) in a week Individuals with IFG Lifestyle modification and IGT and any of the (as above) and/or Metformin* following: пЃ¬<60 years of age пЃ¬BMI eвЂќ35 kg/m2 пЃ¬Family history of diabetes in firstdegree relatives пЃ¬Elevated triglycerides пЃ¬Reduced HDL cholesterol пЃ¬Hypertension пЃ¬A1C >6.0% *Metformin 850 mg twice per day. Figure 3: Lifestyle Modification LowLowCalorie Diet Increased Physical Activity Behavior Therapy 46 Wadden TA, Butryn ML, Byrne KJ. Efficacy of lifestyle modification for long-term weight control. Obes Res 2004;12:151S-162S. Several reviews have found that standard lifestyle modification programs conducted in academic medical centers induce a mean weight reduction of approximately 8вЂ“10% of initial weight in 16вЂ“26 weeks of treatment.36 These studies included people with IGT and other high-risk characteristics for developing diabetes. Lifestyle interventions included diet and moderate-intensity physical activity (such as walking for 2 1/2 hours each week). In the Diabetes Prevention Program, a large prevention study of people at high risk for diabetes, the development of diabetes was reduced 58% over 3 years. In the Diabetes Prevention Program8, people treated with the drug Metformin reduced their risk of developing diabetes by 31% over 3 years. Treatment with Metformin was most effective among younger, heavier people (those 25-40 years of age who were 50 to 80 pounds overweight) and less effective among older people and people who were not as overweight. Similarly, in the STOP-NIDDM Trial8,24, treatment of people with IGT with the drug Acarbose reduced the risk of developing diabetes by 25% over 3 years. Other medication studies are ongoing. Besides lifestyle, various pharmacological treatments have proven their efficacy to reduce the incidence of type 2 diabetes in high-risk individuals, especially in those with impaired glucose tolerance (IGT) and/ or impaired fasting glucose (IFG). Ongoing trials should confirm such a favourable effect with those drugs and may demonstrate a similar protective effect with other pharmacological approaches such as glinides or even basal insulin regimen. Therefore, the distinction between a true preventing effect and simply a masking effect is difficult with glucose-lowering drugs34. In addition, as type 2 diabetes is a progressive disease, it is still questionable whether the effect corresponds to a prevention effect or only to a postponing of the development of the disease. Owing to the pathophysiology of the disease, the only way to block the progression to type 2 diabetes is probably to avoid the progressive loss of beta-cell function and/or mass. Whatsoever, these data obtained in large clinical trials bring further argument to support early treatment of diabetes, even at a Prediabetes state, in order to stop the vicious circle leading to an inevitable deterioration of glycaemia in predisposed subjects. The demonstration by recent randomized controlled trials that type 2 diabetes mellitus is preventable has raised hope for the possibility of reducing cardiovascular morbidity and mortality associated with diabetes. Interventions like lifestyle modifications and pharmacological therapy are recommended in individuals with Prediabetes to achieve the KLE HEALTH SCIENCE JOURNAL, JULY 2008 47 2002; 346:393-403. goal of prevention of diabetes in high -risk population.35 Conclusion Presentations at the 1st International Congress on вЂњPrediabetesвЂќ and the Metabolic Syndrome14, 16 reported that better definition and intense study of Prediabetes and the metabolic syndrome have led to some important insights in the past decade: 1. Prediabetes and the metabolic syndrome are extremely prevalent; 2. People with Prediabetes and the metabolic syndrome are at high risk for diabetes and CVD; 3. Early detection of IFG / IGT in high risk individuals and interventions to prevent progression to diabetes through Intensive lifestyle changes are effective and should be encouraged; and 4. Effective pharmacologic therapies must also be identified. References: 1. Diabetes Atlas. 3rd edition, International Diabetes Federation, 2006; 1 2. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001; 414:782-87. 3. Nathan DM, Davidson MB, DeFronzo RA, et al. Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for Care, Diabetes Care. 2007;30(3):753-59. 8. Chiasson JL, Josse RG, Gomis R, Hanefetd M, Karasik A, Laakso M. the STOP-NIDDM Trial Research Group: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet 2002; 359:2072-7. 9. Torgerson JS, Hauptman J, Boldrin MN, et al. Xenical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004; 27:151-61. 10. Ramachandran A, Snehalatha C, Mary S, et al: Indian Diabetes Prevention Programme (IDPP): the Indian Diabetes Prevention Programme shows that lifestyle modification and Metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006;49:289-97. 11. Gerstein HC, Yusuf S, Boxch J, Pogue J, et al: DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) Trial Investigators: effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006, 368:1096-105. 12. Vague J. Sexual differentiation. A factor affecting the forms of obesity. Presse Med. 1947; 30:339-40. 13. Avogaro P, Crepaldi G, Enzi G, et al. Associazione di iperlipemia, diabete mellito e obesita di medio grado. Acta Diabetol Lat. 1967;4:572-90. 14. Crepaldi G. Origin and development of the metabolic syndrome. Program and abstracts of the 1st International Congress on вЂњPrediabetesвЂќ and the Metabolic Syndrome; Berlin, Germany. 2005;13-6. 15. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26: 3160вЂ“7. 4. Alberti GK, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539-53 5. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005; 365:1415-28. 6. Twigg SM, Kamp MC, Davis TM et al. Prediabetes: a position statement from the Australian Diabetes Society and Australian Diabetes Educators Association. 2007; 186 (9): 461-5 16. Knowler WC, Barrett-Conner E, Fowler SE, et al. The Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or Metformin. N Engl J Med Grundy S. Do we need to expand the metabolic syndrome? Program and abstracts of the 1st International Congress on вЂњPrediabetesвЂќ and the Metabolic Syndrome; Berlin, Germany. 2005;13-16. 17. ADA Clinical Practice Recommendations. Position Statement. Diabetes Care. 2007 S46; 30:1 7. JALI:EARLY DETECTION AND INTERVENTIONS 48 18. Twigg SM, Kamp MC, Davis TM et al. Prediabetes: a position statement from the Australian Diabetes Society and Australian Diabetes Educators Association. 2007; 186 (9): 461-5 28. Diamantopoulos EJ, Andreadis EA, Tsourous GI, et al. Metabolic syndrome and Prediabetes identify overlapping but not identical populations.Exp Clin Endocrinol Diabetes. 2006 ;114(7):377-83. 19. A Ramachandran. Netaji Oration. Epidemiology of Diabetes in India вЂ“ Three Decades of Research. Journal Phy of India. 2005; 53:35-8 29. 20. Graham AH, McCarthy MI, Mohan V et al. The genetics of non-insulin dependent diabetes mellitus in southIndia: An overview. Ann Med 1992; 24:491-7. Mori Y, Hoshino K, Yokota K, et al. Japanese IGT subjects with high insulin response are far more frequently associated with the metabolic syndrome than those with low insulin response. 2006; 29(2):3515. 30. Sahib AK, Sahu SK, Reddy KN. J Indian Med Assoc. 2007; 105(1):25-8. 21. Ramachandran A, Jali MV, Mohan V, et al. High prevalence of diabetes in an urban population in south India. BMJ. 1988; 297(6648):587-90 22. Sherry NA, Tsai EB, Herold KC. Natural History of ГџCell Function in Type 1 Diabetes, Section I: Aspects of Pathophysiology, Diabetes 2005; 54:S32-S39 23. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2006;29:S43-S48. 24. Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or Metformin. N Engl J Med 2002; 346: 393-403. 25. Unwin N, Shaw J, Zimmet P, Alberti KG. Impaired glucose tolerance and impaired fasting Glycaemic: the current status on definition and intervention. Diabet Med 2002; 19: 708-23. 26. Decode Study Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2hour diagnostic criteria. Arch Intern Med 2001; 161: 397-405. 27. Alberti KG, Zimmet P, Shaw J; IDF Epidemiology Taskforce Consensus Group. The metabolic syndrome вЂ” a new worldwide definition. Lancet 2005; 366: 105962. Prediabetes and hypertension. 31. Biuso TJ, Butterworth S, Linden A. A conceptual framework for targeting Prediabetes with lifestyle, clinical and behavioral management interventions. Dis Manag. 2007;10(1):6-15 32. Sinha R, Fisch G, Teague B, Tamborlane WV, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346(11):802-10. 33. Lebovitz H. Changes in beta-cell function over time :UKPDS data, Diabetes Rev. 1999:7, 139-53 34. Scheen AJ. Antidiabetic agents in subjects with mild dysglycaemia: prevention or early treatment of type 2 diabetes? Diabetes Metab. 2007;33(1):3-12. 35. Zargar AH, Bashir MI. Epidemiological aspects of PrediabetesвЂ”review of the current data. J Indian Med Ass. 2005;103(11):591-3 36. Wadden TA, Butryn ML, Byrne KJ. Efficacy of lifestyle modification for long-term weight control. Obes Res 2004;12:151S-162S. KLE Health Sc. Jr. 2008; 1(1):49-53 49 REVIEW ARTICLE NEONATAL VERBAL AUTOPSY : A SYSTEMATIC REVIEW ANGOLKAR M1, KODKANY B. S2 ABSTRACT: In low resource setting areas where deaths occur at home, without any interface with a formal health or vital registration system, data derived from verbal autopsy (VA) are used for health planning and evaluation. In some developing countries it is the only method to know data on cause specific deaths. Currently VA is being used in over 35 countries. In this paper we discuss the varied methods of using VA and conclude that harmonization and standardization of questionnaire, cause of death classification and analytical methods for deriving cause of death are imperative. Key Words: Verbal Autopsy, cause of death, Interview methods, data collection methods Introduction Globally 8 million neonatal deaths occur each year. Of them, 98% occur in the developing world where over 68% of neonatal deaths occur at home, without any interface with a formal health or vital registration system. 1,2,3,4 Further incomplete or inaccurate data available through vital registration are far less than 3% of all neonatal deaths.5 This dearth of data on neonatal deaths produces significant challenges to know the cause and distribution of neonatal deaths.6 Most concerning is that despite gains in reducing the infant mortality rate in India over the past 15 years, neonatal mortality rates remain unchanged.7 It appears that these efforts lack focus and consistency, and interventions have not always been evidence-based. The primary objective of this paper is to critically review the current practices in verbal autopsy (VA) and to discuss options for further improvement. Verbal autopsy is a technique used to ascribe probable biomedical causes of death (COD). During this interview, a systematic description of the signs, symptoms and circumstances preceding death is obtained from the caretakers of the deceased , and a cause of death is assigned.8 VA has been used not only to gather data on the cause of death of certain populations, but also to gather data on outbreaks of infectious diseases and etiology for certain diseases in evaluation of public health interventions. 9-11 1. Co-ordinator MPH Programme institute of public Health, KLE University, Belgaum 2. Director JNMC-UMKC, Research Unit & Director, DOME.J.N.Medical College, Belgaum 590 010 Correspond to: e-mail: [email protected] Currently over 35 Demographic Surveillance Sites (DSS) in 18 countries, the sample Registration System (SRS) sites in India and the Disease Surveillance Point (DPS) system in China regularly use VA on a large scale, primarily to assess the cause of death structure.12-14 A standard VA tool: A standard VA tool comprises a VA questionnaire, cause of death or mortality classification system, and diagnostic criteria (either expert or data derived algorithms) for deriving cause of death.6 (Fig. 1) ur literature search included web based searches and manual review of archives. Online search included Medline free-text and MeSH searches for VA literature published in peer-reviewed journals after 1992 as well as popline data base search to identify additional VA tools and validation studies. Fig1. VA Process and Factors Influencing Cause-specific Mortality Fractions Methods KLE HEALTH SCIENCE JOURNAL, JULY 2008 50 Results вЂњGold standardвЂќ in VA validation studies: Most researchers rely on the diagnosis of the underlying cause of death from clinical records as the вЂњgold standardвЂќ. Others review the case history and, laboratory results(if available) to come to a diagnosis. The reliability of these reference diagnoses remains unclear, particularly in settings where medical documentation is very poor or where explicit diagnoses for stigmatized conditions are absent. Additionally the circumstances and pathological processes that result in a death that occurs in a hospital may be significantly different from those which result in a death in the community. Many authors list the unreliability of their gold standard as a major limitation of their study.6 Comparison of verbal autopsy tools: Currently there are 14 verbal autopsy questionnaires in use, which are specific for children and neonates and four questionnaires are meant for all ages mixed in one form. Each questionnaire has a different format, sequence of questions and wordings. But the key questions on symptoms and signs do not substantially differ. The questionnaires contain both open-ended and closed-ended questions for recording symptoms, signs and circumstances leading to death.15 The Sample Registration System (SRS) child and maternal VA questionnaires in India has a closed section on a few symptoms and signs.14 VA using physician review for deriving neonatal causes of death from close ended questions has less sensitivity than from questionnaires with open ended and those with mixed open and close-ended questionnaire types have the highest sensitivity.16 One could debate that open ended verbatim can contain vital information helping to make right diagnosis but it is very complex to convert this verbatim for analysis. Further in close ended questions diagnosis by diagnostic algorithms will be easier esp. with automated system.6 Open ended questions requires the respondent to recall events specifically. In a particular study it has been reported that converting the information from open ended questions to close ended questions for deriving cause of neonatal death did not increase the agreement between COD arrived by the algorithm and by the physicianвЂ™s panel.17 Validity in VA studies: Validity means the degree to which an assessment instrument measures what it is intended to measure. Most studies have estimated the sensitivity and specificity of VA, but few have assessed the agreement in the cause-specific mortality fraction (CSMF) between the gold standard and the VA diagnosis. The sensitivity and specificity of VA varies by COD between studies for the same causes.6 Most VA researchers consider an acceptable level of diagnostic accuracy at the individual level if the sensitivity and specificity are at least 90%, at the population level, if sensitivity is at least 50%, specificity 90% and the CSMF within 20% of the true value.18 Low sensitivity and specificity does not necessarily imply that VA estimates of CSMF are over or under-estimates, as false positives and false negatives may cancel each other out and not affect the VA estimate.19, 20 Accuracy of the mortality data from VA systems: Misclassification can result in serious over or underestimates of CSMFs.20, 21 This is because the accuracy of VA estimates depends not only on sensitivity and specificity, but also on the true underlying CSMF itself.23 This can be overcome if there is a standard classification of cause of Death that can be Universally accepted and followed. Cause of Death Classification: The International statistical classification of diseases and related health problems, 10th revision (ICD-10) is the mandatory level of coding for international reporting to the WHO database.22 Although it is possible to diagnose all of the categories of COD defined by the ICD-10 classification by clinical judgment and/or laboratory tests, it is impossible to define symptoms and signs for diagnostic algorithms for the complete list of COD. Thus very few VA systems use the entire list of ICD-10 codes; instead most use abbreviated COD lists. 15 The number of causes included in the section for children range from 4120.6 Field Assessment of application of verbal autopsy tools: Apart from factors inherent in the tool other factors that influence the validity of a VA tool are as follows: VA interviewers: The educational background of VA interviewers varies from individuals with secondary, nursing or medical school education. All VA interviewers have to undergo training in interview techniques.6 Proponents of medically-trained interviewers state that they can more accurately determine signs and symptoms from VA interviews. By contrast, others believe that medical knowledge may bias the result towards certain COD familiar to the interviewer.23 Studies support evidence that if culturally and linguistically appropriate questionnaires are used by welltrained lay interviewers, they can obtain accurate information.24-26 Identifying a respondent: Most studies use a relative, who took care of the deceased during the final illness (or the mother in the case of a perinatal death) as the VA respondent. ANGOLKAR , KODKANY : NEONATAL VERBAL AUTOPSY A few sites reported interviewing friends or neighbors if a primary caregiver was not available.6 In a study that examined the effect of age, sex, relationship and language of the respondents, there was no significant effect of these variables; however, the accuracy of the verbal autopsy tool improved if the respondents had taken care of the deceased during their final illness.6, 15 Recall periods - the time from death to VA interview: Currently there is a wide range in the recall period, the interval between the time of death and administration of the VA questionnaire. Some studies have performed interviews as soon as possible after death, while others visit the household after a minimum of 4 weeks to allow an adequate mourning period. The maximum recall period varies from 6 months to an indefinite amount of time. Although there has been the concern that a long recall period may impair a respondentвЂ™s ability to recollect and report relevant information, inadequate time for mourning may also cause emotional distress and influence a respondentвЂ™s willingness and ability to engage in a VA interview.23 One study has shown no effects on sensitivity or specificity using different recall period lengths from 1 to 21 months in adult deaths, although this has yet to be demonstrated in perinatal deaths. 24 Language: In order to minimize misreporting, interviewers must be able to translate freely and incorporate local phraseology.27 In one validation study, using the language other than the mother tongue did not affect the sensitivity and specificity of VA. 24 Analytical Challenges: Deriving causes of Death from verbal autopsy results: Cause of death from VA can be derived by PhysicianвЂ™s review, predefined expert algorithm and data driven algorithms. In a study comparing physicianвЂ™s review to algorithm-based cause of death assignment, only 11% were assigned more than one cause of death by physician review, while 58% of deaths were assigned multiple causes by algorithms.17 Assignment of COD by physician review panels: The most widely used approach to derive COD from VA is physician review, in which a panel of physicians assigns COD based on their clinical judgment, from the information recorded on the VA questionnaire. Typically a COD is reached if 2 physicians independently agree on an underlying cause. This approach has shown a reasonable sensitivity and specificity for selected causes of death. 15,16,19,26,28,29,30. However, alternatives are needed as physician review is relatively expensive and not feasible if large numbers of questionnaires have to be assessed.31 This method is often criticized for its subjectivity and low reliability.32 The published levels of inter-observer 51 reliability are generally high but may merely reflect the expectation of the individual reviewers who are aware of the epidemiological pattern and characteristics of diseases in their area. To date, the mainstay for assigning COD using a VA questionnaire remains Physician Panel review. 6 Algorithms to derive causes of death: Algorithms are a systematic means of deriving cause of death from VA. They help in automation of cause of death coding and increase the reliability of the VA tools. Algorithms validated and standardized for neonatal and childhood deaths in epidemiological settings are available. 33 Assignment of COD by predefined expert algorithm: Another approach to the assignment of COD is the use of expert algorithms Expert algorithm are predefined diagnostic criteria agreed to by a panel of physicians.This method is very quick and hence money and time saving and in addition also reduces the inconsistencies of physician review. The validity of expert algorithm varies but for selected causes of death using this approach has proved 90% concordance with COD derived from physician review.33 Assignment of COD by data driven algorithms: Dataderived algorithms are based on various analytical techniques to derive COD based on linear and other discriminatory techniques (logistic regression), probability density estimation, and decision tree and rule-based methods (including artificial neural networks). There are several potential advantages to this method, including simplification, standardization, replication and comparison.34 Data driven algorithms use only the closed-ended questions of the VA Questionnaire, hence there validity is quite debatable where as the physician panel uses both closed-ended and openended questionnaire for assigning COD.6 Single or multiple causes of Death: Instead of ascertaining a single cause of death, using multiple causes will reflect the interaction of different diseases that led to death. Particularly in children to report only one cause of death would distort mortality estimates and hence potential gains from health interventions.35 Constant inconsistencies have been reported in classifying cause of death in children. These classifications are according to ICD-10 definitions, primary or secondary, or main or underlying cause of death. The method of classifying COD needs to be homogenous between VA systems according to the ICD-10 Rules. The ICD -10 clearly defines the rules for classifying underlying causes of death & contributory causes.22 KLE HEALTH SCIENCE JOURNAL, JULY 2008 52 Time Trends: Sample size is a challenge on measuring trends with VA. Detecting trends in Cause Specific Mortality Fraction (CSMF) requires large sample sizes, depending on the sensitivity and specificity of VA, CSMFs, and changes in the CSMF of the prevailing causes of death.20,21 4. Darmstadt GL, Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet, 2005. 365(9463): 977-88. 5. Setel PW, Sankoh O, Rao C, Velkoff VA, Mathers C, Ganghuan Y, Hemed Y, Jha P, Lopez AD, Sample registration of vital events with verbal autopsy: a renewed commitment to measuring and monitoring vital statistics. Bulletin of the WHO, 2005. 83(8): 611-617. 6. Soleman N, Chandramohan D, Shibuya K. Verbal autopsy: current practices and challenges. Bull World Health Organ 2006; 84(3):164. 7. RCH II National Programme Implementation Proposal (PIP)вЂ”Draft, October 2004. 8. A Standard Verbal Autopsy Method for Investigating Causes of Death in Infants and Children. WHO Website, 1999 (WHO/CDS/CSR/ISR/99.4). 9. Andraghetti R, Bausch D, Formenty P, Lamunu M, Leitmeyer K, Mardel S, et al. Investigating causes of death during an outbreak of Ebola virus haemorrhagic fever: draft verbal autopsy instrument. Geneva: World health organization; 2003 10. Pacque-Margolis S, Pacque M, Dukuly Z, Boateng J, Taylor HR. Application of the verbal autopsy during a clinical trial. Soc Sci Med 1990; 31:585-91. 11. Telishevka M, Chenet L, McKee M. Towards an understanding of the high death rate among young people with diabetes in Ukraina Diabet Med 2001;18:39. 12. Yang G, Hu J, Rao KQ, Ma J, Rao C, Lopez AD. Mortality registration and surveillance in china: History, current situation and challenges. Popul Health Metr 2005;3:3. 13. INDEPTH Network. An international network of field sites with continuous demographic evaluation of population and their health in developing countries. INDEPTH Network; 2005. 14. Centre of Global Health Research. India sample registration system prospective study. Toronto: University of Toronto, Centre for Globle Health Research; 2005. 15. World Health Organization. WHO technical consultation on verbal autopsy tools. Geneva: WHO; 2005. 16. Marsh DR, Sadruddin S, Fikree FF, Krishna C, Conclusion Over the past decade the VA in many middle-and especially low-in-come countries, is the only method currently available to obtain estimates of the distribution of causes of death. The major focus of cause-of-death analysis has shifted from global and regional estimates to national and sub national estimates for monitoring the progress towards the Millennium Development Goals and providing evidence for backing national policies. However introduction of a uniform and reliable method to derive causes of death and standardization of the VA questionnaires are important steps towards further improvement of the VA process. The various limitations of this method, discussed in this paper, must be overcome in order for VA data to be used for international comparisons. Future Suggestions There are many ongoing attempts to harmonize and collaborate. In a recent WHO consultation on VA, the majority of experts agreed on the need for a standardized questionnaire with separate components for deaths of neonates, children and adults. The panel also agreed that an open section and closed sections with filter questions are preferable and information from both sections should be used to maximize the accuracy of VA. For comparisons across locations and over time, there is also a need for a standardized cause-ofdeath classification that lists globally important causes and relates them to ICD-10 codes. Further consensus and agreement on VA tools, in particular algorithms to derive causes of death and the content of VA questionnaires, is urgently needed.15 References: 1. 2. 3. Bryce J, Boschi-Pinto C, Shibuya K, Black RE, WHO Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet, 2005. 365(9465): 1147-52 Lawn JE, Cousens S, Zupan J. 4 million neonatal deaths: when? Where? Why? Lancet, 2005. 365(9462): 891900. Knippenberg R, Systematic scaling up of neonatal care in countries. Lancet, 2005. 365(9464): 1087-98. ANGOLKAR , KODKANY : NEONATAL VERBAL AUTOPSY 53 Carmstadt GL. Validation of verbal autopsy to determine the cause of 137 neonatal deaths in Karachi, Pakistan. 26. Kalter H D, Gray R H, Black R E, Gultiano SA. Validation of postmortem interviews to ascertain selected cases of death in children. Int J Epidemiol. 1990; 19:380-6. 17. Freeman JV. Evaluation of neonatal verbal autopsy using physician review versus algorithm-based causeof-death assignment in rural Nepal. Paediatr Perinat Epidemiol, 2005. 19(4): 323-31. 27. Hoj L, Stensballe J, Aaby P. Maternal mortality in Guinea-Bissau: the use of verbal autopsy in a multiethnic population. Int J Epidemion 1999; 28:70-6. 28. 18. Quigley MA, Chandramohan D, Rodrigues LC. Diagnostic accuracy of physician review, expert algorithms and data draged algorithms in adult verbal autopsis. Int J Epidemiol 1999; 28:1081-7. Rodriguez L, Reyes H, Tome P, Ridaura C, Flores S, Guiscafre H. Validation of the verbal autopsy method to ascertin acute respiratory infection as cause of death. Indian J Pediater 1998; 65:693-84. 29. 19. Chandramohan D, Maude GH, Rodrigues LC, Hayes RJ. Verbal autopsis for adult deaths: their development and validation in a multicentre study Trop Med Int Health 1998; 3:436-46. Chandramohan D, Rodrigues LC, Maude GH, Hayes RJ. The Validity of Verbal Autopsies for Assessing the Cause of Institutional Maternal Death. Stud Fam Plann 1998; 29:414-22. 30. Mobley CC, Boerma JT, Titus S, Lohrke B, Shangula K, Blake RE. Validation Study of a Verbal Autopsy method for causes of childhood mortality in Namibia.J Trop Pediatr 1996; 42:365-9. 31. Byass P, Huong DL, Minh HV. A Probabilistic approach to interpreting verbal autopsies: methodology and preliminary validation in Veatnam. Scand J Public Health, 2003; Suppl 62:32-7. 32. Todd JE, De Francisco A, OвЂ™Dempsey TJ, Greewood BM. The Limitations of Verbal Autopsy in a Malaria endemic region. Ann Trop Paediatr 1994;14:31-6. 33. Quigley MA., Chandramohan, D., Rodrigues LC. Diagnostic accuracy of physician review, expert algorithms and data-derived algorithms in adult verbal autopsies. Int J Epidemiol, 1999. 28(6): 1081-7. 20. Anker M. The effect of misclassification error on reported cause-specific mortality fractions from verbal autopsy. Int J Epidemiol 1997; 26:1090-6. 21. Maude GH, Ross D A. The effect of different sensitivity, specificity and specific mortality functions on the estimation of differences in cause specific mortality rates in children from studies using verbal autopsies. Int J Epidemiol 1997; 26:1097-106. 22. World Health Organization. International Statistical classification of diseases and related health problems, tenth revision, 2nd ed. Geneva:WHO; 1992. 23. Huong DL, Minh HV, Byass P., Applying verbal autopsy to determine cause of death in a rural Vietnam. Scand J Public Health Suppl 2003; 62:19-25. 24. Chandramohan D. Verbal autopsy tools for adult deaths. (PhD Thesis). London School of Hygiene and Tripical Medicine; 2001. 34. Reeves BC, Quigley MA. A Review od Data driven methods for assigning causes of death from verbal autopsy data. Int J Epidemiol 1997; 26:1080-9. 25. Kahn K, Tollman SM, Garenne M, Gear JS. Validation and application of verbal autopsies in rural area of South Africa. Trop Med Int Health 2000; 5:824-31. 35. Bang AT, Bang RA, Diagnosis of causes of childhood deaths in developing countries by verbal autopsy: suggested criteria. Bull World Health Organ 1992; 70:499-507. KLE Health Sc. Jr. 2008; 1(1):54-56 CASE REPORT 54 BOWENвЂ™S DISEASE OF THE UNEXPOSED SKIN B. Siddaramappa1, B S Manjunathswamy2, A M Pandit3, Shilpa Dastikop4, Carol Z Fernandes5, Tanu Sardana6 ABSTRACT BowenвЂ™s disease is a form of intra-epidermal squamous cell carcinoma characterized by persistent, non-elevated, red, scaly or crusted plaque mostly on sun-exposed areas with small potential for invasive malignancy. We present two cases of BowenвЂ™s Disease occurring on the unexposed skin who showed appreciable regression of lesions after 6 weeks of 5% 5Fluorouracil therapy. Key words: BowenвЂ™s disease, unexposed skin Introduction BowenвЂ™s disease is an intra-epidermal squamous cell carcinoma which manifests as erythematous cutaneous plaque. The disease is more prevalent in the elderly (>60 years), on sun exposed skin 2,3 and rare before the age of 30 years 1,2. It is common in women with fair complexion 3. Some cases are due to arsenic ingestion 4,5 (especially true for BowenвЂ™s disease on unexposed skin). The condition may result from Human Papilloma Virus (HPV), especially types 16 and 18 6. However majority of cases (>75% in one study) are present on actinically damaged skin, mostly on head, neck and lower limbs, although any site can be affected 7. Other risk factors are smoking, warts and radiation. The lesion may be solitary (approximately two-third of cases 3) or multiple (10-20%) at the time of presentation 6. Exposure to inorganic arsenic compounds may occur as a result of occupational exposure, from ingestion of contaminated source, or from medicinal use.4 We report two cases of BowenвЂ™s disease occurring on unexposed skin and without any occupational exposure to arsenic compounds. Case Reports : Case No 1: A 72 year old diabetic male presented with a slowly enlarging asymptomatic lesion over the right thigh of eight years duration. Physical examination revealed hyper1. 2. 3. 4. 5. 6. Prof and Head Professor Professor Asst .Professor Asst .Professor Post Graduate Student Department of Dermatology, Venereology & Leprology, Jawaharlal Nehru Medical College, Belgaum 590 010, Karnataka, India Correspond to: Dr. B. Siddaramappa E-mail: pigmented crusted plaque of 6x4 cm, size over the posterior aspect of the right thigh. It was non-tender and unattached to underlying fascia or muscle. There was no regional lymphadenopathy. Systemic examination revealed no abnormality. The laboratory examination, chest radiography and abdominal sonogram showed no abnormality. KLE HEALTH SCIENCE JOURNAL, JULY 2008 55 Case No. 2: A 72-year old male presented with an asymptomatic enlarging lesion over inner aspect of the left forearm since three and a half years. Physical examination revealed a single crusted plaque of 20 x 10 cm size with irregular borders over medial aspect of forearm with no lymphadenopathy. Systemic examination did not reveal any abnormality. Routine investigations were normal. A detailed history relevant to arsenic exposure (fungicide, weed killer or smelting industry) was ruled out in both cases. The histopathology examination of the skin biopsy showed hyperkeratosis, parakeratosis, dyskeratosis, elongation of rete ridges, hyperchromatic nuclei, mitotic figures, intact basement membrane and round cell infiltration in upper dermis, suggestive of BowenвЂ™s disease. Treatment was initiated with application of topical 5% 5-Fluorouracil (5-FU) over the lesions twice daily. Both patients were instructed to protect the surrounding skin with Vaseline and then apply a thin layer of the cream to the target lesion only and rub-in until the cream disappears. Discussion : John Bowen described a crusted lesion in 1912, which was named after him later. BowenвЂ™s disease affects both skin and mucous membrane such as oral mucosa and conjunctiva or cornea 2. BowenвЂ™s disease rarely occurs on penis and is known as Erythroplasia of Queyrat. Risk of developing such a lesion includes lack of circumcision, HPV infection, phimosis, balanitis or any chronic infection of penile skin 8. There are several cases of BowenвЂ™s disease arising in seborrhoeic keratoses and it has also been reported in parakeratosis (disseminated, Mibelli and linear types) and in BeckerвЂ™s nevus2. The apparent relationship between BowenвЂ™s disease and internal malignancies especially of the lung was reported in 1959 and several studies subsequently supported this association. However, some studies found no significant association with internal malignancy. Hence, routine investigations for internal malignancies in patients with BowenвЂ™s disease are not justified 2. Clinical differential diagnosis of BowenвЂ™s disease include actinic keratosis, verrucae, superficial basal cell epithelioma, PagetвЂ™s disease, epidermal nevi, psoriasis and lichen simplex chronicus. BowenвЂ™s disease can be treated with a variety of therapeutic modalities including surgery, chemotherapy, electrodessication and curettage, MohsвЂ™micrographic surgery, topical application of 5% 5-Fluorouracil, 5% imiquimod cream 1,7,8 , LASER, radiation therapy and most recently photodynamic therapy(PDT) and local or systemic injection of interferon alpha or gamma.9 5% 5-fluorouracil 12,13,14 has been used topically for treatment in several studies 2 with a reported 92% cure rate after 2-3 months regimen of twice daily application 9. 5Fluorouracil, a fluoropyrimidine, is an anti-metabolite drug that works both by inhibiting essential biosynthetic processes and through its incorporation into macromolecules such as DNA and RNA. 5-Fluorouracil exerts its cytotoxicity primarily after its conversion to 5-fluoro-2-deoxyuradine monophosphate, an irreversible inhibitor of thymidylate synthatase, that catalyses the rate limiting step in DNA synthesis and by mis-incorporation of its active metabolites into RNA and DNA, inhibiting their normal processing and function. It has been demonstrated that the effects of 5Fluorouracil are potentiated in the presence of several cytokines 2. Efficacy can be increased by combining it with iontophoresis 9. In Erythroplasia of Queyrat, application of 5% 5-Fluorouracil cream twice daily for 4-5 weeks has been recommended2. There are reports describing the efficacy of imiquimod in the treatment of BowenвЂ™s disease, both as single drug therapy or in combination with 5-Fluorouracil 10. Relapse rate for cryotherapy, 5% 5-FU, Grenz ray therapy and excision are 34%, 14%, 6% and 5% respectively 11. Approximately 35% cases of BowenвЂ™s disease evolve into invasive squamous cell carcinoma3, of which 13% metastasize with a mortality of 10% 7. Both of our patients got relief from topical application for 6 weeks of 5%5-fluorouracil. Although other modalities of treatment are available,5-fluorouracil was chosen considering elderly age and large size of the lesions. In most cases, 5-fluorouracil is well tolerated ,except for local skin reactions ,including pruritus and inflammation, which are often dose-related. References: 1. Yeon Jeong Kim, Jin Wou Kim, Bo Kyung Koh. Successful treatment of vulvar BowenвЂ™s disease with topical imiquimod 5%cream. Internat Jour Dermatol 2006:45; 151-153. 2. Cox NH, Eedy DJ, Morton CA. Guidelines for management of BowenвЂ™s Disease. Brit Jour Dermatol 1999:141; 633-641. 3. Dupree MT, Kiteley RA, Weismantle K, Panos R, Johnstone PAS. Radiation therapy for BowenвЂ™s SIDDARAMAPPA, MANJUNATHSWAMI, PANDIT, DASTIKOP, FERNANDES, SARDANA: BOWNвЂ™S DISEASE disease: Lessons for lesions of lower extremity.J Am Acad Dermatol 2001:45;401-404. 56 10. Ondo AL, Mings SM, Pestak RM, Shanler SD. Topical combination therapy for cutaneous squamous cell carcinoma in situ with 5-Fluorouracil cream and imiquimod cream in patients who have failed topical monotherapy. J Am Acad Dermatol 2006:55; 1092-1094. 11. Gordon KB, Robinson J. Carbon dioxide laser vaporization for BowenвЂ™s disease of finger. Arch Dermatol 1994:130;1250-1252. 4. Yerebakan O, Ermis O, Yilmaz E, Basaran E. Treatment of arsenical keratosis and BowenвЂ™s disease with acitretin. Internat Jour Dermatol 2002:41; 84-87. 5. Schwartz RA. Arsenic and the skin. Internatl Jour Dermatol 1997:36; 241-250. 6. Nishimura Y, Kishigawa T, tanaka T. Bilateral BowenвЂ™s disease. Brit Jour Dermatol 2004 :151 ;227-228. 12. 7. Patel G, Goodwir R, Chawla M, Laidler P, Price PE, Finlay AY et al. Imiquimod 5% cream monotherapy for cutaneous squamous cell carcinoma in situ. Am Acad Dermatol 2006: 54;1025-1032. Graham BD, Jetmore AB, Foote JE, Arnold LK. Topical 5-fluorouracil in management of extensive anal BowenвЂ™s disease. Dis Colon Rectum 2005;48; 444-450 13. Bargman H, Hochman J. Topical treatment of BowenвЂ™s disease with 5-Fluorouracil. J Cutan Med Surg 2003:7; 101-105. 14. Welch ML, Grabski WJ, McCollough ML, Skelton HG, Smith KJ, Menon PA, Anderson LL. 5-Fluorouracil iontophoretic therapy for BowenвЂ™s disease. J Am Acad DermatoL 1997:36; 956-958. 8. Schroeder TL, Sengelmann RD. Squamous cell carcinoma in situ of the penis successfully treated with imiquimod 5% cream. J Am Acad Dermatol 2002:46; 545-548. 9. Mackenzie-Wood A, Kossard S, DeLauney J, Wilkinson B, Owens ML. Imiquimod 5% cream in the treatment of BowenвЂ™s disease. J Am Acad Dermatol2001:44; 462470. KLE Health Sc. Jr. 2008; 1(1):57-59 57 CASE REPORT A RARE CASE OF BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS Santosh Hajare1, Nitin Agrawal2, Kapoor N3, Ganesh4, Rizwan5 ABSTRACT Benign recurrent intrahepatic cholestasis (BRIC) is a rare cause of cholestasis. The disease may start in infancy or early childhood. Jaundice persists or recurs throughout life but does not lead to chronic liver disease or cirrhosis. Treatment is mostly symptomatic. The condition has rarey been reported in Indian people. We report an interesting case of BRIC in a 18year-old boy who had recurrent episodes of jaundice since one and a half year. Key words : BRIC, Cholestasis, Jaundice, Cirrhosis Introduction Cholestatic jaundice is commonly due to acute viral hepatitis or is drug induced. However, conditions like chronic hepatitis, WilsonвЂ™s disease, alpha-1 antitrypsin deficiency and liver disease associated with chronic inflammatory bowel disease are also considered in the differential diagnosis. Rare causes include syndromes of intrahepatic cholestasis with familial patterns of occurrence.1 These familial cholestatic syndromes share many clinical similarities with onset in infancy or early childhood. They persist or recur throughout life. At one end of the spectrum is BylerвЂ™s disease which is a progressive familial intrahepatic cholestasis (PFIC) culminating in cirrhosis during teenage years. At the other end is benign recurrent intrahepatic cholestasis (BRIC) which as the name suggests has a benign course and does not lead to chronic liver disease or cirrhosis. There have been isolated case reports of BRIC in foreign literature2,3 but rare in India.4 We report an interesting case of BRIC in a 18-yearold boy. Case Report 18 years old boy presented to Gastroenterology OPD one and half years ago with history of Jaundice of 1 month duration. He was admitted and evaluated for the probable etiology of jaundice. He had no history of prodrom however he developed severe pruritis in next few weeks with persisitently high bilirubine level. All his viral markers for 1. 2. 3. 4. 5. M.D, DNB., DM., Consultant Gastroenterologist , Post Graduate Student Post Graduate Student Post Graduate Student in Homoeopathy, Physician Assistant J. N. Medical College, Nehru Nagar, Belgaum - 590 010 Karnataka. Correspond to: E-mail: drsantosh[email protected] hepatitis A,B,C, and E were negative. There was no history exposure to drugs. Due to prolonged jaundice and cholestasis further investigation like autoimmune markers, serum ceruloplasmin, ferritine were done which were normal. There was no history of consanguineous marriage or significant family history. His Magnetic resonant cholengio pancreatography revealed a normal biliary tree. Patient was put on symptomatic conservative treatment. His jaundice and pruritis recovered gradually over the next 3 months. Following this patient was asymptomatic for a period of one year. Two months ago he again presented with another episodes of gradually increasing jaundice without a prodrome with severe pruritis. His basic investigations were similar to first episode and work up for other etiology for cholestasis was negative. He was again put on conservative treatment to which he showed good response. Until the last follow up the liver functions were gradually approaching to normal. Patient had no evidence of chronic or progressive liver disease (Portal hypertension) and as all other possible causes of jaundice were excluded a diagnosis of BRIC was made. On examination, the patient had icterus, itch marks without pallor, pedal oedema or signs of vitamin deficiencies. There were no signs of liver failure in the form of spider angiomas, palmar erythema or thenar atrophy. Liver was just palpable in right hypochondrium with a span of 12 cm. Spleen was not palpable and there was no evidence of free fluid in the abdomen. Rest of the systemic examination was non contributory. His anthropometric parameters were within normal limits with average height and weight. Investigations revealed hemoglobin of 14 g/dl with normal total and differential count. Total bilirubin was 38.4 mg% with a direct component of 30.6 mg%. Alkaline phosphatase was elevated with a value of 338 IU. Liver enzymes including ALT, AST and gamma glutamyl transpeptidase (GGT) were within normal limits. Serum proteins, albumin globulin ratio and prothrombin time were KLE HEALTH SCIENCE JOURNAL, JULY 2008 58 also normal. Ultrasonography of abdomen showed normal echotexture of liver. Viral markers for hepatitis A, B, C and E were negative and serum ceruloplasmin was within normal limits. Auto-immune markers such as ANA, ASMA, AMA & Anti LKM antibodies were negative. Alpha-1 antitrypsin, ACE, serum calcium and thyroid profile were normal. Magnetic resonant cholangio-pancreatography (MRCP) was normal. In view of the above findings, a possibility of recurrent cholestasis was kept. He was given symptomatic treatment and he started showing improvement within 2 weeks with partial normalization of serum bilirubin and alkaline phosphatase level. As he had no evidence of chronic or progressive liver disease and other possible causes of jaundice were excluded. A diagnosis of benign recurrent intrahepatic cholestasis was made. At two months follow up he was showing improvement in his liver functions to near normal. Discussion Benign recurrent intrahepatic cholestasis is a rare disorder of unknown etiology. Initially described by Summerskill and Walshe as recurrent episodes of jaundice and pruritus now recognized as BRIC/FIC1,5 syndromes due to mutations in ATP8B1, an aminophospholipid transporter.6 A similar phenotype is caused by mutations in BSEP aka ABCB11, the bile salt export pump.7 According to the newest insights, there are at least three forms of BRIC all with similar phenotype. BRIC1 and 2 are transmitted as autosomal recessive diseases. BRIC1 due to mutations in the aminophospholipid lipase ATP8B1 located on chromosome 18q21 8 BRIC2 due to mutations in the bile salt export pump BSEP aka ABCB11 located on chromosome 2q24 ; in OMIM this is still considered a progressive disease (PFIC2 = progressive familial intrahepatic cholestasis) but according to recent data it can also manifest as BRIC and has been proposed to be called BRIC2.7 A third form, not linked to either 18q21 or 2q24 exists and is transmitted as an autosomal dominant disease.9 Characterized by intermittent episodes of cholestasis with normal extra hepatic biliary tree. The attacks can start at any age and last from weeks to months.10 In a large series of patients the age of presentation varied from 1 to 59 yr and duration of icteric phase was also variable lasting from weeks to months.11 In our patient, the first attack started at the age of 17 yrs and each episode lasted for 2 to 3 months. In such cases, during icteric phase serum bilirubin, bile acids and alkaline phosphatase are elevated but gamma glutamyl transferase level is characteristically low or normal. Occasionally alanine aminotransferase (ALT) and aspartate aminofransferase (AST) levels may be markedly elevated but usually there is only mild elevation. In the present case the liver enzymes including (GGT) were within normal limits. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease which is characterized by cholestasis with normal gamma glutamyl transferase level which starts in infancy and progresses to cirrhosis, liver failure and death unless a liver transplantation is performed. Conversely, long term follow up of a number of patients with BRIC has shown that the disease follows a benign course and there is no progression to chronic liver disease.12,13 In the present case, even after 1 year there was no evidence of chronic liver disease or cirrhosis. However, a recent report has suggested that few patients may start with clinical symptoms of BRIC and may progress to PFIC. 14 In view of this new evidence, patients with benign recurrent cholestasis need a regular follow up. Treatment of the condition is purely symptomatic. There are conflicting reports regarding the use of cholestyramine and ursodeoxycholic acid. One report suggested that cholestyramine therapy shortened the duration of icteric phase and ursodeoxycholic acid ameliorated the symptoms of pruritus if present.. 2 However, another report has suggested that no treatment was successful in shortening the duration of symptoms. 11 Some recent reports have shown a beneficial role of rifampicin in remission of cholestasis.15,16 In the present case, the patient was given a trial of cholestyramine and ursodeoxycholic acid which provided symptomatic relief with decrease in pruritus. The patient made an uneventful recovery within 2 months. He is on regular follow up for 2 months and has not suffered another attack. References 1. Whitington PE, Emerick KM, Suchy FJ. Familial hepatocellular cholestasis. In Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver disease in children. 2nd edn. Philadelphia; Lippincott William and Wilkins 2001; 315323. 2. Drees K, a Zaben A, al Amir A, Abdulla A. Benign recurrent intrahepatic cholestasis in a Saudi child. Ann Trop Pediatr 1999; 19: 215-217. 3. Liu CJ, Kao JH, Chen PJ, Lai MY, Mao TL, Wang TH, Chen DS. Benign recurrent intrahepatic cholestasis. J Formos Med Assoc 1997; 96 : 370-373. 4. Samal SC, Kashyap R. Benign recurrent intrahepatic cholestasis. J Assoc Phy India 1995 ; 43 : 569 -570. HAJARE, AGRAWAL, KAPOOR, GANESH, RIZWAN:BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS 5. Klomp LWJ, Vargas JC, Van Mil SW et al.. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatol 2004; 40: 27-38. 6. Tang X, Halleck MS, Schlegel RA, Williamson P. A subfamily of P-type ATPases with aminophospholipid transporting activity. Science 1996; 272: 1495-7. 7. Van Mil SWC, Van Der Woerd WL, Van der Brugge G et. al..Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterol 2004; 127: 379-84. 8. Bull LN, van Eijk MJ, Pawlikowska L et al.. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nature Genet 1998; 18: 219-24. 9. Floreani A, Molaro M, Mottes M et al. Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24. Am J Med Genet 2000; 95: 450-3. 10. Summerskill WHJ, Walshe JM. Benign recurrent intrahepatic obstructive jaundice. Lancet 1959; 2:686вЂ“ 690. 11. Brenard R, Genhel AP, Benhamou JP. Benign recurrent intrahepatic cholestasis : a report of 26 cases. J Clin Gastroenterol 1989; 11 : 546-551. 59 12. Nakamuta M, Sakamoto S, Miyata Y,Sato M, Nawata H. Benign recurrent intrahepatic cholestasis: a long term follow up. Hepatogastroenterology 1994; 41 : 287289. 13. Bijleveld CM, Vonk RJ, Kuipers F, Havinga R, Fernandes J. Benign recurrent intrahepatic cholestasis: a long term followup study of two patients. Hepatology 1989; 9: 532-537. 14. van Ooteghem NA, Klomp LW, van BergeHenegouwen GP, Houwen RH. Benign recurrent intrahepatic cholestasis progressing to Progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. J Hepatol 2002; 36 : 439-443. 15. Balsells F, Wyllie R, Steffen R, Kay M. Benign recurrent intrahepatic cholestasis: improvement of pruritus and shortening of symptomatic phase with rifampicin therapy: a case report. Clin Pediatr (Phila) 1997; 36: 483-485. 16. Cancado EL, Leito RM, Carrilho FJ, Laudanna AA. Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of GGt. Am J Gastroenterol 1998; 93: 1510-1517. KLE Health Sc. Jr. 2008; 1(1):60-61 60 CASE REPORT LEIOMYOMA OF THE BREAST Theophilus V Bhushan1, Mastolimath R. D2 ABSTRACT Intra parenchymal leiomyomas of the breast are quite rare. Areolar lesions are distinguished easily from intra parenchymal lesions. KEY WORDS: Leiomyoma, Breast, Benign Disease Introduction Leiomyomas of the breast are quite rare. Clinically they appear as nodules, and mamographically they show as round lesions. Sonologically few criteria are noted such as hypodense, well demarcated, in homogenous lesions with posterior acoustic shadowing.1 Case Report : A 35 Years lady presented with a history of pain in the right breast around the nipple and areola with occasional discharge on and off since 2 years. On examination the nipple was thick, elongated and cracked. The areola was hyperpigmented on the right side. Palpation revealed a small swelling of the size 1cm x 1/2 cm just under the nipple and areola. It was firm, non tender exhibiting restricted mobility. Fig 1 10 x H&E вЂ“ low power Leiomyoma surrounded by normal breast tissue Investigations such as routine haemogram, urine, serum chemistry, chest x-ray and ECG were normal. The patient underwent excision of the nipple areola complex with 1.5 cm clear margin under short general anaesthesia. The postoperative period was uneventful. 1. Assistant Professor, Department of Surgery, 2. Professor, Department of Patology, J. N. Medical College & KLES Dr.Prabhakar Kore Hospital Belgaum 590 010, Karnataka - India Correspond to: e-mail: [email protected] Fig 2 20 x Hi- power Spindle shaped cells arranged in fascicles & whorls Histopathologic examination of the specimen, macroscopically showed nipple-areola with breast tissue 5 cm x 4 cm x3cm. Cut section showed a sub- areolar mass 2.5 cm 1.2 cm. Microscopy revealed dilated lactiferous ducts with clusters of ductules surrounded by fibrosis. Nipple вЂ“ areola KLE HEALTH SCIENCE JOURNAL, JULY 2008 61 were normal. Sclerosis, adenosis with duct ectasia was present. All features are suggested a well circumscribed benign neoplasm of leiomyoma of the breast. References : 1. Heyer H, Ohlinger R, Schimming A & et al: Parenchymal leiomyoma of the breast-clinical, sonographic, mammographic and histological features. Ultraschall Med. Feb 2006: 27 (1); 55-8 2. Weldon C, Jones B, Daroca P, Beech D: Breast Leiomyoma. J La State Med Soc. 1998:150 (8); 367-70 3. Ackermans Surgical Pathology Vol 2 Eds Juvan Rosai 8th Edn Mosby Harcourt Brace & Co. Asia Pvt. 1996:1633. 4. Kotsuma Y, Wakasa K, Yayoi E et al: Breast cancer. 8 (2): 16. Discussion Smooth muscle neoplasms exist as a spectrum of pathological process ranging from benign leiomyoma to anaplastic leiomyo-sarcoma. Strong in 1913 was credited with the early descriptions of leiomyoma of the mammary gland.2 Leimyomas are thought to arise from muscularis mammillae and areola which are often painful. Leiomyomas usually involve the nipple but occasionally seen in the breast structures.3 Leimyomas are common in the genito-urinary and gastro-intestinal tracts and less frequent in skin and soft tissue. It is uncommon in the breast parenchyma. 4 Only 13 such cases have been reported so far and ours will be the 14th case.4 CONFERENCE CALENDER-2008-09 1. National workshop on Survey of Medicine plants in western Ghats On 27th and 28th Sept. 2008 organized by KLES college of Pharmacy and B.Pharmacy for women, JNMC Belgaum-10 Contact: Organizing secretary Dr.Sunil. S. Jalapure E-mail : [email protected] Mobile : 09448964057. 2. 3rd Global congress on cosmetic technology on 6th and 7th Feb. 2009 Organized by KLES college of Pharmacy, Belgaum. Contact : Organizing secretary Dr. Sunil. S. Jalapure E-mail : [email protected] Mobile : 09448964057 62 KLE Health Sc. Jr. 2008; 1(1):62-64 CASE REPORT In situ ADENO CARCINOMA OF GALL BLADDER IN AN YOUNG ADULT Pangi Ashok C1, Kajagar. B. M.2, Dhaded. V. B3 ABSTRACT An young adult with recurrent upper abdominal pain showed presence of gall bladder polyp, which on surgical removal showed to be in situ adenocarcinoma of the gall bladder with organized sludge. Key words : gall bladder adenocarcinoma, gall bladder polyp Introduction Although uncommon, carcinoma of the gallbladder (GB) is the most common primary hepatobiliary carcinoma, and is the fifth most common malignancy of the GI tract, and predominantly affects older persons with long-standing cholecystolithiasis. GB epithelial tumors tend to behave similarly to other GI adenocarcinoma. When the diagnosis is made incidentally at the time of cholecystectomy, surgical resection can be curative; however, more commonly, the tumor is unresectable and rarely diagnosed preoperatively despite symptoms. Early diagnosis can improve the clinical outcome and cure rate of GB carcinoma. Case Report A 18 year male patient presented with history of recurrent attacks of pain in right hypochondrium associated with nausea, There was no history of jaundice or fever. Few episodes of vomiting present. Examination revealed tenderness in right hypochondrium. There was no mass, or organomegaly. Malignant cells not infiltrating the wall USG abdomen showed presence of gall bladder polyp with sludge, thickening of wall, no pericholecystic collection. No IHBR dilatation. Liver function tests andother base line investigations were within normal limits. On exploration, serosa was normal, and cholecystectomy was performed by duct first method. Gall bladder fossa was normal. Histopathological study revealed in situ adenocarcinoma of the gall bladder with organized sludge. Discussion Gall bladder polyp with organized sludge 1. Asso Prof 2. Asst. Prof 3. Prof J.N.Medical College & KLES Prabhakar Kore Hospital & MRC, Belgaum вЂ“ 590 010. Correspond to: E-mail: [email protected] In the general population, the reported incidence of gall bladder carcinoma is 3 per 100,000 persons, with more than 6500 new patientsвЂ™ diagnosed annually 1 . This condition is found incidentally in 1-3% of cholecystectomy specimens and in 0.5-2.4% of postmortem examinations. The exact etiology of gall bladder carcinoma is unknown; however, several associated factors have been identified. One hypothesis suggests that irritation of the gall bladder mucosa by stones causes chronic inflammation and, followed by repetitive epithelial repair, may cause malignant transformation. Approximately 15 years are 63 required for dysplasia to progress to invasive carcinoma2. Gall bladder carcinoma has a female preponderance. The female-to-male ratio is 3:11. The greatest incidence of gall bladder carcinoma is in persons older than 65 years. Moreover, porcelain (calcified) gall bladder has a high malignant potential and large, sessile polyps (more than 10mm) are more likely to be malignant than multiple, small, pedunculated ones. The incidence of carcinoma gall bladder increases 14.7-fold 20 years after surgery for gastric ulcer3. In affected patients, 60% of gall bladder tumors occur in the fundus, 30% in the gall bladder body, and 10% in the neck. Associated findings and risk factors for gall bladder carcinoma are cholecystolithiasis, which is present in 70-90% of patients, Composition of the bile with cholesterol stones, genetic factors, calcification of the gall bladder wall (carcinoma in 25% of patients with porcelain gall bladder), anomalous pancreatic-biliary duct junction, congenital biliary cysts, infections by salmonella typhi, environmental carcinogens4. The adenocarcinoma is the most common histological type (approximately 80%) of carcinoma gall bladder, but histology varies. Cases of undifferentiated carcinoma occur in 6% and squamous carcinoma in 3%. Cases of adenosquamous, carcinosarcoma and spindle-cell sarcoma of gall bladder have also been reported. A variety of other lesions, including carcinoid tumors, sarcoma, melanoma and lymphomas, have also been found. Early lymphatic spread is to the retroperitoneal, right celiac, and pancreaticoduodenal nodes. Direct invasion occurs in the liver, extra hepatic biliary ducts, and duodenum and colon, intraperitoneal seeding may also occur4. Ultrasound is the imaging modality of choice.US cannot stage the tumor. The visualization of lymph nodes, intraperitoneal disease, and distant metastases is difficult. US are the most commonly used imaging modality for evaluating gall badder carcinoma; however, there have been no identified pathognomonic findings. Polypoid lesions need to be at least 5 mm in size to be detected by ultrasound. Cholesterol polyps generally appear as pedunculated lesions attached to the gallbladder wall by a pedicle. Gall bladder thickening associated with early lesions is rarely detected. More advanced lesions may produce marked mural thickening with irregular and mixed echogenicity; this is the second most common manifestation of gall bladder carcinoma, accounting for 20-30% of patients. The gall bladder may be small, normal, or distended, and gallstones are often present. The polyps or mass are of homogeneous echo texture without evidence of shadowing. The polyps are usually sessile and only rarely have a stalk; this is the least common manifestation of gall KLE HEALTH SCIENCE JOURNAL, JULY 2008 bladder carcinoma, accounting for 15-25% of patients. Gallstones may also be present and may prevent recognition of a small polypoid mass. Tumefactive sludge can mimic a mass. An extra luminal mass is often accompanied by a large mass that replaces the gall bladder fossa. The mass is often complex, with visible areas of necrosis; this is the most common manifestation of gall bladder carcinoma, accounting for 4065% of gall bladder carcinomas5. The current recommendations for resection of gallbladder polyps include any lesion that is enlarging, symptomatic, or greater than 1 cm. The recommendations for lesions less than 1 cm include follow-up and re evaluation of the lesion via repeat imaging studies Benign causes of gall bladder wall thickening can mimic carcinoma, and smaller polyps are often benign The size of the gallstones plays a role in the development of gallbladder cancer. Gallbladders containing gallstones that are greater than 3 cm in diameter have a 10 times greater risk for developing malignancy than those containing gallstones that are 1 cm in diameter. The risk is hypothesized to be due to chronic inflammation. Chronic Salmonella typhi infection has also been linked to adenocarcinoma of the gallbladder Squamous cell carcinoma accounts for up to 12.7% of gallbladder cancers. When compared with adenocarcinoma, it generally presents a worse prognosis. Squamous cell carcinoma is found more often in females than in males; presents at an earlier age than adenocarcinoma, generally from the fourth to sixth decades of life1. Laparoscopic or open cholecystectomy is curative if the diagnosis is unknown and the cancer is diagnosed to be in situ stage on histological examination of the specimen. In case of laparoscopic approach, the use of a specimen retrieval bag should be considered if cancer is suspected 6. In extra luminal mass, operative intervention needs to be individualized requiring segmental resection of liver or palliative bypass. Role of neo adjuvant, adjuvant chemotherapy and post operative radiotherapy are controversial. Acknowledgement: We thank Dr. V.D Patil, Principal, J.N.Medical College, and Dr.M.V.Jali, M.D & C.E.O, KLES Prabhakar Kore Hospital & MRC, for the support and guidance. PANGI, KAJGAR, DHADED:IN SITU ADENO CARCINOMA OF GALI BLADDER References 1. Aldridge MC, Bismuth H. Gallbladder cancer: the polyp-cancer sequence. Br J Surg. 1990: 77(4):363-4. 2. Kobayashi S, Ohnuma N, Yoshida H, Ohtsuka Y, Terui K, Asano T. Preferable operative age of choledochal dilation types to prevent patients with pancreatico biliary malfunction from developing biliary tract carcinogenesis. Surgery. 2006:139(1):33-81. 3. Onoyama H, Yamamoto M, Tseng A. Extended cholecystectomy for carcinoma of the gallbladder. World J Surg.1995; 19(5):758-63. 4. Fong Y, Wagman L, Gonen M, et al. Evidence-based gallbladder cancer staging: changing cancer staging by analysis of data from the National Cancer Database. Ann Surg. 2006:243(6):767-71; 771-74 5. Yamada T, Alpers DH, Owyang C, Powell DW, Silverstein FE, eds. Textbook of Gastroenterology. Vol 2. 2nded. Baltimore,Md: Lippincott Williams & Wilkins; 1999: 2335-40. 6. Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical resection. Ann Surg. 2007:245(6):893-901. 64 KLE Health Sc. Jr. 2008; 1(1):65-67 65 CASE REPORT CHONDROSARCOMA OF THE GREAT TOE A RARE CASE REPORT Murakibhavi V. G.1, S. H. Motimath2, Gururaj. G. Murgod3 ABSTRACT Chondrosarcoma of the great toe is very rare. 1 We present such a case of chondrosarcoma of the proximal phalanx of right great toe who presented with swelling of the region for the last 7 yrs. Sudden increase in size of the swelling was noticed in the last 3 months which was associated with pain and diagnosis was confirmed by FNAC. Disarticulation at the level of first metatarso phalangeal joint was performed and histopathological study confirmed the diagnosis. Key words : Chondrosarcoma, Great toe, Rare case Case report : A 45 year male presented with swelling over the right great toe for last 7 yrs. The swelling increased in size and was associated with pain in the last 3 months (fig1). Fig 1 : PREOPERATIVE PHOTOGRAPH The pain was dull aching and persistent throughout the day. On examination fusiform swelling was present over the right great toe measuring about 4X3 cms encircling the proximal phalanx area . Skin over the swelling was stretched. There were no scars, sinuses, engorged veins or visible pulsations. There was local rise of temperature. Swelling was bony hard in consistency, immobile, tender and adherent to the skin. Metatarsophalangeal joint of right great toe movements were not possible. There was no distal neuro vascular deficit. Routine blood investigations were within normal limits. X- ray left foot showed irregular expansile lytic lesion involving the proximal phalanx of right great toe with multiple specks of calcification and cortical discontinuity(fig2). Fig 2. : PREOPERATIVE X-RAYS (ANTEROPOSTERIOR & LATERAL VIEWS) 1. PROFESSOR 2. ASSOCIATE PROFESSOR 3. Postgraduate student DEPARTMENT OF TRAUMA AND ORTHOPAEDICS, J.N.Medical college, K.L.EвЂ™S Prabhakar Kore Hospital and Medical research center, Belgaum 590 010, Karnataka, India Correspond to: E-mail: [email protected] FNAC was reported as вЂњwell differentiated chondrosarcomaвЂќ. No secondaries were detected in the chest X-ray. Because of unhealthy skin and the size of swelling KLE HEALTH SCIENCE JOURNAL, JULY 2008 66 disarticulation was done at metatarso phalangeal joint and post operative period was uneventful (fig 4). Fig 4: POSTOPERATIVE CLINICAL PHOTOGARPH instead of one). Grade II (or вЂњintermediate gradeвЂќ) is more cellular with a greater degree of nuclear atypia, hyperchromasia and nuclear size. Grade III (or вЂњhigh gradeвЂќ) tumors have significant areas of marked pleomorphism, large cells with more hyperchromatic nuclei than grade II, occasional giant cells and abundant necrosis. Mitoses are frequently detected.9-13 Most chondrosarcoma are low-grade lesions. They are typically seen in adults in their late 20s to 60s. They occur more commonly in men than women. Chondrosarcoma may develop in any part of the body, but are commonly found in the pelvis, rib cage, arms (humerus), shoulder blades (scapula) and lower limbs (proximal femur, tibia). Although any bone can be affected, the long bones, pelvis and shoulder blades are most commonly involved. Metastasis is rare with low-grade tumors, but has been seen, even up to 10 years after diagnosis. Surgery is the main treatment option for chondrosarcoma. Surgical options depend upon the tumorвЂ™s size, and whether the tumor has grown into or around nerves, blood vessels or a joint.14, 15 References Histopathological study showed it to be as вЂњgrade II central chondrosarcomaвЂќ (fig 3) . 1. Fig 3.: HISTOPATOLOGICAL SLIDE (HIGH POWER) CENTRAL CHONDROSRCOMA (GRADE II) Hatori M.Chondrosarcoma of the distal phalanx of the great toe. J Am Podiatr Med Assoc. 2007: 97; 156вЂ“159. 2. Evans H. L., Ayala A.G. Romsdahl M.M. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer. 1977;40; 818-831. 3. Lee F. Y., Mankin H. J., Fondren G., Gebhardt M. C., Springfield D. S., Rosenberg A. E. Jennings L. C. Chondrosarcoma of bone: an assessment of outcome. J Bone Joint Surg Am. 1999: 81; 326-338. 4. Mandahl N., Gustafson P., Mertens F., Akerman M., Baldetorp B., Gisselsson D., Knuutila S., Bauer H. C. Larsson O. Cytogenetic aberrations and their prognostic impact in chondrosarcoma. Genes Chromosomes Cancer. 2002; 33; 188-200. 5. Marchini S., Marrazzo, E., Bonomi R., Chiorino G., Zaffaroni M., Weissbach L., Hornicek F. J., Broggini M., Faircloth G. T. and DвЂ™Incalci M. Molecular characterisation of two human cancer cell lines selected in vitro for their chemotherapeutic drug resistance to ET-743. Eur J Cancer. 2005; 41; 323-333. 6. Marco R. A., Gitelis S., Brebach G. T. Healey J. H. Cartilage tumors: evaluation and treatment. J Am Acad Orthop Surg. 2000: 8; 292-304. Discussion Chondrosarcoma is a malignant cancer whose tumor cells produce a pure hyaline cartilage that results in abnormal bone and/or cartilage growth1. Chondrosarcoma is the second most common primary bone cancer.2-8 Grade I (or вЂњlow gradeвЂќ) tumors resemble normal cartilage, but may surround areas of lamellar bone (which is not seen in benign lesions), or show atypical cells including binucleate forms (cells with two nuclei MURAKIBHAVI, MOTIMATH, MURGOD:CHONDROSARCOMA OF THE GREAT TOE 7. Mirra J. M., Gold R., Downs J. Eckardt J. J. A new histologic approach to the differentiation of enchondroma and chondrosarcoma of the bones. A clinicopathologic analysis of 51 cases. Clin Orthop Relat Res. 1985: 214-237. 8. Marcove R. C., Stovell P. B., Huvos A. G. Bullough P. G. The use of cryosurgery in the treatment of low and medium grade chondrosarcoma. A preliminary report. Clin Orthop Relat Res. 1977:147-156. 9. Terek R. M. Recent advances in the basic science of chondrosarcoma. Orthop Clin North Am. 2006: 37; 914. 10.Pritchard D. J., Lunke R. J., Taylor W. F., Dahlin D. C. Medley B. E. Chondrosarcoma: a clinicopathologic and statistical analysis. Cancer. 1980: 45; 149-157. 67 11. Reith J. D., Horodyski M. B. Scarborough M. T. Grade 2 chondrosarcoma: stage I or stage II tumor?. Clin Orthop Relat Res. 2003: 45-51. 12. Sandberg A. A. and Bridge J. A. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: chondrosarcoma and other cartilaginous neoplasms. Cancer Genet Cytogenet. 2003: 143; 1-31. 13. Sandberg, A. A. Genetics of chondrosarcoma and related tumors. Curr Opin Oncol. 2004: 16; 342-354. 14. Sawyer J. R., Swanson C. M., Lukacs J. L., Nicholas R. W., North P. E. Thomas J. R. Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors. Cancer. 1998: 82; 474-483. KLE Health Sc. Jr. 2008; 1(1):68-69 68 CASE REPORT LOWER URETERIC DIVERTICULUM -A CASE REPORT R.B.Nerli1, ShriShailesh Amarkhed2, I.R.Ravish3, Ashish Koura4 ABSTRACT An adult male who presented with lower abdominal pain revealed a cystic dilatation of the lower end of the right ureter. The cystic lesion was dissected and ureteric ends reimplanted. Key Words: Ureteric diverticulum Case Report A 42-year male presented with history of pain in lower abdomen of 3 months duration. Patient had undergone appendectomy and right lower ureterolithotomy a year ago. Blood biochemistry was normal, urine showed pyuria and microhaematuria. Preoperative uroflow showed a peak flow of 4 ml/sec. Ultrasonography showed right sided moderate degree hydronephrosis with hydroureter, and cystic dilatation of the lower end of right ureter. MR Urogram showed a cystic Fig II : M R Urogram вЂ“ Right Lower Diverticulum Lateral View lesion near the lower end of the right ureter (fig 1 and 2). Fig I: M R Urogram вЂ“ Right Lower Ureteric Diverticulum Cystoscopy revealed a normal bladder. Right-sided RGP was attempted. The contrast material leaked around the catheter. Right lower ureteroscopy was done. Only the distal 2cms of ureter could be visualized. Even a guide wire could not be negotiated beyond that level. 1. Prof and Head Urology 2. M.ch. Asst. Prof 3. M.ch. Asst. Prof 4. M.PG student M.ch Dept of Urology, KLES Kidney Foundation, KLES Dr.Prabhakar Kore Hospital & MRC, Belgaum Correspond to: E-mail: [email protected] Surgical exploration was done. The right ureter could be traced till the cystic lesion. The cystic lesion was dissected easily anteriorly but it was plastered to the surrounding tissues posteriorly. The lesion was incised and clear fluid was drained. The upper communication with the ureter could be easily identified. The distal communication was identified. The cystic lesion was excised with difficulty and the proximal ureteric end was reimplanted into the bladder. Postoperatively, the patient recovered well and the catheter was removed a week later. KLE HEALTH SCIENCE JOURNAL, JULY 2008 69 Discussion Ureteric diverticulaвЂ™s can be congenital or acquired, although most have been discovered in adults. Most diverticulas are solitary outpouchings involving the distal ureters and upper portions of the pelvis. These diverticuli of the ureter have been classified by Gray and Skandalakis1 into three categories: 1) abnormal ureteral duplications (blind ending bifid ureters), 2) true congenital diverticulas containing all tissue layers of the normal ureter, and 3) acquired diverticula representing mucosal herniations. Congenital diverticula are very uncommon and have been reported as arising from the distal ureter above the ureterovesical junction, midureter, and ureteropelvic junction2,3. These diverticula can become very large, and secondary hydronephrosis can ensue. Most patients present with abdominal pain or renal colic and a palpable cystic mass. Occasionally patients may present with repeated infections and colic4. Acquired diverticula may be associated with strictures or calculi and may occur after trauma. Unlike diverticula found in the bladder and urethra, major complications and development of transitional cell carcinoma are rare. Diverticula may be associated with other pathology, such as Ask-Upmark kidney5. References 1. Gray SW, Skandalakis JE. Embryology for surgeons. Philadelphia, WB Saunders, 1972. 2. Culp OS. Ureteral Diverticulum: Classificaton of the literature and report of an authentic case. J Urol 1947:58;309 3. McGraw AB, Culp OS. Diverticulum of the ureter : Report of another authentic case. J Urol 1952:67;262 4. Sharma SK et al. Bilateral incomplete ureteric duplication with a uretric diverticulum. Aust N Z J Surg 1980:51;24 5. Murphy W. Urological Pathology, 2nd ed Philadelphia : WB Saunders, 1997:27. 70 KLE HEALTH SCIENCE JOURNAL, JULY 2008 Guidelines to Contributors......... Contd. from front inside cover Summary and Keywords Ethics The second page should carry the summary (abstract) preferably of not more than 200-300 words, summarizing the work systematically by disclosing context, objectives, design, setting, participants, interventions, main outcome measures, results and conclusions .The abstract should reflect the paper and describe the message succinctly and accurately. The format of the abstract may be based on the standard IMRAD structure (Introduction, Methods, Results And Discussion) of the paper When reporting experiments on human subjects, indicate whether the procedures followed were in accordance with ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975, as revised in 2006. Indicate whether institutions or the Indian Council of Medical ResearchвЂ™s guidelines were followed. 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A rough guide to the length of вЂ�DiscussionвЂ™, however is that it should not be more than one third of the total length of the manuscript (IMRAD) Emphasise and summarise the new and important findings of GUIDELINES FOR CONTRIBUTORS the study and the inferences that follow from them. Discuss possible problems with the methods used. Compare your results with previous work or relate your observations to other relevant studies. Discuss the scientific and clinical implications of your findings. Do not repeat in detail data or other material given in the вЂ�IntroductionвЂ™ or the вЂ�ResultsвЂ™ section. Discuss and analyse the limitations of your study, including suggestion for future work. Conclusions Link the conclusions with the goals of the study but avoid unqualified statements and conclusions not completely supported by your data. Produce a succinct conclusion. 71 Lai LY, et al. Predisposing locus for AlzheimerвЂ™s disease on chromosome 21, Lancet 1989; 1: 352-5. 2. Organisation as author: The Royal Marsden Hospital Bonemarrow Transplantation Team. Failure of syngeneic bonemarrow graft without preconditioning in post-hepatitis marrow aplasia. Lancet 1977;2:742-4. 3. No author given : Coffee drinking and cancer of the pancreas (editorial). BMJ 1981; 283:628. B. Books and other Monographs 1. Personal author(s): Colson JH, Armour WJ. Sports injuries and their treatment, 2nd rev. ed. London: S. Paul, 1986. 2. Editor(s), compiler as authors : Diener HC, Wilkinson M, editors. Drug-induced headache. New York: Springer Verlag, 1988. 3. Chapters in a book: Weinstein L, Swartz MN. Pathologic properties of invading microorganisms. In: Sodeman WA Jr, Sodeman WA, editors. Pathologic physiology: mechanisms of disease. Philadelphia: Saunders, 1974 : 457-72. C. Other published Material Acknowledgements They should be brief and should include reference to the source of technical help, material support and financial assistance. 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