KLE Health Sc. Jr. 2008; 1(1):1
KLE University’s
Health Science Journal
An Official Peer-reviewed, Bi-annual Journal of Health Sciences of
KLE University, Belgaum, Karnataka, India
Aims and Scope: KLE University’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 Hon’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 University’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
“frequency with which the average article in a journal has
been cited in a particular year” 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 “Hot Topics”,
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 “IF” be abolished
and that this measure be renamed in keeping with its actual
role, that merely of a time specific “citation rate index” 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 “Omnipotent”
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
“Impact factor”. 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 computer’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
patient’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 �hub
and spoke model’ 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*
“Not 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 reader”
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 one’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 �publications’ 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 �What
generally happens to manuscripts submitted to a journal’?
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 – 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
�Guide lines for Authors’ 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:
�A well begun is half done’ Author must think before
hand, about “How to write?” “What to write?” and “Where
to submit?” Having affirmed all of the above, with the data of
a well conducted and concluded research project in hand,
author must think of a “clear message” 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 “Uniform requirements
for manuscripts submitted to Biomedical journals” 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 don’t; They
are available on line www.icmje.org.
In addition, the journal’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 “Comparative evaluation of Propofol –
Ketamine and Propofol-Fentanyl in minor Surgery”. 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 –”Comparative
evaluation of Efficiency of Propofol – Ketamine and Propofol
– Fentanyl combinations as sole anaesthetic agents, in
patients undergoing minor Ambulatory Gynecological
operations”.
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 �unstructured’ abstracts and
250 words for �structured’ 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 �home
readiness’ is intended to be studied, the �Post Anaesthetic
Discharge scoring system’ (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 – Ketamine
combination fared well except that there was �excitatory
phenomenon’ 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 – 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 �abstracts’ 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 �Discussion’ in the �Results’ 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 �tense’ 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, �a self
test’ 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 ……………………. 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 O’ 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 O’ 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
.Patient’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 Women’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 Women’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), 0.60–
1.74] and diastolic blood pressure 1.04 mmHg (95% CI, 0.64–
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 Women’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; 342:836–843.
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;144:537–547.
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;
19:3071–3078.
10.
King DE, Mainous AG, Buchanan TA, Pearson WS: Creactive protein and glycemic control in adults with
diabetes. Diabetes Care 26:1535–1539, 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, O’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, 1130–
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;104:974–5
2.
Blake GJ,Ridker PM. Inflammatory bio-markers and
cardiovascular risk prediction. J Intern Med
2002;252:283–94.
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 –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 – 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 – 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 – 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
– 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 “Gastrointestinal Stromal Tumors” 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 Kore’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 & KLE’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
Carney’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 e” 7 cms, high cellularity, mucosal invasion, high nuclear
grade, mitotic counts e” 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 “Tyrosine kinase” 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
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Miettinen M, Monihan J M, Sarlomo-Rikala M et al.
Gastrointestinal stromal tumors/ smooth muscle tumors
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Joss J R. Tumors of the Intestine and Anus. In
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Vranckx H, VanOosterom A, Hagemeijer A, Sciot R.
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Miettinen M, Majidi M, Lasota J. Pathology and
diagnostic criteria of GISTs: a review. Eur J Cancer
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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 E’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, BLDEA’s Shri B.M.Patil
Medical College, Bijapur.
3. Professor & Head
Department of Urology, BLDE’S SBMDMC
4. Professor & Head
Department of Pathology, BLDE’S SBMP, Bijapur
Correspond to:
Dr. Sunita Y. Patil,
Email – [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,
�Intraductal dysplasia.’ 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. Gleason’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.A’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 [16]
6
37.5%
5
31.25%
1
6.25%
4
25%
2 [6]
3
50%
1
16.6%
0
0%
2
33.3%
3 [8]
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 Gleason’s
grading and this pattern is considered to represent cancer13.
However in other studies 1,5,12 Gleason’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 Gleason’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 ’! low grade PIN ’! High grade PIN ’!
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. Anderson’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
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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.
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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 – 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.’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 patient’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 patient’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 patient’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 �cerebral palsy’
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 �Prediabetes’ is
imprecise, the earliest known mention was made by Maranon12
in the early 1940’s, later in humans by Camerini-Davalos13 in
KLE HEALTH SCIENCE JOURNAL, JULY 2008
39
1951 in relation to pregnancy. In the 1960’s, �Prediabetes’ 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 �Prediabetes’ 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 �Prediabetes’ in the 1980’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.
�Prediabetes’ 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
�Prediabetes’ 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.
“Prediabetes” — What’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 “PreDiabetes”. “Pre-diabetes” is a condition that raises a person’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
“Prediabetes” and the Metabolic Syndrome are
extremely prevalent and persons with “Prediabetes and the
Metabolic Syndrome” 16 are at high risk for diabetes and CVD
and they are the ideal target population for prevention or
intervention programmes. In 2005,’ Prediabetes’ 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 – 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 Söderberg and Ramachandran from Sweden and India,
respectively, suggest that the �Prediabetes’ 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 �isolated IGT’ and �isolated IFG’
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
�Prediabetes’ 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 – 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
tests—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 e”126 mg/dl (7.0mmol/L) = Provisional diagnosis
of Diabetes (the diagnosis must be confirmed, as
described below).
пЃ®
2-h PG†<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 e”200 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. †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 “pre-diabetes” 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 “backbone” 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 patient’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 —called lipotoxicity—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 number—the glucagon-producing cells remain about the
same—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 5–
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 85–90% 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 “Latent Onset of Diabetes in
Adults” (LADA) 22, 23, 33. Autoimmune destruction of ß-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 Graves’ disease, Hashimoto’s thyroiditis,
Addison’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 patients’ 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%–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 “reset the clock” 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
BMI e”35 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 8–10% of
initial weight in 16–26 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
“Prediabetes” 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.
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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
“Gold standard” in VA validation studies: Most
researchers rely on the diagnosis of the underlying cause of
death from clinical records as the “gold standard”. 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 physician’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 respondent’s ability to
recollect and report relevant information, inadequate time for
mourning may also cause emotional distress and influence a
respondent’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 Physician’s review, predefined expert algorithm and data
driven algorithms. In a study comparing physician’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)—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, O’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
BOWEN’S DISEASE OF THE UNEXPOSED SKIN
B. Siddaramappa1, B S Manjunathswamy2, A M Pandit3, Shilpa Dastikop4,
Carol Z Fernandes5, Tanu Sardana6
ABSTRACT
Bowen’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
Bowen’s Disease occurring on the unexposed skin who showed appreciable regression of lesions after 6 weeks of 5% 5Fluorouracil therapy.
Key words: Bowen’s disease, unexposed skin
Introduction
Bowen’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 Bowen’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 Bowen’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 Bowen’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. Bowen’s disease affects both skin
and mucous membrane such as oral mucosa and conjunctiva
or cornea 2. Bowen’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 Bowen’s disease arising in seborrhoeic
keratoses and it has also been reported in parakeratosis
(disseminated, Mibelli and linear types) and in Becker’s
nevus2.
The apparent relationship between Bowen’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
Bowen’s disease are not justified 2.
Clinical differential diagnosis of Bowen’s disease
include actinic keratosis, verrucae, superficial basal cell
epithelioma, Paget’s disease, epidermal nevi, psoriasis and
lichen simplex chronicus.
Bowen’s disease can be treated with a variety of
therapeutic modalities including surgery, chemotherapy,
electrodessication and curettage, Mohs’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 Bowen’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 Bowen’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 Bowen’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 Bowen’s Disease. Brit Jour Dermatol
1999:141; 633-641.
3.
Dupree MT, Kiteley RA, Weismantle K, Panos R,
Johnstone PAS. Radiation therapy for Bowen’s
SIDDARAMAPPA, MANJUNATHSWAMI, PANDIT, DASTIKOP, FERNANDES, SARDANA: BOWN’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 Bowen’s disease of finger. Arch
Dermatol 1994:130;1250-1252.
4.
Yerebakan O, Ermis O, Yilmaz E, Basaran E. Treatment
of arsenical keratosis and Bowen’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 Bowen’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 Bowen’s
disease. Dis Colon Rectum 2005;48; 444-450
13.
Bargman H, Hochman J. Topical treatment of Bowen’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 Bowen’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
Bowen’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, Wilson’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 Byler’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: [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; 2:686–
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 – 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 – 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 – 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 patients’ 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.E’S Prabhakar Kore Hospital
and Medical research center,
Belgaum 590 010, Karnataka, India
Correspond to:
E-mail: [email protected]
FNAC was reported as “well differentiated
chondrosarcoma”. 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 “intermediate grade”) is more
cellular with a greater degree of nuclear atypia,
hyperchromasia and nuclear size. Grade III (or “high grade”)
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 tumor’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 “grade II
central chondrosarcoma” (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; 156–159.
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 D’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 “low grade”)
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 – Right Lower Diverticulum Lateral View
lesion near the lower end of the right ureter (fig 1 and 2).
Fig I:
M R Urogram – 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 diverticula’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
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Nevertheless, a fundamental structure is the basis of
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Start on a new page stating clearly the question being
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Though brevity is desirable, describe the selection of
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Present your results in logical sequence in the text, tables
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It is difficult not to write a long and detailed analysis
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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
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71
Lai LY, et al. Predisposing locus for Alzheimer’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. Individuals named must approve their inclusion
in the acknowledgements, before the paper is submitted.
References
The references of the article are the foundation on
which the work of the study is built. They provide the scientific
background that justifies your study, including the methods
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KLE University’s Health Science Journal follows
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1.
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Toate AM, Haynes AR, Owen KJ, Farrall M, James LA,
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1989 Aug. 7; Sect. A:2 (Col.5).
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