Founded 1897 • New Series

Romanian Journal of Vol. CXX • No. 2/2017 • August

Military
Medicine
REVISTA DE MEDICINĂ MILITARĂ

• The story of a journal – The 120th anniversary of the Romanian Journal of Military Medicine
• The concept of operationalization of an integrated platform for scientific research and expertise of war
and bioterrorism biological agents
• Intellectual mobility in medical higher education system
• The influence of homocysteine on osteoporosis
• Efficacy and tolerability of calcium channel alpha-2-delta ligands in psychiatric disorders
• Medicine versus philosophy
• Incidence of peripheral trophic disorders determined by vein thrombosis of the lower limbs correlated
with risk factors by age
• New synthesized oximes active in nerve agents’ hazards
• Ethical considerations in sudden unexpected death in epilepsy (SUDEP)
• Pericardium – An editorial success

Journal included in Index Copernicus International, National Library of Medicine Catalog, Ulrich’s Periodicals Directory
database, OCLC WorldCat, Directory of Open Access Journals, Directory of Research Journals Index, Eurasian Scientific Journal
Index, Scientific World Index, Science Library Index and Open Academic Journals Index.

www.revistamedicinamilitara.ro
Editorial Board of Romanian Journal of Military Medicine
Under the patronage
Honorary Editor
Editors-in-Chief
Executive Editors
Associate Editor
Redactors
Editorial Assistants
Technical Secretary
Publisher
Romanian Association of Military Physicians and Pharmacists
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
Victor Voicu MD, PhD
Florentina Ioniță Radu MD, PhD, MBA
Dan Mischianu MD, PhD
Daniel O. Costache MD, PhD, MBA
Victor L. Purcărea PhD, MBA
Mariana Jinga MD, PhD, MBA
Doina Baltaru MD, PhD – Cluj Napoca
Mihail Tudosie MD, PhD – Bucharest
Roxana Călin MD
Cristina Solea
Oana Ciobanu
Carol Davila University of Medicine and Pharmacy Publishing House

International Editorial Board

Natan Børnstein (Israel)
Cris S. Constantinescu (UK)
Daniel Dănilă (USA)
Mihai Moldovan (Denmark)
Ioan Opriș (USA)
Gerard Roul (France)
Erwin Santo (Israel)
Adrian Săftoiu (Denmark)
Ioanel Sinescu (Romania)
C. Ionescu Târgovişte (Romania)
Radu Ţuţuian (Switzerland)
Shyam Varadarajulu (USA)
Peter Vilmann (Denmark)
Victor Voicu (Romania)

Scientific Publishing Committee

Adrian Barbilian (Bucharest)
Anda Băicuş (Bucharest)
Cristian Băicuş (Bucharest)
Andra Bălănescu (Bucharest)
Mircea Beuran (Bucharest)
Ovidiu Bratu (Bucharest)
Daciana Brănișteanu (Iași)
Dragoș Bumbăcea (Bucharest)
Marian Burcea (Bucharest)
Sofia Colesca (Bucharest)
Dumitru Constantin Dulcan (Bucharest)
Gabriel Constantinescu (Bucharest)
Dan Corneci (Bucharest)
Raluca S. Costache (Bucharest)
Dragoș Cuzino (Bucharest)
Mircea Diculescu (Bucharest)
Cosmin Dobrin (Bucharest)
Gabriela Droc (Bucharest)
Silviu Dumitrescu (Bucharest)
Carmen G. Fierbințeanu (Bucharest)
Cristian Gheorghe (Bucharest)
Liana S. Gheorghe (Bucharest)
Mihai E. Hinescu (Bucharest)
Ruxandra Jurcuț (Bucharest)
Viorel Jinga (Bucharest)
Ovidiu Nicodin (Bucharest)
Tudor Nicolaie (Bucharest)
Bogdan A. Popescu (Bucharest)
Emilian A. Ranetti (Bucharest)
Corneliu Romanițan (Bucharest)
Carmen A. Sîrbu (Bucharest)
Silviu Stanciu (Bucharest)
Ion Țintoiu (Bucharest)
Sorin G. Țiplica (Bucharest)
Dragoş Vinereanu (Bucharest)

REDACTION
B-dul Eroii sanitari, Nr. 8, Sector 5, București, Tel/fax 021/318.07.59, tel. 021/318.08.62/Int. 199; Email rjmilmed@yahoo.com
Romanian Journal of Military Medicine is included in Romanian College of Physicians Medical Publications Index (5 CME hours).

www.revistamedicinamilitara.ro

Romanian Journal of Military Medicine, New Series, vol. CXX, No 2/2017, August
ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

RJMM
Romanian Journal of Military Medicine
Founded 1897 • New Series
Vol. CXX • No. 2/2017 • August
Edited by the Romanian Association of Military Physicians and Pharmacists.

Contents
EDITORIAL
Dan Mischianu
• The story of a journal – The 120th anniversary of the Romanian Journal of Military
Medicine 3
REVIEW ARTICLE
Viorel Ordeanu, Marius Necşulescu, Diana M. Popescu, Lucia E. Ionescu, Simona N. Bicheru, Gabriela V.
Dumitrescu, George Corlan
• The concept of operationalization of an integrated platform for scientific research and
expertise of war and bioterrorism biological agents 9
Iulia Alecu, Horia Mocanu, Ioan E. Călin
• Intellectual mobility in medical higher education system 16
Elena Rusu
• The influence of homocysteine on osteoporosis 22
SYSTEMATIC REVIEWS, META-ANALYSIS
Octavian Vasiliu, Daniel Vasile, Andrei G. Mangalagiu, Bogdan M. Petrescu, Corina Tudor, D. Ungureanu, C.
Cândea
• Efficacy and tolerability of calcium channel alpha-2-delta ligands in psychiatric disorders 27
ORIGINAL ARTICLES
Mirela Radu
32
• Medicine versus philosophy
Georgeta Trucă, Florian Popa, Radu A. Macovei, M. L. Fulga, Gina A. Ciucă, G. Păunică-Panea
• Incidence of peripheral trophic disorders determined by vein thrombosis of the lower
limbs correlated with risk factors by age 37
Mihail S. Tudosie, Bogdan Patrinich, Andreea R. Negrea, Cristina A. Secară
• New synthesized oximes active in nerve agents hazards 47
CLINICAL PRACTICE
Carmen A. Sîrbu, Octavian M. Sîrbu, Anca M. Sandu, Florentina C. Pleșa, Beatrice G. Ioan
• Ethical considerations in sudden unexpected death in epilepsy (SUDEP) 54
VARIA
Teodor Horvat
• Pericardium – An editorial success 58

1
ADMINISTRATIVE ISSUES
Guidelines for authors 64

2
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

EDITORIAL

The story of a journal – The 120th anniversary of

the Romanian Journal of Military Medicine

Dan Mischianu

The Military Medicine Magazine, later became the April 12, 1897, and
Gral (R) Prof DAN MISCHIANU
Romanian Journal of Military Medicine (RJMM)… established that under the
well, I assure you that it did not come out of thin air! leadership of General Prof. Chief of Urology Clinic, Carol
Davila University Central
Dr. Athanase Demosthen – as Emergency Military Hospital
It appeared on September 15, 1897, 120 years ago,
chairman, a new magazine Faculty of General Medicine,
on the initiative of military medical professionals.
called "Military Sanitary Carol Davila University of
I think few of us know that on January 12, 1897, Army Medicine and Pharmacy,
Review” will be born with the
Bucharest, Romania
Corps General Professor Dr. Athanase Demosthen previously mentioned status.
was elected correspondent member of the Medical The companions of General Demosthen for this
Academy of Paris. enterprise were the generals Dr. I. Şerbănescu, N.
Those who celebrated him for success, mostly his Zorileanu, the army pharmacist M. Marinescu, first
students and contemporaries, doctors, pharmacists class regiment physician I.M. Călinescu, second class
and veterinarians (military veterinarians, the cavalry regiment physician Iacob Potârcă (a memorable name
did not disappear – as a fighting weapon!) decided, in Romanian surgery – versus Whitehead
according to the French example, to create a procedure!), pharmacists C. Dumitrescu-Parepa and
magazine with independent statute and organization, Constantin Merișanu (whose bust guards a hospital
and objectives that do not go beyond our present alley).
understanding. Namely: "maintenance of scientific The magazine appeared on 15 September 1897 and
activity and emulation among the members of the the photocopy presented reproduces the first cover
sanitary body, establishment of the collegiality links of the Military Health Magazine (Revista Sanitară
between the sanitary officers, as well as the Militară, 1972, nr. 4-5, pg. 409).
preservation of the scientific and moral prestige that
The "Military Health Magazine" wanted to be, from
they should enjoy in the army and in society, the
the very beginning, "the depository of the work and
culture of all scientific and technical knowledge
activity of the health officers in the realm of
among the members of the military health body
veterinary and human medicine and military
related to the medical, pharmaceutical and veterinary
pharmacy" (Oameni și Fapte din Istoria Medicinii
profession" (Revista Sanitară Militară, 1972, nr. 4-5,
Militare Românești, Gral brig (r) dr. Mircea
pg. 411).
Diaconescu, vol II, pg. 229).
The "Steering Committee" met three months later, on
The Military Health Magazine records a great

3
performance in our medical literature: it appeared in
the same year as the Surgery Magazine – 1897, went
through the same "trials", did not have the same
audience but resisted... An absolutely remarkable
fact!...
Before continuing the "story of the Magazine", I think
it is worth telling you "my story – vs the Magazine".
I may be subjective, and actually I am.
The system, the organization of that time, had
assigned me after graduating from the Faculty as a
"trainee intern" since December 1979. I was assigned,
together with my colleague, to the 2nd Medical
Department, the current Clinic of Internal Medicine
and Gastroenterology of the Central Military Hospital.
We have been extraordinarily well received and
grateful to those people.
I knew about the Magazine, I had read it "en
passant", then there were no "student" magazines, I
did not even dream to publish an article in a
magazine with such background.
Well, those very formidable men – the "workers"
from the editorial office of any long-term magazine,
that is, Col. Dr. Cristea Neculescu and Mr. Nicolae
Dragoi – editorial secretary – considered an absolute
"insignificant" article in time – but perhaps
pompously titled: "Diagnostic significance of the atrial
fibrillation wave amplitude" by D. Mischianu, V.
Andrei, Military Health Magazine, 1980, 1, pg 71-75,
may receive the "good fortune"! It was an article that
sumed up what we, presented to the Students
Session at the Bucharest Medical and Pharmaceutical
4
Institute in the April 1979 session.
I leave aside my memories and come back to the
historical reality, of which nobody understands at all.
The magazine has gone through chaotic and sad
moments.
It had "ups and downs," a sort of "crises" as they are
told today. Most of the causes were of financial
origin, which led to changes in the typographic
format and the continuity of occurrence.
The first syncope is in 1903, so that between 1903-
1905 the magazine no longer appears.
In April 1905, everything goes back to normal the first
exchanges of journals began with other armies:
Italian, English, French, German and everything went
flawless until 1908. The number 2 of 1906 was a
jubilee number; ten years had passed from the
gorgeous initiative of 1897, the number being
dedicated to "the great and mighty King Carol I".
Unfortunately after the numbers 3 and 4 of 1908, the
second syncope is recorded. The Military Health
Magazine ceases to appear until 1913 (Oameni și
Fapte din Istoria Medicinii Militare Românești, Gral
brig (r) dr. Mircea Diaconescu, vol II, pg. 230).
The magazine is coming back shortly. On June 28,
1914, Archduke Franz Ferdinand and his wife were
assassinated in Sarajevo, the three kings – blood
cousins: Kaiser Wilhelm II of Germany, Tsar Nicholas II
of Russia, and King George V of The United Kingdom
of Great Britain, all three good English speakers were
not able to come to terms (they were grandchildren
of the Queen Victoria of Great Britain), the Great War
(or the First World War as it is known today) begins,
our magazine has its third syncope: 1915-1919 .
With all these vicissitudes, in 1917 and 1918, in Iasi
and Bacau appear "the Comptes bulletins from the
Société medico-surgical du russo-roumain, namely
Comptes vendus des seinces from the medical
reunion of II-ème armee, presenting medico-military
communications with participants from Russian and
French allied armies " (Revista Sanitară Militară,
1972, nr. 4-5, pg. 412).
There is also a fourth syncope, after the first numbers
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

appeared in 1919. In fact, the magazine really revived typical Oltenian perseverance, "revives" the Military
in 1928, when things were settled, the country Health Magazine in 1957.
seemed to have emerged from the crisis. It is Miron
In 1972, when the magazine was celebrated for
Costin's word: "There are not the times under the
"three quarters of a century of existence in the
man, but the poor man under the times!"
service of the protection of the health of our
In the review, there are reports of the "continuous soldiers", the technical box of Magazine Sanitary
medical education" sessions – that is the sessions of Military Magazine no. 4-5/ 1972, which we reproduce
the Romanian Military Doctors' Association with the in the facsimile, mentions his name, along with the
subsequent subsidiaries from all the existing Military name of another military doctor dear to my soul –
Hospitals, homage numbers regarding the persona- General Professor Iuliu Șuteu – editor-in-chief of the
lities of the Romanian medicine who came from or magazine at that time.
not from the same "medical strain": General dr. N.
Zorileanu (dermatovenerologist), professor dr. V.
Babeş (bacteriologist), professor dr. Dimitrie Gerota
(surgeon, radiologist), professor dr. Al. Costiniu (ENT),
etc. Articles in French and German also appear
(Revista Sanitară Militară, 1972, nr. 4-5, pg. 413).

The fifth syncope, hopefully the last, is also the

longest: 1949-1957. The times were like they were,
everything was changing, and who needed the
written word of the Romanian military doctors?

We publish the cover of a Magazine published in

1938 in which, in the end, lieutenant physician Dr.
Eugen Mareş publishes an obituary of a generation
colleague (Oameni și Fapte din Istoria Medicinii
Militare Românești, Gral brig (r) dr. Mircea
Diaconescu, vol II).

I also want to remember another name dear to me –

The same man, the same true Romanian military
doctor who I personally met, when he was at the
peak of his profession – Deputy Minister of Health in
socialist Romania and at the end of his life, with a
General Lt. Academician Gheorghe Niculescu, for
many years, editor-in-chief and "living spirit" that
agglutinated the energies and "pencils", stimulating
and promoting those who really had something to say
in this field.
After 1990, fearful, as observed to another journal
"Surgery", changed its name. It became the Journal of
Military Medicine.

5

Probably the term "sanitary" was appropriate in the
beginning, the term "medicine" is common to all
military doctors because we all come from the same
strain – the School of Medicine created by Carol
Davila, who arrived on Romanian soil as a French
civilian and became a Romanian general and
physician!
He has escaped, in this way, of a "complex".
In time there have been other Romanian medico-
military publications.
The Romanian Journal of Military Medicine wishes to
bring up-to-date information to the servants of this
noble profession, and hopes that the puzzling of the
information on the internet, which can make anyone
6
However, the Romanian Journal of Military Medicine
(RJMM) remains unique and emblematic after five
major "syncopes", having in its portfolio "a valuable
scientific and informational forum not only for
military doctors but for all Romanian medicine"
(Oameni și Fapte din Istoria Medicinii Militare
Românești, Gral brig (r) dr. Mircea Diaconescu, vol II,
pg. 232).
The magazine had the power, and those who were
close to it knew how to do it, to reborn always like
the Phoenix bird.
120 years after the first appearance, the Romanian
Journal of Military Medicine remains a magazine that
has its own program, unaltered by the passing of the
ages, even when the inter-war or post-war political
factor implied perhaps another orientation.
out of the question, is presented on-line or printed (I
confess that I deeply dislike these English
barbarisms!) after they have been read and corrected
(not censored!) by a true scholar in the field.
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

I am absolutely convinced that all Romanian, military

or civilian medical officers, descendants of our
common ancestor – General Professor Dr. Carol
Davila – will adhere to this profession of faith and will
continue as long as it is needed!

Happy Birthday Journal of Military Medicine!

Happy Birthday dear readers!

7
8
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

Article received on February 11, 2017 and accepted for publishing on June 12, 2017.
REVIEW ARTICLE

The concept of operationalization of an integrated platform

for scientific research and expertise of war and bioterrorism
biological agents

Viorel Ordeanu1,2, Marius Necşulescu1, Diana M. Popescu1, Lucia E. Ionescu1, Simona N. Bicheru1, Gabriela V.
Dumitrescu1, George Corlan1

Abstract: The international situation requires a strengthening of the national security measures,
including in the field of CBRN and public health. The upgraded microbiology laboratories from DM/
MND must be operated at full capacity for the operationalization of an integrated Platform for the
research and expertise of biological war and bioterrorism agents. This is necessary for reasons of
national security, for CBRN defense and for public health, in the context of biological agents of 3 and
4 risk groups’ epidemics.
The existing upgraded objectives should be operationalized in order to meet the established scope:
scientific research and expertise of biological agents and biological weapons, a laboratory for in vitro
analysis and a bio-base for in vivo analysis. The highly secure lab allows working with any high-risk
agents: biological, genetic, chemical, radiological, etc., being provided with a special room for the
insertion/removal of equipment and their decontamination.
Following an increase in the capability requirements concerning laboratories, we have provided in the
design concept new technical parameters of the platform and the integration of new compartments
with related activities of toxicology, pathology, neuro-psycho-pharmacology, bio-pharmacy, micro-
pharmaceutical, specific testing activities, etc.
Creating the integrated platform and its operationalization is necessary in order to meet the
requirement of the national security strategy as a collective CBRN defense/protection facility and
military-medical scientific research for CBRN medical protection.
Keywords: biological agents, bioterrorism, medical protection, microbiology laboratory, scientific
research, integrated platform, CBRN

INTRODUCTION operationalization of an
integrated Platform for the
The international situation requires a strengthening
scientific research and
of the national security measures, including in the
expertise of biological war
field of CBRN defense (chemical, biological,
and bioterrorism agents.
radiological and nuclear) and public health. The
The project is necessary 1 Military
Medical Research
upgraded microbiology laboratories from the Medical
for national security Center, Bucharest
Department of the Ministry of National Defense 2
purposes, for CBRN Titu Maiorescu University,
(MD/MND) must be operated at full capacity, for the Bucharest
defense and for the public

9
health, in the context of biological agents of 3 and 4
risk groups epidemics, and it responds to current
threats. In risk group 3, are listed extremely
dangerous bacteria and other pathogens such as
warfare biological agents (WBA). In the maximmum
risk group 4, are included 8 species of extremely
dangerous viruses such as Ebola or WBA
viruses.[1,2,3]
Current regulations take into account the provisions
of biosafety (such as internal protection for
operators), of biosecurity (as protection against
facility external hazards) and of bioprotection
(protection of the sample to be analyzed). As a result,
laboratories are properly classified, depending on the
different level of protection. In French literature they
are referred to as P1-4 (Protection).
The key features are: P1 with open work areas for
education; P2 with biosafety hoods, for medical
purposes; P3 special biosafety equipment for the
extremely dangerous bacteria; P4 for the extremely
dangerous viruses, with the maximum level of
biosafety. In English, they are called Biosafety
Laboratory (BSL1-4).[4] In Romanian, they appear as
Basic Labs with a level 1 and 2 of biosafety, Highly
Secured Laboratory with a level 3 of biosafety, and a
highly secure laboratory with a level 4a of biosafety
(with collective protection equipment) and 4b (with
special equipment for individual protection). In the
absence of proper facilities, the biological agents
classified in the risk categories cannot be legally
worked with. [2]
STATE-OF-THE-ART
Nationally, the Ministry of Health has modernized a
microbiology lab at the National Research Institute
“Cantacuzino” as a P3 laboratory and one (under
construction) at the Bucharest Hospital for Infectious
Diseases "Babeș". The Ministry of Agriculture has two
P3 microbiology laboratories at the Bucharest
Institute for Animal Diagnosis and Health. Currently,
in Romania, a P4 highly secure microbiology
laboratory does not exist yet.
Due to the fact that in Romania scientific research for
medical protection against CBRN agents belongs to
10
MND, it is mandatory to have a proper facility.
According to Biosafety in medical laboratories
Guidelines (World Health Organization 2004 and
Ministry of Health 2006) the bacterial biological
agents are expertised in the P3 laboratory, and the
viral agents in a P4 laboratory.
The international context shows that eventhough the
risk of biological warfare has decreased as a result of
the Geneva Convention (BTWC 1972), that was signed
and ratified by more than 90% of the world's
countries, the risk of bioterrorism is as real as the risk
of pandemic, of zooantroponosys, of exotic and
tropical infectious and contagious diseases, etc., as it
is with the recent epidemic of Ebola.[5] As a result,
the WHO, the EU and NATO recommend concrete
measures for decreasing those risks and for
increasing the response capacity of each country, of
the alliance and of the international community.
Given the EU's recommendations to operationalize at
least 40 P4 laboratories within the member countries,
to be designed and operated under standardized
WHO conditions, the project responds to
international demands and also to the national
interest.
The operationalization of an integrated research and
expertise platform for biological warfare and
bioterrorism agents is relevant to the approached
scientific field, following the state of the art (current
stage) character of the research in the field of
protection against biological agents, by implementing
internationally used modern techniques. The project
is based on implementing cutting edge technologies
for diagnostic, prophylactic pre-exposure and post-
exposure, cure and recovery, aspects regarding the
action mechanism in infectious diseases, the thera-
peutic means to counteract the effects of biological
agents and the epidemiological surveillance.[6]
Internationally, there are concerns regarding the
achievement of a coherent system of epidemiological
warning and intervention, the project being in line
with the world situation. Designing and equipping the
platform according to international recommenda-
tions determines that the level of performance of the
proposed infrastructure must be internationally
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
competitive and must take an active role in the global
effort of health protection against biological
agents.[7]
Our concept for the operationalization of the
Integrated Platform of scientific research and
expertise of war and bioterrorism biological agents.
Creating the Integrated Platform will allow the
defensive scientific research and medical expertise
for weapons/biological agents and for the diagnosis
of people infected with particularly dangerous
biological agents, and for the medical intervention in
epidemics or biological attacks.[8,9,10] It involves, in
the first stage, monitoring the continuation and
completion of the upgrading and rehabilitation of
buildings, installations and perimeter security
measures, including strengthening the capacity of
health protection against biological weapons,
bioterrorism and particularly dangerous biological
agents.
It is important to liaise with specialized companies
(selected not only by public tenders) within the
allocated funds, for the execution of the Integrated
Platform, for doing the reception at the time of
commissioning the modernized Laboratory of
Microbiology (declared at the UN as being under
construction) for in vitro analysis, and for doing the
reception at the time of commissioning the
modernized Biobase, for in vivo analysis as well as for
complementary analysis of analytical and
experimental toxicology, neuro-psycho-pharmaco-
logy, bio-pharmacy and the related logistical and
security support.[8]
Taking into account the unique nature of this facility
on national and regional level, as well as the direct
and indirect costs related to the spatial planning,
maintenance, and exploitation of this advanced
technology objective, we rethought the configuration
and the operation of the component objectives for
maximum efficiency.[8] Thus, the facility can provide,
through its equipment and operation, not only the
scientific research and expertise for ABR, bioterrorism
and biocrime, but it can also become practically
involved in the epidemics/ pandemics or zoonoses
with exotic and tropical diseases, that can occur as
major emergencies, as is the recent Ebola outbreak.
This facility with a maximum level of biosafety can
also serve for other specific activities with major risk
level; for example, with chemical warfare agents
(CWA) or accidents with toxic industrial chemicals
(TIC), with radiological warfare agents (RWA) or
accidents with radioactive substances, or for any
other extremely dangerous substances (HazMat).
Changing destination can be achieved operationally,
whenever necessary, even if it is one day to another,
by replacing the work team with specialists from the
DM/MND structures, according to the new
destination and by replacing the specific equipment:
removing from the highly secured working chamber
of the equipment and materials which are no longer
needed (through the decontamination airlock outlet)
and inserting those that are necessary to the new
mission. However, inside the work chamber,
materials deposits are not stored for in vitro analysis.
These are found in the “hand deposit” of the
laboratory, inside the units’ deposit or are purchased
by emergency from different sources.[8,9,10] At the
same time, the Biobase for test animals can serve all
military medical laboratories due to the fact that it is
conceived to immediately adapt to new requirements
for different animal species. In terms of the annex
facilities and amenities, they are basically for general
purposes, for every type of medical laboratory and
they inclusively ensure the proper functioning of the
entire facility in which the integrated Platform is
found. The platform can be adapted without
structural changes to the CBRN agents of any kind,
either separately or combined.
The integrated platform for the scientific research
and expertise of bioterrorism and biological warfare
agents contributes to strengthening the capacity of
scientific research of DM/MND for the expertise of
WBA/CBRN agents. During biological crisis situations,
it can strengthen the National Healthcare System in
terms of providing a microbiological diagnostic to the
sick or suspected to be sick or to the animals, as well
as for the detection, identification and confirmation
of CBRN agents under biosafety and biosecurity
conditions.[11,12] The facility, as a medical-military
objective, can be useful interdepartmentally: Ministry
of National Defense (MND), Ministry of Health (MH),
11
Ministry of Agriculture and Rural Development
(MARD), Ministry of Internal Affairs (MIA), Ministry of
Justice (MJ), Ministry of Environment, Water and
Forests (MEWF) and Romanian Intelligence Service
(RIS).
Studies and procedures for the operationalization
and integration of the Laboratory of Microbiology
and of the Biobase.
The integrated platform consists of complementary
elements acting in algorithm: the Microbiology
laboratory for in vitro analysis, the Biobase for in vivo
analysis, the Mobile team for biological intervention
(EMI-Bio) for field activities, as well as the annex
utilities for the proper functioning of the objective.
The design, the feasibility study and the outline
design for the Integrated platform of the scientific
research and expertise of war and bioterrorism
biological agents also includes the update of the
previously modernized objectives, during 2007-2009
(Laboratory of Microbiology and Biobase), as well as
the utilities and Annex facilities. The commissioning
of the installed equipment and staff training with
accredited supplier firms must be supplemented by
specific new latest technology purchases. The
explanatory memoranda and the feasibility study for
the operationalization of the integrated platform are
necessary because the financial burden is very high
and must be quantified because the investment
proposal submitted to the policy makers needs to be
supported by the necessity and the opportunity of
the investment.[8]
The activity of verifying the conditions related to the
authorisation, the qualification, the certification and
the accreditation of the Integrated platform for
scientific research and expertise of biological agents
- The activity of verifying the conditions related to the
authorisation of the Integrated platform. The process
of modernizing the two objectives was carried out
under the guidance of the National Authority for
Scientific Research and Innovation (ANCSI) after
attending the PNCDI Capacities national competition
and after obtaining government funding through the
Ministry of Education in 2007. As required by the
investor, existing complementary objectives were
12
selected: a laboratory of virology and the vivarium.
ANCSI monitored the design, development and the
endowment with installations and equipment of
modernized objectives and performed the final
inspection for the reception of the works, in 2009.
The report prepared by ANCSI concerns only the
fulfillment of the specific research and acquisitions
objectives. Depending on the technical characteristics
of the newly installed equipment, the owner must
provide the utilities: electricity, cold water, hot water,
distilled water, sewage, lighting, ventilation, heating,
security, specific supplies and specialised staffing.
After the rehabilitation works to the building and
installations have been completed, the Verbal
Proceeding for the works reception will be issued.
Next, follows the sanitation stage of the premises, of
authorization and of commissioning the specific
equipment and devices, by specialized companies and
suppliers. Next, will be purchased consumables,
reagents and inventory objects for the endowment of
laboratories, depending on the tasks.
After establishing work teams with qualified and
specialized staff follows the stage of drawing up the
Verbal Proceeding for the functioning status of the
Laboratory (through self-assessment and internal
auditing). The Technical file for the authorization of
the objective that contains data about the space, the
endowment, about the staff and the work procedures
is submitted to the Territorial Center for Preventive
Medicine (TCPM/DM) in view of the sanitary
authorization inspection of the objective.
After obtaining the sanitary functioning authoriza-
tion, that involves the prior solving of the
rehabilitation at the level of the entire facility,
immediately will be performed a recheck of the
qualification, certification and accreditation
conditions of the Integrated platform for scientific
research and expertise of biological agents.
- The verification of the qualification conditions of the
Integrated platform, according to the Guidelines
head. 7, p. 44-45: "Recommendations for the
qualification of the laboratory and its facilities." The
qualification of the laboratory/its facilities may be
defined as a systematic process of examination and
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
documen-tation, demonstrating that the structural
elements of the laboratory and of the systems and/or
of the system components have been installed,
inspected and tested, in terms of their operation, in
conformity with the national and international
standards.[2]
The laboratories designed to correspond to the
Biosafety Levels 1 to 4, have different qualification
requirements, with increasing levels of complexity.
The geographical and climatic conditions, such as
moisture or extreme temperatures, can also affect
the laboratory structure, and thereby, its qualification
demands. Once the qualification process has been
completed, the significant structural components and
the related systems will be subject to various
conditions, including working conditions, under
imposed conditions, logically possible, that will only
thereafter be approved.
The qualification process and the acceptance criteria
will have to be established from the design phase, of
construction and/or renovation. By knowing the
qualification requirements from the very beginning,
the staff (the architects, engineers, the staff
responsible for the safety and health assessment, as
well as the staff of the laboratory) will be able to
better understand the performance that has to be
achieved by the laboratory.
The qualification process provides the institution and
the community within which it operates a higher
degree of confidence, given the fact that the
structural elements, the electrical systems, the
mechanical and drainage systems, the insulation and
decontamination systems, as well as the security and
alarm systems will function as initially designed,
ensuring secure handling in the laboratory or in the
biobase of any potentially dangerous microorganism.
The qualification activities are generally performed,
from the design stage, continuing as such during the
construction and installation of the laboratory and its
facilities and during the warranty period, which
should cover at least one year after its entry into
service.
The agent assessing the qualification, acts as a guide
for the institution that is building and renovating the
laboratory and must be considered as a member of
the concept team, his early involvement in the
project design being essential. The institution may act
as its own qualification agent, if it has a trained
auditor. In the case of more complex laboratory
facilities, with biosafety level 3 or 4, the institution
may use the services of a qualification agent outside
the institution, with proven experience in the
successful implementation of the qualification of
laboratories and biobases with complex levels of
biosafety. When referring to a freelancer qualification
agent, representatives of the institution will also
participate as team members: the safety officer at
institution level, the project manager, the program
manager and a representative of the technical
service’s maintenance and intervention.
A list will exist to work with, consisting of the
laboratory’s systems and of the components that will
be included in the qualification plan, for testing the
functionality correlated with the degree of securing
the facilities to be built or renovated. This list is not
exhaustive, being adapted to the laboratory specifics.
Clearly, the actual qualification plan must reflect the
complexity of the respective laboratory.
- The verification of the certification conditions of the
Integrated platform according to the Guideline head.
8 p. 45-60: "Recommendations for laboratory
certification and its facilities"; it is similar to the
qualification, but is run by a committee of national
experts approved (the Ministry of Health, RENAR, the
National Association of Medical Laboratories etc.).
The WHO model questionnaire list, shall be
completed during the certification inspection, in the
presence of the institution’s representatives, who
know the objective.[2]
- Verification of the accreditation conditions of the
Integrated Platform.
The Ministry of Health is able to grant accreditation
only up to the P3 level; so, after reaching this level,
the next step would be to resort to an international
organization (WHO, EU, ECDC, NATO etc.), if an
accreditation at maximal level is required and if all
the required conditions are fulfilled and whether
there is adequate funding.[7]
13
The complexity of running operations in a laboratory
with maximal biosafety, exceeds the scope of the
Biosafety Guidelines. More details and information
can be found in the O.M.S. Biosafety Programme
(according to the Biosafety Guidelines, Annex 3). The
available information related to the training courses
and to the profile information materials can be
obtained by written request, for example from the
Biosafety programme, Department of Communicable
Disease Surveillance and Response, World Health
Organization, 20 Avenue Appia, 1211 Geneva 27,
Switzerland (http://www.who.int/csr/).
Basically, the activity of verifying the conditions
related to the authorisation, the qualification, the
certification and the accreditation of the Integrated
platform for scientific research and expertise of
biological agents ascertains whether the objectives
satisfy the requirements and proposes the
accreditation. If the requirements are only partially
met, then the nonconformities will be recorded and
the inspection will be effectively resumed when all
rehabilitation works to the platform’s components
will be completed. Only then, the laboratory may be
declared fully functional at the highest level of
biosafety. If all the imposed requirements cannot be
met, or in the meantime the requirements for
biosafety are amplified and the facility no longer
meets the new requirements, then the facility can be
accredited to a lower level, adding additional
equipment for biological protection or other
appropriate measures, whenever necessary.
OBSERVATION
Following an increase in the capability requirements
concerning laboratories, we have provided in the
design concept new technical parameters of the
platform and the integration of new compartments
with related activities of toxicology, pathology,
neuropsycho-pharmacology, biopharmacy, micro
References:
1. *** Guidelines for the safe transport of infectious
substances and diagnostic specimens, WHO/EMC/97.3
14
pharmaceutical, specific testing activities, etc.
However, the new facility does not allow, in terms of
spaces and technological flows, their permanent
dislocation in the space of the integrated Platform. If
the dislocation of any other laboratories is needed,
other spaces must be designed, built and purchased
that correspond to international standards in the
field, disseminated by the Ministry of Health.
Executing the integrated platform, its operationali-
zation and, implicitly, the investment’s financing is
required in order to meet the requirement of the
E6218 Capability Target, as a collective CBRN
defense/ protection facility and military-medical
scientific research for CBRN medical protection.
The original concept of ABR and bioterrorism
scientific research and expertise was completed over
time, in consultation with the colleagues from other
specialties who are involved in CBRN medical
protection and related areas of expertise that are
complementary to the basic activity, in order to work
under biosafety conditions, in full compliance with
international norms.
CONCLUSIONS
The existing upgraded objectives should be
operationalized so as to fulfill the targeted purpose:
scientific research and expertise of biological agents
and biological weapons, for in vitro and in vivo
analysis. A laboratory with a maximal biosafety level
allows working with any high risk agents, being
versatile. We also provided new compartments with
related activities to toxicology, radiobiology,
anatomic pathology, neuro-psycho-pharmacology,
biopharmacy microproduction and specific testing
etc. The general concept enables the
collaboration/cooperation of all CBRN medical
protection laboratories and the cooperation with
other military, civilian, national and international
entities: NATO, EU or CIMIC.
2. *** Ghid de biosiguranta pentru laboratoare medicale,
Ministerul Sănătăţii, Editura Medicală, Bucureşti, 2006
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
3. *** Protocol for Detection of Bacillus anthracis in
Environmental Samples during the Remediation Phase of an
Anthrax Event, UŞ Environmental Protection Agency,
December 2012
4. *** EU Directive 2000/54/EC of the European parliament
and of the council of 18 September 2000 on the protection
of workers from risks related to exposure to biological
agents at work
5. Lucia Elena Ionescu, Nicoleta Simona Bicheru, (2013) The
21st Century Challenges And Counteraction Ways:
Biological Weapons And Molecular Biology Research,
Strategic Impact, No. 1(46), P.103-110, ISSN 1841-5784;
6. Lucia E. Ionescu, Radu G. Hertzog, Alexandru
Vladimirescu, Marius Necşulescu, Diana M. Popescu,
Nicoleta S. Bicheru, Victoria G. Dumitrescu, Viorel Ordeanu,
(2014), Civilian-Military Cooperation For Detection,
Identification And Confirmation Of Biological Agents, Nato-
Cso-Hfm-239 Symposium On State-Of-The-Art in Research
On Medical Countermeasures Against Biological Agents,
Vilnius, Lituania
7. *** NATO Standard Agreements (STANAGs), including
but not limited to; STANAG 4632 Deployable NBC Analytical
Laboratory” and STANAG 2895 “Extreme climatic conditions
and derived conditions for use in defining design/test
criteria for NATO forces materiel
8. Ordeanu V., şi colaboratorii “Operaţionalizarea unei
Platforme Integrate Pentru Cercetare Ştiinţifică şi Expertiza
de Agenţi Biologici de Război şi Bioterorism” Proiect PSCD
8/2016
9. Ordeanu Viorel, Bicheru Nicoleta Simona, Dumitrescu
Victoria Gabriela, Ionescu Lucia Elena, Necşulescu Marius,
Popescu Diana Mihaela, (2012) Protecţia Medicală Contra
Armelor Biologice (Manual Pentru Pregătire Post-
universitară, Centrul de Cercetări Ştiinţifice Medico-
Militare, Bucureşti,), (ISBN:978-973-0-13973-0)
10. Ordeanu Viorel, Bicheru Nicoleta Simona, Dumitrescu
Victoria Gabriela, Ionescu Lucia Elena, Necşulescu Marius,
Popescu Diana Mihaela, (2012) “Protecţia Medicală Contra
Armelor Biologice - Vademecum”, Centrul de Cercetări
Ştiinţifice Medico-Militare, Bucureşti, (ISBN:978-973-0-
13782-8)
11. Viorel Ordeanu, Lucia Ionescu, Simona Bicheru,
Statutul și rolul Laboratorului Biologic Analitic Dislocabil
Pentru Apărare CBRN în Teatrul de Operații, Revista de
Științe Militare, Nr. 1(34), Anul XIV, 2014, Editată de Secția
de Științe Militare a Academiei Oamenilor de Știință din
România
12. Viorel Ordeanu, Manuel Dogaru, Lucia E. Ionescu,
Constructive Simulation For CBRN Medical Protection
Exercise, Conferinţa Ştiinţifică Internaţională Strategii XXI:
„Complexitatea Şi Dinamismul Mediului de Securitate”
Centrul de Studii Strategice de Apărare şi Securitate
Bucureşti, 11 - 12 Iunie 2015 Vol. 1 Proceedings, p.489-497
15
 Article received on February 12, 2017 and accepted for publishing on May 4, 2017.
REVIEW ARTICLE

Intellectual mobility in medical higher education system

Iulia Alecu1, Horia Mocanu2, Ioan E. Călin1

Abstract: Intellectual mobility brings change, there is the primary factor in the way of progress and
optimal premise of human being development from theoretic and practice regards. Medical Higher
Education, worldwide, is generally similar in structure and consistency, but different in typology of
presentation, teaching, learning and assessment. In fact, general medicine, as a subject refers to the
same biological body, but presented differently depending on culture, space and under various
methods of teaching and learning.
The idiom of intellectual mobility is not new, but according to globalization, which we live at the
present times, brought the mobility in the main plan of Europeanization, a new plan, with continues
sustainable development and maybe of success. By institutional mobility, both for students and for
academic staff, an exchange means a period of one academic year or a semester, for students and,
for two days to several months for academic staff, into a foreign university. These stages of study,
practice, and teaching take place most frequently within the Erasmus + framework, have been of 30
years in Europe and 20 years in Romania. Also, there are other programs that can perform intellectual
mobility, but the most well-known is Erasmus program, where European Commission has allocated
the biggest legal and financial budget framework. Overall activity program features has a variety of
tools to be deployed and an inter-institutional framework with qualified staff to manage it.
Keywords: medical education, recognition, higher education, mobility, Erasmus program

INTRODUCTION handled by the abstract representations. In the field

General Medicine as an
important branch of study
has a special status in the
conduct of mobility as
importance of the field and
also under emotional
aspect.
Intellectual mobility takes
a certain mental patterns
generated by education
and a native predispo-
1 Wallachia University sition, regardless of the
2Titu Maiorescu University, field. Along with this added
Bucharest
dynamic appeal cases
of medicine is worked with a high degree of
abstraction. Or spatial relocation and mobility means
mental derived including concrete way of their
operationalizing in the two phases of the medical
profession: correct diagnosis and treatment of the
patient, not the disease. Appeal to intellectual
mobility, is done often in the holistic approach to the
patient. The doctor represents, on the one hand a
mechanic and on the other hand a sociologist. This
would be the condition of being a successful doctor.
There is also the assumption that both treatment and
technique coordinate the doctor to a successful
performing.
Casuistry with high risk requires determination,

16
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
curiosity and professional beliefs. However, it is
based on a dominant personality characteristic
correlated with a predominantly emotional
intelligence, and then on IQ. But there is a less
explored area of the mind of a physician or a future
doctor, a student, how to manage frustration
generated by failure in high-risk cases, but not only.
Failure, in any other domain generates lessons
learned that are grouped in a simple taxonomy:
1. Lessons indicating approaches “know how";
2. Lessons to refute or confirm hypotheses absolutely
absurd;
3. Lessons to optimize cases generally valid but wrong
managed.
Thus, intellectual mobility in general, depends of
subjective perception of reality itself the objective of
playfulness and cognitive operators with which man
is accustomed routinely to operational abstractions.
Medical education has the same topology and
provides almost the same bibliographic regarding
symptoms of the disease; unfortunately get to treat
the disease using methods quite invasive.
Such patterns of study are known in medical
education through student mobility from one
education system to another. Exchange of
experience, for a period from one university to
another can bring new knowledge, new methods of
learning, but also a personal self, psycho-emotional
development.
Erasmus mobility can bring competitive doctors on
the labor market and ensure a quality structure, but
the real problem is the distribution on the labor
market.
As it is well known Romanian doctors prefer to work
in European hospitals or beyond Europe, which is not
bad, on the one hand, but on the other hand it led to
a destabilization of the health system in Romania. So
Erasmus mobility tended by a medical mass
migration.
Naturally, in this context a basis is economically and
socially disadvantaged in Romanian hospitals and
moral degradation of the system.
MEDICAL HIGHER EDUCATION IN DRESDEN,
ROME AND BUCHAREST
A brief history
A brief history of medicine proves that it was
practiced of ancient times from trained professional.
History and times prove how the society have
changed and it is also in a continuous changes in the
approach to sickness and disorder from ancient
beginnings
It is well known in the world that medical services
were provided for the poor people in monastic
hospitals. The care was rudimentary way and rather
palliative. As we can observe also medical services
and school education, in any domains started from
the monastic area, in churches. As just a thin
remembering it can be named that culture and
civilization started around the human necessity of
norms and rules issued by the spirituality.
In the 9th century there were some medical schools
in Italy. The influence from other nations as: Greek,
Latin, Arabic and Hebrew gave an international
dimension. Students learn three years as preliminary
courses and five years of medical schools. Nowadays
they study five, six or seven years in Europe and in
SUA more than ten years.
Italy is the place where medical universities were
founded, after came France and England which
developed medical schools. So we can see from the
beginning the health science started in an
internationally manner and mobility and migration
are quit ancient and were very important in the
development of it.
Today according to the progress of technology,
techniques and information system mobility is very
used and normal in the society.
Recognition of studies
In order to define studies in Erasmus Program we
have to analyze its framework. The main problem is
the recognition in making Erasmus.
Although there is a desired of full recognition of
Erasmus studies, according to the Erasmus Charter, it
is not possible, discussing the case by case,
17
depending on the curriculum and structure. Of
course, that is an ideal situation that a degree
program can be accepted fully recognized, but there
are features that can be dealt with individually.
Although Erasmus Charter directs the full recognition
and, in general, universities are trying to respect this
principle, even though at the end of the program,
there are people involved in Agencies of Recognition
and Accreditation of Studies from all over Europe, not
easily accept that Erasmus has a special pattern,
easily convertible by ECTS and also has all
instruments and forms provided. We will see a simple
case which presents two distinct situations of
curricula on a few subjects of study. We'll see how a
curriculum in three different states differ and how to
work through the transformation to studies from a
curriculum to another, by grades, ECTS obtained both
from practical or clinical training and courses.
Quantification of studies must be easy and in interest
of students. Of course it is of great important
qualitative component, especially in the field of
medicine. But always should take into account the
socio-cultural characteristics, adjusting the student in
a new cultural space and psycholinguistics barrier.
In the context of Europeanization and for
exemplifying the above situation exposes three major
universities with medical schools, in Europe.
Universitatsklinikum "Carl Gustav Carus" Dresden
Technische Universität of Germany, especially the
ENT discipline; Universita Degli Studi di Sapienza,
Rome, Italy, with examples on general surgery and
internal medicine and Titu Maiorescu University in
Bucharest, Romania, as a university of origin/home
university, which makes recognition and equivalence
studies.
Germany is a country of art, technique and study
continuously, so the team from ENT created a
standardized teaching maneuvers examination by a
small guide, so that students can observe organized
clinical examination of Otolaryngology. Consideration
is made all the standardized by checking maneuvers
in a form, for a period of 6 minutes of examining a
patient. This calculates a score of the exam, and the
form can be filled by two examiners for the compared
results.
18
Such an experience has brought by an academic staff
that has benefited of teaching stage in Dresden.
Today, the ENT method was implemented in
Bucharest for teaching and assessment the subject.
One such example is enlightening to harmonize the
methods of teaching and assessment, job shadowing
lead to the development of new skills.
Regarding the Recognition of Studies facts are the
discussions become slightly rigid and austere
although the program is provided with all the
necessary tools.
A student who chose as subjects of study
maxillofacial surgeon, a course of a single module
named Head has 1 ECTS, but the workload is the
same as that of a course of otolaryngology at
Bucharest, which has 4 ECTS. Also, the grading system
is different. In Germany the scale grades are from 1
to 5, and in Italy from 18 to 30; 1 ECTS has 25 hours
of workload. In Romania, at faculty of medicine 1
ECTS has approximately 14 hours of workload.
Depending on the workload is denoted by ECTS, 30
for a semester and 60 per academic year, which
should be equivalent between higher education
systems, but they are not. Module Thorax includes
the following disciplines: Cardiology, Angiology,
Pulmonology, Vascular Surgery, Thoracic and Cardiac
has a volume of 10 ECTS, if studied together, if it
divides, then the number of ECTS is divided too, in
Romania they are separate disciplines. In Italy,
Internal Medicine and General Surgery is a module
that measures 12 ECTS together, and in Romania
internal Medicine has 6 ECTS for the first semester
and for the second semester it has 5 ECTS, in the end
there are 11 ECTS, just Internal Medicine. General
Surgery is another subject and it has 4 ECTS for the
first semester and 4 ECTS for the second semester;
they are totally different from one system to other.
Such recognition is based on workload and always is
made in the favour of the student, or should be.
In Germany the focus is on clinical stages, more than
in Italy. In Romania, specialized practice/training is
done since of the first year of study, according to the
students’ testimony.
Although there are differences in the three systems
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
of teaching and learning, Erasmus has provided the
tools; study contract/Learning Agreement, and
students can choose their subjects to be studied and
disciplines which will be equate to return. Studies are,
or should be recognized, integrum, full recognition
under the Erasmus Charter. If the student does not
fulfill the learning agreement he/she will support
additional exams from local education until
completion of ECTS number needed to pass the
academic year. These are predetermined patterns of
procedure and related methods for classification and
institutionalization of each institution. What becomes
interesting is the prospect of personal development
of each individual differs from person to another
depending on operators and cognitive education.
There are three factors that can prevent full
recognition, as following:
1. Changing subjects of study during mobility,
Erasmus Learning Agreement provides that rule can
be changed, only in the first 14 days of mobility. Thus,
changing the curriculum content, can prevented full
recognition procedure because of the time period
from the moment of making the new choice of new
disciplines and to the approval by the academic tutor
from home institution.
2. A second factor that keeps the procedure and
otherwise representing a procedural error is soliciting
approvals for the recognition and equivalence studies
to the professors who are tutor of the disciplines.
Thus, the holder of course, may be not sufficiently
informed and decide in the detriment of the student.
Erasmus Rule requires the application of Charter
based on acceptance of Erasmus in function. So is
forbidden that a tutor can decide regarding his/her
discipline.
3. Finally a third factor, which prevents full
recognition, is negative influence of the party who
decide subjective and would not assumes the
recognition of Learning Agreement. These are
isolated cases, and in recent years almost no longer
exist. The procedure for recognition and equivalence
is the essential characteristic of students in the
decision to go in Erasmus mobility.
According to the magazine Prime 2010, only 19% of
students surveyed are convinced that it will not
benefit from an exchange. The rest of the students
who responded to the questionnaire in the same
magazine argued that regardless of the recognition of
studies, mobility itself and experience are more
important than the recognition of studies, thus they
assuming full academic exchange activities. Of course
that always the activity must be tried separately
according to each case. If the student wishes on its
own initiative to have examinations in the subjects of
home university, it is not prevented, or if the student
did not follow important disciplines for future
examinations of competence, then it will have them
at the return from the mobility without charge of any
fee.
There is also a risk that the student take courses that
are done in the near future/years of study in the
home university and through full recognition, the
student would be forced to repeat subject mobility in
the coming years. As such, the choice of subjects,
from a curriculum structured around six years can be
challenging even for academic tutor. This happens
because the curricula are not similar, nor how to be
similar. Bologna process does not seek to standardize
the Higher Education, but seek to a better
harmonization of curricula, a socio-cultural and
economic uniformity.
If the student is studying disciplines in the curriculum
of the home university is doing in a upper year, the
University, study case of this research, recognizes full
program of study at the partner university and
mention the time spent abroad in the Diploma
Supplement, and recognizes discipline by discipline in
the years that match the local program, and to
promote appropriate student take exams in the
subjects of study sessions legal up, and in special
cases can be organized special sessions for Erasmus
students. Whatever, the situation of recognition and
equivalence of studies is made, only in students' favor
without affect the merit place at home university.
Despite these shortcomings of procedures for
recognition of studies, students wishing to repeat the
experience to the extent permitted by the Erasmus
program.
19
Most often students after followed a study program
they would like to follow a clinical internship. From
the experience of the university concerned, they
apply after completing their studies in residency
programs in the world.
University receives per few times a year, forms
requesting certification of studies by agencies of
recognition of medical studies in the USA and
Canada.

Table 1: Example of a model of recognition studies, in Germany

(it can be observed that the students pass more than 5 ECTS at home university)
Name of the subject ECTS Grade in Germany Grade in Romania
Maxillofacial Surgery 1 1,5 10
Cardiology, Angiology, 10 2 9
Pulmonology, Vascular Surgery,
Thoracic and Cardiac
Dermatology & Venereology 3 4 5
Rheumatology 2 attended
Pathophysiology & Medical 9 4 5
Biochemistry and Laboratory
Diagnostics

It is mention were equated the subjects studied in Germany in the V th year, semester 1 of the study, under the Erasmus
Charter, after the student has pass the remaining number of 5 ECTS, as follows:
Name of the subject ECTS Grade in Romania
Pneumology 4 7
Occupational diseases 5 8
Radiology 5 9
Gerontology 10
TOTAL 14

Analyzing the situation of a student who was
Erasmus, in the fifth year of study at the University of
Dresden, after she came back home observed
willingness to continue the study and mobility
training, such as she obtained a period of 2 months in
a hospital in Germany, combining theoretical and
practical work with a clinical internship. Besides the
recognition and equivalence of procedural, student
mobility has made a qualitative leap in medical
education, as well as psycholinguistic improving
linguistic competence and went beyond customary in
the sphere of national education.
CONCLUSION
Mobility in medical education can make steady
progress in what is called globalization,
harmonization of curricula and skills in the labor
market. The main objective of globalization and
mobility function is preventing and overcome poverty
and habits that can hinder knowledge and human
progress. The internationalization of education is a
process of development and a better preparation of
students for a globalized society, based on knowledge
and skills. Higher education institutions have the
main role to prepare graduates for the labor market
in the line with international policies of globalization.
Mobility brings extra value to Europe and is a sine
qua non of human development in relation to the
labor market, the practical problem that remains in
the knowledge era is the economic and political,
social and moral worldwide crisis, otherwise
unmanageable. Now it is felt the effects of the global
turmoil, but concrete results are likely to be known
around 2050.

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1. European Journal of Higher Education - Florin D. Salajan
a & Sorina Chiper B., Value and benefits of European
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6. http://www.utm.ro/relatii-internationale/erasmus-
policy-statement/
7. https://www.studyineurope.eu/grades
8. https://en.wikipedia.org/wiki/History_of_medicine
9. Brussels, 4.5.2011, COM (2011) 248 final,
Communication from the Commission to the European
Parliament, the Council, The Economic and Social
Committee and the Committee of the Regions -
Communication on migration0
10. Brussels, 18.11.2011, COM (2011) 743 final,
Communication from the Commission to the European
11. Parliament, the Council, The Economic and Social
Committee and the Committee of the Regions - The Global
Approach to Migration and Mobility {SEC (2011) 1353 final}.
21
 Article received on January 31, 2017 and accepted for publishing on May 16, 2017.
REVIEW ARTICLE

The influence of homocysteine on osteoporosis

Elena Rusu1

Abstract: Osteoporosis is a major health problem, and the economic costs are expected to rise due to
an increase in life expectancy throughout the world. Its major consequence is fractures, and especially
hip fractures are associated with institutionalization and increased mortality. Homocysteine is an
amino acid intermediate formed during the metabolism of methionine. Homocysteinuria is a rare
autosomal recessive biochemical abnormality which causes elevated plasma concentrations of
homocysteine and severe occlusive vascular disease. In patients with homocysteinuria, there is an
increased prevalence of skeletal deformities, including osteoporosis, which is a primary risk factor for
hip fracture. The high prevalence of osteoporosis among patients with homocysteinuria suggests that
high levels of plasmatic homocysteine may also increase the risk of fractures. Nutritional factors such
as vitamins B12, B6, and folate are cofactors in homocysteine metabolism, and vitamin intakes may
inversely affect plasma homocysteine levels.
Keywords: osteoporosis, homocysteine, hip fracture

INTRODUCTION which bone is removed and replaced during the

Osteoporosis is a major
health problem, and the
economic burden is
expected to rise due to
an increase in life
expectancy throughout
the world. Its major
consequence is frac-
tures, and especially hip
fractures are associated
with institutionalization
and increased mortality.
The prevalence of
osteoporosis increases
with age due to an
1
Titu Maiorescu imbalance in the rate at
University, Bucharest
bone remodeling cycle, which is an important
physiological process that is essential for
maintenance of a healthy skeleton.
Pharmacological interventions may prevent 30-
60% of fractures in patients with osteoporosis.
Common sites for osteoporotic fracture are the
spine, hip, distal forearm and proximal humerus.
The remaining lifetime probability in women at
the menopause of a fracture at any one of these
sites exceeds that of breast cancer
(approximately 12%), and the likelihood of a
fracture at any of these sites is 40% or more in
developed countries [1].
The level of bone mass can be assessed with
adequate precision by measuring bone mineral
density using dual X-ray absorptiometry. It has

22
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
been suggested that bone strength may be
reflected, independently of bone mineral density
level, by ultrasonic measurements of bone and
by measuring bone turnover using specific
serum and urinary markers of bone formation
and resorption.
Physical activity as a way to prevent
osteoporosis is based on evidence that it can
regulate bone maintenance and stimulate bone
formation including the accumulation of mineral,
in addition to strengthening muscles, improving
balance, and thus reducing the overall risk of
falls and fractures. It is well known the
important influence of hormones as well as
dietary and specific nutrient abundance on
bone, growth and health is emphasized and
premature bone loss associated with dietary
restriction and estradiol withdrawal in exercise-
induced amenorrhoea [2].
OSTEOPOROSIS
It is becoming increasingly clear that there is a
relationship between growth and development in
early childhood and bone health in old age. In fact,
suboptimal bone development leads to a reduction in
peak bone mass, and a higher risk of osteoporotic
fracture later in life. Osteoporosis is a skeletal
disorder characterized by low bone mass and micro-
architectural deterioration of bone tissue, with a
consequent increase in bone fragility. Preventative
strategies against osteoporosis can be aimed at either
optimizing the peak bone mass obtained, or reducing
the rate of bone loss.
One of the largest risk factors for fractures is a
reduction in bone mineral density. Risk factors for
fracture can be purely skeletal-related affecting bone
mass, bone geometry, bone micro-architecture and
bone turnover, or solely fall-related such as
neuromuscular dysfunction, poor balance, cognitive
impairment, cardiovascular instability, reduced visual
acuity and sedative medications. Others risks are
both skeletal and fall related such as age, genotype,
and family history of fracture, weight, weight change
and mobility [3]. Falls history is a further independent
risk factor for fracture, in particular in men [4]. About
50% of white women and 20% of men will have an
osteoporosis-related fracture in their lifetimes.
Fractures of the hip and spine may be disabling and
are associated with mortality rates that are about
20% greater than that of an age-matched population.
The goal of any treatment for osteoporosis is to
improve bone strength, thereby decreasing fracture
risk.
Bone remodeling is the result of two opposite
activities, the production of new bone matrix by
osteoblasts and the destruction of old bone by
osteoclasts. The rates of bone production and
destruction can be evaluated either by measuring
predominantly osteoblastic or osteoclastic enzyme
activities or by assaying bone matrix components
released in the bloodstream and excreted in the urine
[5].
Factors which influence negatively the osteogenetic
potential are age, nutrition diseases and
endocrinopathy, ionized radiations treatments and
different toxic factors. It has been scientifically
proved the fact that elder patients have decreased
general biological potential. Regarding the bone
system, there occur structural changes which weaken
the resistance, to which we can add a diminishing of
the response potential towards harmful factors.
These lacks are considered to belong to multiple
causes: a diminishing of the vitamin D action and of
calcitonin, hyperactivity of the parathyroid hormones
with osteoblast inhibition, etc. [6] As a result,
osteolysis-osteo-synthesis dynamics is reversed,
resorbing processes become dominant:
osteodystrophy, osteoporosis, senile osteopenia,
metabolic and endocrine osteopathy, which, affecting
the very bone structure, are the main causes of
diminish in the osteogenic potential in elderly
patients. Nutrition diseases and endocrinopathies
seem to have the most harmful effects on
osteogenesis and the repairing processes of the bone
tissue.
The evaluation of biochemical markers of bone
turnover has been useful in clinical research.
However, the predictive factor of these
23
measurements is not defined clearly, and these
findings should not be used as a replacement for
bone density testing [7]. There is a high prevalence of
calcium, protein and vitamin D insufficiency in the
elderly. Calcium and vitamin D supplements decrease
secondary hyperparathyroi-dism and reduce the risk
of proximal femur fracture, particularly in the elderly
living in nursing homes. Sufficient protein intakes are
necessary to maintain the function of the
musculoskeletal system, but they also decrease the
complications that occur after an osteoporotic
fracture.
HOMOCYSTEINE
Sulfur is the seventh most abundant element
measurable in the human body and is supplied mainly
by the intake of methionine, an indispensable amino
acid found in plant and animal proteins. Inhibition of
cystathionine-β-synthase activity causes the
upstream sequestration of homocysteine and the
downstream drop in cysteine and glutathione [8].
Homocysteine is an aminoacid which contains a thiol
group formed by methionine intracellular
demethylation (alpha amino gama methylthio
butyric). In plasma, homocysteine is found free in
oxidized or disulphidic form, linked to proteins.
Homocysteine has two ways to be metabolised, a
metabolic path is represented by transsulfuration to
cysteine through cystatin synthetasis, enzymes which
need vitamin B6 as co-factor (proving the need of
vitamin B6 administration during the treatment).
Synthesis of cysteine as a product of the
transsulfuration pathway can be viewed as part of
methionine or homocysteine degradation, with
cysteine being the vehicle for sulfur conversion to
end products (sulfate, taurine) that can be excreted
in the urine. Transsulfuration of homocysteine to
cysteine is catalyzed by two pyridoxal 5′-phosphate-
dependent enzymes, cystathionine β-synthase and
cystathionine γ-lyase. The transsulfuration pathway is
responsible for catabolism of the carbon chain of
methionine, release of the amino nitrogen in a form
that can be funneled into pathways of nitrogen
excretion, and transfer of Met sulfur to serine to
synthesize cysteine [9].
24
Another metabolic path is remethylation to
methionine in the presence of methylentetra-
hydrofolate reductase (MTHFR) and methionine
synthesis in the presence of folic acid as an under
layer for vitamin B12 as co-enzyme (proving the need
of folic acid and vitamin B12 administration during
the treatment). There are studies which proved that
the level of homocysteine in blood is inversely
proportional with folate levels, vitamin B12, vitamin
B6 and oxygen intake induced by these vitamins [10].
Homocysteinuria is a rare autosomal recessive
biochemical abnormality which causes elevated
plasma concentrations of homocysteine and severe
occlusive vascular disease. In patients with
homocysteinuria, there is an increased prevalence of
skeletal deformities, including osteoporosis, which is
a primary risk factor for hip fracture. Blood levels of
total homocysteine increase throughout life in men
and women. Prior to puberty, both sexes enjoy
optimally healthy levels (6 µmol/L). During puberty,
levels rise, more in males than women, reaching, on
average, almost 10 µmol/L in men and more than 8
µmol/L in women. As we age, mean values of
homocysteine continue to rise and the
concentrations usually remain lower in women than
in men. Adults without homocysteinuria who have
high homocysteine levels are also at risk for fractures.
Thus, elevated plasma homocysteine concentrations
(>14 μmol/L) are associated with osteoporosis and
may increase the risk of hip fracture, in both men and
women. These can lead to substantial disability, high
medical costs, and death [11]. Elevated plasma
homocysteine concentrations are associated with
reduced physical performance and muscle strength in
older women [12].
Hyperhomocysteinemia may contribute to the
development of osteoporosis. High hyper-
homocysteine and low vitamin B12 concentrations
were significantly associated with low bone turnover
markers, high markers of bone turnover, and
increased fracture risk [13]. Folate and vitamins B12
and B6 are major determinants of homocysteine
concentrations in older persons [14]. The B vitamins
folate, B12, and B6 are important cofactors in
homocysteine metabolism, and low status of these
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
nutrients is the primary determinant of elevated
plasma homocysteine concentrations in elders.
Patients with pernicious anemia have decreased bone
mineral density at the lumbar spine, and in
comparison with the general population they have
almost double the risk of hip fracture. Gene
polymorphisms related to homocysteine metabolism
also may result in high homocysteine levels. Thus,
nutritional factors such as B12/folate deficiency and
genetic factors may affect homocysteine levels and
contribute to fracture risk.
Hyperhomocysteinemia is regarded as a risk factor
for ischemic stroke and for hip fractures in
Parkinson's disease patients receiving levodopa [15].
The high prevalence of osteoporosis among patients
with homocysteinuria suggests that
hyperhomocysteine may also increase the risk of
fractures [16]. Higher plasma levels of total
homocysteine and folate were independent
predictors of coronary heart disease [17]. In the
Framingham study authors had shown that plasma
total homocysteine concentration is inversely related
to the intake and plasma levels of folate and vitamin
B6 as well as vitamin B12 plasma levels. Almost two-
thirds of the prevalence of high homocysteine is
attributable to low vitamin status or intake. Elevated
homocysteine concentrations in plasma are a risk
factor for prevalence of extracranial carotid artery
stenosis of at least 25% in both men and women [18].
Some researchers want to determine if there is a
possibility that plasma total homocysteine may serve
as an indicator of the status and perhaps the intake of
a number of vitamins, including folic acid, vitamin
B12, and vitamin B6. This possibility derived from the
large number of studies that implied that methionine
metabolism is tightly regulated and from other
studies that showed that deficiencies in the above
vitamins are often associated with hyper-
homocysteinemia.
It was shown that premenopausal women have lower
homocysteine levels than men and postmenopausal
women. Higher plasma levels of total homocysteine
concentrations in men than in women may be
explained by differences in muscle mass, hormone
and vitamin status [19]. Factors that influence total
homocysteine plasma levels in the general population
include diet, in particular folate intake, blood levels of
folate, vitamin B12, and betaine, renal function, and
the MTHFR 677C>T polymorphism [20]. There are
studies to establish that increasing evidence that
plasma total homocysteine is inversely associated
with bone health. It has been speculated that
moderately elevated total homocysteine levels could
contribute to osteoporotic changes, based on the fact
that osteoporosis is a common phenomenon in
homocysteinuria. High total homocysteine and low
vitamin B12 concentrations are significantly
associated with high levels of markers of bone
turnover, and relations have been reported between
total homocysteine and markers of bone resorption
[13].
Elevated plasma total homocysteine, deficiencies of
folate and vitamin B12 are associated with risk of
osteoporosis and fracture. In some studies, there
were examined whether plasma levels of elevated
plasma total homocysteine, folate, and vitamin B12
predicted hip fracture [21]. They found that elevated
plasma total homocysteine is a predictor for hip
fracture among elderly men and women.
CONCLUSION
In patients with homocysteinuria, there is an
increased prevalence of skeletal deformities,
including osteoporosis, which is a primary risk factor
for hip fracture. The high prevalence of osteoporosis
among patients with homocysteinuria suggests that
hyperhomocysteine may also increase the risk of
fractures. Nutritional factors such as vitamins B12,
B6, and folate are cofactors in homocysteine
metabolism, and vitamin intakes may inversely affect
plasma homocysteine levels.
25
References:
1. Kanis JA, Burlet N, Cooper C, et al. European guidance
for the diagnosis and management of osteoporosis in
postmenopausal women. Osteoporos Int. 2008;19(4):399–
428.
2. Borer KT. Physical activity in the prevention and
amelioration of osteoporosis in women: interaction of
mechanical, hormonal and dietary factors. Sports Med.
2005;35(9):779-830
3. Allolio B. Risk factors for hip fracture not related to bone
mass and their therapeutic implications. Osteoporosis Int.
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4. Edwards MH, Jameson K, Denison H, et al. Clinical risk
factors, bone density and fall history in the prediction of
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5. Garnero P, Delmas PD. Contribution of bone mineral
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morfologice si histologice ale tesutului osos. Rev. Rom. de
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8. Ingenbleek Y, Kimura H. Nutritional essentiality of sulfur
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10. Henry OR, Benghuzzi H, Taylor HA Jr, et al. Suppression
of homocysteine levels by vitamin B12 and folates: age and
gender dependency in the Jackson Heart Study. Am J Med
Sci. 2012; 344(2):110-5
11. McLean R.R., Jacques PF, Selhub J,et al. Homocysteine
as a Predictive Factor for Hip Fracture in Older Persons N.
Engl. J. Med. 2004; 350: 2042-2049.
12. Swart KM, Enneman AW, van Wijngaarden JP, et al.
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Homocysteine and the methylenetetrahydrofolate
reductase 677C-->T polymorphism in relation to muscle
mass and strength, physical performance and postural
sway. Eur J Clin Nutr. 2013;67(7):743-8.
13. Dhonukshe-Rutten RA, Pluijm SM, de Groot LC, et al.
Homocysteine and vitamin B12 status relate to bone
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fractures in healthy elderly people. J Bone Miner Res. 2005;
Jun 20(6):921-9.
14. Johnson MA, Hawthorne NA, Brackett WR, et al.
Hyperhomocysteinemia and vitamin B-12 deficiency in
elderly using Title IIIc nutrition services. Am J Clin Nutr
2003;77:211-220
15. Sato Y, Iwamoto J, Kanoko T, et al. Homocysteine as a
predictive factor for hip fracture in elderly women with
Parkinson's disease. Am J Med. 2005; 118(11):1250-5.
16. Sato Y, Honda Y, Iwamoto J, et al. Homocysteine as a
predictive factor for hip fracture in stroke patients. Bone.
2005; 36(4):721-6.
17. Gopinath B, Flood VM, Rochtchina E, et al. Serum
homocysteine and folate but not vitamin B12 are predictors
of CHD mortality in older adults. Eur J Prev Cardiol.
2012;19(6):1420-9.
18. Selhub J. The many facets of hyperhomocysteinemia:
studies from the Framingham cohorts. J Nutr. 2006;136(6
Suppl):1726S-1730S
19. Refsum H, Smith AD, Ueland PM, et al. Facts and
recommendations about total homocysteine
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20. Refsum H, Nurk E, Smith AD,et al. The Hordaland
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 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

Article received on February 25, 2017 and accepted for publishing on June 19 2017.
SYSTEMATIC REVIEW

Efficacy and tolerability of calcium channel alpha-2-delta

ligands in psychiatric disorders
Octavian Vasiliu1, Daniel Vasile1,2, Andrei G. Mangalagiu1, Bogdan M. Petrescu1, Corina Tudor1, D.
Ungureanu1, C. Cândea1

Abstract: Matching drugs with anxiolytic properties- but without the potential of inducing
dependence or abuse- with clinical manifestations of various affective disorders is a very important
challenge for psychiatrists. Although the first line of pharmacologic treatment for anxiety disorders
remains antidepressants with serotoninergic properties, calcium channel alpha-2-delta ligands are
adjuvant agents which could be useful for augmenting antidepressant agents’ clinical effects.
Unfortunately, calcium channel alpha-2-delta ligands efficacy and tolerability are not very well
known, due to a lack of large scale, randomized, placebo-controlled trials focused on psychiatric
disorders. Data regarding pregabalin and gabapentin pharmacology and clinical effects are reviewed
and conclusions with pragmatically impact based on the discovered evidence are formulated
accordingly.
Keywords: calcium channel alpha-2-delta ligands, generalized anxiety disorder, fibromyalgia, social
anxiety disorder, pregabalin, gabapentin

PHARMACOLOGICAL PROPERTIES OF CALCIUM delta type 1 protein and

CHANNEL α2δ-LIGANDS demonstrated anticonvul-
sant, analgesic, and anxio-
Alpha-2-delta subunits of voltage-gated calcium
lytic properties in precli-
channels (VGCC) have an important role in
nical models [1,2].
modulation of the calcium currents and participate in
important cellular and inter-cellular phenomena like Pregabalin is rapidly ab-
muscular excitability, neurotransmission, re-gulation sorbed after oral adminis-
of gene expression etc. As a consequence, drugs with tration, with a bioavaila-
alpha-2-delta VGCC antagonist properties could bility value higher than
improve symptoms of fibromyalgia and neuropatic 90%; peak plasma concen-
pain, but they are also used for treatment of several trations are reached after
psychiatric disorders, the most extensive researched 1-1.5h, steady-state con-
being the field of anxiety disorders. centrations are achieved
within 24-48h after 1
Pregabalin is a structural analog of the inhibitory Carol Davila University
repeated administration, Emergency Central Military
neurotransmiter γ-aminobutyric acid (GABA). This Hospital, Bucharest
and if used with food there
drug reduces the synaptic release of several 2Carol Davila University of
is no clinically significant
neurotransmitters through binding to the alpha2- Medicine and Pharmacy,
Bucharest

27
effect on the drug’s absorption; pregabalin half-life is
about 6 hours, it does not bind to plasma proteins,
and 90% of a dose is eliminated unchanged in urine
[3].
Gabapentin is derived from gamma-aminobutyric acid
(GABA) by addition of a cyclohexyl group and crosses
several lipid membrane barriers through L-amino acid
transporters system [4]. Gabapentin has a bio-
availability that varies inversely with dose (between
35% and 60%), a volume of distribution of 0.6-0.8
l/kg, cerebrospinal fluid concentrations are 20% of
plasma concentrations and brain tissue values are
80% the plasma level; gabapentin is not metabolized
in humans and is eliminated unchanged in the urine
[5].
CLINICAL PHARMACOLOGY OF GABAPENTIN
AND PREGABALIN
Agents from alpha-2-delta ligands class have a large
number of indications in psychiatry and neurology,
but this paper focused only on the first area of
interest. Regarding the second domain, pregabalin
and gabapentin are used for diabetic neuropathy,
post-herpetic neuralgia, pain associated with spinal
cord lesions, diverse types of seizures etc [6]. We also
included in this paper trials focused on fibromyalgia,
since this pathology usually requires an
interdisciplinary approach, and psychiatrists are
included in the consultation teams.
Pregabalin combined with duloxetine lead to good
results in depression associated with fibromyalgia,
according to a randomized, double-blind trial, which
reported lower final Beck Depression Inventory–II
(BDI-II) scores compared to placebo (p<0.05) [7].
Another randomized, placebo-controlled trial
targeting fibromyalgia patients with asociated
affective symptoms showed significant improvement
on Hospital Anxiety and Depression Scale – Anxiety
and Depression (p<0.001) [8].
Pregabalin used as augmentation agent to
amitriptyline, venlafaxine, or paroxetine in old age
patients with fibromyalgia improved overall
symptoms, including depressive scores on Center for
Epidemiological Studies Depression Scale (CESDS),
28
and the highest tolerability was detected in
pregabalin+ paroxetine group [9].
Pregabalin had a good therapeutic effect in anxious
depression, according to a case series [10]. Adjunctive
pregabalin to conventional antidepressants in partial
responders with major depressive disorder and
residual anxiety decreased Hamilton Depression
Rating Scale overall scores and anxiety/somatization
subscale scores after 8 weeks with 65% response rate
and 35% remission rate [11]. Therefore, pregabalin
could be recommended as add-on agent in unipolar
depressed patients with significant levels of anxiety
and 49.1% of overall consecutive diagnosed
outpatients that received pregabalin had a diagnosis
of mood disorder, followed by 21.9% generalized
anxiety disorder [10,12].
A review of 3 randomized controlled trials that
compared efficacy and safety of pregabalin with
placebo in social anxiety disorder- generalized form
revealed a good efficacy in patients who couldn’t
tolerate or didn’t respond well enough to SSRIs or
SNRIs, which recommend pregabalin as either
alternative to antidepressants or add-on agent to
pharmacotherapy or cognitive-behavioural therapy
[13].
Pregabalin is considered by expert opinion a safe and
efficacious agent for generalized anxiety disorder,
with favourable properties like absence of active
metabolites and no interactions with CYP450
enzymes [14]. A pooled analysis of 6 studies
confirmed the efficacy of pregabalin in depressive
symptoms associated with generalized anxiety
disorder, and the most beneficial response was
detected at 300-450 mg daily dose [15]. A recent
post-hoc analysis of a multicenter, prospective, 6-
month study evaluated the effectiveness of
pregabalin in resistant generalized anxiety disorder
and severe depressive symptoms and concluded
reduced with more than 50% Hamilton Anxiety Scale
total score, and Montgomery-Asberg Rating Scale
score, when combined with antidepressants and/or
benzodiazepines [16].
Pharmaco-economic analysis of augmentation SSRIs
treatment with pregabalin versus switch to
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
pregabalin in treatment resistant generalized anxiety
disorder reported significantly health-care costs
reductions at 6 months in both treatment algorithms
[17]. Pregabalin was associated with significantly
higher QALY gain in refractory generalized anxiety
disorder when compared to usual care in a cost-
effectiveness model based on data derived from a
large scale trial [18]. Also, pregabalin was superior to
SSRI and SNRI in benzodiazepine-refractory
generalized anxiety disorder in terms of QALY gain,
but increased health-care costs and drug costs [19].
Treatment augmentation with pregabalin in patients
with combat-related chronic posttraumatic stress
disorder (PTSD) was efficient in a 6-week placebo-
controlled trial as it improved PTSD Check List-
Military Version scores (p<0.05), although severity of
depression, anxiety and quality of life parameters
didn’t differ significantly between the two groups
[20]. An open label pilot study with accident-related
posttraumatic stress disorder showed pregabalin
augmentation to antidepressant treatment as an
effective and well tolerated option [21]. However, a
retrospective analysis of US service members who
suffered burns didn’t detect differences in
posttraumatic stress disorder onset rate in patients
that received pregabalin or gabapentin after trauma
for pain, compared to patients who didn’t receive this
kind of drugs [22].
Pregabalin proved itself efficacious and well tolerated
in a single-blind randomized trial with active control
(clonidine) that targeted opioid withdrawal
symptoms [23]. In alcohol dependence, pregabalin
was efficacious, by decreasing of the craving and
withdrawal symptomatology [24]. A review showed
positive results for pregabalin in both treatment of
alcohol dependence and benzodiazepine dependence
[25].
Although the use of pregabalin as add-on agent in
bipolar disorder maintenance treatment has not been
extensively investigated, some authors suggest its
potential use for this indication [26]. Pregabalin could
increase the response to quetiapine in acute mania
[27], and also could help in decreasing affective
symptoms in treatment-resistant manic episodes
[28]. An open trial of pregabalin as adjunctive
treatment in acute and maintenance phase of
resistant bipolar disorder showed mood-stabilizing
effect, antidepressant effect or antimanic effect in
the acute phase, and also with good efficacy on long
term [29].
Data extracted from a metaanalysis focused on
dopaminergic and non-dopaminergic medications in
restless legs syndrome found 11 studies with α2δ-
ligands supporting good efficacy for gabapentin,
gabapentin enacarbil, and pregabalin [30].
Use of pregabalin, as well as buspirone, added to
antipsychotics in cases of schizophrenia with anxiety
(almost 65% of patients with schizophrenia have
anxiety symptoms), could be considered as an
efficient therapeutic option [31]. Case reports suggest
efficacy of pregabalin in treatment-resistant insomnia
(in a patient who didn’t respond to benzodiazepines,
antidepressants with sedative properties, or
antipsychotics) [32], and Charles Bonnet syndrome
associated visual hallucinations [33], but also an
enhancement of sexual desire in overdose [34].
Gabapentin significantly improved abstinence rates
and heavy drinking in patients with current alcohol
dependence, during a 12-week, double-blind,
placebo-controlled trial, with linear dose-effects
relation in mood, sleep, and craving domains [35].
Abstinence rates in this trial corresponded to a NNT
value of 8 for 1800 mg daily, while lack of heavy
drinking corresponded to a NNT value of 5 for the
same dose [35]. Gabapentin reduced the stress-
induced GABA activation in amygdala that is
associated with alcohol dependence and therefore
could be useful in this addiction [36].
Patients with opioid withdrawal that received
adjunctive treatment with gabapentin in addition to
methadone for 3 weeks reported significant
improvement of general status as reflected by
Subjective Opiate Withdrawal Scale (SOWS) and
doses of 1600 mg/day were significantly superior to
medium doses of 900 mg/day in decreasing
symptoms’ severity [37].
A Cochrane analysis of gabapentin efficacy in
fibromyalgia associated pain didn’t found good
evidence to support or contradict the
29
recommendation of this drug in daily doses of 1200-
2400 mg [38]. However, the quality of evidence was
rated as very low due to the fact that only one trial
corresponded to the inclusion/exclusion criteria
established by authors [38].
Gabapentin proved itself efficient in reducing
symptoms of social anxiety disorder and it was also
well tolerated [39].
Gabapentin wasn’t efficient in bipolar depression,
according to a large randomized controlled trial
which compared standard mood stabilizers versus
gabapentin 600-3600 mg/day [40].
A cross-over, double-blind study, showed gabapentin
is efficient in treatment of sensory and motor
symptoms in restless legs syndrome, improving also
sleep architecture in periodic leg movements during
sleep [41].
CONCLUSION
Pregabalin and gabapentin are efficient anxiolytics,
pregabalin being more supported by evidence in
social anxiety disorder, generalized anxiety disorder,
depression with significant anxiety, and also in
posttraumatic stress disorder, including cases of
combat-related PTSD.
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1. Taylor CP, Angelotti T, Fauman E. Pharmacology and
mechanism of action of pregabalin: the calcium channel
alpha2-delta subunit as a target for antiepileptic drug
discovery. Epilepsy Res 2007;73(2):137-50.
2. Ryvlin P. Defining success in clinical trials—profiling
pregabalin, the newest AED. Eur J Neurol 2005; 12(Suppl
4):12-21.
3. Blommel ML, Blommel AL. Pregabalin: an antiepileptic
agent useful for neuropathic pain. Am J Health Syst Pharm
2007;64(6):1475-82.
4. Taylor CP. Mechanisms of action of gabapentin. Rev
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5. Rose MA, Kam PCA. Gabpentin: pharmacology and its use
in pain management. Anaesthesia 2002;57:451-462.
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pregabalin in neurology, psychiatry and addiction: a
qualitative overview. Curr Pharm Des 2013;19(35):6367-74.
7. Gilron I, Chaparanno LE, Tu D et al. Combination of
30
Pregabalin is a well supported indication for
fibromyalgia treatment, with a high efficacy-to-
adverse-effects ratio. Pregabalin had a significant
impact not only over pain, as the core fibromyalgia
symptom, but also over affective symptoms
associated with this disorder.
Gabapentin recommendation is more supported by
evidence than pregabalin in alcohol dependence and
opioid withdrawal, but pregabalin has some support
in the treatment of benzodiazepine dependence.
None of the alpha-2-delta ligands were associated
with high quality positive evidence in bipolar
disorder.
In restless legs syndrome pregabalin and gabapentin
are efficient for primary symptoms and associated
clinical manifestations, and gabapentin improved
sleep architecture in sleep related periodic leg
movements.
Occasional reports of pregabalin efficacy in
schizophrenia associated anxiety, treatment resistant
insomnia or Charles-Bonnet syndrome need further
exploration in randomized clinical trials.
pregabalin with duloxetine for fibromyalgia: a randomized
controlled trial. Pain 2016;157(7):1532-40.
8. Arnold LM, Sarzi-Puttini P, Arsenault P et al. Efficacy and
safety of pregabalin in patients with fibromyalgia and
comorbid depression taking concurrent antidepressant
medication: a randomized, placebo-controlled study. J
Rheumatol 2015;42(7):1237-44.
9. Ramzy EA. Comparative efficacy of newer
antidepressants in combination with pregabalin for
fibromyalgia syndrome: a controlled, randomized study.
Pain Pract 2017;17(1):32-40.
10. Anderson C, George D, Quante A. Pregabalin in acute
treatment of anxious depression: a case series. Psychiatry
Res 2014;215(1):246-8.
11. Vitali M, Tedeschini E, Mistretta M et al. Adjunctive
pregabalin in partial responders with major depressive
disorder and residual anxiety. J Clin Psychopharmacol
2013;33(1):95-8.
12. Dobrea C, Buoli M, Arici C et al. Tolerability and use in
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co-administration of pregabalin in affective patients: a 6-
month prospective naturalistic study. Expert Opin Drug Saf
2012;11(6):893-9.
13. Kawalec P, Cierniak A, Pilc A, Nowak G. Pregabalin for
the treatment of social anxiety disorder. Expert Opin
Investig Drugs 2015;24(4):585-94.
14. Buoli M, Caldiroli A, Serati M. Pharmacokinetic
evaluation of pregabalin for the treatment of generalized
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2017;20:1-9.
15. Stein DJ, Baldwin DS, Baldinetti F, Mandel F. Efficacy of
pregabalin in depressive symptoms associated with
generalized anxiety disorder: a pooled analysis of 6 studies.
Eur Neuropsychopharmacol 2008;18(6):422-30.
16. Olivares JM, Alvarez E, Carrasco JL et al. Pregabalin for
the treatment of patients with generalized anxiety disorder
with inadequate treatment response to antidepressants
and severe depressive symptoms. Int Clin Psychopharmacol
2015;30(5).
17. Alvarez E, Olivares JM, Carasco JL et al. Clinical and
economic outcomes of adjunctive therapy with pregabalin
or usual care in generalized anxiety disorder patients with
partial response to selective serotonin reuptake inhibitors.
Ann Gen Psychiatry 2015; 14(1):2.
18. De Salas-Cansado M, Alvarez E, Olivares JM et al.
Modelling the cost-effectiveness of pregabalin versus usual
care in daily practice in the treatment of refractory
generalized anxiety in Spain. Soc Psychiatry Psychiatr
Epidemiol 2013;48(6):985-96.
19. De Salas-Cansado M, Olivares JM, Alvarez E et al.
Pregabalin versus SSRIs and SNRIs in benzodiazepine-
refractory outpatients with generalized anxiety disorder: a
post-hoc cost-effectiveness analysis in usual medical
practice in Spain. Clinicoecon Oucomes Res 2012;4:157-68.
20. Baniasadi M, Hosseini G, Fayyazi Bordbar MR et al.
Effect of pregabalin augmentation in treatment of patients
with combat-related chronic posttraumatic stress disorder:
a randomized controlled trial. J Psychiatr Pract
2014;20(6):419-27.
21. Pae CU, Marks DM, Han C et al. Pregabalin
augmentation of antidepressants in patients with accident-
related posttraumatic stress disorder: an open label pilot
study. Int Clin Psychopharmacol 2009;24(1):29-33.
22. Fowler M, Garza TH, Slater TM et al. The relationship
between gabapentin and pregabalin and posttraumatic
stress disorder in burned sevicemembers. Journal of Burn
Care and Research 2012;33(5):612-618.
23. Krupitsky EM, Iluk RD, Mikhailov AD et al. A
randomized single blind study of the efficacy of pregabalin
in the treatment of opioid withdrawal syndrome. Zh Nevrol
Psikhiatr Im S S Korsakova 2016;116(7):29-36.
24. Martinotti G, Di Nicola M, Tedeschi D et al. Efficacy and
safety of pregabalin in alcohol dependence. Adv Ther
2008;25(6):608-18.
25. Oulis P, Konstantakopoulos G. Pregabalin in the
treatment of alcohol dependence and benzodiazepines
dependence. CNS Neurosci Ther 2010;16(1):45-50.
26. Dimitrakopoulos S, Konstantakopoulos G.
Pharmacological agents under research for the
maintenance treatment in bipolar disorder. Psychiatriki
2015;26(3):169-80.
27. Oulis P, Florakis AA, Tzanoulinos G, Papadimitriou GN.
Adjunctive pregabalin to quetiapine in acute mania. Clin
Neuropharmacol 2009;32(3):174
28. Conesa ML, Roio LM, Plumed J, Livianos L. Pregabalin in
the treatment of refractory bipolar disorders. CNS Neurosci
Ther 2012;18(3):269-70.
29. Schaffer LC, Schaffer CB, Miller AR et al. An open trial
of pregabalin as an acute and maintenance adjunctive
treatment for outpatients with treatment resistant bipolar
disorder. J Affect Disord 2013;147(1-3):407–410
30. Hornyak M, Scholz H, Kohnen R et al. What treatment
works best for restless legs syndrome? Meta-analyses of
dopaminergic and non-dopaminergic medications. Sleep
Med rev 2014;18(2):153-64.
31. Temmingh H, Stein DJ. Anxiety in patients with
schizophrenia: epidemiology and management. CNS Drugs
2015;29(10):819-32.
32. Di Iorio G, Matarazzo I, Di Tizio L, Martinotti G.
Treatment-resistant insomnia treated with pregabalin. Eur
Rev Med Pharmacol Sci 2013;17(11):1552-4.
33. Sawant NS, Bokdawala RA. Pregabalin in the treatment
of Charles Bonnet syndrome. J Pak Med Assoc
2013;63(4):530-1.
34. Osman M, Casey P. Pregabalin abuse for enhancing
sexual performance: case discussion and literature review.
Irish Journal of Psychological Medicine 2014;31(4):281-286.
35. Mason BJ, Quello S, Goodell V et al. Gabapentin
treatment for alcohol dependence: a randomized clinical
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dependence. J Neurosci 2008;28(22):5762-5771.
37. Salehi M, Kheirabadi GR, Maracy MR, Ranjkesh M.
Importance of gabapentin dose in treatment of opioid
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of 8 adults. Prim Care Companion J Clin Psychiatry
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31
 Article received on January 28, 2017 and accepted for publishing on May 15, 2017.
ORIGINAL ARTICLES

Medicine versus philosophy

Mirela Radu¹

Abstract: The ancient Greek medicine was based on the principle that philosophy influences all
natural sciences as a whole. The doctor had, first of all, a humanistic formation followed by study of
applied sciences specific to medicine. If humanism is purely theoretical, medicine is an applied science
and the two-philosophy and medical knowledge, despite the apparent antinomy are able to create a
union to the benefit of humanity. Medicine is the art of treating patients, identifying diseases and
malady prevention. In its endeavor, medicine is based on the findings of numerous other fields such as
physics, chemistry, anatomy, physiology, etc. Philosophy, on the other hand, can be defined as an
attempt to understand human life as a whole. It is inevitable that the two ways of dealing with
human beings to have influenced each other and the history of mankind. Both forms of knowledge
have a major impact and influence on the world. Philosophy, understood in its older meaning, urged
towards the prophylaxis and treatment of diseases of the soul whereas medicine, relying on
philosophical teachings is aimed at healing the body and study its psychosomatic features.
Keywords: medicine, physician, philosophy, methodology, metaphysics

Medicine and philosophy knowledge.

have influenced each other
along mankind’s history.
The present article aims
and present the way in
which renowned physici-
ans have blended the strict
knowledge of medical
science with the more
humanistic philosophical
approach.
Attempts of demonstrating
how philosophy clout over
medicine have existed
since Ancient times. Our
paper is just a glimpse in
the outstanding synthesis
1
Titu Maiorescu University,
between the two apparen-
Bucharest tly incongruent areas of
Claudius Galenus of Pergamum (129-216) is one of
the first physicians who sensed the need of a
philosophical foundation of clinical practice. The
beginnings of his scientific training originate in
studying Aristotle’s texts. Galen, who stated that a
good physician should first of all be a philosopher, is
the one who realized the necessity of associating
medicine with the philosophy in order to achieve
better results in human treatment. Personal physician
for Marcus Aurelius, Galen received his medical
expertise in a gladiators’ school. His name links to the
first cataract surgeries, our knowledge of the spinal
cord and the functioning of the kidneys. He divided
the intercellular fluid into humors: blood, bile, lymph
and spleen.
What brought Galen brought new during his times
was an experimentalist approach. But he abandoned
his original humanist-philosopher formation, after

32
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
having a dream, for the practical practice of medicine,
“intensively dealing with philosophy yet, confident
peripatetic, he is still a syncretistic, which is better
seen in his logic.” [1]
During a great fire large part of his writings were
destroyed yet his Institutio Logica was kept. His
contribution to philosophy consists in demarcation
made between logic and philosophy by postulating
the theory of equivalence and by introducing of the
fourth figure in syllogism.
Abu Bakr Muhammad ibn Zakariya' al-Razi (865-
925), known in the western world as Rhazes, was of
Persian origin and promoted experimental medicine
bringing significant contributions in pediatrics,
neurosurgery, nephrology and ophthalmology. In his
early life, Al-Razi was more interested in studying
music and alchemy. Rhazes, physician at the court
and a hospital director in Baghdad, was prolific in the
scientific field through the books he wrote. Some of
the most important papers signed by the Arab
scientist include Medicine Treaty for Mansur
(dedicated to the governor of Rayy containing ten
chapters for diseases which was to be translated in
Latin, by scholar Gerard of Cremona, under the name
Liber ad Almansoris), the study Smallpox and
measles, works on applied medicine (About surgery),
books meant to popularize medicine (The book to
one who cannot reach the doctor), as well as doctors’
guide aimed at his fellow physicians (The guide of the
nomad physician and Royal medicine).
Al-Razi believed that in serious cases of leprosy and
cancer, the doctor cannot blamed or kept responsible
for the inability of curing the patient. Furthermore,
the physician-philosopher wrote extensively about
medical ethics. His area of interest included medical
chemistry, in which he made experiments with
mercury, sulfuric acid, alcohol, and paraffin. In the
field of pharmacy, Al-Razi made his mark by
introducing devices such as mortar, vials and spatula.
Neither the field of metaphysics and philosophy were
foreign to him as his papers in these fields
recommend his as an inborn scholar. Relying on
Aristotelian system and Plato’s philosophical thinking,
Al-Razi wrote an ambitious paper ambitious in nine
volumes, Virtuous life, book in which he accused
Galen of not supporting his medical findings on too
many case studies. Another important work with
great impact, this time on the general public, The
book to one who cannot reach the doctor, has the
merit of explaining some diseases and associated
treatments on the simple men’s understanding. The
book talks about some of the most encountered
afflictions such as headaches, colds, coughing, piles,
diabetes, and other gastric ailments such as
dysentery, ophthalmic and ear conditions, which
were associated to medical treatments in order to be
healed. He was the first physician who associated
allergic rhinitis to the scent of flowers.
Al-Razi believed that a physician cannot really be a
good practitioner unless he was a philosopher. The
Persian doctor was a follower of the Euclidean theory
of the space considered homogeneous and isotropic,
regardless of the spatial distribution of matter. For al-
Razi, to this absolute space and mechanical time
corresponds the world to which man is reported.
Also, Democritus’ theory, that the world is composed
of atoms structured into matter and vacuum was
adopted by the philosopher of Arab origin. His
metaphysical system is based on the belief that the
soul is intelligent and that the three-dimensional
reality consists of time, space and matter. Al-Razi
believed in afterlife.
In order to overcome the fear of nothingness, people,
in his opinion, should instruct in areas such as religion
and esotericism. Among his works on the border
between medicine, philosophy and religion we can
mention Spiritual medicine, Philosophical approach,
Metaphysics, Small treatise on deism, Modern
philosophy, etc.
Avicenna (980-1037), philosopher, physician and
writer of Persian origin, in his paper Canon Medicinae
(1025) set out methods of understanding,
differentiation and variability of phenomena,
considered methodology, which currently is regarded
as vital in inductive logic and scientific methodology.
In another treatise, Sanatio (1027), the Persian
thinker brought criticism to the Aristotelian methods
of inference, because they had, according to him, an
33
absolute value. As such, the Arab polymath
developed a complex of examination and testing
methods meant to meet scientific challenges.
Francis Bacon (1561- 1626) has influenced science, in
general and medicine, in particular. Renowned writer,
philosopher and scientist he was the originator of
empiricism as a way to test all the scientific
achievements. He initiates controlled experiments. In
his New Organon, Bacon stances diametrically
opposed to the deductive, Aristotelian thinking. For
Bacon induction is one that takes precedence as it is
meant to “substitute once for all idealistic Scolastico-
medieval one based on syllogistic deduction (..).” [2]
Bacon talked about mind and soul as tantamount
notions. Efficacious treatment of the body in
medicine, according to the English thinker, implies a
thorough study of the organism.
If practitioners of medicine fail in achieving their
goals is due to lack of visionary perspective: the body
is a complex mechanism which cannot be treated on
parts, rather as a whole. In order to learn as much as
possible about the human body implies clinical
observation, along with the analogy of different
bodies, vivisections and careful scrutiny of
pathological changes. The physician has a double
role: to reestablish the well-being of the diseased as
well as to reduce suffering of those who are
terminally-ill. What Bacon brought new to the field of
medicine is the larger perspective of this field. He
made no distinction between medical area and
natural sciences. Philosophy of medicine is just a
particular type of the more general knowledge of
philosophy.
Jean-Paul Marat (1743-1793) was born in Boudry,
nowadays Switzerland, but played an important role
during the French Revolution. During his teenage
period, he left home searching for fame and to build
a stable financial situation. Marat studied medicine in
Paris but failed to obtain a diploma in this area.
However, he published a study about the way he
treated his friends for gonorrhea, which propelled
him in the medical world. In 1773, Marat published a
paper entitled Essay on human philosophy. This work
has the ambition to present, as scientifically as
34
possible, the relationship between the human body
and the soul and the way in which the two are
interrelated. Thus, Marat believed that the soul and
body were separate entities, which could, however,
affect each other through the liquid within the
nervous system. Marat, in this essay, analyzed the
way in which, physiologically, the body can respond
to emotional experiences through the excitement of
the cardiac plexus.
Marat's work has the merit to connect the two planes
– physiological and spiritual – into a unitary whole.
The author analyzes, through his knowledge of
human anatomy and physiology, how the body folds
onto affects. The bodies can influence, in the
physician-philosopher’s opinion, the mode of
existence of the soul. Thus, there are what we call
qualities such as wisdom, stupidity, prudence, reason,
imagination, memory, delicacy, sagacity and genius.
The influence of his medical studies can be seen by
how Marat relates and, therefore, builds his
philosophical edifice on diseases such as spina bifida
and microcephaly. The essay remarks itself by
references the author made to areas of knowledge
such as history, literature and botany.
In 1775, Marat obtained from the University St.
Andrews references necessary to work effectively as
a physician which would bring him, two years later,
his appointment as the guard physician for Count
d'Artois, who would become Charles X. In London,
Marat published a paper dedicated to eye diseases
and their way of treating: Enquiry into the Nature,
Cause, and Cure of a Singular Disease of the Eye. His
reputation grows and the financial situation is
improving. With the money earned, he established a
laboratory marquise l'Aubespine’s house.
His experiments would end in his work Marat’s
findings related to fire, electricity and light (1779).
Based on experiments, his scientific work continues.
A year later, in 1780, he published About the physics
of fire. Unfortunately, the Academy of Sciences did
not approve his work since Marat had had the
courage to call into doubt some of Newton's
conclusions about refraction. His growing influence
increase within scientific circles and personalities in
the field recognized his value. They include Benjamin
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
Franklin and Goethe. In 1788 he published another
work based on experimental method: Research on
the physics of light. Fascinated by the subject,
meanwhile, the French philosopher published essays
related to electricity and medical applications of
optics Memories on medical electricity (1783) and
Basic optical notions (1784).
But his exuberant personality did not keep him away
from politics. Enlightened spirit and with an incisive
tone, Marat advocated equality of men. His political
beliefs had to find a place in the newspaper The
people’s friend, originally named Publiciste parisien,
which he edited beginning with 1789. In 1782, due to
his radical views, inspired by Rousseau and Cesare
Beccaria, Marat was publishing Public plan in criminal
legislation that supported the idea that the death
penalty should apply regardless of social status,
advocating the idea of an ombudsman institution.
Member of the Jacobin movement, which played an
important role during the reign of terror Marat would
end assassinated by stabbing, in his bath by Charlotte
Corday Marie-Anne d'Armont.
Arthur Schopenhauer (1788-1860), German
philosopher who would influence numerous other
philosophers such as Nietzsche, Freud, Bergson,
Ludwig Wittgenstein and Cioran, had a great impact
on the literature of psychological character, writers
such as Tolstoy, Eminescu, Proust and Thomas Mann.
One of his main works was The world as will and
representation (1818). Initially, in 1809 he entered
the Medicine University of Göttingen which he would
abandon in favor of philosophy, becoming a doctor
with a thesis on the fundamental principles of
thinking: The quadruple root of the principle of
sufficient reason (1813). The reason for which the
philosopher had as first option the study of medicine
was that he wanted to know the world objectively,
scientifically before starting his theoretical
speculation.
Incidentally, later, Schopenhauer concludes that
absolute knowledge can only take place in the
presence of solid knowledge about natural sciences.
The courses he attended as a medical student were
extremely varied: physics, chemistry, mathematics,
botany, mineralogy, physiology, comparative
anatomy, humanities as well as humanistic sciences
such as linguistics, ethnography, history. The great
biologist and anatomist Johann Friedrich
Blumenbach, who connected the human being with
the study of natural sciences and linked his name to
identifying five human race, would play an important
role in the shaping of the future philosopher.
Just that anatomist’s love towards animals made
Schopenhauer reluctant to vivisections and
determined him to step towards more academic
areas. During his medical studies period,
Schopenhauer himself had a poodle with whom he
used to take long walks. During the second half of the
first year in medicine, the one who was to influence
generations of philosophers discovered the writings
of Plato, Kant, Schelling and Upanishads. During his
second year of medicine Schopenhauer concluded
that he needed to change his studies, by choosing
philosophy.
His philosophical system, set up during his medical
studies, is based on the principle that, the basis of
reality, is suffering. The first argument is that
happiness is an illusion, life being nothing but a
permanent deception. Yet, reality may be dominated
by will. The very basis of the will is a necessity.
Schopenhauer considers individual goals to have no
rational basis because everything is evanescent, the
only certainty being only death. According to the
German philosopher, there are two teleologies: an
external one (human beings’ goals) and internal
(understanding the purpose of life) and the one that
should be taken into consideration is non-
existence.[3]
Although tempted to teach in the University of Berlin,
Schopenhauer renounces to academic life aspirations.
In 1839 he becomes member of the Norwegian
Society of Sciences. His true recognition occurs
following the publication of a volume of philosophical
essays Parerga and Paralipomena (1851).
Not being a religious spirit, the German philosopher
feels attracted more towards oriental doctrines, such
as Hinduism and Buddhism, the mystical practices
and Theurgy than to Christianity. Although Freud
35
denied Schopenhauer's influence in his clinical work,
there were others who stated a close correlation
between hard practice and Freudian theories of
Schopenhauer. It is about Freudian theories of
repression and sexuality that coincide with the ideas
of the German philosopher.[4]
Karl Theodor Jaspers (1883-1969) saw daylight in
Lower Saxony, in Oldenburg. Although initially
prepared to study law, Jaspers chose, in 1902,
medical studies which he completed seven years
later. His work in the hospital of Heidelberg as a
psychiatrist brought him dissatisfaction with the state
of psychiatry at the time, therefore, in 1913, when he
had the chance, he would choose a teaching career at
the University of Heidelberg. In time, Jaspers began
to connect the knowledge acquired clinically with the
study of philosophy. The work that propelled him in
psychology was Treaty of general psychopathology.
In 1932, more and more concerned with the study of
philosophy, Jaspers signed another reference work
(Philosophy) that subscribes to the existentialist
current. Like Schopenhauer, Jaspers felt more
attracted to Eastern religions than to Western
theological doctrines. Consciousness of guilt (1946)
came to blame the indifference and even the moral
guilt of the people whose citizen he was, representing
a wake-up call “partly utopian toward self-analysis in
order to overcome the chaos, a sense of guilt that
seemed to be put under possession of souls
Germans.”[5] The guilt of the German population is
References:
1. Anton Dumitriu, History of logics; 1975, p. 264
2. Francis Bacon, The New Organon, translation by N.
Petrescu and M. Florian, introductive study byAl. Posescu,
1957, p. 3
3. Wessel Stoker, Is the quest for meaning a quest for
God?The religious ascription of meaning in relation to the
36
the complicity to the Nazi’s genocide. In 1947 Jasper
signed a book that seems to reveal the link between
the scientific and the spiritual side of its author:
Philosophical logic. Jaspers's influence in the medical
field translates into identifying premises of psycho-
pathology: descriptive principle, that of comprehen-
sion and of causality. Jaspers’ methodology proposes
a clear, clinical, study of mental pathologies such as
psychosis and schizophrenia.
If in modern society the connection between
medicine and psychology becomes a more profound
by the fact that medical psychology brings together
knowledge from various areas of science such as the
fields of border such as sociology, anthropology,
psychopathology, holistic, experiential and dynamic
psychology, psychoanalysis, chronobiology, ethology
and neurophysiology, in the past this connection
almost did not exist. Psychology has made the
junction between medicine and philosophy.
Medicine as a branch of scientific knowledge is a form
of cognitive understanding while philosophy is a
science although it has only partially cognitive
aspiration to become an area of scientific knowledge.
Psychology became the first bond between the two.
Gradually, both medical science and philosophy have
found in common their nomological value. And the
merit of physicians is to succeed, and not in few
cases, to make the junction between these areas so
apparently opposing.
secular ascription of meaning. A theological study.
Amsterdam-Atlanta, GA, 1996 , p. 123
4. Ernest Jones, The Life and Work of Sigmund Freud, New
York, 1953-57, III
5. Nicoleta Dabija, Karl Jaspers- Consciousness in a trial
with history, in Romanian Life Magazine, no. 5/2009.
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

Article received on February 20, 2017 and accepted for publishing on July 14, 2017.
ORIGINAL ARTICLES

Incidence of peripheral trophic disorders determined by vein

thrombosis of the lower limbs correlated with risk factors by
age
Georgeta Trucă1,2, Florian Popa2, Radu A. Macovei2,3, M. L. Fulga1, Gina A. Ciucă2,5, G. Păunică-Panea1,4

Abstract: Introduction: Venous thromboembolism (VTE), in its clinical spectrum, includes both deep
venous thrombosis (DVT) and pulmonary embolism (PE). It is a disease with high incidence and
morbidity in hospital and community settings. Venous thromboembolism has various risk factors and
there are studies proving that the risk of increasing the incidence of the disease is proportional to the
risk factors.
Diagnosis, treatment and complications of lower limb deep vein thrombosis (DVT) depend on the
anatomical location and extent of the process. The post-thrombotic syndrome (PTS) is the most
common complication of deep vein thrombosis (DVT) and clinically it is characterized by chronic pain,
edema, enlarged veins, skin induration and other signs of the affected limb, while, in severe cases, it
can develop venous ulcers. The incidence of peripheral trophic disorders by age and the prevalence of
risk factors for deep vein thrombosis of the lower limbs were examined in this regard.
Materials and method: A retrospective study (January 2013 - December 2015) was conducted by
collecting data from medical documents available in "Floreasca" Emergency Hospital Bucharest,
Romania.
The patients diagnosed with deep vein thrombosis, on the basis of Doppler ultrasound, were divided
into two groups, according to age: group A (59 patients aged ≤50 years) and group B (130 patients
aged> 50 years). A number of data from the medical anamnesis, along with clinical and paraclinical
data were collected by us and we were interested in the incidence of peripheral trophic disorders
caused by deep vein thrombosis of the lower limbs correlated with the risk factors.
The study showed the incidence of deep venous thrombosis in a certain age and a
certain environment of origin. The incidence of patients who have had a VTE history is
half the patients with deep vein thrombosis who have had prophylactic anticoagulant
therapy before hospitalization. The incidence of patients who have had prophylactic
anticoagulant therapy before hospitalization is 61.1% of the patients with deep vein
1 Sanitary Post High School
thrombosis and a VTE history. The incidence of trophic disorders caused by deep vein
thrombosis of the lower limbs in patients who have had prophylactic anticoagulant “Fundeni”-Bucharest
2 Carol Davila University of
therapy before hospitalization and in patients who also had a history of VTE is higher
in those over 50 years old. The study showed the association of some risk factors for Medicine and Pharmacy,
Bucharest
venous thrombosis with an age-related factor.
3 Toxicology Clinic,
Conclusions: Improving preventive strategies and an optimally efficient utilization of
these strategies for patients at risk of venous thrombosis can lead to improved clinical “Floreasca” Emergency
Hospital, Bucharest
outcomes in practice and also to the post-thrombotic syndrome prevention. Taking
4 Surgery Clinic, “Sf.
into consideration the risk factors by age group and a better understanding of
Pantelimon” Emergency
epidemiology and the risk factors for the first or recurrent venous thrombosis can lead
Hospital, Bucharest
to optimal use of prophylactic strategies and improved quality of life. DVT affects all 5
Carol Davila University
age groups and the incidence associated with PTS is high, therefore the prevalence of
Emergency Military
PTS in general population is considerable. Hospital, Bucharest

37
 Thrombosis is also associated with impaired quality of life, especially when post-thrombotic syndrome
develops. To assess the overall risk of VTE in every patient, individual risk factors or combinations of
these should be carefully analyzed, an aspect that may have important implications for the type and
duration of appropriate prophylaxis.
Keywords: peripheral trophic disorders, post-thrombotic syndrome, venous thrombosis, risk factors,
age groups

INTRODUCTION especially when the post-thrombotic syndrome

develops [8.9].
Deep vein thrombosis (DVT) is characterized by the
formation of blood clots (thrombi) in the deep veins
MATERIALS AND METHOD
and usually affects the deep veins of the legs or the
deep veins of the pelvis [1]. Venous The study was retrospective (January 2013 -
thromboembolism (VTE) is manifested as deep December 2015) and the data were collected from
venous thrombosis (DVT) or pulmonary embolism medical documents available in "Floreasca"
(PE) and occurs at an incidence of approximately 1 Emergency Hospital Bucharest, Romania. The method
per 1,000 annually in adult populations [2]. used in this paper is the observational, non-
experimental, descriptive study. In the study group
About two-thirds of the episodes manifest
there were included patients diagnosed with deep
themselves as DVT and a third as PE, with or without
vein thrombosis of the lower limbs, based on the
DVT. [3]. VTE is a very common medical problem that
Doppler ultrasound, hospitalized in various wards of
occurs either in isolation or as a complication of other
the Emergency Hospital, such as, internal medicine,
diseases or procedures [4]. It is predominantly a
orthopedics, cardiology and general surgery wards.
disease of older adults and has a slight
The Doppler ultrasound determined the presence of
preponderance of males [1]. To prevent potentially
chronic venous insufficiency, the type of venous
fatal acute complications of pulmonary embolism (PE)
thrombosis - deep or superficial and its location -
and long-term complications of post-thrombotic
proximal and distal.
syndrome and pulmonary hypertension, an accurate
diagnosis of DVT is extremely important. The group of patients with deep vein thrombosis
(DVT) comprises 189 patients, of which 54 have
It is also important to avoid unjustified anticoagulant
superficial vein thrombosis (SVT). According to their
therapy in patients diagnosed with high risk of
age, we divided the patients into two groups: group A
bleeding [5]. DVT prevention through prophylaxis,
(59 patients aged ≤50 years) and group B (130
recognition in due time and DVT treatment and
patients aged> 50 years). For each patient we
prevention of recurrent DVT will continue to have the
collected general data (age, gender, origin), and
greatest impact on reducing the global burden of
clinical and paraclinical data. The clinical data have
post-thrombotic syndrome. Despite considerable
identified the presence of unilateral leg edema or the
progress in the diagnosis and treatment of deep vein
entire leg edema and the presence of peripheral
thrombosis (DVT) of the lower extremities, one in
trophic disorders (erythema, infiltration, skin
every 2-3 patients will develop post-thrombotic
induration, cellulitis and venous ulcers).
sequelae within two years, which are severe in about
10% of cases and produce considerable socio- From the anamnesis data we identified the presence
economic consequences [6]. of comorbidities and risk factors, namely
immobilization before hospitalization, a history of
DVT affects all age groups and the incidence
venous thromboembolism (VTE) and pulmonary
associated with PTS is high, therefore the population
thromboembolism (PE), anticoagulation prior to
prevalence of PTS is considerable [7]. Thrombosis is
hospitalization, various medical conditions, a history
also associated with impaired quality of life,

38
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

of surgical conditions (orthopedic, gynecological, MedCalc, we analyzed the relationship between

urological, abdominal), neoplasm and antineoplastic variables and there are 72 patients taking
treatment, cerebrovascular accident associated with anticoagulants before admission, namely 24 (40.68%)
motor deficiency, congestive heart failure, renal in the first group and 48 (36, 92%) in the second
disease (renal lithiasis, nephrotic syndrome, group. According to the test, there is no statistically
hydronephrosis, chronic kidney disease, enlarged significant link (Sig = 0.622) between the presence in
prostate), obesity, diabetes, hypertension, a history one of the two groups and the existence of
of heart attack, fractures before admission, alcohol anticoagulant prior to admission. The OR estimation
consumption, smoking. is not statistically significant because Sig = 0.622.
From the group of patients with deep vein
We used SPSS, version 15.0, to statistically analyze
thrombosis the incidence of patients who had
the data. For some additions to the statistical analysis
prophylactic treatment with anticoagulants before
we used the MedCalc program. Some of the graphics
admission is 38.09% and among those the incidence
were done with Excel 2007 and other graphics with
of the patients who had a history of VTE is 50%.
SPSS. The vast majority of the data were nominal
(Yes, No); for these we did the analysis using the Chi The incidence rates of a history of VTE, of PE at
square test. For the type of numeric data we did an admission and in the personal history for these 72
ANOVA analysis. An OR (Odds Ratio) risk assessment patients are presented in Table 1.
was calculated for risk factors with the Mantel-
Haenszel test. We also used binary logistic regression. Table 1. The incidence rates of a history of VTE, of PE
The statistical differences and dependencies were at admission and in the personal history
statistically significant for Sig <0.05.
≤ 50 > 50 Total
Sex
N % N % N %
RESULTS
History of VTE 12 50.0% 24 50.0% 36 50.0%
The group of patients with deep vein thrombosis PE at admission 2 8.3% 1 2.1% 3 4.2%
(DVT) comprises 189 patients, of which 54 (28.6%) History of PE 2 8.3% 2 4.2% 4 5.6%
have superficial vein thrombosis (SVT). We divided
patients into two groups: patients aged ≤50 years From the group of patients with deep vein
(31.22%) and patients aged> 50 years (68.78%). thrombosis, the incidence of VTE in patients who had
Applying ANOVA with a variable depending on age a history of VTE (58 patients) is 30.68% and were
and an independent variable belonging to one of the distributed as follows: 19 (32.2%) in the first group
two groups, we obtained as a result the average age and 39 (30.0%) in the second group. Among those
of the patients of the first group as 37.71 years old patients who had a history of VTE, 38.9% had a
with SD = 8,445, and for those of the second group as history of VTE without Prophylactic anticoagulation
68.50 with SD = 11,133. The difference between the treatment and 61.1% had a history of VTE with
two means is statistically significant (Sig <0.001). In prophylactic anticoagulant treatment. The incidence
the first group we have 23 (38.98%) women and 36 rate of PE at admission and in the personal history
(61.02%) men and in the second 62 (47.69%) women among these 58 patients are presented in Table 2.
and 68 (52.31%) men.
Table 2. The incidence rates of PE at admission and in
In the first group we have 9 (15.25%) patients in rural
the personal history
areas and 50 (84.75%) patients in urban areas, and in
the second we have 30 (23.08%) patients in rural ≤ 50 > 50 Total
History of VTE
areas and 100 (76 92%) patients in urban areas. N % N % N %
Therefore, the prevalence of patients in urban areas PE at admission 2 10.5% 2 5.1% 4 6.9%
is very high, about 80%. By using Chi square analysis History of PE 3 15.8% 3 7.7% 6 10.3%
and an OR estimation performed with SPSS and

39
Taking this aspect into consideration enables us to
optimally use the prophylactic strategies against
venous thromboembolism. A better understanding of
epidemiology and the risk factors for the first and the
recurrent venous thrombosis can lead to improved
clinical outcomes in practice. To assess the overall
risk of VTE in every patient, individual risk factors or
combinations of these should be carefully analyzed,
an aspect that may have important implications for
the type and duration of appropriate prophylaxis.
The incidence of trophic disorders caused by venous
thrombosis of the lower limbs in patients who had
prophylactic anticoagulant therapy before
hospitalize-tion is 23.6% venous ulcers, 93% edemas,
83.3% different trophic disorders (reddish–brown
cutaneous depigmentation, indurated fibrous skin,
redness, irritation or dermatitis) and 12.5% cellulitis.
Statistical analysis by age group reveals that the
incidence is higher in patients over 50 years old,
namely 24.5% venous ulcers, 93.9% swelling, 91.83%
different trophic disorders and 14.28% cellulitis. In
patients who are under 50 years old there was an
incidence of21.73% venous ulcers, 91.30% edemas,
65.21% various trophic disorders and 8.7% cellulitis.
The incidence of trophic disorders caused by venous
thrombosis of the lower limbs in patients who had
prophylactic anticoagulant therapy before
hospitalize-tion and history of VTE by age group
reveals that the incidence is higher in patients over
50 years old, namely 45.83 % venous ulcers, 100%
swelling, 91.66% various trophic disorders and 25%
cellulitis. In patients under 50 years old there was an
incidence of 41.6% venous ulcers, 100% swelling,
66.7% various trophic disorders and 16.7% cellulitis.
According to the data provided by Chi square analysis
and OR estimation performed with SPSS and MedCalc
test, there is a statistically significant link (Sig = 0.003)
between the presence in one of the two groups and
the presence of chronic venous insufficiency. There
are 78 patients with chronic venous insufficiency: 15
(25.42%) in the first group and 63 (48.46%) in the
second group. Cont. Coef. = 0.212 is the strength of
that link. Sig = 2.758 and OR = 0.003, therefore it is
statistically significant. Chronic venous insufficiency is
more present in the second group.
40
By using Chi square analysis and OR estimation
performed with SPSS and MedCalc, we analyzed the
relationship between variables, specifically the risk
factors present in the database, considered to be risk
factors for DVT, for each group separately (Table 3).
We obtained statistically significant values:
o For Varicose veins, there is a statistically significant
link (Sig = 0.016) between the presence in one of the
two groups and the presence of the analyzed risk
factors. Cont. Coef. = 0.173 is the strength of that
link. OR = 2.471 and Sig = 0.018, therefore it is
statistically significant. Varicose veins are more
common in the second group.
o For Congestive heart failure, there is a statistically
significant link (Sig <0.001) between the presence in
one of the two groups and the presence of the
analyzed risk factors. Cont. Coef. = 0.352 is the
strength of that link. OR = 63.328 and Sig = 0.004,
therefore it is statistically significant. Congestive
heart failure is present only in the second group.
o For Fractures before admission, there is a
statistically significant link (Sig = 0.006) between the
presence in one of the two groups and the presence
of the analyzed risk factors. Cont. Coef. = 0.197 is the
strength of that link. OR = 0.326 and Sig = 0.007,
therefore it is statistically significant. Fractures before
admission are more common in the first group.
o For Smoking, there is a statistically significant link
(Sig = 0.027) between the presence in one of the two
groups and the presence of the analyzed risk factors.
Cont. Coef. = 0.159 is the strength of that link. OR =
0.494 and Sig = 0.028, therefore it is statistically
significant. Smokers are more present in the first
group.
o For HTN (hypertension), there is a statistically
significant link (Sig <0.001) between the presence in
one of the two groups and the presence of the
analyzed risk factors. Cont. Coef. = 0.499 is the
strength of that link. OR = 53.833 and Sig <0.001,
therefore it is statistically significant. HTN is present
almost entirely in the second group.
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

Table 3. Analysis of risk factors by age group.

≤ 50 years > 50 years Chi square

Odds ratio
Risk factors No Yes No Yes analysis
N (%) N (%) N (%) N (%) Cont coef Sig OR Sig
Immobilization before
47 (79.66%) 12 (20.34%) 88 (67.69%) 54 (41.54%) 0.122 0.091 1.869 0.094
admission/hospitalization
Varices 48 (81.36%) 11 (18.64%) 83 (63.85%) 47 (36.15%) 0.173 0.016 2.471 0.018
History of VTE 40 (67.80%) 19 (32.20%) 91 (70.00%) 39 (30.00%) 0.022 0.761 0.902 0.761
PE at admission 53 (89.83%) 6 (10.17%) 124 (95.38%) 6 (4.62%) 0.105 0.147 0.427 0.157
History of PE 55 (93.22%) 4 (6.78%) 125 (96.15%) 5 (3.85%) 0.064 0.380 0.550 0.386
Obesity 35 (59.32%) 24 (40.68%) 84 (64.62%) 46 (35.38%) 0.051 0.485 0.799 0.485
Congestive heart failure 59 (100.00%) 0 (0.00%) 85 (65.38%) 45 (34.62%) 0.352 <0.001 63.328 0.004
COPD or pulmonary cond. 49 (83.05%) 10 (16.95%) 111 (85.38%) 19 (14.62%) 0.030 0.680 0.839 0.680
Anemia 44 (74.58%) 15 (25.42%) 81 (62.31%) 49 (37.69%) 0.119 0.099 1.774 0.101
Fractures prior to admission 44 (74.58%) 15 (25.42%) 117 (90.00%) 13 (10.00%) 0.197 0.006 0.326 0.007
Smoking 30 (50.85%) 29 (49.15%) 88 (67.69%) 42 (32.31%) 0.159 0.027 0.494 0.028
HTN 57 (96.61%) 2 (3.39%) 45 (34.62%) 85 (65.38%) 0.499 <0.001 53.833 <0.001
Peripheral artery disease 59 (100.00%) 0 (0.00%) 113 (86.92%) 17 (13.08%) 0.207 0.004 18.348 0.044
Type 2 diabetes 56 (94.92%) 3 (5.08%) 85 (65.38%) 45 (34.62%) 0.300 <0.001 9.882 <0.001
Lipid alterations 39 (66.10%) 20 (33.90%) 67 (51.54%) 63 (48.46%) 0.135 0.062 1.834 0.063
Alcohol consumption 45 (76.27%) 14 (23.73%) 114 (87.69%) 16 (12.31%) 0.143 0.046 0.451 0.050
Extensive distal localization
11 (18.64%) 48 (81.36%) 9 (6.92%) 121 (93.08%) 0.174 0.015 3.081 0.019
(calf)
Extensive proximal DVT
25 (42.37%) 34 (57.63%) 36 (27.69%) 94 (72.31%) 0.144 0.045 1.920 0.047
localization
Patients with medical
47 (79.66%) 12 (20.34%) 25 (19.23%) 105 (80.77%) 0.500 <0.001 16.450 <0.001
conditions
Patients with a history of
51 (86.44%) 8 (13.56%) 76 (58.46%) 54 (41.54%) 0.266 <0.001 4.530 <0.001
surgical conditions
History of major
gynecological surgical 58 (98.31%) 1 (1.69%) 115 (88.46%) 15 (11.54%) 0.162 0.024 7.565 0.053
interventions
History of major urological
50 (84.75%) 0 (0.00%) 114 (87.69%) 16 (12.31%) 0.201 0.005 17.149 0.049
surgical interventions
Hip or knee arthroplasty. Hip
48 (81.36%) 11 (18.64%) 112 (86.15%) 18 (13.85%) 0.062 0.396 0.701 0.398
surgery
History of heart attacks 59 (100.00%) 0 (0.00%) 120 (92.31%) 10 (7.69%) 0.157 0.029 10.369 0.108
Renal conditions (CKD.
Hydronephrosis renal 55 (93.22%) 4 (6.78%) 109 (83.85%) 21 (16.15%) 0.127 0.078 2.649 0.087
lithiasis)
Neoplasia 57 (96.61%) 2 (3.39%) 95 (73.08%) 35 (26.92%) 0.265 <0.001 10.500 0.002
CVA (mainly associated with
59 (100.00%) 0 (0.00%) 121 (93.08%) 9 (6.92%) 0.149 0.038 9.305 0.127
motor deficiency)

o For Peripheral arterial disease, there is a of the analyzed risk factors. Cont. Coef. = 0.207 is the
statistically significant link (Sig = 0.004) between the strength of that link. OR = 18.348 and Sig = 0.044,
presence in one of the two groups and the presence

41
therefore it is statistically significant. Peripheral
artery disease is present only in the second group.
o For Type 2 diabetes, there is a statistically
significant link (Sig <0.001) between the presence in
one of the two groups and risk factors analyzed.
Account. Coef. = 0.300 is the strength of that link. OR
= 9.882 and Sig <0.001, therefore it is statistically
significant. Type 2 diabetes is now almost entirely
present in the second group.
o For Alcohol consumption, there is a statistically
significant link (Sig = 0.046) between the presence in
one of the two groups and the presence of the
analyzed risk factors. Cont. Coef. = 0.143 is the
strength of that link. OR = 0.451 and Sig = 0.050,
therefore it is statistically significant. Alcohol
consumption is more present in the first group.
o For Extensive distal location (calf), there is a
statistically significant link (Sig = 0.015) between the
presence in one of the two groups and the presence
of the analyzed risk factors. Cont. Coef. = 0.174 is the
strength of that link. OR = 3.081 and Sig = 0.019,
therefore it is statistically significant. Extensive distal
location (calf), is more present in the second group.
o For Extensive proximal DVT localization, there is a
statistically significant link (Sig = 0.045) between the
presence in one of the two groups and the presence
of the analyzed risk factors. Cont. Coef. = 0.1144 is
the strength of that link. OR = 1.920 and Sig = 0.047,
therefore it is statistically significant. Extensive
proximal DVT localization is more present in the
second group.
o For Patients with medical conditions, there is a
statistically significant link (Sig <0.001) between the
presence in one of the two groups and the presence
of the analyzed risk factors. Cont. Coef. = 0.500 is the
strength of that link. OR = 16.450 and Sig <0.001,
therefore it is statistically significant. Medical
conditions are highly present in the second group.
o For Patients with a history of surgical conditions,
there is a statistically significant link (Sig <0.001)
between the presence in one of the two groups and
the presence of the analyzed risk factors. Cont. Coef.
= 0.266 is the strength of that link. OR = 4.530 and Sig
42
<0.001, therefore it is statistically significant. Surgical
conditions are more present in the second group.
o For History of major gynecological surgical
interventions, there is a statistically significant link
(Sig=0.024) between the presence in one of the two
groups and the presence of the analyzed risk factors.
Cont. Coef. = 0.162 is the strength of that link. OR =
7.567 and Sig=0.053, therefore it is statistically
significant. The major gynecological surgical
interventions are more present in the second group.
o For History of major urological surgical
interventions, there is a statistically significant link
(Sig=0.005) between the presence in one of the two
groups and the presence of the analyzed risk factors.
Cont. Coef. = 0.201 is the strength of that link. OR =
17.149 and Sig=0.049, therefore it is statistically
significant. The major urological surgical interventions
are present only in the second group.
o For History of heart attacks (myocardial
infarctions), there is a statistically significant link
(Sig=0.029) between the presence in one of the two
groups and the presence of the analyzed risk factors.
Cont. Coef. = 0.157 is the strength of that link. OR =
10.369 and Sig=0.108, therefore it is statistically
significant. The heart attack is present only in the
second group.
o For Neoplasms, there is a statistically significant
link (Sig<0.001) between the presence in one of the
two groups and the presence of the analyzed risk
factors. Cont. Coef. = 0.265 is the strength of that
link. OR = 10.500 and Sig=0.002, therefore it is
statistically significant. Neoplasms are more present
in the second group.
o For CVA (mainly associated with motor deficiency),
there is a statistically significant link (Sig=0.038)
between the presence in one of the two groups and
the presence of the analyzed risk factors. Cont. Coef.
= 0.149 is the strength of that link. OR = 9.305 and
Sig=0.127, therefore it is statistically significant. CVA
is present only in the second group.
A logistic regression for age was performed with all
these factors as covariates and the following result
present in table 4 was obtained.
 Vol. CXX • No. 2/2017 • August• Romanian Journal of Military Medicine

Table 4. Logistic regression for age

B S.E. Wald df Sig. OR

Immobilization before admission 1.020 0.997 1.047 1 0.306 2.774
Varices 0.179 0.678 0.070 1 0.791 1.197
History of VTE -0.401 0.644 0.387 1 0.534 0.670
PE at admission -0.186 1.098 0.029 1 0.865 0.830
History of PE -1.460 2.001 0.532 1 0.466 0.232
Obesity -0.602 0.647 0.867 1 0.352 0.548
Congestive heart failure 17.980 4725.744 0.000 1 0.997 6E+007
COPD or pulmonary conditions -2.264 1.010 5.024 1 0.025 0.104
Anemia -0.286 0.686 0.174 1 0.677 0.751
Fractures before admission -4.041 1.886 4.591 1 0.032 0.018
Smoking 0.037 0.558 0.004 1 0.947 1.038
HTN 4.046 1.528 7.011 1 0.008 57.163
Peripheral artery disease 20.165 7631.510 0.000 1 0.998 6E+008
Type 2 diabetes 0.917 1.050 0.763 1 0.382 2.502
Lipid alterations -0.479 0.730 0.430 1 0.512 0.620
Alcohol consumption -0.635 0.739 0.738 1 0.390 0.530
Extensive distal location (calf) 0.021 0.496 0.002 1 0.965 1.022
Extensive proximal DVT location 0.088 0.544 0.026 1 0.872 1.092
Patients with medical conditions 1.028 0.832 1.527 1 0.217 2.797
Patients with a history of surgical conditions 1.953 1.083 3.250 1 0.071 7.048
History of major gynecological surgical interventions -0.482 2.100 0.053 1 0.819 0.618
History of major urological surgical interventions 16.465 8232.574 0.000 1 0.998 1E+007
Hip or knee arthroplasty; hip surgery -0.753 1.615 0.217 1 0.641 0.471
History of heart attacks 17.258 8314.948 0.000 1 0.998 3E+007
Renal conditions (CKD, hydronephrosis, renal lithiasis) -0.120 0.882 0.019 1 0.892 0.887
Neoplasia 0.720 1.482 0.236 1 0.627 2.055
CVA (mainly associated with motor deficiency) -2.435 12313.405 0.000 1 1.000 0.088

The Cox-Snell’s multiple coefficient of determination
R2 was 0.587 and Nagelkerke’s was 0.782, which
signifies that the model explains 78% of the variation
in covariates distribution by age. The Hosmer and
Lemeshow's test showed the significance Sig = 0.910,
which means that the calculated model fits the
included variables.
COPD (Sig = 0.025, OR = 0.104) and fractures before
admission (Sig = 0.031, OR = 0.018) occur mainly in
patients under 50 years old, while hypertension (Sig =
0.008, OR = 57.163) manifests especially in patients
over 50 years old.
A logistic regression for SVT was performed by age,
gender, origin, venous ulcers, edemas, various
peripheral trophic disorders (brown or reddish skin
depigmentation, fibrous and indurated skin, redness,
irritation or dermatitis), diffuse cellulitis and chronic

43
venous insufficiency as covariates and the following result was obtained and are presented in Table 5.

Table 5. A logistic regression for SVT was performed by age, gender, origin, venous ulcers, edemas, various peripheral
trophic disorders

B S.E. Wald df Sig. OR

Age -0.800 0.339 5.580 1 0.018 0.449
Sex -0.275 0.355 0.601 1 0.438 0.760
Origin 0.459 0.426 1.161 1 0.281 1.582
VU 0.738 0.491 2.256 1 0.133 2.091
Edemas -1.059 0.682 2.413 1 0.120 0.347
Various trophic
0.221 0.522 0.180 1 0.672 1.247
disorders
Cellulitis 0.854 0.705 1.469 1 0.225 2.349
CVI 1.781 0.434 16.827 1 0.000 5.938

The Cox-Snell's multiple coefficient of determination
R2 was 0.316 and Nagelkerke’s was 0.422, which
means that the model explains 42% of the variation in
covariates distribution by SVT. Hosmer and
Lemeshow's test showed the significance Sig = 0.464
which means that the calculated model fits the
included variables. The age (Sig = 0.018, OR = 0.449)
shows that SVT is manifested especially in patients
under 50 years old. CVI (Sig <0.001, OR = 5.938)
occurs predominantly in patients with SVT.
DISCUSSION
Thrombosis, as described by Virchow's triad, occurs
as a result of hypercoagulability, endothelial damage
or stasis, or a combination of these all. The risk of VTE
for each patient should be individually assessed when
prophylaxis is needed. Universal preventive
guidelines were made with difficulty due to
differences between individuals, such as age, medical
history and social history [10]. DVT prevention by
using thrombo-prophylaxis, effective in patients with
high risk of recurrence and the minimization of the
risk of DVT reduce the frequency of post-thrombotic
syndrome (PTS). The identification of the patients at
high risk for PTS, the assessment of the role of
thrombolysis in preventing PTS and the optimal
evaluation of compression stockings in preventing
and treating PTS are issues that should be the
concern for future research, as well as researching
and evaluating the new therapies for treating PTS.
The post-thrombotic syndrome (PTS) is the most
common complication of deep vein thrombosis (DVT),
it is cumbersome and expensive for patients and for
the community, because of its high prevalence,
severity and chronicity and has received little
attention from clinicians and researchers [11].
Initially, venous thromboembolism (VTE) was
perceived as a complication of hospitalization for
major surgery or was associated with late-stage
terminal illness, but studies have shown a risk of VTE
in hospitalized patients with medical conditions
comparable to those seen after major general
surgery. The epidemiological studies have shown that
between one quarter and one half of all symptomatic
VTE, clinically recognized, occur in people who are
not either hospitalized or recovering from a major
illness, which involves expanding the populations at
risk that could benefit from prophylaxis and
challenges doctors to carefully examine the risk
factors for VTE [12].
Clinical evaluation for the diagnosis of venous
thrombosis in itself cannot be invoked for patient
management but remains useful in determining the
need for further testing, namely impedance
plethysmography, which is particularly useful in
excluding DVT in patients with suspicious signs and
symptoms. The medical history for identifying risk

44
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
factors for VTE is as important as physical
examination [13]. When clinical probability is
estimated before the diagnostic tests, the diagnostic
accuracy for DVT is improved. The patients who
experience low clinical probability of DVT have a
prevalence of less than 5% and the diagnosis of DVT
can be excluded without using ultrasound, while for
the patients with clinical suspicion of DVT the results
should not affect clinical decisions [14].
Patients with symptomatic DVT may present an
increase in volume of the affected limb, spontaneous
pain or on palpation in the calf or thigh muscles,
increased pain on the flexion of the foot (the Homans
sign), high temperature and purplish coloration of the
affected lower limbs. Less than 10% develop severe
symptoms including thrombophlebitis, pain, swelling,
leg ulcers or skin induration [15].
The present study has shown that DVT is more
common in patients over 50 years old and it is more
frequent in men and in patients who have the urban
environment as origin.
Despite the anticoagulation treatment, VTE recurs
frequently in the first few months after the initial
event, with a recurrence rate of ≈7% at 6 months.
Death occurs in ≈6% of DVT cases and 12% of PE
cases within 1 month of diagnosis. The seasons of the
year may affect the occurrence of VTE, with a higher
incidence in winter than in summer. Early mortality
after VTE is strongly associated with the presentation
as PE, advanced age, cancer and underlying
cardiovascular disease [2]. Despite universal
thromboprophylaxis, patients with critically severe
surgical or medical conditions remain at risk for deep
vein thrombosis of the lower limbs [1].
VTE is rare in adolescents and it is predominantly a
disease of old age. The incidence of deep vein
References:
1. Kesieme E, Kesieme C, Jebbin N, Irekpita E, Dongo A.
Deep vein thrombosis: a clinical review. J Blood
Med.2011;2:59-69. doi: 10.2147/JBM.S19009. Epub 2011
Apr 29.
2. White RH. The epidemiology of venous thrombo-
thrombosis and pulmonary embolism increases
exponentially with age [16]. Venous thrombo-
embolism is a major national health problem,
especially among the elderly. While the incidence of
DVT remains the same for men and increases for
older women, the incidence of pulmonary embolism
has decreased over time [17]. The incidence rates
after the age of 45 years old are generally higher in
males, while the incidence rates in women are
somewhat higher during the reproductive years. For
both sexes, with increasing age, PE represents a
growing proportion of VTE [17]. The annual rate of
venous thromboembolism events has increased
despite the progress made in the identification,
prevention and treatment. These increases may be
due to the increased sensitivity of diagnostic
methods, especially for PE. This fact implies that the
current prevention and treatment strategies are less
than optimal [18].
Currently, the prophylaxis is both mechanical and
pharmacological. The goals of the treatment are to
prevent the spread of thrombosis, pulmonary
embolism, thrombosis recurrence and the
development of complications such as post-
thrombotic syndrome and pulmonary hypertension.
CONCLUSIONS
Thromboprophylaxis could have a tremendous
potential if it was efficiently and optimally
administered to patients at risk of venous
thrombosis. Understanding the risk factors and
epidemiology of the first and recurrent venous
thrombosis enables the optimal and efficient use of
prophylactic strategies against VTE and would
prevent post-thrombotic syndrome and improve
clinical outcomes in practice.
embolism. Circulation 2003;107:I-4–I-8. Circulation. 2003
Jun 17;107(23 Suppl 1):I4-8.
3. Cushman M. Epidemiology and Risk Factors for Venous
Thrombosis. Seminars in hematology. 2007;44(2):62-69.
doi:10.1053/j.seminhematol.2007.02.004.
45
4. López JA, Kearon C, Lee AY. Deep venous thrombosis.
Hematology Am SocHematolEduc Program. 2004:439-56.
5. Hirsh J, Hoak J. Management of deep vein thrombosis
and pulmonary embolism. A statement for healthcare
professionals. Council on Thrombosis (in consultation with
the Council on Cardiovascular Radiology), American Heart
Association. Circulation. 1996;93(12):2212–2245.
6. Prandoni P, Kahn SR. Post-thrombotic syndrome:
prevalence, prognostication and need for progress. Br J
Haematol 2009; 145:286.
7. Susan R. Kahn, Anthony J. Comerota, Mary Cushman,
Natalie S. Evans, Jeffrey S. Ginsberg, Neil A. Goldenberg,
Deepak K. Gupta, Paolo Prandoni, Suresh Vedantham, M.
Eileen Walsh and Jeffrey I. The Postthrombotic Syndrome:
Evidence-Based Prevention, Diagnosis, and Treatment
Strategies A Scientific Statement From the American Heart
Association (Circulation. 2014;130:1636-1661.October 28,
2014
8. van Korlaar IM, Vossen CY, Rosendaal FR, Bovill EG,
Cushman M, Naud S, et al. The impact ofvenous thrombosis
on quality of life. Thromb Res 2004;114:11–18.
9. Kahn SR, Ducruet T, Lamping DL, Arsenault L, Miron MJ,
Roussin A, et al. Prospective evaluation of health-related
quality of life in patients with deep venous thrombosis.
Arch Intern Med 2005;165:1173–1178.
10. Hsu P, Basu CB, Venturi M, Davison S. Venous
Thromboembolism Prophylaxis. Seminars in Plastic Surgery.
2006;20(4):225-232. doi:10.1055/s-2006-951580.
11. Susan R. Kahn .The Post-thrombotic Syndrome: The
Forgotten Morbidity of Deep Venous Thrombosis Journal of
46
Thrombosis and Thrombolysis, February 2006, Volume 21,
Issue 1, pp 41–48
12. Anderson FA Jr, Spencer FA. Risk factors for venous
thromboembolism. Circulation. 2003 Jun 17;107(23 Suppl
1):I9-16.
13. Wheeler H B. Diagnosis of deep vein thrombosis.
Review of clinical evaluation and impedance
plethysmography. Am J Surg. 1985;150:7–13.
14. Wells P S, Owen C, Doucette S, Fergusson D, Tran H.
Does this patient have deep vein thrombosis? JAMA.
2006;295:199–207.
15. Cook D, Crowther M, Meade M, Rabbat C, Griffith L,
Schiff D, Geerts W, Guyatt G. Deep venous thrombosis in
medical-surgical critically ill patients: prevalence, incidence,
and risk factors. Crit Care Med. 2005 Jul;33(7):1565-71.
16. Anderson FA, Jr, Wheeler HB, Goldberg RJ, et al. A
population-based perspective of the hospital incidence and
case-fatality rates of deep vein thrombosis and pulmonary
embolism. The Worcester DVT Study. Arch Intern Med.
1991 May;151(5):933-8.
17. Silverstein MD, Heit JA, Mohr DN, Petterson TM,
O’Fallon WM, Melton LJ., 3rd Trends in the incidence of
deep vein thrombosis and pulmonary embolism: a 25-year
population-based study. Arch Intern Med. 1998 Mar
23;158(6):585-93.
18. Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer
FA. Secular trends in occurrence of acute venous
thromboembolism: the Worcester VTE study (1985-2009)
Am J Med. 2014 September; 127(9): 829–839.e5.
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

Article received on February 17, 2017 and accepted for publishing on July 15, 2017.
ORIGINAL ARTICLES

New synthesized oximes active in nerve agents’ hazards

Mihail S. Tudosie1, Bogdan Patrinich2, Andreea R. Negrea3, Cristina A. Secară2

Abstract: Object: The aim of the study is to select the most active new imidazolium-quinuclidinum-
oxime, from some similar chemical compounds synthesized in our chemistry department, with
sufficient efficacy to decrease the acute toxicity of neurotoxic organophosphates known as nerve
agents. Method: The experimental study consist in vivo testing the antidotal efficacy of obidoxime
and of selected imidazolium oximes synthesized in our chemistry department. Each oxime was
included, by equimolar replacing the obidoxime, in an antidotal formula, which also contains
atropine. The above mentioned formula containing atropine and obidoxime was used as reference.
The protective ratio, defined as the ratio between the lethal median dose of the poisoned and treated
study group and the median lethal dose (LD50) of the poisoned and untreated study groups was one
of the used parameters in order to select a new active chemical structure in counteracting the
neurotoxic organophosphorus compounds acute toxicity. Another studied parameter was the
erythrocyte acetylcholinesterase value measured in whole blood 24 hours after exposure. Results: The
protective ratio against an organophosphorus compound were the follow: obidoxime chloride: 2; 1,3-
dimethyl-2-hydroxyethyl-imidazolyliodide: 1,75;3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-
2oxapropyl]quinuclidin-dichl-oride: 2,5; 1-methyl-quinuclidin-3-iodide: 1,5. The erythrocyte
acetycholinesterase main values were the following: the unpoisoned and untreated study group:3,45
±0,13mmol/dl; the poisoned and untreated study group: 0,89 ±0,09 mmol/dl; the poisoned and 3-
oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-2oxapropyl]quinuclidindichloride treated study
group:2,89 ±0,11 mmol/dl; the poisoned and obidoxime treated study group: 2,53±0,15 mmol/dl.
Conclusions: 3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-2oxapropyl] quinuclidindichloride
synthesized in our chemistry department, has shown a better protective ratio and a more prolonged
surviving time than the reference (obidoxime). It has shown the best AChE reactivation of all the
synthetized compounds. This compound can be a cheap and good option for replacing obidoxime in
the antidotal formula active in nerve agent exposure.
Keywords: obidoxime chloride; 1,3-dimethyl-2-hydroxyethyl-imidazolyl-iodide;3-oxime-[3-(2-
hidroxyimino-methyl-1-imidazolyl-)-2oxapropyl] quinuclidin dichloride; 1-methyl-quinuclidin-3-on-
iodide; organophosphorus compounds; nerve agents

INTRODUCTION target of such actions.

Strategic expert analyzes have shown that in the next Neurotoxic organophospho-
1Carol Davila University of
period, there may be international conflicts, rus compounds (sarin, so-
Medicine and Pharmacy,
amplifying the risk of attempts to use highly toxic man, tabun, most insecti- Bucharest
chemicals as weapons of mass destruction.[1] cides) are chemical com- 2Military Medical
pounds, phosphonic acid Research Center,
Romania through its geostrategic position, being the Bucharest
esters with central and 3
member of NATO, can provide a better potential Intermedica Healthcare,
Bucharest

47
peripheral properties, acetyl-cholinesterase and
butyryl-cholinesterase irreversible inhibitors with
toxic effects on smooth and striated muscles and
central nervous system.[2-4]
They were registered on the list of substances to be
destroyed in accordance with international
regulations (Convention on the Prohibition of
Development, Production and Stockpiling Chimice-
Geneva).
Although banned by international conventions, these
toxic substances have been used in terrorist attacks
against civilians (Tokyo 1995 Halabja in 1987, Anfal-
1988). In this context geostrategic and due to soaring
use of organophosphorous insecticides, development
of medical measures to protect against the lethal
toxicity is one of the priorities of research within
specialized programs of NATO (NBC – Science for
Peace) and European Union (Chemical Program
Weapons, Monitoring and Protection, created in the
OPCW).
The acute toxicity of organophosphorus compounds
known as nerve agents mainly result from their action
as irreversible inhibitors of acetylcholinesterase
(AChE). They suffer some conformational and
chemical changes, resulting a phenomenon known as
"aging", whose speed of appearance is directly
proportional to the toxicity of compounds.[5,6]
Accumulation of acetylcholine stimulation leads to
persistent cholinergic muscarinic receptors that
trigger the syndrome whose symptoms include
miosis, salivation, bronchial hypersecretion,
bradycardia, bronchoconstriction, hypotension and
diarrhea.[7]
Another effect of organophosphate anticholin-
esterases is the desensitization of nicotinic receptors
followed by overstimulation, translated by skeletal
muscle twitching and subsequent paralysis.[8] Central
nervous system toxic effects include anxiety,
restlessness, confusion, ataxia, tremors, convulsions,
paralysis, cardiorespiratory effects and coma [9].
The treatment of nerve agents poisoning is based on
an antimuscarinic agent (atropine), and an acetyl-
cholinesterase reactivator called oxime according to
48
its chemical structure. Atropine blocks the effects of
accumulated acetylcholine resulting overstimulation
of muscarinic receptors.[9,10]
Acetylcholinesterase reactivators dephosphorylate
the acetylcholinesterase – organophosphorus
complex, reactivating the enzyme activity.[11] The
early appeared seizures were counteracted by
benzodiazepines.
Currently available oximes (pralidoxime, obidoxime),
have been shown to be less effective against one of
the most toxic nerve agents (soman tabun). There is a
strong interest in developing new, more potent acetyl
cholinesterase reactivators with oxime structure.[12]
The present paper represents an in vivo screening
study in selecting more potent chemical compounds,
active in counteracting the nerve agents acute
toxicity. The paper describes an experimental test of
antidotal efficiency of some compounds containing
imidazolium, or quinuclidinium rings, which
equimolar replace obidoxime chloride in the
antidoltal formula.
The results were expressed as the protective ratio
representing the ratio between the DL50 of the
neurotoxic compound administred to the poisoned
and treated rat study group and the DL50
administered to the organoposphate compound of
the poisoned and untreated study group.
MATERIAL AND METHODS
Chemicals
- obidoxime chloride (CAS number 111-90-9);
- atropine sulphate (CAS number 5908-99-6) were
purchased from Sigma Aldrich;
- diclorvos (PESTANAL CAS number 62-73-7) were
purchased from Sigma Aldrich.
- the experimentally tested quinuclidinium-imida-
zolium oximes were synthetized in the chemistry
department of Medical Military Research Center.
Animals
Male Wistar rats (150-200g) were maintained on rice
husk in polypropylene cages. Wistar free access to
water and rodent pellet food. The study was
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
approved by the Ethical Committee on Animal
Experimentation.
Acetycholinesterase measurement method: Elisa kit.
The kit is a sandwich enzyme immunoassay for in
vitro quantitative measurement of
Acetylcholinesterase in human serum, plasma and
other biological fluids.
Target Information: Acetylcholinesterase hydrolyzes
the neurotransmitter, acetylcholine at neuromuscular
junctions and brain cholinergic synapses, and thus
terminates signal transmission. It is also found on the
red blood cell membranes, where it constitutes the Yt
blood group antigen.
Figure 1: The chemical structure of the in vivo tested
compounds as acetycholinesterase reactivators
1methyl-quinuclidine-3-on-iodide
1,3-dimethyl-2-hidroxyethyl-imidazolyl-iodide
3oxim[3(2-hidroxy-iminomethyl-1-imidazolyl)-2oxapropyl]
quinuclidine dichloride
Treatments
120 Wistar rats were divided into 12 groups, each,
including ten rats as follows:
- 1st group: control group unpoisoned, untreated
- 2nd group: poisoned with diclorvos (1,5 DL50) and
untreated;
- 3rd group: poisoned with diclorvos (1,5 DL50,) after
one minute, were administered the antidotal formula
including atropine (2mg) and obidoxime chloride (250
mg);
- 4th group: poisoned with diclorvos (1,5 DL50), after
one minute, were administered the antidotal formula
including atropine (2 mg) 1methyl-quinuclidine 3-on
iodide in an equimolar dose with obidoxime chloride
(78,5 mg);
- 5th group: poisoned with diclorvos (1,5DL50,) after
one minute were administered the antidotal formula
including atropine (2 mg), 1,3- dimethyl-2-hidroxy-
ethylimidazolyl iodide in an equimolar dose with
obidoxime chloride (61,94 mg/kg);
- 6th group: poisoned with diclorvos (1,5 DL50), after
one minute, were administered the antidotal formula
including atropine (1,5 mg) and 3oxim[3(2-hidroxy-
iminomethyl-1-imidazolyl)-2oxapropyl] quinuclidine
dichloride (118 mg/kg).
The above mentioned oximes were experimentally
tested against 1.5, 1.75, 2, 2.5, DL50.
24 hours after poisoning mortality, protective ratio
was registered and erythrocyte achetylcolinesterase
activity values were measured.
RESULTS
The aim of the study is to evaluate the most active
newly synthesised imidazolquinuclidine-oxime with
the great efficacy in reactivating the phosphorylated
acetylcholinesterase through some similar chemical
compounds synthesized in our chemistry department,
able to decrease acute neurotoxic compounds
toxicity.
The protective ratio of the obidoxime and
experimentally tested formulas correlated with their
efficacy as acetylcholinesterase reactivators are
represented in the Table 1.
The 3 oxim[3(2-hidroxyiminomethyl-1-imidazolyl)-2-
oxapropyl] quinuclidine dichloride protective ratio
correlated with its acetylcholinesterase reactivator
activity is greater than the obidoxime, resulting a
49
better antidotal efficacy.
Statistical analysis Student's t-test probability
associated with statistically significant differences
between mean values of erythrocyte acetyl-
cholinesterase between the control study group and
the poisoned and treated study groups is represented
in tables 2-7.
The poisoned and untreated group statistically
significantly differs from normal in terms of the
acetylcholinesterase inhibition.
Neurotoxic organo-phosphorous compounds cause in
the intoxicated group and untreated study group an
acetylcholinesterase inhibition of 75.08%, incompa-
tible with survival.
Obidoxime and new synthesized imidazolium-
quiniclidinium oximes highlighted new capabilities of
acetylcholinesterase reactivation correlated with the
protection index.
3-oxime compound [3-(2-hidroxyiminomethyl-1-imi-
dazolyl)-2oxapropyl]-quinuclidine-dichloride-quinucli-
dine 3-on iodide revealed a protection index bigger
than other obidoxime and other imidazolium
compounds studied.
Explanation of this is that the quinuclidine ring, by its
position intensifies allosteric oxime group (Table 1).
Tables 2-7 reveals that the intoxicated untreated
control group differs statistically significantly from
normal and so the intoxicated study groups were
treated with different therapeutic formulations.

Table 1: The protective ratio of the antidotal formulas containing the experimentally tested imidazolium oximes as AChE
reactivators
Dose of Protective Acetylcholinesterase
Study Acetylcholinesterase
reactivators ratio reactivation due to oxime
group reactivator
(mg/kg) (DL50 ) (%)
2 - - -
4 1methyl-quinuclidine 3-on
78.58 1.5 47.82
iodide
8 1,3-dimethyl-2-
hidroxyethyl-imidazolyl 61.94 1.75 60.28
iodide
10 obidoxime chloride 100 2 73.33
12 3 oxim[3(2-
hidroxyiminomethyl-1-
118.88 2.5 82.31
imidazolyl)-2oxapropyl]
quinuclidine dichloride

Table 2: Statistical analysis of the probability P (T test) associated with average values of erythrocyte AchE of unpoisoned
and poisoned and untreated study groups
The main value of
Study erythrocyte P
Observations
group acetylcholinesterase (T test)
(mmol/dl)
1 3.45 ± 0.13 P ≤ 0.05 statistically significant
0.003
2 0.86 ± 0.09 difference between groups
Legend:
Study group 1: unpoisoned and untreated study group;
Study group 2: paraoxon poisoned and untreated study group

50
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

Table 3: Statistical analysis of the probability P (T test) associated with average values of erythrocyte acetylcholinesterase of
poisoned, untreated and poisoned and obidoxime treated study groups
The main value of
Study erythrocyte P
Observations
group acetylcholinesterase (T test)
(mmol/dl)
10 2.53 ± 0.15 P ≤ 0.05 statistically significant
0.007
2 0.86 ± 0.09 difference between groups
Legend:
Study group 10: paraoxon poisoned and obidoxime treated study group;
Study group 2: paraoxon poisoned and untreated study group.

Table 4: Statistical analysis of the probability P (T test) associated with average values of erythrocyte acetylcholinesterase of
poisoned, untreated and poisoned and 1,3-dimethyl-2-hidroxyethylimidazolyl iodide treated study groups
The main value of
Study erythrocyte P
Observations
group acetylcholinesterase (T test)
(mmol/dl)
8 2.01 ± 0.07 P ≤ 0.05 statistically significant
0.004
2 0.86 ± 0.09 difference between groups
Legend:
Study group 8: paraoxon poisoned and 1,3-dimethyl-2-hidroxyethylimidazolyl iodide treated study group;
Study group 2: paraoxon poisoned and untreated study group.

Table 5: Statistical analysis of the probability P (T test) associated with average values of erythrocyte acetylcholinesterase of
poisoned, untreated and poisoned and 1methyl-quinuclidine 3-on iodide study groups
The main value of
Study erythrocyte P
Observations
group acetylcholinesterase (T test)
(mmol/dl)
4 1.65 ± 0.03 P ≤ 0.05 statistically significant
0.009
2 0.86 ± 0.09 difference between groups
Legend:
Study group 4: paraoxon poisoned and iodide treated study group;
Study group 2: paraoxon poisoned and untreated study group

Table 6: Statistical analysis of the probability P (T test) associated with average values of erythrocyte acetylcholinesterase of
poisoned, untreated and 3-oxim[3(2-hidroxyiminomethyl-1- imidazolyl)-2oxapropyl] quinuclidine dichloride- quinuclidine 3-
on iodide treated study groups
The main value of
Study erythrocyte P
Observations
group acetylcholinesterase (T test)
(mmol/dl)
12 2.84 ± 0.05 P ≤ 0.05 statistically significant
0.0002
2 0.86 ± 0.09 difference between groups
Legend:
Study group 12: paraoxon poisoned and 3-oxim[3(2- hidroxyiminomethyl-1- imidazolyl)-2oxapropyl] quinuclidine dichloride- quinuclidine 3-
on iodide treated study group;
Study group 2: paraoxon poisoned study group

51
Table 7: Statistical analysis of the probability P (T test) associated with average values of erythrocyte acetylcholinesterase of
poisoned, obidoxime treated and 3-oxim[3(2-hidroxyiminomethyl-1-imidazolyl)-2oxapropyl] quinuclidine dichloride-
quinuclidine 3-on iodide treated study groups
The main value of
Study erythrocyte P
Observations
group acetylcholinesterase (T test)
(mmol/dl)
12 2.84 ± 0.05 P ≤ 0.05 statistically significant
0.01
10 2.53 ± 0.15 difference between groups
Legend:
Study group 12: paraoxon poisoned and 3-oxim[3(2-hidroxyiminomethyl-1-imidazolyl)-2oxapropyl] quinuclidine dichloride-quinuclidine 3-on
iodide treated study group;
Study group 10: paraoxon poisoned and obidoxime treated study group

Table 8: The correlation between administered dose of acetylcholinesterase reactivator and the
pharmacodynamic effect
Study Reactivator dose used in the AChE Correlation coeficicient
group. antidotal formula Mmol/ml
(mg)
4 61,94 1,65
8 78,58 2,01 0,9927

10 100 2,53
12 118,88 2,84
Legend:
Study group 4: poisoned study group and 1methyl-quinuclidine 3-on iodide treated;
Study group 8: poisoned study group and 1,3-dimethyl-2-hidroxyethyl-imidazolyl iodide treated;
Study group 10: poisoned study group and obidoxime chloride treated;
Study group 12: poisoned study group and 3 oxim[3(2-hidroxyiminomethyl-1-imidazolyl)-2oxapropyl] quinuclidine dichloride treated;

From a medical standpoint, an organophosphoric reactivators used in the antidotal formulas are
nerve poisoning that caused inhibition of acetyl- correct, being those that cause maximum
cholinesterase survival limit was applied. pharmacodynamic effect.

This intoxication was further antagonized with

different formulas containing the synthesized
imidazoliumquinuclidinium oximes and obidoxime as
antidotes.
They showed mean values of acetylcholinesterase
significantly different from the poisoned and
untreated group. The studied imidasolium
quinuclidinium oximes showed average values of
acetylcholinesterase statistically significantly different
between them, thus emphasizing that the doses used
may cause significant variations in therapeutic effect.
CONCLUSION
• 3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-
2-oxapropyl] quinuclidindichloride synthesized in the
Medical Military Research Centre Chemistry
Department has shown a better protective ratio and
a more prolonged surviving time than obidoxime
considered as reference.
• It has shown the best acetylcholinesterase
reactivation of all the synthetised compounds and
obidoxime

Table 8 highlights the so-called "dose finding", the • The very good correlation dose-effect highlights
correct correlation between dose and pharmaco- that the correct dose of acetylcholinesterase
dynamic effect. The correlation coefficient of 0.9927 reactivator was chosen in order to obtain the better
demonstrates that doses of acetylcholinesterase pharmacodynamic effect.

52
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
• 3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-
2-oxapropyl] quinuclidindichloride can be considered
an efficient antidote in neuroparalytic organo-
phosphorous hazards.
• 3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-
2-oxapropyl] quinuclidindichloride can be a cheaper
References:
1 Eddleston M, Szinicz L, Eyer P, Buckley N. Oximes in acute
organophosphorus pesticide poisoning: a systematic review
of clinical trials. QJM 2002;95:275-83.
2 Thunga G, Sam KG, Khera K, Pandey S, Sagar SV.
Evaluation of incidence, clinical characteristics and
management in organophosphorus poisoning patients in a
tertiary care hospital. J Toxicol Environ Health Sci
2010;2:73-6.
3 Mégarbane B. Toxidrome-based Approach to Common
Poisonings. Asia Pac J Med Toxicol 2014;3:2-12..
4 Worek F, Bäcker M, Thiermann H, Szinicz L, Mast U,
Klimmek R, et sl. Reappraisal of indications and limitations
of oxime therapy in organophosphate poisoning. Hum Exp
Toxicol 1997;16:466-72.
5 Due P. Effectiveness of High dose Obidoxime for
Treatment of Organophosphate Poisoning. Asia Pac J Med
Toxicol 2014;3:97-103.
6 Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J.
Oximes for acute organophosphate pesticide poisoning.
Cochrane Database Syst Rev. 2011;(2):CD005085.
7 Worek F, Thiermann H, Szinicz L, Eyer P. Kinetic analysis
and better option for replacing obidoxime in the
antidotal formula active in nerve agent poisoning.
• Thus one can conclude that the result of the
experimental study is consistent with the proposed
object.
of interactions between human acetylcholinesterase,
structurally different organophosphorus compounds and
oximes. Biochem Pharmacol 2004;68:2237-48.
8 Blain PG. (2011). Organophosphorus poisoning (acute).
Clin Evid. [Online] Available from www.ncbi.nlm.nih.gov/
pubmed/21575287. [Accessed February, 2012].
9 M Pohanka (2011) Cholinesterases, a target of
pharmacology and toxicology. Biomedical Papers Olomouc
155(3): 219-229.
10 Peter JV, Moran JL, Graham P. Oxime therapy and
outcomes in human organophosphate poisoning: an
evaluation using meta-analytic techniques. Crit Care Med
2006;34:502-10.
11 F Worek, P Eyer, N Aurbek, L Szinicz, H Thiermann
(2007) Recent advances in evaluation of oxime efficacy in
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53
 Article received on February 12, 2017 and accepted for publishing on June 10, 2017.
CLINICAL PRACTICE

Ethical considerations in sudden unexpected death in

epilepsy (SUDEP)
Carmen A. Sîrbu1,4, Octavian M. Sîrbu², Anca M. Sandu3, Florentina C. Pleșa1,4, Beatrice G. Ioan5

Abstract: Epilepsy is one of the world's oldest diseases. Social stigma, misunderstanding and thus,
discrimination have surrounded patients and their families from the beginnings until nowadays.
Approximatively up to 80% of epilepsy cases worldwide are found in developing regions. The risk of
premature death is two to three times higher than for the general population. There is contradictory
evidences concerning the question of whether to inform patients about the possibility of sudden
unexpected death in epilepsy (SUDEP). Actual guidelines states that individuals with epilepsy and their
families or careers should be given access to information on SUDEP. We have information about how,
when and what to say to the patients and families about SUDEP. But it's a delicate subject, and some
patients do not want to know that they are at risk for this.

Keywords: epilepsy, SUDEP, ethics

INTRODUCTION different parts of the brain cells. It is consider that up

to 10% of people worldwide have one seizure during
Despite age, racial, social,
their lifetimes. Epilepsy is defined by two or more
geographic or national
unprovoked seizures. Only one fourth of affected
boundaries, epilepsy remain
people in developing countries get the treatment
a prevalent chronic neuro-
they need and only 70% of these respond to
logical disorder.
medication. Mortality is higher in patients with
The incidence of epilepsy epilepsy than in general population. People with
1Carol Davila University was estimated at 24-53 per epilepsy and their families can suffer from stigma and
Central Emergency 100,000 people. discrimination in many parts of the world. For
Military Hospital,
Bucharest example in China and India, epilepsy is a reason for
World Health Organization
2Bagdasar-Arseni prohibiting or annulling marriages.
(WHO) estimates that
Emergency Clinical
Hospital, Bucharest around 50 million people In the United Kingdom, a law forbidding people with
3 C.I. Parhon National worldwide have epilepsy, epilepsy to marry was repealed only in 1970. In the
Institute of Endocrinology 80% from developing re- USA, until the same years, it was illegal that people
Bucharest
4Titu Maiorescu
gions. Epilepsy is character- with seizures have access to restaurants, theatres,
University, Bucharest rized by recurrent seizures
5 Gr.T. Popa University of due to excessive electrical Corresponding author: Florentina C Pleșa,
Medicine and Pharmacy,
Iași
discharges in a group of plesacristina@yahoo.com

54
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
recreational centers and other public buildings. Even
nowadays patients have reduced access to health and
life insurance, to obtain a driving license, to get a job
or have other limitations.[1-5] Still now a person may
be identified as an ‘‘epileptic” rather than ‘‘a person
with epilepsy”.[6] SUDEP is the second death cause in
epilepsy after status epilepticus. Unusually, the
diagnostic of SUDEP is retrospective. Is defined as
sudden, unexpected, witnessed or unwitnessed, non-
traumatic and non-drowning death in patients with
epilepsy, with or without evidence of a seizure and
excluding documented status epilepticus, in which
postmortem examination does not reveal a
toxicological or anatomical cause of death. [7] It is
responsible for 7.5–17% of all epilepsy deaths and
has an incidence among adults between 1:500 and
1:1000 patients per year. [8] Epileptologists agreed
that SUDEP is mainly, but not exclusively, a problem
for patients with refractory epilepsy. Epilepsy-related
mortality is a significant risk in pregnancy, 1:1000
women died from epilepsy (mostly SUDEP) during or
shortly after pregnancy. [9] SUDEP has an estimated
annual incidence rate of 0.81 cases per 100000
population, or 1.16 cases per 1000 patients with
epilepsy. Comparing years of potential life lost from
SUDEP with selected other neurologic diseases,
SUDEP ranks second only to stroke. [4] There are
some risk factors like: generalized tonic-clonic
seizures (GTCS), nocturnal seizures, variability of EEG
records, and duration of the disease ranging from 15
to 20 years, early onset of epilepsy, poly-medications,
cold temperatures, alcohol abuse, and street drugs.
[10-14] It has been suggested that the most common
pathogenic mechanism underlying SUDEP is heritable
arrhythmogenic syndromes, or cardiac channelo-
pathies, such as familial long QT syndrome
(LQTS).[15,16] LQTS associated with syncope, seizures
and sudden cardiac death is caused by mutations in
more than 10 genes, encoding potassium and sodium
ions channels.
Among cardiac arrhythmias, respiratory dysfunction,
neurogenic pulmonary edema and dysregulation of
systemic and cerebral circulation are other proposed
pathophysiological events implicated in SUDEP.[17-
19]
ETHICS ON SUDEP
There is a reasonable question about SUDEP: must it
be discussed with all patients with epilepsy who are
at risk of SUDEP, or not? The Task Force of the
American Epilepsy Society and the Epilepsy
Foundation have guidelines concerning what, how,
when SUDEP should be discussed with patients, their
families and caregivers. In Europe, the National
Institute of Clinical Excellence (NICE) has the same
attitude. [3]
The topic of SUDEP involves many moral dilemmas,
most of which do not have absolute solutions.
Advocates of universal SUDEP counseling cite the
“right to know,” but others point to the “right not to
know”. There is neither empirical evidence nor
consensus on the question of whether to inform
patients and parents about the possibility of
SUDEP.[20]
Arguments to inform patients about SUDEP
In recent times there has emerged a debate regarding
the obligation to warn even newly diagnosed patients
of the risk of SUDEP. If there is a reasonable chance
of preventing SUDEP, it must be discussed with all
patients with epilepsy who are at highest risk of
SUDEP. A few strategies that patients with epilepsy
and their careers can take to reduce death risk could
then be share by the physician.
On the other hand, the term “unexpected” is
improper used because in some patients with risk
factors SUDEP could be expected.[7] Precise
definition and classification of SUDEP is necessary to
scientific and medical communication, and is also
important from a legal point of view. The new
classification consists of six classes and definitions:
1. Definite SUDEP
1a. Definite SUDEP Plus (preexisting condition could
have contributed to the death),
2. Probable SUDEP, (meets criteria for SUDEP, but no
postmortem examination was done to exclude
another pathologic process)
3. Possible SUDEP (postmortem examination may
have identified drowning)
4. Near SUDEP (cardiorespiratory arrest that is
successfully resuscitate),
55
5. Not SUDEP when a clear cause of death is known.
6. Unclassified: incomplete information available; not
possible to classify
The patient suffering from epilepsy is, in many
respects, no different to any other patient being
treated by medical practitioner. [21] The ethical
principle of patient autonomy in health care involve
the patient’s right to know about medical condition
and prognosis. Information should be provided
promptly to patients, their families and caregivers if
they ask about the potential adverse consequences of
the seizures or about the mortality risk associated
with epilepsy.
In learning about SUDEP, parents expressed a need to
be informed of the risk of that. There was a
consensus that it should be the parents' decision as
to whether or not the child should be present at the
meeting or when to inform the child about the risk of
SUDEP.[22]
In some cases the risk of SUDEP may need to be
emphasized to encourage compliance with medical
and surgical therapy for epilepsy. Recent evidence
from a meta-analysis of randomized clinical trials of
adjunctive AEDs at efficacious doses provides strong
support for AED treatment as mono- or polytherapy
to increase seizure control and protect against SUDEP
in patients with refractory epilepsy.
For patients for whom seizure control is unattainable,
supervision or monitoring may prevent SUDEP,
though this has never been formally tested. [15]
Increasing awareness of SUDEP may facilitate
improved seizure control and possibly decreasing
SUDEP incidence.[23]
Furthermore, SUDEP discussion can be encouraging
to patients with very low SUDEP risk. Patients with
absence epilepsy or benign epilepsy syndromes must
know that their risk of SUDEP is negligible.
Arguments for not informing patients about SUDEP
By low, failure to discuss SUDEP with a patient
suffering from epilepsy cannot constitute negligence
because the outcome cannot be as a consequence of
the actions of the doctor based upon current
knowledge.
56
Mainly, if the patient has not asked about his distress,
there is not the basis for litigation against the doctor
who chooses not to discuss this topic.[20]
Until now, no interventional measures are known to
stop the outcome, so we get nothing by warning of
SUDEP. To admit the SUDEP, it may seriously
deteriorate quality of life. In this case the doctor may
deliberately omit information to avoid patient fear
and anxiety, respecting in this way the right „do not
harm”. The negative influence on quality of life may
represent a form of negligence.
It may be possible to show causal connection
between impaired quality of life and the doctor
divulging information that the patient did not
explore. Polymedication is an important risk factor for
SUDEP, but a necessary intervention for the epilepsy
management. So many patients requiring polytherapy
have been refused it for fear of SUDEP.[14]
CONCLUSIONS
Duty of care dictates open and frank discussion if the
patient wishes information about mortality and
epilepsy. The big dilemma concerning ethics
considerations in SUDEP is: the ‘‘right to know’’ or the
converse which is the ‘‘right not to know’’?
This conflict, places the clinician in a serious ethical
difficulty because it requires the balancing of these
diametrically opposed concepts and demands a value
judgement on the part of the clinician. SUDEP is
essentially unpredictable for any individual patient. It
also confirms that ‘‘never’’ and ‘‘always’’ are
dangerous terms when used by doctors.
To assure the patient of something which cannot be
assured may represent another form of negligence
and failure of duty of care. The doctor provide the
patient with accurate and informed response to
questions raised .Where the detailed information will
not alter the outcome for the patient, failure to
provide it cannot be deemed to represent negligence.
The ethical consideration is met if the doctor tries to
ascertain what the patient wants to know and
responds accordingly by providing that information
which the patient requests. Thus, each case must be
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
managed individually and doctors are advised to
document the decision-making process. The patient
References:
1. Nakano H, Inoue Y. Epidemiology and cause of epilepsy.
Nihon Rinsho. 2014 May ; 72 (5) : 785-9.: [ accessed 2014
Jul 07 ] http://www.ncbi.nlm.nih.gov/pubmed/ 24912276
2. Atlas Epilepsy Care in the World 2005,World Health
Organization, ISBN-13 9789241563031, ISBN-10
9241563036, 2005: 1-91
3. The Epilepsies. The Diagnosis and Management of the
Epilepsies in Adults and Children in Primary and Secondary
Care. London: NICE; 2012 [accessed 21.06.14]
http://www.nice.org.uk/nicemedia/live/13635/57784/5778
4.pdf
4. Thurman DJ, Hesdorffer DC, French JA. Sudden
unexpected death in epilepsy: Assessing the public health
burden.Epilepsia. 2014 Jun 5 [ accessed 2014 jul 01 ];
http://www.ncbi.nlm.nih.gov/pubmed/24903551
5. WHO-Epilepsy-Fact sheet N°999 -October 2012
6. Beran RG. Epilepsy and law. Epilepsy & Behavior 12
(2008) 644–651
7. Nashef L, So EL, Ryvlin P, Tomson T. Unifying the
definitions of sudden unexpected death in epilepsy.
Epilepsia, 2012, 53: 227–233.
8. Scorza FA1, Cysneiros RM, de Albuquerque M, Scattolini
M, Arida RM. Sudden unexpected death in epilepsy: an
important concern.Clinics (Sao Paulo). 2011;66 Suppl 1:65-
9.
9. Edey S, Moran N, Nashef L. SUDEP and epilepsy-related
mortality in pregnancy. Epilepsia. 2014 Apr 22. [accessed
2014 Jul 07]: http://www.ncbi.nlm.nih.gov/pubmed/
24754364
10. Majkowski J, Sudden Unexpected Death In Epilepsy
(SUDEP) – an update. Journal of Epileptology 2013 (21): 37–
54.
11. Surges R, Thijs RD, Tan HL, Sander JW. Sudden
unexpected death in epilepsy: risk factors and potential
pathomechanisms. Nat Rev Neurol.2009;5:492–504
12. Hirsch LJ, Hauser WA. Can sudden unexplained
death in epilepsy be prevented? Lancet. 2004; 364:2157–8.
13. Aurlien D., Larsen J.P., Gjerstad L., Taubøll E.: Increased
risk of sudden unexpected death in epilepsy in females
using lamotrigine: a nested, case-control study. Epilepsia,
care is like a balance between what the career offers,
and what the patient accepts.
2012, 53: 258–266.
14. Hesdorffer D.C., Tomson T. Sudden Unexpected Death
in Epilepsy: Potential role of antiepileptic drugs. CNS Drugs.
2013 Feb;27(2):113-9. [accessed 2014 jul 01 ]; Available
from: http://www.ncbi.nlm.nih.gov/pubmed/23109241
15. Agostini S.D., Aniles E., Sirven J., Drazkowski J.F.: The
importance of cardiac monitoring in the epilepsy
monitoring unit: a case presentation of ictal asystole.
Neurodiagn. J., 2012, 52: 250–260
16. Tu E, Bagnall RD, Duflou J, Semsarian C. Post-Mortem
Review and Genetic Analysis of SuddenUnexpected Death
in Epilepsy (SUDEP). Cases Brain Pathol. 2011 Mar; 21
(2):201-8
17. Schuele SU, Widdess-Walsh P, Bermeo A, Lu¨ ders
HO. Sudden unexplained death in epilepsy: the role of the
heart. Cleve Clin J Med.2007; 74:S121–27.
18. Meyer S., Shamdeen M.G., Gottschling S., Strittmatter
M., Gortner L.: Sudden unexpected death in epilepsy in
children.J. Paediatr. Child. Health., 2011, 47: 326–331
19. Velagapudi P., Turagam M., Laurence T., Kocheril
A.Cardiac arrhythmias and sudden unexpected death in
epilepsy (SUDEP). Pacing Clin. Electrophysiol., 2012, 35:
363–370.
20. Beran R G, Weber S, Sungaran R, Venn N. Review of the
legal obligations of the doctor to discuss Sudden
Unexplained Death in Epilepsy (SUDEP)- a cohort controlled
comparative cross-matched study in an outpatient epilepsy
clinic Seizure 2004, 13, 523—528.
21. Beran RG. Informed consent, a legal requirement in the
management of patients with epilepsy. In: Beran RG, editor.
Epilepsy: duty of care. Tel Aviv: Yozmot; 2000.p.25—50.
22. Rajesh RamachandranNair, S. M. Jack, B. F. Meaney, G.
M. Ronen. SUDEP: What do parents want to know? Epilepsy
& Behavior 2013, 29:560-564.
23. Hirsch LJ, Donner EJ, So EL, Jacobs M, Nashef L,
Noebels JL, Buchhalter JR. (2011) Abbreviated report of the
NIH/NINDS workshop on sudden unexpected death in
epilepsy. Neurology 2011 May 31; 76(22): 1932-8,
http://www .ninds.nih.gov/news_and_events /proceedings
/SUDEP_workshop_nov2008.htm
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 Article received on March 10, 2017 and accepted for publishing on June 2, 2017.
VARIA

Pericardium – An editorial success

Teodor Horvat1

PERICARDIUM. Anatomy, physiology, department.

pathophysiology, pathology and surgery At the beginnings, we were just a few of us,
Lieutenant Colonel (Lt Col) Dr Vasile Cândea and
By Teodor Horvat and Daniel Fudulu
Lieutenant Dr Horvat. Later, Dr Richard Florescu, a
non-military doctor and my medical school colleague
Why did I write this book? I keep asking myself this
joined us. He immigrated later to Germany. After a
question... Why did I write it? Maybe because
few months Captain Dr Ion Țintoiu – cardiologist,
cardiovascular surgery was my first rotation during
my residency that I started after
graduating with a first honors degree
(gold medal), from the Faculty of
Medicine Bucharest in 1975.

My destiny in the winter of 1976, was to

be allocated to start my first rotation in
the newly formed Military Department of
Cardiovascular Surgery, Fundeni Clinical
Hospital, under the supervision of
Lieutenant Colonel (Lt Col) Dr Vasile
Cândea. Because this unit was not fully
functional, I started working under
Professor Ioan Pop D. Popa and then in
the Vascular Surgery Department where I
had the opportunity to meet a brilliant,
master surgeon – Professor Tiberiu
Ghițescu. Finally, I started Captain Dr Alexandru Popa – anesthetist, Major Dr
working in the Military Ioan Condor surgeon and Captain Dr Ioan Mociorniță
Department of Cardio- – surgeon joined us. Our senior scrub nurse was Mrs
vascular Surgery in August Rodica Poreceanu and she was an exceptional first
1976, 7 months after the assistant. I’ve rarely seen such manual dexterity that
1
Carol Davila University of completion of the official she had. So, I started as a second assistant while she
Medicine and Pharmacy, paperwork certifying the was the first assistant for Dr Cândea. I have learned a
Bucharest lot from her. She was unique. I have never met a
opening of this new

58
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

clone of her. doctors but more amongst civilians. They are only a
few cardiac surgeons within this specialty but they
Week by week our department grew and this
there is an intense rivalry and hate between them. If I
culminated with the first open heart operation – an
would put aside the parasites who used to copy their
atrial septal defect that was corrected in the February
personalities, you had what to learn from these
of 1977. The operation was a success. All of us were
remaining doctors – both surgery and medicine.
very cheery until the great disaster came – March the
4th, 1977 – The Great Earthquake. I have worked directly, as an intern, both at the
bedside and in the operating theatre with doctors
Both the old and new Fundeni Hospital buildings
outside the Military Departments such as: Professor
were affected; the old building was in a terrible state.
Pop D. Popa, Clinical Lecturer, Dr Dan Făgarăsanu
I remember our department being affected very
towards the end and with Dr Ilie Pavelescu who was
badly, the interior walls were full of cracks because
going to become later a professor in Timisoara. I also
this was located on level 2 where the flexion and
worked with Dr Martin Constantinescu, a great loss
extension of the walls happened. Not even level 3 –
for Romanian Surgery by his immigration, Dr Tiberiu
Professor Ghițescu’s Vascular Surgery Department
Ghițescu – the great master, Dr Traian Stefănescu, Dr
was spared from these cracks. Above level 4, there
Francisc Proinov – Fundeni Hospital Medical Director,
was less damage. The old building was beyond any
Dr Dan Mogoș, specialty doctor, later Professor of
description. No medical treatments and of course no
Surgery in Craiova, Dr Vasile Sârbu – specialty doctor
surgery could be performed there. All the
later Professor of Surgery and Dean of Constanța
departments were moved, in the end, into the new
Faculty of Medicine, Dr Radu Nemeș – specialty
building, the most robust out of all.
doctor, currently Professor of Surgery at Craiova, Dr
The Department of General Surgery led by Professor Șoimaru – specialty doctor, Dr Roth – specialty doctor
Dan Setlacec had to move too. Here, in the new who later immigrated to Germany and many others.
building, at floor level, in the building with three
I remember our top cardiologists: Dr Daniel
levels, I saw The Professor for the first time. He was
Constantinescu, Dr Tudorică Popa, Dr Ion Ținotoiu, Dr
going to supervise me later as general surgery
Sichitiu and our devoted anaesthetists: Dr Aurelia
resident. I’ve spotted Professor Dan Setlacec in a big
Bălan (“Tanti”), Dr Teodora Petrilă, Dr Radu
group of young surgeons. I could see only his head,
Făgarașanu and Dr Alexandru Popa – they have all
his short haircut and his bushy, unmissable eyebrows.
taught me a lot.
That’s what I could only see!
I was in close relationship with the Department of
After the rubble was scooped and some renovation
Haemotology led by Professor Ștefan Bereceanu. I
was undertaken, I went to see Lt Lieutenant Colonel
used to be very happy when my expertise was
(Lt Col) Cândea and I asked his permission to leave his
needed by: Dr Dan Coliță later Professor and Clinical
department. He asked the reasons for leaving. I’ve
Lead of the Haematology Department, by Dr Adriana
had to explain: “I started building the “surgical
Coliță – later clinical lecturer in Haematology, by
house” with the roof rather than the” foundation”. I
clinical lecturer Dr Elena Butoianu, the second in the
have started in the “super-specialty” of
department hierarchy. I was happy because they
Cardiovascular Surgery without having a basic surgical
were asking for my help, whom I was a beginner at
foundation. In other words, I have started without
that time, a non-initiated in the art of surgery. They
completing a general surgical rotation.
used to refer patients for lymph node biopsies and
So, I left. We ended up our collaboration in good this is how I became an operator, by doing lymph
terms, and we kept in touch until today. I learned a node, muscle and skin biopsies. Over the years, our
lot from surgeon Cândea, both about surgery but also work collaboration grew and this time they were no
about interpersonal relations. I have seen and heard longer referring lymph node biopsies but complex
a lot in these 14 months not only amongst military mediastinal tumors with haematological implication.

59
But let us get back to my career story. I left Fundeni
Hospital in March 1977, intern in surgery, and I
returned specialty doctor in general surgery, to build
up the foundations of my surgical house.
I have met Professor Dan Setlacec in November 1977.
In January 1978, the General Surgical Department
moved to the old building where I worked until the
spring of 1980 when I moved to the Central Military
Hospital, General and Thoracic Surgery Department II,
led by Professor General Dr Traian Oancea. I first
visited this department on Thursday, 9th of October
1969, when I was a first-year medical student, but I
will write this story in another book.
In Professor Setlacec’s department everyone was
focused on work, on performance. There was no
rivalry amongst the surgeons, it was a true school of
general surgery that was overseen by The Professor.
He was The Master, the conductor of the surgical
orchestra. He was producing “true” surgeons. Here, I
assisted daily in operations. Not one operation, but
two, three even four major operations. We had no
minor or simple procedures. I was the operator’s
“second hand “, the “first assistant” in English
language. I have learned a lot from the surgeons in
the old building. Here I started to build the
foundations of my surgical school. I believe that every
surgeon, regardless of the pursued specialty needs to
learn the basic surgical skills, the principles of surgery
in general surgery not in an “super-specialty“, like I
have started. Luckily, I have realized I made a mistake
and I repaired it. I like to believe I made the right
choice and that I have succeeded!
Because Professor Traian Oancea was also doing
general thoracic surgery not only general surgery I
was attracted by this specialty. Thoracic Surgery was
also performed by other two surgeons there: Colonel
Dr Therdor-Stefănescu Galați and Major Dr Gheroge
Voicu – later promoted to lieutenant colonel and
then colonel. Both of them were working in the
department of thoracic surgery located on the 5th
floor of the surgical building. I have never returned to
the field of cardiovascular surgery, however, I have
encountered and treated in my practice surgical
conditions at border between the thoracic and
cardiac surgery. I have always cultivated and
60
consolidated my relations with the cardiovascular
surgeons and anesthetists.
Now, let me return to my first question. Why did I
write this book? Well… because sometimes I feel
guilty and regret I have abandoned and never
returned to cardiovascular surgery – it is an argument
that we must consider. But, the most powerful
reason is because as a pure thoracic surgeon I often
used to cross the “pericardial border” during major
lung or mediastinal surgery but also when addressing
surgically diseases of the thoracic wall or the
diaphragm.
We also need to take into consideration the
malignant pericardial effusions that were associated
to pleural effusions (both conditions having a
common cause) that required concomitant surgical
treatment, under the same anesthesia. Not only the
associated pericardial effusions but also the isolated
pericardial effusion caused by a malignant a condition
are mainly treated within my specialty – thoracic
surgery.
In addition to the points mentioned above, it is
mandatory for a “complete” thoracic surgeon to be
familiarized with the pericardiotomy approaches, to
know how to approach the superior vena cave both
intra- or extra-pericardially; he has to know how to
dissect and isolate the major heart vessels in order to
safely repair the various vascular or cardiac injuries
but also to be able to control a cataclysmic surgical
bleeding; he needs to know how to harvest a
pericardial flap to reinforce the bronchial stump, to
reconstruct the tracheal wall but also to do a patch
repair of the major vessels – particularly patch
angioplasty of the pulmonary artery; they have to
know how to perform a pericardial window via
classical or minimally invasive approach; they have to
know how to perform pericardiocentesis to
decompress a cardiac tamponade and finally to
master the technique of pericardiectomy and
“geometric” pericardial cavity reconstruction.
I can confirm, without doubts, that a thoracic surgeon
approaches the pericardial cavity more often than a
cardiac surgeon approaches the pleural cavity.
From what I remember seeing in my early years of
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
surgical practice, there were thoracic surgeons that
never crossed the pericardium. In other words, they
used to declare tumors inoperable even if there was
slight involvement of the extrapericardial pulmonary
vessels. I have always asked myself asked myself why
they do not dare to cross the pericardium; the
explanation is in their early days of training. In
Romania, thoracic surgery, as stated by Professor
Alexandru Boțianu from Târgu Mureș, was born
because of Professor Dr Cărpinișan and a disease of
his time – tuberculosis. In such circumstances,
thoracic surgery was born with a ’’limp’’, without the
esophageal surgery but with the pericardial surgery
for the relief of pericardial constriction due to
tuberculosis. Unfortunately, after the founder of
thoracic surgery passed away, in Romania, the
interest in the pericardium had almost disappeared
amongst his descendants.
In the year of 1986, while I was working at Filaret
Hospital, under Prof Dr Constantin Coman, to
complete my general thoracic surgery fellowship (e.g.
after completion of my general surgery training), I
have never witnessed the pericardium being opened
to approach the intrapericardial pulmonary vessels.
I remember a day in 1987 when I was working in the
Central Military Hospital and I had to scrub to assist
Professor Traian Oancea to perform a left
pneumonectomy for a lung cancer. The tumor
appeared unresectable. Despite this, I persuaded my
ex-boss and Professor to open the pericardium. After
a moment of reflection, he turned to me and asked:
’’Have you ever been inside the pericardium?’’ I
responded without hesitation: ’Yes! I’ve been there
before!’’ He replied: ’’OK then, let’s open it!’’ It was
the first intrapericardial dissection of the pulmonary
vessels that I ever assisted and observed. The
operation was a success.
Anyone who had seen Professor Oancea operating,
remained deeply impressed, like me, of his delicate
surgical gestures, of his control of the situation and
his safeness and many others skills and attributes
that I do not have enough space here to enumerate.
The years have passed and the work volume in
thoracic surgery increased exponentially, with cases
that were more and more difficult to tackle.
However, I have never seen again a case being
declared inoperable based on extrapericardial
involvement. The majority of the pneumonectomies
were performed using an intrapericardial approach.
Pericardial resections for lung tumors invading the
pericardium had followed. In selected cases, we even
performed atrial, mediastinal, chest wall or
diaphragmatic resection associated with geometric
pericardial reconstructions.
We admitted more and more cases of malignant
pericardial effusions either isolated or associated to
unilateral or bilateral pleural effusions and even
peritoneal effusions.
In the Thoracic Surgery Department at the Central
Military Hospital, that I led for 15 years, we were the
first ones to perform nationally: pericardial-
peritoneal fenestration, the pericardial-pleural
window performed with the use of a endostapler
(right and left), VATS pericardoscopy (right and left)
and subxiphoid pericardoscopy.
I was unpleasantly surprised by a certain event, in
addition to many other disappointments or
harassments choreographed by the Central Military
Hospital management. The first assistant who helped
me perform the first subxiphoid pericardoscopy
followed by a VATS pericardial resection, published
this novel procedure under his own signature, in the
‘’Journal of Military Medicine’’ – the case operated by
me. I am going to say only this – I was helped by Dr
Cornel Savu and this is the end of the story, and it is
not worth expanding on this.
Certainly, all thoracic surgeons who trained in the
Thoracic Surgery Department at the Central Military
Hospital learned all the various pericardial
procedures that they use when needed. These
surgeons are the ones who either have not moved: Dr
Claudiu Nistor, Dr Adrian Ciuche, Dr Constantin
Grozavu, or the ones that work in other parts:
Professor Ioan Cordoș, Dr Codin Saon Dr Mihnea
Orghidan, Dr Radu Matache, Dr Cornel Savu from
Filaret Hospital, Professor Alexandru Nicodin from
Timișoara, Dr Cezar Pavelescu, Dr Laurentiu
Marinescu from Floreasca Emergency Hospital, Dr
61
Madalina Grigoroiu and Dr Codruț Stănescu at
Fundeni Hospital, Dr Constantin Mitrofan at Iași, Dr
Emanuel Palade who worked in Wagen, Germany,
then Freiburg and at present in Lubeck – Clinical Lead,
Dr Marius Paraschiv at Bagdasar-Arsene Hospital, Dr
Cristescu and Dr Brânză from Brașov, Dr Hugoi from
Oradea, Dr Demetrian and Dr Dobrinescu from
Craiova and others. All these thoracic surgeons will
teach the new comers to work on the land of thoracic
surgery. They will teach them about the pericardial
border, how to approach and go pass it without risks,
incidents or accidents.
Like them, I had to move to another hospital along
with Dr Cezar Motaș, Dr Mihnea Davidescu, Dr
Natalia Motaș, Dr Corina Bluoss, Dr Rus Ovidiu, Dr
Daniel Fudulu, Dr Andrei Bobocea. We arrived at the
Institute of Oncology, on the Fundeni platform. For
me it was like in the fairy tales, I have returned at old
age where I used to work when I was young but in
another building.
Here pericardial diseases are more frequently
referred than at the Military Hospital. All the surgical
pericardial conditions used to be referred to our
neighbors, across the fence, to the Cardiovascular
Department at Fundeni, before our arrival.
I cannot remember the day and the month, but I
remember the year of 2007 when I went to visit the
thoracic surgery theatres at the Military Hospital. The
younger surgeons were not allowed to discuss with
me or request my help for the various cases at that
time. This was imposed by the new clinical lead that
was supported by the management. So, I used to go
uninvited. I used to go like I used to do in the
previous years. During that day, Dr Cezar Motaş was
assisted by Dr Natalia Motaş – his wife. Dr Motaş told
me he was operating a malignant pericardial effusion
and that he approached the pericardium from the left
side of xiphisternum. I said: ‘’Well done!’’ and left.
After a few steps, I came back to him and told him:
‘’This was never done, take some pictures! It is an
original procedure’’ It was and it is indeed the ‘’left
paraxiphoid approach to the pericardial cavity’’. The
procedure was published in the ‘’Interactive Journal
of CardioVascular and Thoracic Surgery’’ in January
2010 under the heading: ‘’New Ideas in Oncology’’.
62
The idea was applied and published by a Romanian
thoracic surgeon – Dr Cezar Motaş who unfortunately
passed away too early in the year of 2013, month
October, the 30th.
Because we had a lot of clinical and operative
experience in pericardial surgery accumulating
throughout the years I thought this will be a very
good topic to study by a young medical student,
future doctor and future thoracic surgeon. Therefore,
more than 10 years ago, a young medical student
from Bucharest approached me and asked my
permission to observe a thoracic surgical procedure.
He proved to be a responsible and serious student
and later a thoracic surgery trainee and sponsored
PhD student. His name is Daniel Fudulu.
His graduation diploma thesis was based on the
surgical experience of the Thoracic Surgery Clinic II,
University of Medicine and Pharmacy ‘’Carol Davila’’
in the treatment of pericardial diseases. The above
academic surgical department functioned until 2009
at the Military Hospital and from October 2009 was
moved to the Institute of Oncology Bucharest.
The plan was for this subject to be further explored
and researched in the form of a PhD thesis for which
Dr Fudulu successfully obtained sponsorship of his
tuition fees. He had to abandon his PhD when he
immigrated to England in 2010.
This distance was not an obstacle or a reason to
abandon the writing of the monograph ‘’The
Pericardium – Anatomy, Physiology, Pathophysiology,
Pathology and Surgery’’. Therefore, we decided to
write this book. Some of the drawings are done by Dr
Fudulu while others are done by a young and
talented drawer – Eugen Tudorache. I want to thank
them both for the detailed and exceptionally clear
illustrations.
Together with Dr Fudulu I also published on CTSNet –
‘’Pericardial Reconstructions in Thoracic Surgery’’.
Thank you to Professor Mark Ferguson from Chicago
for accepting to publish our work and all his editing
work and advice. The article was published online on
December 2010.
In this chapter, I have told you the story of my career
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

path and the motivations behind writing this book.
This monograph is written from the point of view of a
senior thoracic surgeon and of a thoracic surgery
trainee – we have nothing against the cardiac
surgeons! On the contrary, it is our meeting point at
the border between the thoracic and cardiac surgery.
This book is written for anyone who has the desire to
read and learn regardless of their position. It is
intended for students, junior trainees, registrars,
consultants, academics and no academics.
I do hope it will prove useful!

63
 ADMINISTRATIVE ISSUES
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Romanian Journal of Military Medicine (RJMM) is the
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 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine

MANUSCRIPT CATEGORIES AND SPECIFICATIONS to the reader if the author responds to questions that
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(year); (vol): [this issue]. disorder of interest together with two figures of high
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RJMM welcomes reviews of important topics across the submission may take the form of a case report or may
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MANUSCRIPT PREPARATION
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Style
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words and up to 75 references and 3–7 figures or tables.
Spelling. The journal uses US spelling and authors should
Meta-Analyses or Systematic Reviews
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Webster’s Collegiate Dictionary.
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Education and Imaging
author's institutional affiliations at which the work was
The Editors welcome contributions to the Education and
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One to two key images will then be presented. It is helpful

65
industrial links and affiliations. In the case of clinical trials or
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66
example: (Chercheur X, unpublished data). If the owner of
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3. A statement outlining how ethical clearance has been
obtained for the research, particularly in relation to studies
involving human subjects, and animal experimentation. The
institutional ethics committees approving this research
 Vol. CXX • No. 2/2017 • August • Romanian Journal of Military Medicine
must comply with acceptable international standards (such
as the Declaration of Helsinki) and this must be stated.
4. For research involving pharmacological agents, devices or
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 Romanian Journal of Military Medicine
New Series, Vol. CXX, No 2/2017, August
ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126