no. 2/2017 military medicine - revistamedicinamilitara.ro · constantin merișanu (whose bust...

• 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

www.revistamedicinamilitara.ro

Founded 1897 • New Series

Vol. CXX • No. 2/2017 • August

REVISTA DE MEDICINĂ MILITARĂ

Military Medicine

Romanian Journal of

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.

Editorial Board of Romanian Journal of Military Medicine

Under the patronage Romanian Association of Military Physicians and Pharmacists Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Honorary Editor Victor Voicu MD, PhD

Editors-in-Chief Florentina Ioniță Radu MD, PhD, MBA Dan Mischianu MD, PhD

Executive Editors Daniel O. Costache MD, PhD, MBA Victor L. Purcărea PhD, MBA

Associate Editor Mariana Jinga MD, PhD, MBA

Redactors Doina Baltaru MD, PhD – Cluj Napoca Mihail Tudosie MD, PhD – Bucharest

Editorial Assistants Roxana Călin MD Cristina Solea

Technical Secretary Oana Ciobanu

Publisher 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 [email protected]

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

1

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

• 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

Mihail S. Tudosie, Bogdan Patrinich, Andreea R. Negrea, Cristina A. Secară

• New synthesized oximes active in nerve agents hazards

32

37

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

RRJJMMMM Romanian Journal of Military Medicine

2

ADMINISTRATIVE ISSUES Guidelines for authors

64


3

The story of a journal – The 120th anniversary of

the Romanian Journal of Military Medicine

Dan Mischianu

The Military Medicine Magazine, later became the

Romanian Journal of Military Medicine (RJMM)…

well, I assure you that it did not come out of thin air!

It appeared on September 15, 1897, 120 years ago,

on the initiative of military medical professionals.

I think few of us know that on January 12, 1897, Army

Corps General Professor Dr. Athanase Demosthen

was elected correspondent member of the Medical

Academy of Paris.

Those who celebrated him for success, mostly his

students and contemporaries, doctors, pharmacists

and veterinarians (military veterinarians, the cavalry

did not disappear – as a fighting weapon!) decided,

according to the French example, to create a

magazine with independent statute and organization,

and objectives that do not go beyond our present

understanding. Namely: "maintenance of scientific

activity and emulation among the members of the

sanitary body, establishment of the collegiality links

between the sanitary officers, as well as the

preservation of the scientific and moral prestige that

they should enjoy in the army and in society, the

culture of all scientific and technical knowledge

among the members of the military health body

related to the medical, pharmaceutical and veterinary

profession" (Revista Sanitară Militară, 1972, nr. 4-5,

pg. 411).

The "Steering Committee" met three months later, on

April 12, 1897, and

established that under the

leadership of General Prof.

Dr. Athanase Demosthen – as

chairman, a new magazine

called "Military Sanitary

Review” will be born with the

previously mentioned status.

The companions of General Demosthen for this

enterprise were the generals Dr. I. Şerbănescu, N.

Zorileanu, the army pharmacist M. Marinescu, first

class regiment physician I.M. Călinescu, second class

regiment physician Iacob Potârcă (a memorable name

in Romanian surgery – versus Whitehead

procedure!), pharmacists C. Dumitrescu-Parepa and

Constantin Merișanu (whose bust guards a hospital

alley).

The magazine appeared on 15 September 1897 and

the photocopy presented reproduces the first cover

of the Military Health Magazine (Revista Sanitară

Militară, 1972, nr. 4-5, pg. 409).

The "Military Health Magazine" wanted to be, from

the very beginning, "the depository of the work and

activity of the health officers in the realm of

veterinary and human medicine and military

pharmacy" (Oameni și Fapte din Istoria Medicinii

Militare Românești, Gral brig (r) dr. Mircea

Diaconescu, vol II, pg. 229).

The Military Health Magazine records a great

EDITORIAL

Gral (R) Prof DAN MISCHIANU

Chief of Urology Clinic, Carol Davila University Central

Emergency Military Hospital Faculty of General Medicine,

Carol Davila University of Medicine and Pharmacy,

Bucharest, Romania

4

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

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


5

appeared in 1919. In fact, the magazine really revived

in 1928, when things were settled, the country

seemed to have emerged from the crisis. It is Miron

Costin's word: "There are not the times under the

man, but the poor man under the times!"

In the review, there are reports of the "continuous

medical education" sessions – that is the sessions of

the Romanian Military Doctors' Association with the

subsequent subsidiaries from all the existing Military

Hospitals, homage numbers regarding the persona-

lities of the Romanian medicine who came from or

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).

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

typical Oltenian perseverance, "revives" the Military

Health Magazine in 1957.

In 1972, when the magazine was celebrated for

"three quarters of a century of existence in the

service of the protection of the health of our

soldiers", the technical box of Magazine Sanitary

Military Magazine no. 4-5/ 1972, which we reproduce

in the facsimile, mentions his name, along with the

name of another military doctor dear to my soul –

General Professor Iuliu Șuteu – editor-in-chief of the

magazine at that time.

I also want to remember another name dear to me –

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.

6

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.

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.

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

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.


7

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!


9

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

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

The international situation requires a strengthening

of the national security measures, including in the

field of CBRN defense (chemical, biological,

radiological and nuclear) and public health. The

upgraded microbiology laboratories from the Medical

Department of the Ministry of National Defense

(MD/MND) must be operated at full capacity, for the

operationalization of an

integrated Platform for the

scientific research and

expertise of biological war

and bioterrorism agents.

The project is necessary

for national security

purposes, for CBRN

defense and for the public

REVIEW ARTICLE

1 Military Medical Research Center, Bucharest

2 Titu Maiorescu University, Bucharest

10

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

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

11

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),

12

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

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


13

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]

14

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

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.

References:

1. *** Guidelines for the safe transport of infectious substances and diagnostic specimens, WHO/EMC/97.3

2. *** Ghid de biosiguranta pentru laboratoare medicale, Ministerul Sănătăţii, Editura Medicală, Bucureşti, 2006


15

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

16

Article received on February 12, 2017 and accepted for publishing on May 4, 2017.

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

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-

sition, regardless of the

field. Along with this added

dynamic appeal cases

handled by the abstract representations. In the field

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,

REVIEW ARTICLE

1 Wallachia University



17

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,

18

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.

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


19

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.

20

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, Pulmonology, Vascular Surgery, Thoracic and Cardiac

10 2 9

Dermatology & Venereology 3 4 5

Rheumatology 2 attended

Pathophysiology & Medical Biochemistry and Laboratory Diagnostics

9 4 5

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.


21

References:

1. European Journal of Higher Education - Florin D. Salajan a & Sorina Chiper B., Value and benefits of European student mobility for Romanian students: experiences and perspectives of participants in the ERASMUS Programme, Publisher: Routledge

2. PRIME 2010, Problems of Recognition in Making Erasmus, Eren Dicle, Julia Fellinger, Luyedan Huang, Igor Kalinic, Justina Pisera, Julia Trawinska, Edona Vinca

3. Revue Valaque D’ Etudes Economiques, Volume 6, no 3 - Ion Pârgaru, Iulia Alecu

4. The International Conference “Education and creativity for a knowledge based society’’– Economic Science, X edition, Iulia Alecu and Dragos Condrea, The Volunteer Management in a Knowledge Era. Valahian Journal of Economic Studies, Volume 5 (19, issue 1/2014) – Ion Pârgaru, Iulia Alecu şi Marian Neacşu, Academic Migration – Major factor in globalisation

5. Vademecum in Medical Career, Coordinator – Carmen Adella Sîrbu, ed. Universitara, chaper 6 th The oportunities of being student, Iulia Alecu

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}.

22

Article received on January 31, 2017 and accepted for publishing on May 16, 2017.

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

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

imbalance in the rate at

which bone is removed and replaced during the

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

REVIEW ARTICLE



23

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

24

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].

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


25

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.

26

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.

1999;9(suppl 2):S9–16.

4. Edwards MH, Jameson K, Denison H, et al. Clinical risk

factors, bone density and fall history in the prediction of

incident fracture among men and women. Bone. 2013;

52(2):541-7

5. Garnero P, Delmas PD. Contribution of bone mineral

density and bone turnover markers to the estimation of risk

of osteoporotic fracture in postmenopausal women. J

Musculoskelet Neuronal Interact. 2004;4(1):50-63

6. Anghelina AM, Cristescu CD, Cristescu V, Rusu E. Aspecte

morfologice si histologice ale tesutului osos. Rev. Rom. de

Reumatologie. 2013; vol XXII (2):74-78

7. Lane NE. Epidemiology, etiology, and diagnosis of

osteoporosis. Am J Obstet Gynecol. 2006;194(2 Suppl):S3-

11.

8. Ingenbleek Y, Kimura H. Nutritional essentiality of sulfur

in health and disease. Nutr Rev. 2013;71(7):413-32.

9. Stipanuk MH, Ueki I. Dealing with methionine/

homocysteine sulfur: cysteine metabolism to taurine and

inorganic sulfur. J Inherit Metab Dis. 2011; 34(1):17-32.

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.

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

turnover markers, broadband ultrasound attenuation, and

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

determinations: an expert opinion. Clin Chem. 2004;50:3–

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20. Refsum H, Nurk E, Smith AD,et al. The Hordaland

Homocysteine Study: a community-based study of

homocysteine, its determinants, and associations with

disease. J Nutr. 2006;136(6 Suppl):1731S-1740S

21. Gjesdal CG, Vollset SE, Ueland PM, et al. Plasma

homocysteine, folate, and vitamin B 12 and the risk of hip

fracture: the hordaland homocysteine study. J Bone Miner

Res. 2007; 22(5):747-56.


27

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

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

CHANNEL α2δ-LIGANDS

Alpha-2-delta subunits of voltage-gated calcium

channels (VGCC) have an important role in

modulation of the calcium currents and participate in

important cellular and inter-cellular phenomena like

muscular excitability, neurotransmission, re-gulation

of gene expression etc. As a consequence, drugs with

alpha-2-delta VGCC antagonist properties could

improve symptoms of fibromyalgia and neuropatic

pain, but they are also used for treatment of several

psychiatric disorders, the most extensive researched

being the field of anxiety disorders.

Pregabalin is a structural analog of the inhibitory

neurotransmiter γ-aminobutyric acid (GABA). This

drug reduces the synaptic release of several

neurotransmitters through binding to the alpha2-

delta type 1 protein and

demonstrated anticonvul-

sant, analgesic, and anxio-

lytic properties in precli-

nical models [1,2].

Pregabalin is rapidly ab-

sorbed after oral adminis-

tration, with a bioavaila-

bility value higher than

90%; peak plasma concen-

trations are reached after

1-1.5h, steady-state con-

centrations are achieved

within 24-48h after

repeated administration,

and if used with food there

is no clinically significant

SYSTEMATIC REVIEW

1 Carol Davila University Emergency Central Military Hospital, Bucharest

2 Carol Davila University of Medicine and Pharmacy, Bucharest

28

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),

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


29

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

30

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.

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.

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31

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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).

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Article received on January 28, 2017 and accepted for publishing on May 15, 2017.

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

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

between the two apparen-

tly incongruent areas of

knowledge.

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

ORIGINAL ARTICLES



33

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

34

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

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


35

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

36

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

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.

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

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.


37

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

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 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 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 venous thrombosis with an age-related factor. Conclusions: Improving preventive strategies and an optimally efficient utilization of these strategies for patients at risk of venous thrombosis can lead to improved clinical outcomes in practice and also to the post-thrombotic syndrome prevention. Taking into consideration the risk factors by age group and a better understanding of epidemiology and the risk factors for the first or recurrent venous thrombosis can lead to optimal use of prophylactic strategies and improved quality of life. DVT affects all age groups and the incidence associated with PTS is high, therefore the prevalence of PTS in general population is considerable.

ORIGINAL ARTICLES

1 Sanitary Post High School “Fundeni”-Bucharest


3 Toxicology Clinic, “Floreasca” Emergency Hospital, Bucharest

4 Surgery Clinic, “Sf. Pantelimon” Emergency Hospital, Bucharest

5 Carol Davila University Emergency Military Hospital, Bucharest

38

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

Deep vein thrombosis (DVT) is characterized by the

formation of blood clots (thrombi) in the deep veins

and usually affects the deep veins of the legs or the

deep veins of the pelvis [1]. Venous

thromboembolism (VTE) is manifested as deep

venous thrombosis (DVT) or pulmonary embolism

(PE) and occurs at an incidence of approximately 1

per 1,000 annually in adult populations [2].

About two-thirds of the episodes manifest

themselves as DVT and a third as PE, with or without

DVT. [3]. VTE is a very common medical problem that

occurs either in isolation or as a complication of other

diseases or procedures [4]. It is predominantly a

disease of older adults and has a slight

preponderance of males [1]. To prevent potentially

fatal acute complications of pulmonary embolism (PE)

and long-term complications of post-thrombotic

syndrome and pulmonary hypertension, an accurate

diagnosis of DVT is extremely important.

It is also important to avoid unjustified anticoagulant

therapy in patients diagnosed with high risk of

bleeding [5]. DVT prevention through prophylaxis,

recognition in due time and DVT treatment and

prevention of recurrent DVT will continue to have the

greatest impact on reducing the global burden of

post-thrombotic syndrome. Despite considerable

progress in the diagnosis and treatment of deep vein

thrombosis (DVT) of the lower extremities, one in

every 2-3 patients will develop post-thrombotic

sequelae within two years, which are severe in about

10% of cases and produce considerable socio-

economic consequences [6].

DVT affects all age groups and the incidence

associated with PTS is high, therefore the population

prevalence of PTS is considerable [7]. Thrombosis is

also associated with impaired quality of life,

especially when the post-thrombotic syndrome

develops [8.9].

MATERIALS AND METHOD

The study was retrospective (January 2013 -

December 2015) and the data were collected from

medical documents available in "Floreasca"

Emergency Hospital Bucharest, Romania. The method

used in this paper is the observational, non-

experimental, descriptive study. In the study group

there were included patients diagnosed with deep

vein thrombosis of the lower limbs, based on the

Doppler ultrasound, hospitalized in various wards of

the Emergency Hospital, such as, internal medicine,

orthopedics, cardiology and general surgery wards.

The Doppler ultrasound determined the presence of

chronic venous insufficiency, the type of venous

thrombosis - deep or superficial and its location -

proximal and distal.

The group of patients with deep vein thrombosis

(DVT) comprises 189 patients, of which 54 have

superficial vein thrombosis (SVT). According to their

age, we divided the patients into two groups: group A

(59 patients aged ≤50 years) and group B (130

patients aged> 50 years). For each patient we

collected general data (age, gender, origin), and

clinical and paraclinical data. The clinical data have

identified the presence of unilateral leg edema or the

entire leg edema and the presence of peripheral

trophic disorders (erythema, infiltration, skin

induration, cellulitis and venous ulcers).

From the anamnesis data we identified the presence

of comorbidities and risk factors, namely

immobilization before hospitalization, a history of

venous thromboembolism (VTE) and pulmonary

thromboembolism (PE), anticoagulation prior to

hospitalization, various medical conditions, a history


39

of surgical conditions (orthopedic, gynecological,

urological, abdominal), neoplasm and antineoplastic

treatment, cerebrovascular accident associated with

motor deficiency, congestive heart failure, renal

disease (renal lithiasis, nephrotic syndrome,

hydronephrosis, chronic kidney disease, enlarged

prostate), obesity, diabetes, hypertension, a history

of heart attack, fractures before admission, alcohol

consumption, smoking.

We used SPSS, version 15.0, to statistically analyze

the data. For some additions to the statistical analysis

we used the MedCalc program. Some of the graphics

were done with Excel 2007 and other graphics with

SPSS. The vast majority of the data were nominal

(Yes, No); for these we did the analysis using the Chi

square test. For the type of numeric data we did an

ANOVA analysis. An OR (Odds Ratio) risk assessment

was calculated for risk factors with the Mantel-

Haenszel test. We also used binary logistic regression.

The statistical differences and dependencies were

statistically significant for Sig <0.05.

RESULTS

The group of patients with deep vein thrombosis

(DVT) comprises 189 patients, of which 54 (28.6%)

have superficial vein thrombosis (SVT). We divided

patients into two groups: patients aged ≤50 years

(31.22%) and patients aged> 50 years (68.78%).

Applying ANOVA with a variable depending on age

and an independent variable belonging to one of the

two groups, we obtained as a result the average age

of the patients of the first group as 37.71 years old

with SD = 8,445, and for those of the second group as

68.50 with SD = 11,133. The difference between the

two means is statistically significant (Sig <0.001). In

the first group we have 23 (38.98%) women and 36

(61.02%) men and in the second 62 (47.69%) women

and 68 (52.31%) men.

In the first group we have 9 (15.25%) patients in rural

areas and 50 (84.75%) patients in urban areas, and in

the second we have 30 (23.08%) patients in rural

areas and 100 (76 92%) patients in urban areas.

Therefore, the prevalence of patients in urban areas

is very high, about 80%. By using Chi square analysis

and an OR estimation performed with SPSS and

MedCalc, we analyzed the relationship between

variables and there are 72 patients taking

anticoagulants before admission, namely 24 (40.68%)

in the first group and 48 (36, 92%) in the second

group. According to the test, there is no statistically

significant link (Sig = 0.622) between the presence in

one of the two groups and the existence of

anticoagulant prior to admission. The OR estimation

is not statistically significant because Sig = 0.622.

From the group of patients with deep vein

thrombosis the incidence of patients who had

prophylactic treatment with anticoagulants before

admission is 38.09% and among those the incidence

of the patients who had a history of VTE is 50%.

The incidence rates of a history of VTE, of PE at

admission and in the personal history for these 72

patients are presented in Table 1.

Table 1. The incidence rates of a history of VTE, of PE

at admission and in the personal history

Sex ≤ 50 > 50 Total

N % N % N %

History of VTE 12 50.0% 24 50.0% 36 50.0%

PE at admission 2 8.3% 1 2.1% 3 4.2%

History of PE 2 8.3% 2 4.2% 4 5.6%

From the group of patients with deep vein

thrombosis, the incidence of VTE in patients who had

a history of VTE (58 patients) is 30.68% and were

distributed as follows: 19 (32.2%) in the first group

and 39 (30.0%) in the second group. Among those

patients who had a history of VTE, 38.9% had a

history of VTE without Prophylactic anticoagulation

treatment and 61.1% had a history of VTE with

prophylactic anticoagulant treatment. The incidence

rate of PE at admission and in the personal history

among these 58 patients are presented in Table 2.

Table 2. The incidence rates of PE at admission and in

the personal history

History of VTE ≤ 50 > 50 Total

N % N % N %

PE at admission 2 10.5% 2 5.1% 4 6.9%

History of PE 3 15.8% 3 7.7% 6 10.3%

40

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.

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


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




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.


41

Table 3. Analysis of risk factors by age group.

Risk factors

≤ 50 years > 50 years Chi square analysis

Odds ratio No

N (%) Yes

N (%) No

N (%) Yes

N (%) Cont coef Sig OR Sig

Immobilization before admission/hospitalization

47 (79.66%) 12 (20.34%) 88 (67.69%) 54 (41.54%) 0.122 0.091 1.869 0.094

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 (calf)

11 (18.64%) 48 (81.36%) 9 (6.92%) 121 (93.08%) 0.174 0.015 3.081 0.019

Extensive proximal DVT localization

25 (42.37%) 34 (57.63%) 36 (27.69%) 94 (72.31%) 0.144 0.045 1.920 0.047

Patients with medical conditions

47 (79.66%) 12 (20.34%) 25 (19.23%) 105 (80.77%) 0.500 <0.001 16.450 <0.001

Patients with a history of surgical conditions

51 (86.44%) 8 (13.56%) 76 (58.46%) 54 (41.54%) 0.266 <0.001 4.530 <0.001

History of major gynecological surgical interventions

58 (98.31%) 1 (1.69%) 115 (88.46%) 15 (11.54%) 0.162 0.024 7.565 0.053

History of major urological surgical interventions

50 (84.75%) 0 (0.00%) 114 (87.69%) 16 (12.31%) 0.201 0.005 17.149 0.049

Hip or knee arthroplasty. Hip surgery

48 (81.36%) 11 (18.64%) 112 (86.15%) 18 (13.85%) 0.062 0.396 0.701 0.398

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 lithiasis)

55 (93.22%) 4 (6.78%) 109 (83.85%) 21 (16.15%) 0.127 0.078 2.649 0.087

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 motor deficiency)

59 (100.00%) 0 (0.00%) 121 (93.08%) 9 (6.92%) 0.149 0.038 9.305 0.127

o For Peripheral arterial disease, there is a





42

therefore it is statistically significant. Peripheral

artery disease is present only in the second group.

o For Type 2 diabetes, there is a statistically


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




therefore it is statistically significant. Alcohol

consumption is more present in the first group.

o For Extensive distal location (calf), there is a





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



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



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)


the presence of the analyzed risk factors. Cont. Coef.

= 0.266 is the strength of that link. OR = 4.530 and Sig

<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



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





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





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)


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.


43

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

44

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 disorders

0.221 0.522 0.180 1 0.672 1.247

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


45

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

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.

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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.


47

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

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

Strategic expert analyzes have shown that in the next

period, there may be international conflicts,

amplifying the risk of attempts to use highly toxic

chemicals as weapons of mass destruction.[1]

Romania through its geostrategic position, being the

member of NATO, can provide a better potential

target of such actions.

Neurotoxic organophospho-

rus compounds (sarin, so-

man, tabun, most insecti-

cides) are chemical com-

pounds, phosphonic acid

esters with central and

ORIGINAL ARTICLES


2 Military Medical Research Center, Bucharest

3 Intermedica Healthcare, Bucharest

48

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

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


49

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


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


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

50

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

Study group

Acetylcholinesterase reactivator

Dose of reactivators

(mg/kg)

Protective ratio

(DL50 )

Acetylcholinesterase reactivation due to oxime

(%)

2 - - -

4 1methyl-quinuclidine 3-on

iodide 78.58 1.5 47.82

8 1,3-dimethyl-2-

hidroxyethyl-imidazolyl

iodide

61.94 1.75 60.28

10 obidoxime chloride 100 2 73.33

12 3 oxim[3(2-

hidroxyiminomethyl-1-

imidazolyl)-2oxapropyl]

quinuclidine dichloride

118.88 2.5 82.31

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

Study group

The main value of erythrocyte

acetylcholinesterase (mmol/dl)

P (T test)

Observations

1 3.45 ± 0.13 0.003

P ≤ 0.05 statistically significant

difference between groups 2 0.86 ± 0.09

Legend: Study group 1: unpoisoned and untreated study group; Study group 2: paraoxon poisoned and untreated study group


51

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

Study group



P (T test)

Observations

10 2.53 ± 0.15 0.007



Legend: Study group 10: paraoxon poisoned and obidoxime treated study group; Study group 2: paraoxon poisoned and untreated study group.


poisoned, untreated and poisoned and 1,3-dimethyl-2-hidroxyethylimidazolyl iodide treated study groups

Study group



P (T test)

Observations

8 2.01 ± 0.07 0.004



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.


poisoned, untreated and poisoned and 1methyl-quinuclidine 3-on iodide study groups

Study group



P (T test)

Observations

4 1.65 ± 0.03 0.009



Legend:

Study group 4: paraoxon poisoned and iodide treated study group;

Study group 2: paraoxon poisoned and untreated study group


poisoned, untreated and 3-oxim[3(2-hidroxyiminomethyl-1- imidazolyl)-2oxapropyl] quinuclidine dichloride- quinuclidine 3-

on iodide treated study groups

Study group



P (T test)

Observations

12 2.84 ± 0.05 0.0002



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

52


poisoned, obidoxime treated and 3-oxim[3(2-hidroxyiminomethyl-1-imidazolyl)-2oxapropyl] quinuclidine dichloride-

quinuclidine 3-on iodide treated study groups

Study group



P (T test)

Observations

12 2.84 ± 0.05 0.01



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 group.

Reactivator dose used in the antidotal formula

(mg)

AChE Mmol/ml

Correlation coeficicient

4 61,94 1,65

0,9927 8 78,58 2,01

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

nerve poisoning that caused inhibition of acetyl-

cholinesterase survival limit was applied.

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.

Table 8 highlights the so-called "dose finding", the

correct correlation between dose and pharmaco-

dynamic effect. The correlation coefficient of 0.9927

demonstrates that doses of acetylcholinesterase

reactivators used in the antidotal formulas are

correct, being those that cause maximum

pharmacodynamic 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

• The very good correlation dose-effect highlights

that the correct dose of acetylcholinesterase

reactivator was chosen in order to obtain the better

pharmacodynamic effect.


53


2-oxapropyl] quinuclidindichloride can be considered

an efficient antidote in neuroparalytic organo-

phosphorous hazards.


2-oxapropyl] quinuclidindichloride can be a cheaper

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.

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

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 nerve agent poisoning by in vitro analysis. Toxicol Appl Pharmacol 219(2-3): 226-234.

12 Banerjee I., Tripathi S.K. and Roy A.S. (2012). Clinicoepidemiological characteristics of patients presenting with organophosphorus poisoning. North Am J Med Science., 4, 147-50.

54

Article received on February 12, 2017 and accepted for publishing on June 10, 2017.

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

Despite age, racial, social,

geographic or national

boundaries, epilepsy remain

a prevalent chronic neuro-

logical disorder.

The incidence of epilepsy

was estimated at 24-53 per

100,000 people.

World Health Organization

(WHO) estimates that

around 50 million people

worldwide have epilepsy,

80% from developing re-

gions. Epilepsy is character-

rized by recurrent seizures

due to excessive electrical

discharges in a group of

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

to 10% of people worldwide have one seizure during

their lifetimes. Epilepsy is defined by two or more

unprovoked seizures. Only one fourth of affected

people in developing countries get the treatment

they need and only 70% of these respond to

medication. Mortality is higher in patients with

epilepsy than in general population. People with

epilepsy and their families can suffer from stigma and

discrimination in many parts of the world. For

example in China and India, epilepsy is a reason for

prohibiting or annulling marriages.

In the United Kingdom, a law forbidding people with

epilepsy to marry was repealed only in 1970. In the

USA, until the same years, it was illegal that people

with seizures have access to restaurants, theatres,

CLINICAL PRACTICE

1 Carol Davila University Central Emergency Military Hospital, Bucharest

2 Bagdasar-Arseni Emergency Clinical Hospital, Bucharest

3 C.I. Parhon National Institute of Endocrinology Bucharest


5 Gr.T. Popa University of Medicine and Pharmacy, Iași

Corresponding author: Florentina C Pleșa,

[email protected]


55

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),

56

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.

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


57

managed individually and doctors are advised to

document the decision-making process. The patient

care is like a balance between what the career offers,

and what the patient accepts.

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,

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

58

Article received on March 10, 2017 and accepted for publishing on June 2, 2017.

Pericardium – An editorial success

Teodor Horvat1

PERICARDIUM. Anatomy, physiology,

pathophysiology, pathology and surgery

By Teodor Horvat and Daniel Fudulu

Why did I write this book? I keep asking myself this

question... Why did I write it? Maybe because

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

working in the Military

Department of Cardio-

vascular Surgery in August

1976, 7 months after the

completion of the official

paperwork certifying the

opening of this new

department.

At the beginnings, we were just a few of us,

Lieutenant Colonel (Lt Col) Dr Vasile Cândea and

Lieutenant Dr Horvat. Later, Dr Richard Florescu, a

non-military doctor and my medical school colleague

joined us. He immigrated later to Germany. After a

few months Captain Dr Ion Țintoiu – cardiologist,

Captain Dr Alexandru Popa – anesthetist, Major Dr

Ioan Condor surgeon and Captain Dr Ioan Mociorniță

– surgeon joined us. Our senior scrub nurse was Mrs

Rodica Poreceanu and she was an exceptional first

assistant. I’ve rarely seen such manual dexterity that

she had. So, I started as a second assistant while she

was the first assistant for Dr Cândea. I have learned a

lot from her. She was unique. I have never met a

VARIA



59

clone of her.

Week by week our department grew and this

culminated with the first open heart operation – an

atrial septal defect that was corrected in the February

of 1977. The operation was a success. All of us were

very cheery until the great disaster came – March the

4th, 1977 – The Great Earthquake.

Both the old and new Fundeni Hospital buildings

were affected; the old building was in a terrible state.

I remember our department being affected very

badly, the interior walls were full of cracks because

this was located on level 2 where the flexion and

extension of the walls happened. Not even level 3 –

Professor Ghițescu’s Vascular Surgery Department

was spared from these cracks. Above level 4, there

was less damage. The old building was beyond any

description. No medical treatments and of course no

surgery could be performed there. All the

departments were moved, in the end, into the new

building, the most robust out of all.

The Department of General Surgery led by Professor

Dan Setlacec had to move too. Here, in the new

building, at floor level, in the building with three

levels, I saw The Professor for the first time. He was

going to supervise me later as general surgery

resident. I’ve spotted Professor Dan Setlacec in a big

group of young surgeons. I could see only his head,

his short haircut and his bushy, unmissable eyebrows.

That’s what I could only see!

After the rubble was scooped and some renovation

was undertaken, I went to see Lt Lieutenant Colonel

(Lt Col) Cândea and I asked his permission to leave his

department. He asked the reasons for leaving. I’ve

had to explain: “I started building the “surgical

house” with the roof rather than the” foundation”. I

have started in the “super-specialty” of

Cardiovascular Surgery without having a basic surgical

foundation. In other words, I have started without

completing a general surgical rotation.

So, I left. We ended up our collaboration in good

terms, and we kept in touch until today. I learned a

lot from surgeon Cândea, both about surgery but also

about interpersonal relations. I have seen and heard

a lot in these 14 months not only amongst military

doctors but more amongst civilians. They are only a

few cardiac surgeons within this specialty but they

there is an intense rivalry and hate between them. If I

would put aside the parasites who used to copy their

personalities, you had what to learn from these

remaining doctors – both surgery and medicine.

I have worked directly, as an intern, both at the

bedside and in the operating theatre with doctors

outside the Military Departments such as: Professor

Pop D. Popa, Clinical Lecturer, Dr Dan Făgarăsanu

towards the end and with Dr Ilie Pavelescu who was

going to become later a professor in Timisoara. I also

worked with Dr Martin Constantinescu, a great loss

for Romanian Surgery by his immigration, Dr Tiberiu

Ghițescu – the great master, Dr Traian Stefănescu, Dr

Francisc Proinov – Fundeni Hospital Medical Director,

Dr Dan Mogoș, specialty doctor, later Professor of

Surgery in Craiova, Dr Vasile Sârbu – specialty doctor

later Professor of Surgery and Dean of Constanța

Faculty of Medicine, Dr Radu Nemeș – specialty

doctor, currently Professor of Surgery at Craiova, Dr

Șoimaru – specialty doctor, Dr Roth – specialty doctor

who later immigrated to Germany and many others.

I remember our top cardiologists: Dr Daniel

Constantinescu, Dr Tudorică Popa, Dr Ion Ținotoiu, Dr

Sichitiu and our devoted anaesthetists: Dr Aurelia

Bălan (“Tanti”), Dr Teodora Petrilă, Dr Radu

Făgarașanu and Dr Alexandru Popa – they have all

taught me a lot.

I was in close relationship with the Department of

Haemotology led by Professor Ștefan Bereceanu. I

used to be very happy when my expertise was

needed by: Dr Dan Coliță later Professor and Clinical

Lead of the Haematology Department, by Dr Adriana

Coliță – later clinical lecturer in Haematology, by

clinical lecturer Dr Elena Butoianu, the second in the

department hierarchy. I was happy because they

were asking for my help, whom I was a beginner at

that time, a non-initiated in the art of surgery. They

used to refer patients for lymph node biopsies and

this is how I became an operator, by doing lymph

node, muscle and skin biopsies. Over the years, our

work collaboration grew and this time they were no

longer referring lymph node biopsies but complex

mediastinal tumors with haematological implication.

60

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

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


61

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

62

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’’.

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


63

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!

64

Guidelines for authors

Thank you for your interest in Romanian Journal of Military Medicine. Please read the complete Author Guidelines carefully prior to submission, including the section on copyright. To ensure fast peer review and publication, manuscripts that do not adhere to the following instructions will be returned to the corresponding author for technical revision before undergoing peer review. Note that submission implies that the content has not been published or submitted for publication elsewhere except as a brief abstract in the proceedings of a scientific meeting or symposium. Once you have prepared your submission in accordance with the Guidelines, manuscripts should be submitted online at [email protected]. We look forward to your submission.

EDITORIAL AND CONTENT CONSIDERATIONS Aims and Scope Romanian Journal of Military Medicine (RJMM) is the official journal of the Romanian Association of Military Physicians and Pharmacists. The Journal publishes peer-reviewed original papers, reviews, meta-analyses and systematic reviews, and editorials concerned with clinical practice and research in the fields of medicine. Papers cover the medical, surgical, radiological, pathological, biochemical, physiological, ethical and historical aspects of the subject areas. Clinical trials are afforded expedited publication if deemed suitable. RJMM also deals with the basic sciences and experimental work, particularly that with a clear relevance to disease mechanisms and new therapies. Case reports and letters to the Editor will not be considered for publication. Editorial Review and Acceptance The acceptance criteria for all papers and reviews are based on the quality and originality of the research and its clinical and scientific significance to our readership. All manuscripts are peer reviewed under the direction of an Editor. The Editor reserves the right to refuse any material for review that does not conform to the submission guidelines detailed throughout this document, including ethical issues, completion of an Exclusive License Form and stipulations as to length.

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ADMINISTRATIVE ISSUES


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MANUSCRIPT CATEGORIES AND SPECIFICATIONS All articles, with the exception of Editorials, must contain an abstract of no more than 250 words. Abstracts for original articles should be formatted into subheadings, as detailed below. Titles must not be longer than 120 characters (including spaces). Editorials These are invited by the Editor-in-Chief or their delegated editor, and should be a brief review of the subject concerned, with reference to and commentary about one or more articles published in the same issue of RJMM. Editorials are generally 1200–1500 words, may contain one table or figure and cite up to 15 references, including the source article [this should be cited as Military Med. Today (year); (vol): [this issue]. Review Articles RJMM welcomes reviews of important topics across the scientific basis of medicine, and advances in clinical practice. Most published reviews are in response to editorial invitation, including thematically related “mini-series” of reviews. Authors considering submitting a review for RJMM are advised to canvas their possible review with the Editor-in-Chief or a colleague editor; this avoids early rejection if the subject matter is not deemed a high priority for the Journal at the time of submission. Reviews are limited to 3500–5000 words, with an abstract of up to 250 words and up to 75 references and 3–7 figures or tables. Meta-Analyses or Systematic Reviews RJMM particularly welcomes submission of Meta-Analyses and Systematic Reviews, which underpin evidence-based medicine. Guidelines for preparation of Meta-Analysis and Systematic Reviews are similar to other reviews, and articles are subject to the usual peer review process. Meta-Analyses and Systematic Reviews have a word limit of 3500–5000 words, with an abstract of up to 250 words and up to 75 references and 3–7 figures or tables. Original Articles (including clinical trials) RJMM welcomes original articles concerned with clinical practice and research in the fields of medicine. Papers can cover the medical, surgical, radiological, pathological, biochemical, physiological, ethical and/or historical aspects of the subject areas. Clinical trials are afforded expedited publication if deemed suitable. RJMM also deals with the basic sciences and experimental work, particularly that with a clear relevance to disease mechanisms and new therapies. Original articles are limited to 3000 words, with an abstract of up to 250 words and up to 50 references and 3–7 figures and tables. Education and Imaging The Editors welcome contributions to the Education and Imaging section. The purpose is to present imaging for the evaluation of unusual features of common conditions or diagnosis of unusual cases. Contributions will be reviewed by the Education and Imaging Coordinating Editors. The format of the Images pages involves two parts, each of which will occupy up to one journal page. In part 1, a case will be described briefly, including a summary of the presentation, clinical features and key laboratory results. One to two key images will then be presented. It is helpful

to the reader if the author responds to questions that follow from the images of the case, such as ‘What is your diagnosis? What are the features indicated on the CT scan? What is the differential diagnosis?’ Part 2 will briefly describe the imaging features, particularly those that lead to diagnosis or which are critical for management. Differential diagnosis should be mentioned. It will be useful to include either further images or pathological details that validate the imaging diagnosis. Occasionally, presentation of analogous cases or related images from a similar case might be appropriate. Please include between one and three references to definitive studies and appropriate reviews of the subject. The format of the Images page involves a brief background to and description of the disorder of interest together with two figures of high quality. Colored photographs are encouraged. The submission may take the form of a case report or may illustrate particular features from more than one patient.

MANUSCRIPT PREPARATION Style Manuscripts should follow the style of the Vancouver agreement detailed in the International Committee of Medical Journal Editors’ revised ‘Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication’, as presented at http://www.ICMJE.org/. Spelling. The journal uses US spelling and authors should therefore follow the latest edition of the Merriam-Webster’s Collegiate Dictionary. Units. All measurements must be given in SI units as outlined in the latest edition of Units, Symbols and Abbreviations: A Guide for Biological and Medical Editors and Authors (Royal Society of Medicine Press, London). Abbreviations should be used sparingly and only where they ease the reader’s task by reducing repetition of long technical terms. Initially use the word in full, followed by the abbreviation in parentheses. Thereafter use the abbreviation. Trade names should not be used. Drugs should be referred to by their generic names, rather than brand names. Parts of the Manuscript The manuscript should be submitted in separate files: title page; main text file; figures. Title page The title page should contain (i) a short informative title that contains the major key words. The title should not contain abbreviations; (ii) the full names of the authors (if possible, not more than 5 authors per title); (iii) the author's institutional affiliations at which the work was carried out; (iv) the full postal and email address, plus telephone number, of the author to whom correspondence about the manuscript should be sent; (v) disclosure statement; and (vi) acknowledgements. The present address of any author, if different from that where the work was carried out, should be supplied in a footnote. Disclosure statement The source of financial grants and other funding should be acknowledged, including a frank declaration of the authors’

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industrial links and affiliations. In the case of clinical trials or any article describing use of a commercial device, therapeutic substance or food must state whether there are any potential conflicts of interest for each of the authors: failure to make such a statement may jeopardize the article being sent out for peer-review. Acknowledgments The contribution of colleagues or institutions should also be acknowledged. Thanks to anonymous reviewers are not allowed. Main text As papers are double-blind peer reviewed the main text file should not include any information that might identify the authors. The main text of the manuscript should be presented in the following order: (i) abstract and key words, (ii) text, (iii) references, (iv) tables (each table complete with title and footnotes), (vii) figure legends. Figures and supporting information should be submitted as separate files. Footnotes to the text are not allowed and any such material should be incorporated into the text as parenthetical matter. Abstract and keywords Original articles must have a structured abstract that states in 250 words or less the purpose, basic procedures, main findings and principal conclusions of the study. Divide the abstract with the headings: Background and Aim, Methods, Results, Conclusions. The abstracts of reviews need not be structured. The abstract should not contain abbreviations or references. Three to five keywords should be supplied below the abstract and should be taken from those recommended by the US National Library of Medicine’s Medical Subject Headings (MeSH) browser—(http://www.nlm.nih.gov/ mesh/meshhome.html). Text Authors should use subheadings to divide the sections of their manuscript: Introduction, Methods, Results, Discussion Acknowledgments and References. References The Vancouver system of referencing should be used. In the text, references should be cited using superscript Arabic numerals in the order in which they appear. If cited only in tables or figure legends, number them according to the first identification of the table or figure in the text. In the reference list, the references should be numbered and listed in order of appearance in the text. Cite the names of all authors when there are six or less; when seven or more list the first three followed by et al. Names of journals should be abbreviated in the style used in MEDLINE. Reference to unpublished data and personal communications should appear in the text only. References should be listed in the following form: Number references in the order cited as Arabic numerals in parentheses on the line. Only literature that is published or in press (with the name of the publication known) may be numbered and listed; abstracts and letters to the editor may be cited, but they must be less than 3 years old and identified as such. Refer to only in the text, in parentheses, other material (manuscripts submitted, unpublished data, personal communications, and the like) as in the following

example: (Chercheur X, unpublished data). If the owner of the unpublished data or personal communication is not an author of the manuscript under review, a signed statement is required verifying the accuracy of the attributed information and agreement to its publication. Use Index Medicus as the style guide for references and other journal abbreviations. List all authors up to six, using six and "et al." when the number is greater than six. Tables Tables should be self-contained and complement, but not duplicate, information contained in the text. Number tables consecutively in the text in Arabic numerals. Type tables on a separate page with the legend above. Legends should be concise but comprehensive – the table, legend and footnotes must be understandable without reference to the text. Vertical lines should not be used to separate columns. Column headings should be brief, with units of measurement in parentheses; all abbreviations must be defined in footnotes. Footnote symbols: †, ‡, §, ¶ should be used (in that order) and *, **, *** should be reserved for P-values. Statistical measures such as SD or SEM should be identified in the headings. Figure legends Type figure legends on a separate page. Legends should be concise but comprehensive – the figure and its legend must be understandable without reference to the text. Include definitions of any symbols used and define/explain all abbreviations and units of measurement Indicate the stains used in histopathology. Identify statistical measures of variation, such as standard deviation and standard error of the mean. Figures All illustrations (line drawings and photographs) are classified as figures. Figures should be numbered using Arabic numerals, and cited in consecutive order in the text. Each figure should be supplied as a separate file, with the figure number incorporated in the file name. Preparation of Electronic Figures for Publication: Although low quality images are adequate for review purposes, publication requires high quality images to prevent the final product being blurred or fuzzy.

SUBMISSION REQUIREMENTS Manuscripts should be submitted online at [email protected] A cover letter containing an authorship statement should be included. The cover letter should include a statement covering each of the following areas: 1. Confirmation that all authors have contributed to and agreed on the content of the manuscript, and the respective roles of each author. 2. Confirmation that the manuscript has not been published previously, in any language, in whole or in part, and is not currently under consideration elsewhere. 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


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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 medical technology, a clear Conflict of Interest statement in relation to any funding from or pecuniary interests in companies that could be perceived as a potential conflict of interest in the outcome of the research. 5. For clinical trials, that these have been registered in a publically accessible database. If the above items are not included in the cover letter, manuscripts cannot be sent for review. Please also note that the cover letter does not require a detailed or lengthy description of the content or structure of the manuscript itself. Two Word-files need to be included upon submission: A title page file and a main text file that includes all parts of the text in the sequence indicated in the section 'Parts of the manuscript', including tables and figure legends but excluding figures which should be supplied separately. The main text file should be prepared using Microsoft Word, doubled-spaced. The top, bottom and side margins should be 30 mm. All pages should be numbered consecutively in the top right-hand corner, beginning with the first page of the main text file. Each figure should be supplied as a separate file, with the figure number incorporated in the file name. For submission, low-resolution figures saved as .jpg or .bmp files should be uploaded, for ease of transmission during the review process. Upon acceptance of the article, high-resolution figures (at least 300 d.p.i.) saved as .eps or .tif files will be required.

PUBLICATION PROCESS AFTER ACCEPTANCE Accepted papers will be passed to production team for publication. The author identified as the formal

corresponding author for the paper will receive an email, being asked to complete an electronic license agreement on behalf of all authors on the paper. Accepted Articles The accepted ‘in press’ manuscripts are published online very soon after acceptance, prior to copy-editing or typesetting. Accepted Articles are published online a few days after final acceptance, appear in PDF format only, are given a Digital Object Identifier (DOI), which allows them to be cited and tracked. After print publication, the DOI remains valid and can continue to be used to cite and access the article. Given that copyright licensing is a condition of publication, a completed copyright form is required before a manuscript can be processed as an Accepted Article. Proofs Once the paper has been typeset, the corresponding author will receive an e-mail alert containing instructions on how to provide proof corrections to the article. It is therefore essential that a working e-mail address is provided for the corresponding author. Proofs should be corrected carefully; the responsibility for detecting errors lies with the author. The proof should be checked, and approval to publish the article should be emailed to the Publisher by the date indicated; otherwise, it may be signed off on by the Editor or held over to the next issue. Offprint A PDF reprint of the article will be supplied free of charge to the corresponding author. Additional printed offprint may be ordered for a fee.

COPYRIGHT, LICENSING AND ONLINE OPEN Details are on the Copyright Agreement Form that must be completed and signed when the Article is accepted.

Romanian Journal of Military Medicine

New Series, Vol. CXX, No 2/2017, August

ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126

no. 2/2017 military medicine - revistamedicinamilitara.ro · constantin merișanu (whose bust...

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