Founded 1897 • New Series

Romanian Journal of
Vol. CXXI • No. 2/2018 • August

Military
Medicine
REVISTA DE MEDICINĂ MILITARĂ

• Brief notes about the Great War, Romanian military doctors and the Great Union
• Reactive nitrogen species and cardiovascular diseases
• Ethical limits between aesthetic and cosmetic dentistry
• History of medicine on the border between philosophy and science
• Therapeutic management of schizophrenia and substance use disorders dual diagnosis – clinical
vignettes
• Patient reported outcome measures and joint replacement
• Physical effort – an underused preventable method in colorectal cancer
• The communication and promotion policies of the medical organizations in the marketing of Romanian
healthcare services
• Medical applications of the GC/MS method in the acute intoxication with dimethoate – clinical case
• Rare case of Stevens-Johnson-TEN overlap syndrome caused by mycotoxins
• Uncommon giant sphenoidal tumor. Case report

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Editorial Board of Romanian Journal of Military Medicine
Under the patronage
Honorary Editor
Editors-in-Chief
Executive Editors
Associate Editor
Redactors
Editorial Assistants
Technical Secretary
Publisher
Romanian Association of Military Physicians and Pharmacists
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
Acad. Victor Voicu MD, PhD
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Dan Mischianu MD, PhD
Daniel O. Costache MD, PhD, MBA
Victor L. Purcărea PhD, MBA
Mariana Jinga MD, PhD, MBA
Raluca S. Costache MD, PhD, MBA – Bucharest
Mihail S. Tudosie MD, PhD – Bucharest
Ioana Oprea MD
Cristina Solea
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Carol Davila University of Medicine and Pharmacy Publishing House

International Editorial Board

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Romanian Journal of Military Medicine, New Series, vol. CXXI, No 2/2018, August
ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

RJMM
Romanian Journal of Military Medicine
Founded 1897 • New Series
Vol. CXXI • No. 2/2018 • August
Edited by the Romanian Association of Military Physicians and Pharmacists.

Contents
EDITORIAL
Dan Mischianu
 Brief notes about the Great War, Romanian military doctors and the Great Union 5
REVIEW ARTICLE
Gabriel Gorecki, Elena Rusu, Horaţiu Moldovan, Ioan S. Tudorache
 Reactive nitrogen species and cardiovascular diseases 11
Marina Melescanu Imre, Elena Preoteasa, Ana Maria C. Tancu, Cristina T. Preoteasa, Mihaela Pantea, Paula
Perlea
 Ethical limits between aesthetic and cosmetic dentistry 16
Mirela Radu
 History of medicine on the border between philosophy and science 21
ORIGINAL ARTICLES
Octavian Vasiliu
 Therapeutic management of schizophrenia and substance use disorders dual diagnosis –
clinical vignettes 26
Alexandra Șopu
 Patient reported outcome measures and joint replacement 35
Mihăiță Pătrășescu, Petruț Nuță, Raluca S. Costache, Săndica Bucurică, Bogdan Macadon, Vasile Balaban,
Andrada Popescu, Roxana Călin, Ioana Răduță, Daniel Pantile, Florentina Ioniță Radu, Mariana Jinga
 Physical effort – an underused preventable method in colorectal cancer 41
Bogdan I. Coculescu, Victor L. Purcărea, Elena C. Coculescu
 The communication and promotion policies of the medical organizations in the marketing of
Romanian healthcare services 46
CLINICAL PRACTICE
Genica Caragea, Mihail S. Tudosie, Radu A. Macovei, Ilenuţa L. Dănescu, Mihai Ionică
 Medical applications of the GC/MS method in the acute intoxication with dimethoate –
clinical case 50
Cristian Cobilinschi, Radu C. Țincu, Mihail S. Tudosie, Zoie Ghiorghiu, Radu A. Macovei
 Rare case of Stevens-Johnson-TEN overlap syndrome caused by mycotoxins 58

1
 R. Hainăroșie, Irina Ioniță, Cătălina Pietroșanu, S. Pițuru, Mura Hainăroșie, V. Zainea
 Uncommon giant sphenoidal tumor. Case report 64
ADMINISTRATIVE ISSUES
Guidelines for authors 68

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Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
EDITORIAL
Brief notes about the Great War, Romanian
military doctors and the Great Union
Dan Mischianu
Motto: “L’Histoire, c’est la rencontré d’une volonté et d’une
évènement” – Charles de Gaulle, 1890-1970
This short notice, largely iatrohistoric, appear in the
100th year since the Great Union out of the desire to
know more about what has happened.
In Romania, there was a lot of talk about the First
World War. The Germans remember this war under
the name of "der Erste Weltkrieg worde von 1914 bis
1918 in Europa, in Naken Osten, in Africa, Ostasien and
auf dez ozeanen gefurt". Obviously this first
conflagration was the army of "Zweiter Weltkrieg"!
The British preferred the denomination of the
"European War" or, more correctly, they named it "the
Great War".
It appears that this name is slowly but surely
penetrating our literature, following "World War I"
which, referring to the title of this editorial only makes
us Romanians remind that we have also had a Small
Union (1859), followed by the Great Union of 1918.
It must be remembered that the Romanian literature
between 1948-1989 wrote about the Great War in an
abbreviated manner, because of two reasons: the
Eastern neighbors had "turned history" – things did
not happen as planned and the contribution and
participation of the Romanian Royalty to the final
victory was extremely important but also very
embarrassing that it had to be silenced.
The Great War began in Sarajevo in 1914 and ended at
Versailles in 1949 in the Gral (R) Prof DAN MISCHIANU
Mirror Hall, with multiple Chief of Urology Clinic, Carol
European implications... Davila Central Emergency
Military Hospital
Then, at Versailles in the Faculty of General Medicine,
Grand Trianon Palace, a treaty Carol Davila University of
Medicine and Pharmacy,
was signed on June 4, 1920
Bucharest, Romania
between 16 allied states
(including Romania) and the successor state of the
Austro-Hungarian Empire. At the beginning of the war,
Romania, a "very small country", in the form of "L",
had 137,000 km2 and a population of 7.2 million
inhabitants, and after Trianon, it was reunited and
became „The Great Romania", with an area of 295,000
km2 and a nation of 18 million people. It is certainly
why, in the collective mentality of a neighboring
nation, that this situation is perceived as unacceptable
even after 100 years!
After the assassination of the crown Prince of Austria-
Hungary – Franz Ferdinand on June 28, 1914 the
actors, both big and small, began to enter the stage:
Central Powers – Germany, Austria-Hungary, Turkey,
Bulgaria and Antanta or the Triple Alliance, England,
Russia followed by Italy, Romania, USA...
The Kingdom of Romania had passed through a recent,
unforgettable experience for the army and especially
for the military doctors. In 1913, during the Second
Balkan War, the Romanian troops that had easily
entered the northern half of Bulgaria lost 1,600 lives
due to the cholera epidemic – a fearful "enemy".
5
Evidently, the accusations have risen, obviously
committees for dysfunctions research have been
named, obviously the responsible military doctors –
Constantin Papilian (1852-1917) and Senator G-ral (r)
Prof. Dr. Athanase Demosthen (1846-1925) informed
I.C. Bratianu – Prime Minister and Minister of War
about all this.

Certainly, the two years of neutrality have chosen

better and more efficient organizational lines, as
"stage sanitation, semi-hospital evacuation,
evacuation hospitals, auxiliary hospitals, and infirmary
station ".
Just after two years of "armed expectancy" war began,
for Romania as well as for other nations, how all wars
start "suddenly and unprepared!". We do not insist in
geostrategic and political-economic details. We
present only the result and brief considerations about
military doctors truly involved in the "Perpetual Drama
of War".
What Prof. Dr. Vasile Sârbu, a Templar Knight of
Romanian Surgery and Iatrohistory, presented with his
known erudition a few months ago, is perfectly true:
"In this war, 400 military doctors died out of 2,800
participants." 2,400 health workers have also died out
of 14,000 participants, as well as 14 pharmacists and
20 students of the Military Health Institute. These
numbers do not say much. If we compare them with
the other "weapons", we will be surprised to learn that
this group of people is on the 2nd place after the
infantry, which made King Ferdinand to offer them the
right to wear the "combatant weapon" badge.
He became Professor of Experimental Medicine at the
Faculty of Medicine in Bucharest at the age of 38 and
was appointed in 1908 as General Manager of the
Health Service to "Effectively fight epidemics, set up
isolation hospitals and pavilions, rural infirmaries and
bacteriological laboratories". In the Bulgarian
campaign he successfully ordered the vaccination in an
epidemic environment, called and known as "the great
Romanian experience."
He conducted the Civil Public Health and Military
Public Health Directorate during the Great War, a true
Ministry of Health, which allowed him to organize anti-
choleric vaccination and fight against exanthematic
typhus, typhoid fever and smallpox – having the rank
of Col. Dr. of the Romanian Army.

"This was the result!..."

Among the personalities, the first name to be quoted

with gratitude and piety is that of Prof. Dr. Ion
Cantacuzino – Jean Cantacuzen for the French,
descendant of Byzantine emperors, a medical school
creator, graduate of the French medical school, born
in 1863 in Bucharest, student of Ilia Mecinikov,
founder of the Romanian School of Immunology and
Experimental Pathology, doctor of medicine with a
thesis on the destruction of the vibrio cholera. The
subject of the thesis, supported in 1894, and its
findings will prove useful in almost 20 years, as in the
novels of Alexandre Dumas.
In 1920, together with Nicolae Titulescu and Mihai
Ciucă, his student, participated, as the Romanian state
delegate, at the Treaty of Trianon. He enjoyed a high
prestige, he had an important word to say, was even a
friend of French Prime Minister Georges Clemenceau,
a distinguished neurologist... On April 1, 1921, as a
result of his unrelenting thought, effort, and

6
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
determination, he founded the "Serum and Vaccine
Institute", by royal decree, which will then bear its
name.
O tempora, o mores!...
In 1911 the General Dr. Nicolae Vicol (1861-1936), as
Director of the Health Department of the Ministry of
War, organizes two preparatory sanitary maneuvers
around Bucharest that have proven to be beneficial in
the future. In August 1916, when he signed the troops
mobilization he followed the General Constantin
Prezan – the head of the General Headquarters,
unfortunately not having total decision-making power
and being obliged to listen to the Minister Constantin
Angelescu. Since February 1917, when the Public
Health Directorate was founded, led by the supreme
authority in the field – Colonel Prof Dr Ion Cantacuzino,
he starts a great collaboration with him.
The General Dr. Iacob Potarca (1866-1942), a graduate
of the Bucharest Faculty of Medicine, specialized in
general surgery in Paris, physician colonel in 1916,
head physician of the First Army’s Corp, general in
1917, then Sanitary Inspector of the First Army – who
fought in the Mărăști-Mărășești sector, was not only
an illustrious military physician in the war. In 1924 he
becomes General Inspector of the Army's Sanitary
Service, but it is worth mentioning that he is the first
Romanian surgeon to have operated the esophagus,
having other remarkable surgical researches quoted
by Professor Dan Setlacec in his formidable
monograph "Romanian Medicine, European medi-
cine".[3]
The drama on the battlefront at the end of 1917 – the
beginning of 1918, was almost at its peak. In absolute
anarchy a single thought seemed to be clear! The
thought of the Great Union!
In August 1917, at Mărășești, there were "many other
doctors from the old country, young, learned able-
bodied: Victor Papilian, Titu Vasiliu, Odiseu Apostol,
Grigore T. Popa, Constantin, Mihail Kerubach, and
many, many others”.[4]
The name Col (r) Prof. Iacob Iacobovici (1879-1959) is
worth mentioning from the beginning, not only for
being the founder of the Surgery School in Cluj, after
the Great Union and of the first Emergency Hospital in
Romania, the one in Bucharest, but also an involved
participant in the Bulgarian campaign and the
commander of the 7th Evacuation Hospital of the
Second Army in Bacau in 1917.
Professor Iuliu Moldovan (1882-1966) attended the
Faculty of Medicine in Vienna and Prague, and then,
what a few know (4), he worked as a military doctor at
the Department of Dermatovenerology and at the
7
Central Laboratory of Bacteriology of the Austro-
Hungarian Army.
In July 1914 he was mobilized and appointed the head
hygienist of one of the Austro-Hungarian armies,
effectively engaging in the eradication of some
epidemics. On the 1st of December 1918 he took part
in the works of the Great National Assembly in Alba-
Iulia. Between 1919 and 1920, he became the
professor of the Department of Hygiene and Social
Hygiene of the Faculty of Medicine in Cluj, general
secretary of the Social Protection Resort of the
Transylvanian Conducting Council and he also
organized the Transylvanian Medical Service.
I think it is worth mentioning the contribution of other
illustrious physicians to the Great Union just to
contradict Albert Camus, who said with cynicism:
"Forgetting is the first faculty of man!"
Iuliu Hatieganu (1885-1959) the first professor of a
8
Medical Clinic, dean of the new Faculty of Medicine in
Cluj, "Magnificus rector", precursor, visionary, called
the "Hippocrates of the Romanians", was also a
participant in the Great National Assembly in Alba-
Iulia.
The last, but not the last, because the number of the
unknown is overwhelmingly large, is Dr. Alexandru
Vaida Voievod (1872-1950).
He was a graduate of the Faculty of Medicine in
Vienna, doctor of medicine, who established in
Carlsbad where he trained as an intern and
balneologist, later attracted to the political activity,
debuted in the Chamber of Budapest and the one who
has read, on the 18th of October 1918 in the Hungarian
Chamber, the Declaration of Self-Determination of the
Romanian People from Transylvania. He was a
member of the ministry cabinet of Ion I.C. Brătianu, he
also joined the Peace Conference delegation in Paris
and formed and led the first Government of the United
Romania.
When Romania was finally united, things seemed to be
on an upward trend.
The Romanian military doctors, as well as the civilian
physicians, great personalities or unknown remarkable
people, have fulfilled their duty.
Regarding "The Map of Great Romania in 1924" we
have only one comment: the year 1924 was the year
in which, in Germany, the ideology of Nazism has
started to blossom.[5]
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
Our history, of the Romanian people, has implied over
the years a steady climb with a lot of difficulties. The
Great Union was accomplished in stages, all springing
up from the ideal of unity of our nation, never
forgotten.
References
1. Stoica Leontin – Serviciul Sanitar al Armatei Romane în
perioada 1918-1919, Teză de doctorat, Academia de Ştiinţe
a Moldovei, Institutul de Istorie şi Drept, Chişinău 2012
2. Sârbu Vasile - Participarea medicilor la Războiul de
Întregire a Neamului şi la Marea Unire din 1918
3. Setlacec Dan – Medicina românească, medicină
The unification of the Romanian states is the nation's
greatest act, which configures and fully certifies our
existence among other nations of the world.
europeană (1918-1940), Ed. Humanitas 1995
4. Florea Marin – Medicii şi Marea Unire, Ed. Tipomur, 1993,
pg. 30
5. Peter Ross Range – 1924, anul care l-a creat pe Hittler, Ed.
Litera, Bucureşti, 2018
9
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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

Article received on March 21, 2018 and accepted for publishing on June 18, 2018.
REVIEW ARTICLE

Reactive nitrogen species and cardiovascular diseases

Gabriel Gorecki1, Elena Rusu1, Horaţiu Moldovan1,2, Ioan S. Tudorache1

Abstract: Oxidative stress plays a major part in the development of chronic and degenerative diseases
such as cancer, arthritis, aging, autoimmune disorders, cardiovascular and neurodegenerative
diseases. Cardiovascular disease is the leading cause of death in the United States and Europe and is
poised to become the most significant health problem worldwide. Reactive nitrogen species are
involved in the regulation of cardiovascular motor tone, modulation of myocardial contractility, control
of cell proliferation and inhibition of platelet activation, aggregation, and adhesion. Cellular
constituents of our body are altered in oxidative stress conditions, resulting in various disease states.
The oxidative stress can be effectively neutralized by enhancing cellular defenses in the form of
antioxidants. To understand the mechanism of action of antioxidants, it is necessary to understand the
generation of free radicals and their damaging reactions.
Keywords: Oxidative stress, ROS, antioxidants, CVD

INTRODUCTION capable of independent existence that contains one or

more unpaired electrons”.
Normal biochemical reactions, increased exposure to
This unpaired electron(s)
the environment, and higher levels of dietary xeno-
usually gives a considerable
biotics result in the generation of reactive oxygen
degree of reactivity to the free
species (ROS) and reactive nitrogen species (RNS). ROS
radical.
and RNS are responsible for the oxidative stress in
different pathophysiological conditions. An imbalance between oxi-
dants and antioxidants in
Cellular constituents of our body are altered in
favor of the oxidants, poten-
oxidative stress conditions, resulting in various disease
tially leading to damage, has
states.
been defined “oxidative
Oxidative stress plays a major part in the development stress”.
of chronic and degenerative diseases such as cancer,
It soon appeared that nitric
arthritis, aging, autoimmune disorders, cardiovascular
oxide (NO) plays a key role in
and neurodegenerative diseases [1].
the physiological regulation of
1
Free radicals are defined as “any chemical species the cardiovascular system, Faculty of Medicine, Titu
Maiorescu University,
since abnormalities in its Bucharest, Romania
Corresponding author: Assoc. Prof. Elena Rusu PhD productions and/or bioavaila- 2Sanador Hospital,
elenarusu98@yahoo.com bility accompany or even Bucharest, Romania

11
precede diseases such as hypertension, athero-
sclerosis and angiogenesis-associated disorders.
Cardiovascular disease (CVD) is the leading cause of
death in the United States and Europe and is poised to
become the most significant health problem
worldwide.
Free radicals are generated from either endogenous or
exogenous sources. Endogenous free radicals are
generated from immune cell activation, inflammation,
mental stress, excessive exercise, ischemia, infection,
cancer and aging. Exogenous free radicals result from
air and water pollution, cigarette smoking, alcohol,
heavy metals, certain drugs (cyclosporine, tacrolimus),
industrial solvents, cooking and radiation.
ROS and RNS products can bring about reversible or
irreversible chemical changes (oxidation, nitrosylation
and nitrosation) in proteins, lipids, and DNA, resulting
in diminished biochemical functions [2]. The greater
the amounts of ROS and RNS, the more extensive the
chemical changes in these targets. ROS and RNS can
induce adducts to DNA, leading to DNA fragmentation
[3].
Reactive nitrogen species (RNS) are free radicals which
are associated with the nitrogen atom: nitric oxide
(NO), nitrogen dioxide (NO2) and peroxy-nitrite
(ONOO-). Reactive species are produced by regulate
enzyme such as nitric oxide synthase (NOS), and
isoforms of NADPH oxidase, or as by-products from
not so well regulated sources, such as mithocondrial
electron-transport chain.
Nitric oxide is a biatomic free radical containing an
unpaired electron. Until now have been described
three forms of NO, nitrosonium cation (NO+), nitric
oxide (NO.), and nitroxyl anion (NO-) with nitrogen
oxidation number +3, +2, and +1, respectively. NO can
react with oxygen free radical to form peroxynitrate
(ONOO-). This last molecule is involved in protein
oxidation reaction under physiological conditions.
CARDIOVASCULAR DISEASES
Cardiovascular diseases are prevalent in human
population and most of them are related to diet but
genetic lipid abnormalities such as hypercholeste-
rolemia, hypertriglyceridemia, HDL metabolism
12
disorders, and combined hyperlipidemias are more
severe. Cardiovascular disease is one of the major
causes of mortality and morbidity worldwide and the
costs that involve handling this disorder are huge. The
2008 overall rate of death attributable to
cardiovascular disease was 244.8 per 100 000
individuals and this rate is critically growing [4]. Recent
evidence demonstrates that cardiovascular disorders
are usually associated with increased level of stress
hormones [5, 6].
Cardiovascular risks such as defects in angiogenesis/
vasculogenesis or vessel repair are major
complications of coronary artery disease (CAD) which
are mostly seen in aged people. Similarly, CVD risks
have also increased in women during pregnancy which
is an important issue for management of their
cardiovascular health [7]. Conventional risk factors
such as cigarette smoking, diabetes, hyperlipidemia,
and hypertension are absent in 15-20% of patients
with CVD. Atherosclerosis is the main cause of death
in the world through causing ischemic heart disease. It
is peripheral arterial disease, most prevalent, morbid,
and mortal disease. It is one of the most common
disorders among the elderly, because of depression
prevailed in the old age and rates of very high
atherosclerosis. Atherosclerosis is characterized by
endothelial dysfunction, vascular inflammation, and
the buildup of lipids, cholesterol, calcium, and cellular
debris within the intimae of the walls of large and
medium size arteries.
Abnormal proliferation of vascular smooth muscle is
implicated in various pathological situations including
atherosclerotic lesions, restenosis after balloon
angioplasty, and vascular wall thickening in
hypertension. NOS may play protective role by
inhibiting proliferation of vascular smooth muscle cell
[8]. For example, leiomyosarcoma, which is an
aggressive mesenchymal tumor with differentiation
toward smooth muscle tissue, represents up to 9% of
all primary malignant tumors. Some cases of
leiomyosarcoma presumed to be infective
endocarditis [9].
THE CHEMISTRY OF RNS
Nitric oxide (NO.) is a small molecule generated in
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
biological tissues by specific nitric oxide synthase
(NOS) which metabolizes arginine and citrulline with
the formation of NO. via a five electron oxidative
reaction [10]. Nitric oxide synthase utilize L-arginine as
the substrate, and molecular oxygen and reduced
nicotinamide-adenine-dinucleotide phosphate –
NADPH as co-substrat.
NO is involved in the regulation of cardiovascular
motor tone, modulation of myocardial contractility,
control of cell proliferation and inhibition of platelet
activation, aggregation, and adhesion [11].
Hypertension is also associated with NO synthesis [12].
The enzyme nitric oxide synthase produce reactive
nitrogen species (RNS), such as nitric oxide (NO˙) from
arginine.
L-Arg + O2+ NADPH → NO. + citruline
An inducible nitric oxide synthase (iNOS) is capable of
continuously producing large amount of NO˙, which
act as a O2˙−quencher. The NO˙ and O2˙− react together
to produce peroxynitrite (ONOO−), a very strong
oxidant, hence, each can modulate the effects of
other. Although neither NO˙ nor O2˙− is a strong
oxidant, peroxynitrite is a potent and versatile oxidant
that can attack a wide range of biological targets.
Peroxynitrites can interact with several cellular
components and are implicated in NO signaling
mechanisms involving protein modifications.
NO˙+ O2˙− → ONOO−
In aqueous aerobic solutions NO predominantly forms
nitrite (NO2-). In the presence of oxyhemoglobin and
oxymioglobin, NO is completely oxidized to nitrate
(NO3-). Covalent interactions of NOS with cellular
macromolecules are responsible for its many
physiological and pathological effects. Protein
containing iron and thiol groups are the major cellular
target of NOS [13].
There are three types of NOS, neuronal nitric oxide
synthase (nNOS), endothelial nitric oxide synthase
(eNOS which plays a very important role in the
vascular homeostasis) and inducible nitric oxide
synthase (iNOS; it is found in myocytes, macrophages
and ECs and is activated by immunological and
inflammatory stimuli). Under septic conditions iNOS
and nNOS are upregulated in endothelial and muscle
cells, respectively, leading to over-production of NO in
the microvasculature and arteriolar dysfunction.
Neuronal NOS is constitutively expressed in specific
neurons of the brain and its enzymatic activity is
regulated by Ca+2 and calmodulin. This NOS isoform
has been identified also in the spinal cord, in the
sympathetic nerves, in epithelial cells of various
organs, in pancreatic islet cells, in the vascular smooth
muscle and in the skeletal muscle [14, 15].
Endothelial NOS is mostly expressed in endothelial
cells; Ca2+-activated calmodulin is important for the
regulation of eNOS activity because Ca 2+ induces the
binding of calmodulin to the enzyme. Endothelial NOS
appears to be a homeostatic regulator of numerous
essential cardiovascular functions and also controls
the expression of genes involved in
atherogenesis. The blood vessel wall NO is mainly
produced from l-arginine by endothelial NOS.
Nitric oxide as a key endothelial vasodilator also
directly affects metabolism by competing with
mithocondria for oxygen and consequently inhibiting
switching the metabolism to some other pathways.
Also, some studies suggested that NO is implied in the
response of Candida albicans species to the oxidative
stress and also against some azoles drugs. Candida
albicans is a commensal species of the human
gastrointestinal tract, in which it lives without adverse
effects on the host, but yeast-to-hypha transition has
been associated with increased virulence, mucosal
invasiveness and biofilm formation. Candidemia and
invasive candidiasis are frequently associated with
high morbidity and high mortality rates [16].
ANTIOXIDANTS AND DEFENSE MECHANISMS
Overproduction of ROS (arising either from
mitochondrial electron-transport chain or excessive
stimulation of NADPH) results in oxidative stress, a
deleterious process that can be an important mediator
of damage to cell structures, including lipids and
membranes, proteins, and DNA. In contrast, beneficial
effects of ROS/RNS (e.g. superoxide radical and nitric
oxide) occur at low/moderate concentrations and
involve physiological roles in cellular responses to
13
noxia, as for example in defense against infectious
agents, in the function of a number of cellular signaling
pathways, and the induction of a mitogenic response
[2]. Cellular constituents of our body are altered in
oxidative stress conditions, resulting in various disease
states. The oxidative stress can be effectively
neutralized by enhancing cellular defenses in the form
of antioxidants. Low levels of antioxidants have been
associated with the heart disease and cancer.
When ROS/RNS are generated in vivo, their actions are
opposed by intricate and coordinated antioxidant lines
of defense systems. These include enzymatic and non-
enzymatic antioxidants that keep in check ROS/RNS
level and repair oxidative cellular damage. The
antioxidant enzymes reduce the levels of lipid
hydroperoxide and H2O2, thus they are important in
the prevention of lipid peroxidation and maintaining
the structure and function of cell membranes.
The major enzymes, constituting the first line of
defense, directly involved in the neutralization of
ROS/RNS are: superoxide dismutase (SOD), catalase
(CAT) and glutathione peroxidase (GPx). SOD is a
cytoplasmic and mitochondrial enzyme, which
accelerate the dismutation of superoxide. They are
present in almost all aerobic cells and in the
extracellular fluids. They contain metal ions that can
be copper, zinc, manganese or iron. In humans, the
copper/zinc superoxide dismutase is present in the
cytosol, while manganese superoxide dismutase is
present in the mitochondria. CAT, an exclusively
peroxisomal enzyme in most tissues, converts H2O2 to
water and O2. However, the most important H2O2-
removing enzymes are the selenoprotein GPx
enzymes. GPx enzymes remove H 2O2 by using it to
oxidize reduced glutathione (GSH) to oxidized
glutathione (GSSG). Glutathione reductase, a
flavoprotein enzyme, regenerates GSH from GSSG,
with NADPH as a source of reducing power.
Glutathione peroxidase also catalyses the reduction of
unstable hydroperoxides at the expense of GSH [17].
The nonenzymatic antioxidants are of two types, the
References:
1. Kabel AM. Free radicals and antioxidants: role of enzymes
14
natural antioxidants and the synthetic antioxidants.
Vitamin C, vitamin A and plant phytochemicals like
phenolics that inhibit the oxidation chain initiation and
prevent chain propagation represented the second
line of defense. Vitamin A has a vital antioxidant
contribution in protecting human LDL against copper
stimulated oxidation. Lipid-soluble antioxidants such
as α-tocopherol localize mainly to membranes and
lipoproteins where they serve to limit lipid
peroxidative damage. Vitamins E and C have been
demonstrated to reduce the progression of
atherosclerosis. Vitamin E (α-tocopherol) is the most
important lipid-soluble antioxidant and protects cell
membranes against oxidation by reacting with the
lipid radicals produced in the lipid peroxidation chain
reaction and removing the free radical intermediates.
Phenolics are therefore an integral part of the diet,
with significant amounts being reported in vegetables,
fruits, teas and traditional plants. Epidemiological
evidence indicates that consumption of fruit,
vegetables and teas may reduce the risk of
cardiovascular disease and it is increasingly suggested
that this may due to their antioxidants that include ß-
carotene, vitamin C, vitamin E and polyphenolics.
Dietary antioxidant phenolics may quench reactive
oxygen and nitrogen species and, hence potentially
modify pathogenic mechanisms relevant to
cardiovascular disease [18]. Vitamin C regenerates
vitamin E in cell membranes in combination with
glutathione or compounds capable of donating
reducing equivalents.
Low levels of antioxidants have been associated with
the heart disease and cancer. Antioxidants provide
protection against a number of disease processes such
as aging, allergies, algesia, arthritis, asthma,
atherosclerosis, autoimmune diseases, broncho-
pulmonary dyspepsia, and cancer. The other disorders
to which antioxidants provide protection are cataract,
cerebral ischemia, diabetes mellitus, eczema,
gastrointestinal inflammatory diseases, and genetic
disorders.
and nutrition. World J. Nutrit. Health, 2014, 2 (3):35-38.
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2. Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M et al.
Free radicals and antioxidants in normal physiological
functions and human disease. Int J Biochem Cell Biol, 2007,
39 (1): 44-84.
3. Martin LJ. DNA damage and repair: relevance to
mechanisms of neurodegeneration. J Neuropathol Exp
Neurol. 2008; 67:377–387.
4. Roger V.L., Go A.S., Lloyd-Jones D.M., et al., AHA statistical
- update heart disease and stroke statistics. Update
Circulation, 2012; 125, e2-e220
5. Vogelzangs N., Beekman A.T.F., Milaneschi Y., et al.
Urinary cortisol and six-year risk of all-cause and
cardiovascular mortality, J. Clin. Endocrinol. Metabol. 2010,
95(11):4959-64
6. Manenskijn L., Van Kruysbergen R.G.M., De Jong F.H., et
al., Shift work at young age is associated with elevated long-
term cortisol levels and body mass index, J.Clin.
Endocrinol.Metabol, 2011, 96(11):E1862-5
7. J. W. Rich-Edwards, A. Fraser, D. A. Lawlor, and J. M. Catov,
“Pregnancy characteristics and women's future
cardiovascular health: an underused opportunity to improve
women's health?” Epidemiologic Reviews, 2014, 36,1: 57–70
8. Loscalzo J, Vita AJ. Nitric oxide and the cardiovascular
system. Spinger Science & Business Media, 2000.
9. Jurcut R, Savu O, Popescu BA, Florian A, Herlea V,
Moldovan H, Ginghina C. Primary cardiac leiomyosarcoma.
When valvular disease becomes a vascular surgical
emergency. Circulation, 2010, 121(21):e415-e418
10. Kurutas EB. The importance of antioxidants which play
role n cellular response against oxidative nitrosative stress:
current state. Nutrition J. 2015, 15:71, doi.10.1186/s12937-
016-1086-5
11. Napoli C., Paolisso G, Casamassimi A, Al-Omran M,
Barbieri M, Sommese L, Infante T, Ignarro LJ. Effects of nitric
oxide on cell proliferation: novel insights. J Am Coll Cardiol.
2013 Jul 9;62(2):89-95.
12. Misra MK., Sarwat M., Bhakuni P., Tuteja R., Tuteja N.
Oxidative stress and ischemic myocardial syndromes. Med.
Sci. Monit. 2009, 15(10): RA209-219
13. Ignarro Louis J. Nitric oxide: Biology and Pathobiology,
Academis Press, 2000.
14. Forestermann U., Closs EI., Pollock JS., Nakane M.,
Schwarz P., Gath I., Kleinert H. Nitric oxide synthase
isoenzyme, Characterization, purification, molecular cloning,
and functions. Hypertension, 1994, 23:1121-1131
15. Forestermann U., Sessa WC. Nitric oxide synthase:
regulation and function. Eur Heart J., 2012, 33(7):829-837
16. Rusu E, Sarbu I, Pelinescu D, Nedelcu I, Vassu T,
Cristescu C, et all. Influence of associating nonsteroidal anti-
inflammatory drugs with antifungal compounds on viability
of some Candida strains. Rev. Rom. de Boli Infectioase ISSN
1454-3389, 2014, vol. XVII nr.2:86-90
17. Bahorun T., Soobrattee MA., Luximon-Ramma V.,
Arouma OI. Free radicals and antioxidants in cardiovascular
health and disease. Internet J Med Update, 2006, 1(2):25-41
18. Shahidi F, Wanasundara PKJPD. Phenolic antioxidants.
Crit. Rev. Food. Sci. Nutr. 1992;32:67-103.
15
 Article received on February 09, 2018 and accepted for publishing on May 28, 2018.
REVIEW ARTICLE

Ethical limits between aesthetic and cosmetic dentistry

Marina Melescanu Imre1, Elena Preoteasa1, Ana Maria C. Tancu1, Cristina T. Preoteasa1, Mihaela Pantea1,
Paula Perlea1

Abstract: Esthetics is the “new trend” in dental medicine as a natural consequence of the development
of modern society, with implications in practice and training. Like any rule in art, but also within the
medical field, esthetics must be known and addressed in relation to other medical or non-medical
principles (dental cosmetic), respect the ethics rules.
Aim. Literature study designed to focus on the current problems that modern dentistry is facing, in
relation to esthetic requirements. The literature search strategy in electronic databases: EBSCO Data
Base, Dentistry & Oral Sciences Source, Pub Med indexed articles, used Boolean Operators.
As a conclusion, the dentist must be familiar with the differences between esthetic and dental cosmetic,
must minimize the subjective component of the examination, identify the reasons of presentation,
guide the patient in choosing the optimal treatment, including obtaining the desired esthetic results,
within the ethical boundaries of the noble medical profession.
Keywords: ethics, esthetics, cosmetic dentistry

INTRODUCTION As professionals we are flooded with an information

Nowadays, more and more
frequently, within dental,
practical or training activi-
ties, we are dealing with
matters related to esthe-
tics. Patients often require
esthetic restorations with-
out being able to specify
most of the time, what
exactly they would like.
Students show an increa-
sing interest in esthetic
dentistry aspects.
1 Faculty
of Dental
Medicine, University of
Medicine and Pharmacy
Carol Davila, Bucharest
influx both through scientific publications and dental
materials producers, with a dental esthetics value.
After the implant, esthetics is the “new trend” in
dental medicine as a natural consequence of the
development of modern society.
Esthetic concerns existed since forever, from the first
protagonist of scientific esthetics Pythagoras, who
defined the “golden ratio”, combined with dynamic
symmetry discovered in 1920 by Jay Hambridge and Sir
D’Arcy Thompson who explained how natural beauty
can be quantified and how it can be reproduced in art,
architecture and other crafts.
For dentistry, as terminology, in the Glossary of
Corresponding author: Ana Maria C. Tancu MD, PhD
amctancu@yahoo.com

16
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
Prosthodontic terms, esthetic dentistry is defined as
the part which studies beauty, creating harmonious
results through prostheses, and ethics is a moral
principle or a set of moral values of an individual or
group of individuals, in our case – the ones involved in
the treatment (doctors, technicians). Cosmetic
dentistry is not a term indexed by GPT, its definition
being present in the Collins dictionary, like maneuvers
aimed to beautify without purpose or functional form.
The medical profession has ethical obligations [1]
centered to prevent and treat diseases, in order to
rehabilitate the dento-masticatory apparatus
functionality, namely mastication, phonation, and the
patient's physiognomy.
Questions related to dental esthetics are: What are the
ethical boundaries of the esthetic trends in dentistry?
Can anything be done from a medical standpoint for
the sake of obtaining an esthetic outcome? Are we
ready for this new challenge as physicians who took
the Hippocratic Oath for the “primum non nocere”
principle? Are we trained as trainers, academics, in
order to educate students so that they become true
professionals in esthetic dentistry? What are the limits
of esthetic dentistry and dental cosmetic, as a new
term in our vocabulary?
These are some of the questions that have led us to
write this paper. This study is a literature one designed
to focus the current problems that modern dentistry is
facing in relation to esthetic requirements. The
original aspect of this work is related to the definition
(both for patient and doctor) of these two terms, their
character being a little bit confusing, also being
capable to lead to legal aspects, even malpractice.
MATERIAL AND METHOD
A comprehensive literature study was completed in
October 2015. There were selected publications in
English, peer reviews, articles from academic
publications, dated January 2000 to December 2015.
There was obtained a total of 1248 articles, including
full text criteria, of which 580 articles were retained,
and after applying the selection criteria only 14
publications remained. Identified as directions of
interest were: (a) dental esthetics as part of dentistry
– boundaries; (b) the difference between esthetic and
dental cosmetic, from an ethical point of view; (c)
esthetics, the reason for treatment and clinical
examination; (d) medical training, scientific publica-
tions, patient information, consent. The search
strategy was conducted using EBSCO Data Base
Dentistry & Oral Sciences Source with the aid of
Boolean Operators. The following keywords were
combined: ethics, esthetic, and cosmetic dentistry.
The search was limited to English peer reviewed
articles, full text and years limitation January 2000 -
October 2015 academic journals.
RESULTS
There was obtained a total of 1248 articles, including
full text criteria, of which 580 articles were retained,
matching the search criteria requested. After applying
the search criteria 10 publications became relevant.
Furthermore, there was done a manually electronic
search on themed websites. In the end, 14
publications that included the search criteria were
selected.
Among the issues raised by the retained
publications, there were identified 4 axes of interest:
1. Dental esthetics as part of dentistry – boundaries. 

2. Difference between esthetics and dental cosmetic
from the ethics point of 
view. 

3. Esthetics, as a reason for treatment and clinical
examination. 

4. Training the physicians, scientific publications,
informing the patient – consent.
DISCUSSION
Dental Esthetics as Part of Dentistry – Boundaries
At this point two issues detach themselves –
functionality and bias. As noted in the introduction,
there is a definition of dental esthetics in the GPT,
however this is rather vague, making reference to
“beauty, following the art’s rules and principles''. In
dentistry, the therapeutic dental restorations are not
only esthetic, but they should primarily ensure the
dento-masticatory apparatus and the dental occlusion
functionality. For example, dental fillings can be done
medically with physiognomic or non-physiognomic
materials, both having advantages and disadvantages,
17
the dominant criteria for the physician must be based
on clinical experience, choosing the optimal method of
treatment in order to meet the basic medical principle,
“primum non nocere”. [2]
The medical profession bases its treatment on clinical,
objectively examination of the patient. When
regarding the esthetics dental problems, subjectivity
might occur; hence, the need to establish clear criteria,
both objective and subjective, for the examination in
dental esthetics. Indeed esthetic sense is not a
criterion for graduation from the Faculty of Dentistry;
it has a great variability from person to person, from
clinician to clinician, as well as from patient to
clinician. Given these difficulties related to the
subjective issues, it was suggested a hierarchy of the
esthetic aspects in dentistry, starting from basic
esthetic rules where the smile’s coordinates comply to
the classical principles of the golden ratio, symmetry,
dental and dento-facial proportions, smooth line
smiling.
The next level is represented by the cultural and
regional subjective aspects, for example in the United
States the so-called Hollywood smile is a social
standard, the whiteness and perfect alignment of
teeth being associated with wealth, social and
financial success. At last, the latest level is the so-
called virtual level – the one that a computer program
sets as ideal for the patient, from the esthetic point of
view. [3]
Is dental esthetics a part of the patient’s general
health state? Yes, it was clinically proven that the
esthetic restoration brings an important psychological
benefit to the patient. [3]
Difference between Esthetics and Dental Cosmetic
from the Ethics Point of View
Within the last years, appearing the dental cosmetic
term, that was medically not registered otherwise,
there have been many misunderstandings between
this term and the esthetic dentistry, both among
patients and practitioners.
Traditionally, dental medicine as a medical specialty is
centered, ethically speaking, on the prophylaxis and
the treatment of the dental tissues in order to ensure
18
a good health state, respecting, of course, the dento-
masticatory functions. So, we are talking about
affected tissues, or with such potential. [4]
Dental cosmetic seeks only embellishment, often
without any consideration for functionality, interfering
with healthy tissues, without clinical impairment for
beautifying intentions. Often, these maneuvers
contradict even the esthetics concept – defined as
being an integration concept of beauty in natural
proportions, with a humane dimension. Is it
esthetically the completely unnatural pure white smile
of an 80 years old lady? Is it not against the
physiological processes of aging teeth, with natural
tooth staining due to time passage? Therefore, the
difference between cosmetic and esthetic dentistry
must be properly ethically and medically
differentiated [5,6]. Moreover, some cosmetic
maneuvers might damage a healthy dental tissue – for
example when applying veneers, esthetic crowns,
excessive grinding, applying adhesive – without pulp
protection – can lead to tooth loss – defined as
disfigurement, from the ethical point of view. [3]
One must respect, from the ethical point of view, the
principle of minimally invasion; the so-called enamel
sacrifice on the altar of vanity [7, 8, 9] does not
correspond to the principles of medical ethics. On
long-term, the biological implications of the
maneuvers consequences that were performed only
for cosmetic purposes should be correctly assessed by
practitioners. [10] Esthetic would mean beauty, form
and function – and cosmetic only beauty. [2]
Esthetics, as a reason for treatment and clinical
examination
As shown, although the boundary between esthetic
and cosmetic maneuvers may seem “too fine”
sometimes, the practitioner disposes of objective
criteria when deciding the treatment plan. [11]
Patients who address the dentist for solving the
esthetic problems divide into two categories – among
these reasons are dental crowding, discoloration,
unsightly tooth discoloration, missing teeth, multiple
teeth with coronal restorations. The patients’ reasons
may be esthetic ones, but after a properly conducted
clinical examination, the dentist will establish the
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
functional problems – occlusion problems, migration
and others that, from an objective medical point of
view, should be rehabilitated in order to restore the
morpho – functional, esthetic, masticatory and
phonetic balance. The dentist will decide the patient's
treatment plan, single or multidisciplinary
orthodontics (teeth alignment through braces),
conservative treatment (bleaching, esthetic
restorations, and ceramic veneers), and dental
prosthetic (crowns coverage, dental implants). A
second category refers to patients without enough
arguments – patients suffering from narcissism,
personality disorder, patients who can’t accept their
age. As in the first group, the dentist is the one that
will make a “proper diagnose” considering the medical
history and clinical examination.
Patients with such presentation reasons will
permanently be unsatisfied with the treatment
outcome. Unlike the ones with consistent esthetical
grounds that will be satisfied once the esthetic
problem is solved, for the second class the result will
not be acceptable even if it has improved the esthetic
aspect. [2] These are the most common candidates for
dental cosmetic, for whom the “primum non nocere”
principle must be respected from the ethical
viewpoint. [10]
And not least, after the clinical examination, if the
dentist is in a doubtful situation, he should, according
to "when in doubt, it is probably not ethical" [7] test
himself with "The Daughter Test" – Would I proceed
with this intervention on my daughter? [8,12]
Training the physicians, scientific publications,
informing the patient – consent
Another important aspect is the dentists training, in
addition to the fundamental principles of dental
esthetics already learned in college; the profession
currently faces numerous specialty publications in
which the so-called academic articles are praising
esthetic results obtained – the ethical aspect of the
presented cases being often questionable from the
fairness of the dimension’s vertical occlusion point of
view, occlusion stability and durability of these
restorations. Publishing some insufficiently and
superficially documented cases – medically speaking,
designed only to beautify, can be really dangerous,
especially for young doctors who didn’t benefit from
enough clinical experience and being pressured by
patients in order to obtain esthetic results, can guide
their therapeutic conduct, based on good faith. [10]
In the modern age, consumer society pushes dentists
to features, such as advertising, with the temptation
for many dentists to promise spectacular results with
a negative impact on the professionalism of the entire
profession [6], we must not forget the fundamental
nature of our medical profession profile, namely the
professional doctor [13] and not the beautifying one.
In this context it is important, ethically speaking, the
doctor-patient communication regarding the dental
esthetic issues – the doctor is required in this type of
treatment to inform the patient in order to receive his
consent over long-term implications (especially in
younger patients). Communication must be made in
terms that the patient will be able to understand (not
necessarily medical terms), assisted by pictures,
drawings, suggestive dental casts. It is also required to
present to the patient, where appropriate, one or
more treatment alternatives, including the less
esthetic alternative, before signing the informed
consent [3]. Esthetic dentistry requires less
accommodation, incorporates acceptable biologic
technology for long-term survival, functions suitably,
and mimics the pristine state of the natural dentition.
Cosmetic and esthetic dentistry are different in
definition, concept, and execution [14].
CONCLUSIONS
As a result of this extensive literature study on a very
actual dentistry issue – ethical considerations of
esthetics and dental cosmetic, we came up with some
interesting conclusions intended to clarify the often
encountered confusion regarding these terms. Dental
Esthetics regroups several dental maneuvers, often
interdisciplinary, aiming the morfo-functional rehabi-
litation of the dento-masticatory apparatus, following
universal esthetic principles harmoniously integrated
into the overall health and harmony of the human
body as part of dentistry. Dental cosmetic is a set of
maneuvers that, although have a medical character,
do not seek the reconstruction of the maxillary device
19
functionality, just have a beautifying character,
intervening on healthy tissues without any
prophylactic role, often with disabling long-term
implications. In terms of bioethics, the “primum non
nocere” principle is not respected within these
maneuvers.
Therefore, it is important for the dentist to know the
differences, the fundamental dental esthetic concepts,
in order to minimize the subjective component of the
examination, to succeed the clinical examination with
identification of the presentations reasons, to be
trained for all medium- and long-term treatment
References:
1. Astarastoae V., Triff B.A., Essentialia in Bioetica, Cantes
Publishing, Iasi, 1998 
 8. Hancocks S., The Ethics of Cosmetics, British Dental
2. Ahmad I., Risk management in clinical practice. Part 5.
Ethical considerations for dental enhancement procedures,
British Dental Journal, 209:207-214, 2010 
 & Restorative Dentistry-Journal Compilation Blackwell
3.Liebler M., Devigus A., Randall R.C., Trevor Burke F.J.,
Pallesen U., Cerutti A., Putignano A., Clauchie D., Kanzler R.,
Koskinen P., Skjerven H., Strand G.V., Vermaas R.W.A, Ehics
of Esthetic Dentistry, Quintessence International, 35:456-
465, 2004
4. Williams J., FDI Dental Ethics Manual, ISBN 0-953 9261-5-
X, 2007
5. Glick K., Cosmetic Dentistry is Still Dentistry, Journal
Canadian Dental Association, 66:88-91, 2000
6. Hussey D.L., Where is the Ethics in Aesthetic Dentistry,
British Dental Journal, 192-6 Conference, 2002
7. Faith K.E., The Ethics of Cosmetic Dentistry: Beneficence,
20
implications, in order to be able to present to his
patient all treatment alternatives and guide him to
choose the optimal treatment option for obtaining the
desired esthetic results within the ethical boundaries
of this noble profession. The theme being new and the
boundary between esthetics and cosmetic dentistry
being quite subjective, no doubt that they still have to
be studied, there are needed further studies and
research that will clarify the differences between them
on an evidence-based scientific system.
Acknowledgements
All authors had equal contribution in this paper elaboration.
Beauty or “Bucks’’?, Oral Health Group.com, 10/01/2010 

Journal, 211-11 Editorial, 2011 

9. Jackson R.D., Judging Ethics Ethically, Journal of Esthetic
Munksgaard, 19:181-182, 2007
10. Kelleher M., Ethical Issues, Dilemmas and Controversies
in “Cosmetic” or Aesthetic Dentistry. A Personal Opinion,
British Dental Journal, 212:365-367, 2012 

11. Owsiany D.J, The Intersection of Dental Ethics and Law,
Journal of the American college of Dentists, 75:47-54, 2008
12. Kelleher M., “The Daughter Test” in Esthetic or Cosmetic
Dentistry, Dental Update, Jan/Feb 2010 

13. Poonam et al, Ethics in Medicine and Dentistry: A Review,
Indian Journal of Dental Sciences, 5:152-154, 2013
14. Touyz LZ1, Raviv E, Harel-Raviv M. Cosmetic or esthetic
dentistry? Quintessence Int. Apr;30(4):227-33,1999.
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

Article received on January 31, 2018 and accepted for publishing on May 16, 2018.
REVIEW ARTICLE

History of medicine on the border between philosophy and

science

Mirela Radu 1

Abstract: Physicians have represented a long time the main transmitters of knowledge as they were
real scholars. If Renaissance promoted the study of the human body anatomy and physiology, the next
step made by practitioners of medicine was to spread the enlightenment. That meant the shift of the
very purpose of their profession: from passive opposition to ailments towards an active involvement
into the lives of the impoverished. In order to change the odds in the battle against diseases, physicians
had the great burden to enlarge the cultural horizons of those whose health was in their hands.
Therefore, one way of imparting knowledge was by publishing and spreading their attainments to the
general public in a comprehensible way. Once people gained awareness of the dangers entailed by bad
hygiene, the physicians’ role in society switched towards more cultural realms. At the beginning of the
20th century health care professionals achieved the next step in the becoming of medicine: setting up a
new science to link humanities with pure science. In Romania, the main promoters of this new border
science were Victor Gomoiu and Valeriu Bologa and they co-opted other intellectuals.
Keywords: philosophy, science, history of medicine, alchemy, folklore

The new involves acknowledging the past, gathering various ethno-

transforming it and bypassing mistakes. The 20th graphic materials and
century met the expectations of those who wanted to photos from all corners of
know this history by setting up the Institute of History our country.
of Medicine in 1921 in Cluj. “More and more are those
The Romanian physician
who pretend to have a spiritual imitation in the past to
Valeriu Bologa (1892-1971)
save the intellectual character of modern medicine.
is the exponent of a whole
This postulate translates practically into the
caste: that of doctors
multiplication of medical-historical literature and
aware of the modeling
giving a growing importance to the history of
power of culture. He
medicine.”[1] One of the first teachers to honor the
dedicated himself to the
Romanian institute was the French Jules Guiart (1870-
study of natural sciences
1965) who taught for three years this subject. Those
(at the University of Jena)
who strongly supported him were Valeriu Bologa and
and, afterwards, he was
Emil Racoviţă. Guiart, fascinated by what he had
attracted to the medical 1Faculty of Medicine,
discovered on the Romanian realm, would also work
studies in Austria and Cluj. Titu Maiorescu
as an ethnographer, travelling intensively and University, Bucharest
The pride he felt for the art

21
of healing practiced by the Romanians led him to lay
the foundations of a new branch of science: the history
of medicine. Between 1949-1971 he presided the
International Society of Medicine History. Feeling that
the progress can only be heard through the knowledge
of the past, Bologa devoted many books to the facts of
the medicine in the past. One of the first important
papers signed by the Romanian physician focused on
the special situation of the Hippocratic profession
practiced by the Transylvanian Romanian doctors who
had to face not only the lack of material means but
also the political repression: Contributions to the
history of medicine in Transylvania (1927). Three years
later, Bologa signed a second monograph, The
Beginnings of Romanian Scientific Medicine for which
he would receive in 1931 the V. Adamachi Prize of the
Romanian Academy. But until 1927, the physician
signed only a studies with great historical significance,
dedicated to some of the most diverse themes – from
midwifery, to the forerunners of doctors, from
ophthalmology to medical lexicology formation:
Spells, old women and midwives today and the past
(1921); New data for Ioan Molnar (1925); About
Romanian Occultists (1925); Medicine in Moldavia
(1925); Between physiology and medicine (1925);
Romanian Medical Terminology of doctor I. Molnar
(1926).
Furthermore, Bologa dedicates himself to the
construction and endowment of a museum dedicated
to medical science in Romania. The Romanian scholar
was particularly fond of two sections of the museum:
Old Romanian Medicine and Medicine in the
Transylvanian past. The great importance he gave to
the knowledge of the old times of the profession he
revered could be felt from the appreciation with which
he emphasizes the importance of those early times,
but also the respect he had for his ancestors. For the
reader of any age is visible the attachment and esteem
that doctor Bologa carries to those who have done
medical pioneering work, especially in the
Transylvanian region: “From this rich Romanian
medical library can be reconstituted the hard work of
the first gatherers of new roads in Romanian science.
It is possible to see the influences from the outside, it
can be seen how gradually a Romanian medical
terminology was formed, it can be noticed how, from
22
the great Davila, our medicine goes from the
assimilation phase to the one of creation, as more and
more characteristically forms a Romanian medical
current. The old Transylvanian medical literature was
represented equally well at the beginning – from the
16th century – by the works of the German doctors,
later with those of the Hungarians, finally from the
18th century and with the first Romanian medical
translations.”[2]
But Bologa was not the only one who fought for this
new branch of medicine. He was helped in his efforts
by the fellow surgeon Victor Gomoiu (1882-1960) who
founded museums dedicated to the history of
medicine in Târgu-Jiu and Craiova. Gomoiu, in turn,
published a monograph entitled From the History of
Medicine and Romanian Medical Education (1923) and
during the interwar period he was elected president of
the International Society of Medicine History (1936).
Gomoiu was also the one who signed the first History
of the Medical Press in Romania (1936), the work of
collecting and organizing numerous medical papers
and writings. But Gomoiu was not just an encyclopedic
spirit. He also actively contributed to the struggle that
doctors used to do with illnesses whose mortality
reaches worrying odds. Director of the Osteoarticular
Tuberculosis Sanatorium for Children in Techirghiol,
eventually Gomoiu would practice surgery in
Bucharest. His surgical work is quantified by the large
number of innovative articles he has written, by
implementing the term solarectomy (resection of
lymph nodes), initiated the inguinal approach of
varicocele (Gomoiu-Phocas method). Intransigent
character, Gomoiu was removed from academic
education. His merit in the history of medicine is to
insist on the Romanian contribution to the
international folk medicine fund. This brought, at least
historically, the Romanian medicine at the level of the
other countries reducing the gap. A proof of his ideal
and his effort to bring medicine to the Western level
are the three works published by the Romanian
physician in 1938: La Croix dans la Folclor medical
roumain, Histoire du Folclore medical en Roumanie
and Medicine in the Romanian folk prose.
Bologa also corresponded intensely with Mircea
Eliade, whom he intended to co-opt in his work at the
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
Institute of Medical History. Eliade, despite the fact he
had no necessary time for active participation in this
approach, had a special esteem for the intellectual
physician, as is also apparent from the lines written by
the philosopher in an epistle addressed to the
physician-historian, a letter dated 23 October 1928: “I
testify that whenever I skim through your work and
meditate on the situation of the history of sciences in
our country – I am remorseful that I do not write more
often, warmer and harder, in the papers that are at my
fingertips. I know that, personally, for the scientific
history studies I'm interested in – I have to thank you.
Not to mention what others owe you, especially
doctors and historians. The Institute makes
«environment» scientific history, we, isolated ones,
can at most, make the atmosphere. If an association
for such studies can be woken up, I always think that
the courage of the achievements has been with the
production of the Cluj Institute.“[3] Even in India,
Eliade maintains contact with the Romanian physician
for whom he does not hesitate to admit he has a great
cult of his extraordinary work of a huge volume: “The
passion of science – that is, the slow, precise, technical
sorting of the material our culture provides us – is the
great temptation that brings me closer to you .” (Letter
dated 16.02.1930, Calcutta)[4]
The reason why Eliade particularly appreciated Bologa
resides in the philosopher's aspiration to write a few
stories on traditional Indian medicine branches. Eliade
admired the founder of medical history the ability to
synthesize the huge volume of works, objects and
manuscripts. It was the systematization work that
occupied the author of Religious History Treaty and
History of Religious Beliefs and Ideas all the time. At
the same time he was better equipped to understand
the enormous sacrifice of time and resources involved
in ordering, ranking, and organizing such amount of
information. Frustrated by the huge volume of notes,
contact with Bologa developed philosopher's
rationalization and ability to think more rigorously.
Eliade's interest in medicine crystallizes in 1936 when,
following a lecture held at an International Congress of
History, Eliade publishes History of Medicine in
Romania. The affection borne by the philosopher of
the religions to this new emerging branch stems from
the support given to the history of medicine which he
perceives as a means of producing: “real services to
the humanism of our age.”[5] Folk medicine is viewed
with reverence by Eliade because it represents the
immaterial and immutable connection with the
ancestors of the nation. Since 1926, Eliade
collaborated with Aldo Mieli, who was the publisher of
Archeion magazine, producing short studies of the
history of various sciences, medicine and folklore.
That's how Eliade got to correspond with Bologa. The
latter wanted to develop a collaboration with Miel's
Archeon by making contributions in the form of
articles devoted to Italian influences on Romanian
medicine.
For Eliade, the whole science represents, at least in the
initial phase, a single corpus. Subsequently, science
has specialized and subspecialized over time. What
could bring back all these disparate fragments to one
place would be the philological field. In fact, even
Bologa was aware that his scientific approach was far
more philological. This is how one can explain the help
that he Bologa asked from the philosopher. Another
connection between the two, Bologa and Eliade, was
the scientific curiosity to study botany. As a small child,
Eliade devoted much energy to catching, studying,
analyzing and cataloging various insects. At the age of
fourteen, Eliade published a study titled Silkworm’s
Enemy, under the pen name Eliade Gh. Mircea, which
showed the passion he has for insect biology. The
marvelous journey of the five beetles in the land of the
red ants-sketch of the novel – was written in the same
period. More the outline of a teenager fascinated by
the world of gangs, behind the modest mise-en-place
is hiding a satire, an annoyance of the enemy (ants) by
five elite bettles. It is a mockery of the human society
reduced to the microcosm of insects.
The step to science would come when Eliade
participated and won a contest that proposed the
literary approach of a scientific subject. The title of the
essay (How I found the philosopher's stone) is an
epiphany of the future path that the teenager Eliade
would take. The essay written by a youngster seems to
have amazed the author himself when, over the years,
he said, “How much I would like to be able to reread
this story now, understand what that mysterious
character revealed to me, what alchemical operations
23
he assisted! I had found the philosophical stone in my
dream ... I could only understand, decades later, after
I read Jung, the meaning of this oniric symbolism!”[6]
The short story, though a fantastic text loaded with
supernatural, has as its starting point in Eliade's
interest in chemistry and alchemy. Although he had
promised Bologa that he would make his contribution
to writing a history of Romanian medicine, Eliade's
departure to India would break this momentum.
Though time did not allow him, for the young Eliade
was trying to absorb the new information that was
crowded him, the philosopher gathers medical
material inspired by yoga practices and even offers to
write to the Romanian physician an article about
Ayurvedic medicinal products, as we find out from a
letter dated February 6, 1930: “I have a considerable
number of facts on pharmaceutical medicine and
magic in India, some of them astounding, such as those
relating to vagus nerve control.”[7]
For Eliade, alchemy is the gate open to an occult form
of practice. Alchemy is the first type of objective report
that leave leave, over the history of humanity, truly
scientific discoveries; a kind of ancestor of rational
knowledge. This preparatory, pseudo-scientific phase,
the first attempt of structuring scientific knowledge
was the one that attracted Eliade from his youth
because of its esoteric character. In 1928 Eliade wrote
an article (Marcelin Berthelot and alchemy) dedicated
to a French chemist and biologist who imposed his
name in the field of thermodynamics. Conscious of the
enormous gap between Romanian and Western
science at the beginning of the 20th century, Eliade
sensed, from the philologist and philosopher point of
view, the need to systematize the totality of
historiographical material in order to be saved from
oblivion: “We cannot wait until Romanian science
reaches a European level to promote the validity of
historical-scientific studies. There is no discipline that
can be postponed.”[8] The philosopher's insight was to
build a methodology in this vast field of history of
medicine. The history of science would be appropriate,
with a takeover from a chemist and American historian
Sarton, a new form of intellectual movement that
would put man and science in the center: “Eliade
understands a new interpretation or vision of man not
derived from philological studies (textual), as it was
24
Renaissance humanism, but in the history of science -
understood as «any systematized knowledge»
(Sarton), therefore more than «positive sciences».”[9]
Eliade, great admirer of George Sarton (1884-1956),
intuited in the Belgian chemist the innovative spirit.
Sarton embraced the history of science as a branch of
gnoseology and aimed at linking science and
humanism to a comprehensive one: the philosophy of
science. Eliade was in the current with the theories of
the American and hence the enthusiasm at the
moment when a homologous branch was formed on
the Romanian realm. The only ones of sufficient
intellectual scope that Valeriu Bologa could count on
were Mircea Eliade and Nicolae Iorga.
If alchemy was the gate open to science, popular
creation and ancestral healing practices were the
preamble of modern science. And Eliade felt this
correlation, especially as the prose was anchored in
folklore: “In his writings, the folkloric elements
intertwine with those of the history of religions or
ethnology. His stories take place in illo tempore,
somewhere outside of physical time, and the
characters have supernatural powers, their existence
enrolling in an eternal present, and the facts being
predetermined in advance. Witches, queens, beautiful
women who make pact with the evil, curative herbs
and charm plants, here are some of the ingredients
with which Eliade sows his writings inspired by
folklore.”[10]
The pioneering work of building a frontier science in
our country like the history of science did not frighten
Eliade. We find out from a letter addressed to Bologa
that, on the contrary, ostentatiously, he protects this
new branch of knowledge, although he is aware of the
weight of action in a rebellious society to the new: “I
defend a science against the envy and imbecility of our
intellectuals. I do not even think that our science will
soon become popular. But it must not be ignored and,
above all, dishonored by the elite to which it is de jure
and de facto aimed at.”[11]
What brought together a physician (Valeriu Bologa)
and a philosopher (Mircea Eliade) were the folk
traditions with application in medicine. Apparently
two opposing personalities collaborated efficiently
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
and discovered the common denominator, the
unspoken binder between a scholar spirit and a
metaphysical one, for “the research of Valeriu Bologa
met the interests of Mircea Eliade and although they
did not sign articles or books, the mere fact that they
References:
1. Valeriu Bologa, Wheat Grains, in Institute of History of
Medicine, Pharmacy and Folklor Medicine of Cluj, no. 6, June
1932, pp. 205-206
2. Valeriu Bologa, Wheat Grains, in Institute of History of
Medicine, Pharmacy and Folklor Medicine of Cluj, no. 6, June
1932, pp. 218
3. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas
Publishing House 1999, Foreword and Care of the Edition by
Mircea Handoca, p 76
4. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas
Publishing House 1999, Foreword and Care of the Edition by
Mircea Handoca, p 78
5. Mircea Eliade, History of Medicine in Romania in Journal
of the Royal Foundation, no. 6, June 1936
6. Mircea Eliade, Memories, 1907-1960, 2nd Edition
Revision and Index by Mircea Handoca, Bucharest,
Humanitas Publishing House, 1997, p. 63
shared their opinions meant much for the later
developments of both.”[12]
7. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas
Publishing House 1999, Foreword and Care of the Edition by
Mircea Handoca, p. 79
8. Mircea Eliade, History of Medicine in Romania in The
Word, year IV, no. 1174, 30 July 1928, pp. 1-2
9. Mac Linscott Ricketts, Romanian Roots of Mircea Eliade,
1907-1945, vol. 1, Bucharest, Criterion Publishing House,
2004, p. 288
10. Mihaela Gligor, Between philosophy and medicine. The
medical folklore in the vision of Mircea Eliade and Valeriu
Bologa, Cluj University Press, 2014, p. 94
11. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas
Publishing House 1999, Foreword and Care of the Edition by
Mircea Handoca, p. 85
12. Mihaela Gligor, Between philosophy and medicine. The
medical folklore in the vision of Mircea Eliade and Valeriu
Bologa, Cluj University Press, 2014, p. 138
25
 Article received on March 25, 2018 and accepted for publishing on June 29 2018.
ORIGINAL ARTICLE

Therapeutic management of schizophrenia and substance

use disorders dual diagnosis – clinical vignettes
Octavian Vasiliu1

Abstract: Patients with schizophrenia are frequently diagnosed with addictive comorbidities, and data
in the literature support a 10 to 70% prevalence of this dual diagnosis. Nonetheless, substance use
disorders can be missed during the initial interview with a psychotic patient, if the clinician is focused
only on the more obvious manifestations. Therefore, using psychometric scales and structured
interviews in patients with schizophrenia is strongly encouraged because the case manager will base
his/her therapeutic decisions on quantifiable data about these patients’ symptoms and functional
status. Clinical management in dual diagnosis cases must address both conditions simultaneously, as
the delay in the initiation of substance withdrawal treatment may hinder the recovery from a psychotic
episode. An important issue is represented by the potential pharmacologic interactions between drugs
administered for schizophrenia and those targeting substance withdrawal and substance dependence.
Other important aspects refer to (1) the therapeutic adherence, which can influence the prognosis of
both conditions, (2) the negative impact of residual psychotic symptoms and substance-related
disorders over the patient quality of life and daily functioning, (3) the necessity to integrate variables
like the patient’s specific needs, lifestyle, and psychological resources in the therapeutic decision. These
clinical vignettes are focused on clinical, biological, psychometric, and pharmacological dimensions,
supporting the formulation of treatment recommendations based on monitoring both psychiatric and
biological profiles.
Keywords: schizophrenia, substance use disorders, antipsychotics, dual diagnosis,
cannabis, nicotine, alcohol dependence

BACKGROUND Prevalence of dual diagnosis (substance use disorder

1
Carol Davila University
Emergency Central Military
Hospital, Bucharest
Substance-related disor-
ders are very common
throughout the course of
schizophrenia, and this
phenomenon is responsible
for poorer quality of life,
higher impairment of daily
functioning, lower rate of
treatment response, lower
therapeutic adherence,
leading to a worse prog-
nosis in these patients.
and psychotic disorders) ranges from 10 to 70% in a
large-scale trial for schizophrenia [1].
Many hypotheses about the link between cannabis use
and schizophrenia are still tested, cannabis being
considered an independent risk factor for psychosis
and a variable that may worsen prognosis in
schizophrenia patients [2]. A cannabinoid hypothesis
of schizophrenia has been suggested, based on the
observed alteration of endocannabinoid system
(abnormalities in cannabinoid type 1 receptor binding
properties and modified levels of anandamide in the
cerebrospinal fluid) [2]. Cannabis use was associated

26
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
with an earlier onset of schizophrenia, more severe
forms of disorder, higher rates of relapse, and longer
hospitalizations [3-5]. Longitudinal studies report that
cannabis use in childhood and adolescence doubles
the risk of psychosis onset later in life, which supports
a causal role of this drug in the development of
schizophrenia [6]. Certain alleles of the type 1 cannabis
receptor gene (CNR1) may confer susceptibility to
schizophrenia [7].
Also, the overlap of nicotine dependence and
schizophrenia has been debated as a form of self-
medication for schizophrenia-related cognitive
deficits, based on the fact that the nicotine receptors
activation increases the release of dopamine in
cortical and subcortical areas [8,9]. Still, cigarette
smoking decreases the bioavailability of many
psychotropics that are metabolized through the
CYP450 1A2 isoenzymes and consequently may
diminish the clinical effect of these drugs and delay the
patients recovery [10]. Multiple genes have been
linked to both conditions, e.g. binding protein genes,
protein modification genes, and energy production
genes involved in cognitive functions and neuronal
plasticity [11].
Alcohol use disorder was found in 33.7% of patients
diagnosed with schizophrenia or schizophreniform
disorder in the Epidemiologic Catchment Area study
[12]. A dysregulation of the dopamine transmission
has been suggested as common neurological basis, but
shared genetic vulnerability factors have also been
investigated (e.g. KPNA3, or alcohol dehydrogenase
variants) [13-16]. A review of the current evidence for
common risk factors in alcohol use disorders and
schizophrenia supports a highly polygenic model, with
rare penetrant alleles and frequent alleles with small
effects [16].
Patients diagnosed with schizophrenia tend to abuse
anticholinergic drugs. These agents are often used for
the treatment of antipsychotic-induced extrapyra-
midal symptoms, and a national database analysis
showed that patients with schizophrenia took 20 times
more frequently antiparkinsonian agents than
patients with Parkinson disease [17]. Trihexyphenidyl
abusers may claim this drug improve their daily
functioning and their affect, and a possible
pharmacological explanation is that this agent has a
structural similarity with phencyclidine [18,19]. The
risk of biperiden and orphenadrine abuse was
relatively small in a large database analysis [17].
CLINICAL VIGNETTES
The first patient, M.S., is a 29-year old male, diagnosed
since 2015 with schizophrenia according to the DSM-5
criteria [20], currently at his third psychotic episode.
He was hospitalized after he presented at the
Emergency Department with delusions of persecution
and auditory hallucinations (“there are people who
want me dead because of my soul, they want to collect
my psychic energy”, “I can hear them through the
walls, day and night, they are plotting against me, and
they are saying bad things about my family”, “They are
forcing me to do evil things, like cursing strangers with
no reason”). These manifestations led to changes in his
behavior, he became reclusive, didn’t go out of his
house for weeks and spoke with his family only by
phone, refusing to see them (“I can protect them if I’m
not seen with them”). He recently abandoned his job
as a salesman and didn’t want to see her girlfriend
anymore because of the belief that she was in cahoots
with the persecutors who want him dead.
The pharmacological history in this case included
olanzapine 20 mg/day as the main treatment for his
first psychotic episode. After hospital discharge, he
received the same antipsychotic for 8 months, then he
dropped out and relapsed after about 6 months. The
overall clinical status during the second admission was
similar to the first episode of psychosis, with
persecutory delusions and auditory hallucinations
(both conversing and imperative voices) and induced
defensive behavior- the patient refused to go out by
himself because of the fear of being watched and
plotted against. Olanzapine was re-initiated, but
shortly after this the patient was switched on
aripiprazole 30 mg/day due to concerns related to his
metabolic status (240 mg/dl for the total cholesterol,
150 mg/dl for LDL-cholesterol, and 250 mg/dl for
triglycerides). The evolution was favorable during the
hospitalization and the patient was recommended to
work in a controlled environment and to participate in
occupational therapy. However, after 7 months he
27
discontinued treatment and soon relapsed, so that a by the case manager when the therapeutic strategy
new hospitalization was required. This time the was formulated. Aripiprazole was preferred because
patient was stabilized on aripiprazole, but for the of its good metabolic profile [25], and a long acting
maintenance phase the long acting injectable form of injectable formula was selected because of the more
aripiprazole 400 mg every 4 weeks was selected, in stable plasma concentrations and lower risk of
order to diminish the risk of therapeutic non- discontinuation. The patient received counselling for
adherence. his addictive behavior, and he participated in 4
individual sessions focused on smoking cessation and
The patient was also diagnosed during the current
alcohol use relapse prevention. Alcohol withdrawal
psychotic episode with alcohol use disorder,
symptoms were mild-to-moderate and remitted after
moderate, based on the DSM-5 criteria, admitting a
B-vitamin therapy, parenteral rehydration, and oral
daily intake of 8 drinks, consisting mainly in beer and
lorazepam 3 mg/day for 7 days, with gradual dose
wine for more than 12 months. Also, he is smoking 20
reduction. Naltrexone, 50 mg/day, was initiated for
cigarettes daily, with a value of 10 pack-year.
alcohol dependence after the withdrawal symptoms
Biochemistry panel reflected the liver damage, with
remission, and nicotine replacement therapy was
values for gamma-GT, GOT and GPT of 156 U/l, 70 U/l,
suggested, but the patient refused. There are no data
and 67 U/l, respectively. No abnormalities were
reported about pharmacokinetic interactions between
detected on his chest X-ray and abdominal ultrasound
aripiprazole and naltrexone in the literature, which
exam (except for hepatic steatosis).
supports this therapeutic recommendation.
The psychological evaluation realized during the initial
Follow-up visits: The patient was monitored for 4
visit for the third episode showed a 98 score on PANSS
months, using psychometric instruments, in order to
[21], with high values on both positive and negative
document psychotic symptoms, severity of addictions,
sub-scales. CRDPSS [20] score was 17, based mainly
and overall clinical status evolution under treatment.
on hallucinations, delusions and abnormal
Global functioning improved once the psychotic
psychomotor behavior. AUDIT [22] score was 14,
positive symptoms remitted, although the negative
reflecting a moderate risk of harm related to the
symptoms persisted at a lower level of severity (as
alcohol use, and the severity of nicotine dependence
reflected by PANSS and CRDPSS scores).
was high, as supported by the FTND [23] score of 9.
GAF score at admission was 45, based on symptoms Table 1. Psychologic evaluations during the first patient’s
severity and functional impairment, while the CGI-S initial visit
score was 5, which means a “markedly ill” clinical Clinical scale Results
status.
PANSS 98
Therapeutic challenges analysis: This patient CRDPSS 17
presented a history of therapeutic non-adherence GAF 45
which triggered two relapses. He was diagnosed with CGI-S 5
two substance use disorders (alcohol and nicotine
FTND 9
dependence), which were not therapeutically
AUDIT- Interview Version 14
approached during his two previous psychotic
episodes, and this could be also a factor that may
Alcohol use disorder had a favorable evolution and the
contribute to relapse in schizophrenia [24]. There is a
AUDIT scores diminished gradually, but the nicotine
lack of social and professional insertion in this case,
dependence persisted and the mean number of
related to both positive and negative symptoms. The
cigarettes increased with 25%, while the FTND score
patient lacks familial support and he discontinued
increased with 10%. Biochemistry panel reflected an
occupational therapy. Moreover, the metabolic profile
improvement of the liver status after 4 months, with
and the hepatic functional status were abnormal. All
values for gamma-GT, GOT and GPT of 56 U/l, 23 U/l,
these negative prognosis factors have been evaluated

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

and 37 U/l, respectively, and the metabolic
parameters improved, also: 190 mg/dl for the total
cholesterol, 120 mg/dl for LDL- cholesterol, and 170
mg/dl for triglycerides.
Conclusion: Addictive behaviors must be approached
as soon as possible by the case manager in patients
with schizophrenia, because the risk of therapeutic
non-adherence, somatic complications, and reduced
functionality is higher if these conditions are left
untreated or if the appropriate treatment is delayed.
In this particular case, naltrexone was efficient in the
treatment of alcohol use disorder, and the patient had
also significant decrease of the psychotic symptoms.
However, nicotine dependence could not be
addressed pharmacologically because the patient
refused, and he participated only in a few counseling
sessions, which led to the persistence of his substance
related condition.

Fig.1. Evolution of the clinical variables during the first 4 months of

treatment
100

80

60
Score

40

20

0
0 7 14 28 60 90 120

PANSS CRDPSS GAF CGI-S FTND AUDIT

The second patient, E.D., is a 30-year old female,
diagnosed with schizophrenia for 6 years, currently in
a partial remission, who presented to her psychiatrist
asking for a therapeutic change because of
galactorrhea and irregular periods. She attributed
these symptoms to risperidone, which was initiated by
the psychiatrist during her latest psychotic relapse,
about 3 months ago.
This patient had 4 psychotic episodes since the onset
of her disease at age of 22 and received for her first
episode haloperidol 15 mg/day for 2 months, followed
by amisulpride 800 mg/day for 10 months; for her
second episode, she was treated with olanzapine 15
mg/day, for 16 months; during her third episode she
received haloperidol 20 mg/day for the acute phase,
and again olanzapine 15 mg/day for an indefinite
period of time, and for the last episode she received
risperidone 6 mg/day maintenance dose. Changes in
the antipsychotic regimen were determined by
adverse events- extrapyramidal symptoms during
haloperidol treatment, hyperprolactinemia during
amisulpride administration, and weight gain during
olanzapine therapy.
This patient presented also criteria for nicotine and
cannabis use disorder, both of moderate severity,
according to the DSM-5 criteria. She was on cannabis
for more than 2 years, with very few short periods of
abstinence, and regarding nicotine use she admitted
she was smoking 15 cigarettes daily for at least 8 years.
She admitted she did not recognized cannabis
addiction in front of her psychiatrist until the current
visit. She was never offered nicotine replacement
therapy or any other type of treatment targeting
nicotine dependence.
The psychological evaluation during her third episode
sh owed a PANSS score of 69, with low values on both
positive and negative sub-scales. CUDIT-R [26] score
was 16, supporting severe cannabis dependence, and
the severity of nicotine dependence was high, as
reflected by the FTND score of 7. GAF score at

29
admission was 60, based on symptoms severity and and 75%, respectively. Also, the quality of life
functional impairment, while the CGI-S score was 4, improved, both on the visual analogic scale (+17%),
which means “moderately ill” clinical status. EuroQoL and on its subscales (depression/anxiety -50% and
(EQ-5D-5L) [27,28] visual analogic scale score was 67, usual activities -33%). The Clinical Global Impression-
which seems to be correlated more with her Severity improved with 50%, and the patient was
substance-related symptoms than with her psychotic considered after 4 months “borderline mentally ill”.
manifestations. Quality of life domains that seemed Minimal QTc prolongation was detected on ECG after
more affected by her current status were 4 months (+1.3%), but it didn’t reach the level of
anxiety/depression (a score of 4) and usual activities (a significance (considered to be 460 msec in women,
score of 3). after correction with Fredericia’s formula). No
metabolic abnormalities were detected during the
Her somatic status was good, with no abnormalities on
monitoring period, and the BMI decreased with 2.1%
CBC or serum biochemistry panel. Also, her ECG and
compared to baseline.
chest X-ray didn’t suggest any abnormalities.
Conclusion: Targeting the cannabis and nicotine use
Therapeutic challenges analysis: This patient has a
disorders may improve the overall functionality and
history of adverse events to several antipsychotics
patient’s quality of life, reducing further
(haloperidol, amisulpride, olanzapine) which were
schizophrenia-associated symptoms, like depression,
severe enough to grant changes in the antipsychotic
apathy, anhedonia or anxiety. In this case, the patient
treatment. The patient received a new antipsychotic,
was compliant to the therapeutic suggestions, and
ziprasidone 160 mg/day, which has been associated
participated in counselling sessions focused on
with low risk for hyperprolactinemia, weight gain, and
substance use relapse prevention, while being
extrapyramidal syndrome [29]. A gradual switch was
adherent to the pharmacologic treatment. Her
preferred due to the different pharmacodynamic
evolution was favorable and the therapeutic switch
profiles of risperidone and ziprasidone [29-31]. ECG
from risperidone to ziprasidone was well tolerated. No
monitoring was initiated, and periodic measurement
pharmacokinetic interactions were anticipated
of metabolic parameters was continued throughout
between the treatment for nicotine use disorder
the duration of the antipsychotic therapy. The
(replacement therapy), cannabis use disorder
presence of cannabis use disorder raises an important
(gabapentin) and schizophrenia (ziprasidone).
question because there is no pharmacological
treatment with clear evidence of efficacy in patients Table 2. Psychologic evaluations during the second
diagnosed with this disorder, while data about patient’s initial visit
psychotherapy effects are still debatable [32]. Clinical scale Results
However, gabapentin and N-acetylcysteine have been
PANSS 69
suggested as possible therapies [32], and gabapentin
CRDPSS 9
was preferred in this case because of its positive effect
GAF 60
on anxiety and low risk of pharmacokinetic
interactions [33]. Nicotine replacement therapy with CGI-S 4
nicotine patch 25 mg/16h for 8 weeks, followed by FTND 7
gradual dose reduction, combined with psychological AUDIT – R 16
counselling, was accepted by the patient. EuroQoL
Visual analogic scale 67
Follow-up visits: The evolution of the psychotic Mobility 1
symptoms was favorable, as reflected in the PANSS (- Self-care 2
10%) and CRDPSS (-11%) scores. The overall Usual activities 3
Pain/discomfort 2
functionality increased significantly (+33%) compared Anxiety/depression 4
to baseline, and this improvement seems related to
the decrease in both FTND and CUDIT scores, with 71%

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

Fig.2. Evolution of the clinical variables during the first 4 months of

treatment
100

80

Score 60

40

20

0
0 7 14 28 60 90 120

PANSS CRDPSS GAF CGI-S

FTND CUDIT-R EuroQoL-VAS

The third patient, S.G., was diagnosed for the first time stabilization, the drug may be administrated every 12
with acute psychotic disorder 3 months ago. Her weeks. She agreed to be initiated on paliperidone long
symptoms at hospital admission consisted in acting after stabilization of acute symptoms.
psychomotor agitation, grandiose (“I am very
The patient was smoking 30 cigarettes daily, with a
powerful, and I can make any wish come true, like
value of 9 pack-years. She fulfilled the DSM-5 criteria
Santa Claus, only better”) and persecutory (“there is a
for nicotine use disorder and accepted treatment for
group of forces trying to kill me and take my powers”)
this condition. She received nicotine replacement
delusions, auditory and visual hallucinations (“I can
therapy, but she declined the invitation to join a group
hear them talking about me and trying to make me feel
therapy focused on abstinence.
miserable… they are cursing me and telling lies about
me and my family”, “They are moving through the Her ECG was normal, as were chest X-ray, cerebral CT-
light, I can see them… they are like some green scan, CBC and serum biochemistry panel. The
shadows”), disorganized behavior, and diminished toxicology exam was also negative.
emotional expression. She was 27 years old when she
Table 3. Psychologic evaluations during the third patient’s
was first admitted in hospital, and her psychotic
initial visit
symptoms had an insidious onset over at least 4
Clinical scale Results
months. First, she was initiated on risperidone 6
mg/day, and her response was good, but discontinued PANSS 88

oral treatment because she had to take this drug twice CRDPSS 14
a day. The patient developed positive symptoms of GAF 35
psychosis after one month of no treatment, and she CGI-S 5
was readmitted in the Psychiatry Department. The FTND 9
selected drug for clinical stabilization was risperidone
because of her previous good response. She was Therapeutic challenges analysis: This patient is still in
informed that a long acting injectable form of this the early phase of disease, as her diagnosis of
antipsychotic exists, which requires administration schizophrenia was just established. She met the
every two weeks. Also, she was informed that necessary criteria for this diagnosis- time (more than 6
paliperidone, the active metabolite of risperidone, has months including pre-hospitalization period of active
two long acting injectable formulations, with symptoms), clinical manifestations, functionality, and
administration of one dose every 4 weeks, and after differentials. The challenge is to select a treatment

31
regimen that could be more readily accepted by a not expected to be modified by cigarette smoking, in
young and active person (she has to travel often case substance use disorder treatment fails.
because she has contracts with different enterprises),
Follow-up visits: The evolution of psychotic symptoms
while targeting both schizophrenia and nicotine
was favorable, as reflected in the PANSS and CRDPSS
addiction symptoms. One advantage in this case is the
scores, which decreased with 40% and 65%,
insight of the patient and her willingness to continue
respectively. The favorable trend maintained even
the treatment. She understood the therapeutic
after switching on the long-acting formulae (PP1M and
options her psychiatrist presented, and she has chosen
PP3M). The slower rate of improvement after day 36
the treatment which allows her less time for
is related to the stabilization of the clinical status,
administration and medication-supplying procedures
which is a condition for switching on long-acting
(visits to her GP, treating psychiatrist, and local
antipsychotic formula. The patient reported that she
pharmacy). Therefore, paliperidone was considered
could return to her job after 6 weeks of treatment and
the most appropriate option for her, and after
her professional performances were fair. The cigarette
stabilization with oral medication, she was switched
use declined during the first 4 weeks, but she admitted
on paliperidone palmitate (PP1M) 100 mg monthly as
she smoked during nicotine replacement therapy and
maintenance dose for 4 months, and paliperidone
after its discontinuation. Therefore, after 11 months
palmitate (PP3M) 350 mg every 3 months after 4
her FTND score reflected a moderate dependence. She
months. Regarding her nicotine use disorder, she
refused a new trial of nicotine replacement therapy
received 25mg/16 h nicotine patches and nicotine
and counselling sessions, as she states “smoking is not
spray administered prn, in case of withdrawal
a problem for me anymore… I’m only smoking when
symptoms, with gradually dose reduction, and
I’m feeling nervous”. Her BMI increased with 3.5%
termination after 3 months. The nicotine spray was
compared to baseline, but no significant alterations in
recommended because the patient is a heavy smoker,
plasma lipids, blood glucose, hepatic enzymes or QTc
and because she had no asthma, chronic sinusitis, or
were reported.
other related diseases. Paliperidone is not a substrate
for CYP1A2, therefore its plasma concentrations are

Fig.3. Evolution of the clinical variables during the first 11 months of

treatment
100

80

60
Score

40

20

0
0 14 21 28 36 66 96 127 156 248 337

PANSS CRDPSS GAF CGI-S FTND

CONCLUSIONS psychiatrist and the patient is crucial in order to assure

an adequate level of therapeutic adherence. The
In young patients who experience first episode of
psychiatrist should consider the lifestyle of the patient,
psychosis establishing therapeutic relationship could
her psychological resources and specific needs, and to
be a difficult challenge. Communication between the

32
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
formulate the most appropriate therapeutic strategy.
In this case a long-acting formula of an atypical
antipsychotic was preferred because of the active
lifestyle of the patient, and her expressed preference
for a treatment which could be easily administered.
The treatment for nicotine dependence has been a
challenge, as the patient did not quit completely
smoking, but only diminished it. Paliperidone could be
useful in patients who smoke because it is not
metabolized through CYP1A2, and its plasma
concentrations remain stable even if this isoenzyme
gene is induced by the polycyclic aromatic
hydrocarbons of the tobacco smoke [34].
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Abreviations list
AUDIT = Alcohol Use Disorders Identification Test
BMI = Body mass index
CBC = Complete blood count
CGI-S = Clinical Global Impression- Severity
CRDPSS= Clinician-Rated Dimensions of Psychosis Symptoms
Severity
CUDIT-R = Cannabis Use Disorders Identification Test –
Revised
EuroQoL 5D-3L= EuroGroup Quality of Life Scale
FTND = Fagerstrom Test for Nicotine Dependence
GAF = Global Assessment of Functioning
PANSS = Positive and Negative Syndrome Scale
PP1M = paliperidone palmitate with monthly administration
PP3M = paliperidone palmitate administered every 3 months
prn = pro re nata
Disclaimer
The author was speaker for Servier, Eli Lilly and Bristol-
Myers, and participated in clinical trials funded by Janssen
Cilag, Astra Zeneca, Otsuka Pharmaceuticals, Sanofi-Aventis,
Sunovion Pharmaceuticals.
9. Picciotto MR, Corrigall WA. Neuronal systems underlying
behaviors related to nicotine addiction: neural circuits and
molecular genetics. J Neurosci. 2002;22:3338–3341.
10. Theng YM, Wahab S, Wahab NA, et al. Schizophrenia
and nicotine dependence: What psychopharmacological
treatment options are available for the duo perturbations?
Curr Drug Targets 2017; doi:10.2174/
1389450118666171017163741.
11. Chen J, Bacanu SA, Yu H, et al. Genetic relationships
between schizophrenia and nicotine dependence. Sci Rep
2016;6:25671.
12. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of
mental disorders with alcohol and other drug abuse: Results
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is associated with schizophrenia, major depression, opiate
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The Alcohol Use Disorders Identification Test : Guidelines for
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dependence and Fagerstrom Tolerance Questionnaire: a
brief review. J Substance Abuse 1989;1:471-7.
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LB. Substance use: a powerful predictor of relapse in
schizophrenia. Schizophr Res 1996;20:145-151.
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improved brief measure of cannabis misuse: the Cannabis
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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

Article received on October 19, 2017 and accepted for publishing on November 9, 2017.
ORIGINAL ARTICLES

Patient reported outcome measures and joint replacement

Alexandra Sopu 1

Abstract: PRO (Patient Reported Outcome) is a clinically based questionnaire filled directly by patients,
and other variant types of measures, in clinics and hospitals that gather patients’ stance on their
conditions in treatment. PRO is different from Patient Based Outcomes whereby the latter addresses
the patient’s concerns but do not necessarily enquire from them. However, PRO gather strictly from
patients themselves through interviews, self-administered questionnaires and other available
measures. The patient’s perspective on issues that is significant in enacting certain particular clinical
policies and regulations such as approval of a medication/drug. Most PROM constitutes one (one-
dimensional) or more underlying assessments (multidimensional) connoted as constructs, which bear
several levels of scale to assess degree.
Keywords: PROMs, orthopaedics, patients, hip replacement, knee replacement, healthcare system

OBJECTIVE locomotion, daily living activities and personal care. In

addition, Health Related Quality of Life (HRQoL),
The questionnaire or interview used to gather
health status, general health experience and rating of
information is referred to as measures, tools or
healthcare facilities and
instruments. Commonly, there are two types of PROM
operations [2].
questionnaires.
Analysis of PROMs is
Generic PROMs, which are used to assess generally
usually conducted using
across numerous diseases in a broad spectrum
approved analysis tools for
perspective, and condition-targeted PROMs that are
proper interpretation such
developed for a particular medical condition [1].
as Rasch analysis or confir-
This paper critically examines patient-reported matory factor analysis.
outcome measures (PROMs) and joint replacement PROMs are often validated
from a broad perspective. using particular tools and
methodologies, such as
METHODS Linguistic validation for
Most PROMs measure aspects such as Quality of Life population’s differences
(QoL) that is fulfilment of needs and impact of and others to ensure that
restrictions on emotional wellbeing, and drug side they are effective in gathe-
effects. Others include symptoms/impairments that is ring relevant information.
1Royal Stoke University
pain and depression, functioning during disability, Patient grouping too
Hospital, UK

35
should be reliable and conform to ideal scaling,
development and psychometric standards. Examples
of renowned PROMs include the SF-36 Health Survey,
EuroQol (EQ-5D), SF-12 Health Survey, Profile, Quality
of Well-Being Scale, Health Utilities Index and
Consumer Assessment of Healthcare Providers and
Systems (CAHPS) [3].
These are examples of generic PROMs. Ideal examples
of condition-targeted PROMs include Adult Asthma
Quality of Life Questionnaire (AQLQ), Seattle Angina
Questionnaire (SAQ), Kidney Disease Quality of Life
Instrument, Epilepsy Surgery Inventory, National Eye
Institute Visual Functioning Questionnaire, Ankylosing
Spondylitis Quality of Life questionnaire (ASQoL) and
Migraine Specific Quality of Life (MSQOL) [4].
With the advent of PROMs and the role they play in
medicine, individual countries such as England’s
National Health Service (NHS) have made it a
prerequisite for particular surgical operations to
provide non-compulsory PROMs before the procedure
and following the procedure (ideally three months
after procedure); these include hip, knee and other
joint replacements, hernia surgery and varicose vein
surgeries.
England used the PROMs to assess the effectiveness
and effects of the surgeries on its national a patients
and deduced that the frequency of operations/
surgeries should be maintained. Due to their efficiency
and importance in quality health service, PROMs are
updated monthly as a policy in most developed
countries. PROMs are currently used to grade health
facilities with scores parameters according to patient
satisfaction. In England, HES (Hospital Episode
Statistics) use PROMs to rate hospital services across
the state and their use are gaining impetus across the
global health sector [5].
There is a general dataset that PROMs include in
questionnaires; Generic and condition-specific
measures of self-reported health status. Patient-
identifiable information included in the PROMs, which
is used for relation purposes, is strictly not availed for
wider analysis, due to confidentiality. Additional
questions inquiring into the patient’s health status
include whether they have antecedent conditions such
36
as diabetes or arthritis [6]. The outcomes of a health
procedure can be ascertained from the patient’s
perspective, through self-reported symptoms and
functional status, by comparing and determining the
differences in data between the pre-operative and
post-operative PROMs.
However, the PROMs are not compulsory for patients
to fill. More so, consent from patients who participate
in the PROMs has to be sought before their data is
used for analysis [7]. The patient’s identifiable
information is only used to electronically fetch for his
or her National Health Number in government
database during analysis of PRO data. The rest of the
data is transferred to a database, such as the HES in
England, from where the PRO analysis consequently
occurs. Pre-operative and post-operative PROMs from
the same patients are identifiable in the dataset since
they possess similar serial numbers from which they
are linked. After analysis, data in the HES is
pseudonymised before it is made available to the
public for download for analysis and scrutiny and
hospital/clinical scoring [8]. Other uses of PROMs
include: allows managers and clinicians to benchmark
their own performance with regards to others, they
are used for research purposes and draw relations to
effectiveness and cost-effectiveness of health
procedures to care. It is also used to compare
implications of presence and absence of the treatment
or rather alternative treatment, searching for
healthcare inequalities, and research on relationship
between pre-existing health and social conditions and
risk of deterioration after procedure. Other than the
anonymised data that is availed to the public for
scrutiny and further personalized analysis, PROMs can
be availed to service providers of patient care through
provider level extract only with patient’s approval.
More so, extract service of particular requested data
sub-subs by customers can be availed at an
administrative fee depending on complexity of the
request [9].
There are variant methodologies in which PROMs are
used to score and rate health facilities. Some examples
of standardised PROMs that are analysed by specific
methodologies include the five-dimensional descript-
tive system EQ-5DTM health questionnaire and the
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
EuroQol Group’s visual analogue scale (EQ-VAS) [10].
Most PROMs used for joint replacement procedure,
such as hip and knee replacement, are condition-
targeted. Most common post-operative PROM
questions include an inquiry into the patient’s health
status after procedure such as their state of mobility
or other operative complications.The EQ-5D is a
simple, generic measure of health for clinical and
economic appraisal [11].
The PROM with single indexing values for health
status and an unsophisticated descriptive profile is
widely used in economic and clinical evaluation of
healthcare and in health surveys of populations. The
EQ-5D provided in joint replacements contains a
descriptive system with issues on mobility, discomfort
/pain, self-care e.g. washing and dressing, anxiety and
depression and normative activities e.g. work,
housework, study, family or leisure activities etc. Each
of these five dimensions has several level statements
which the patients tick against the most appropriately
descriptive of his or her condition.
Each dimension has a score digit for each level
statement hence every patient has five string scores
thence the connotation ‘5D’ [12]. Using a formula, the
five string score are converted into a singular summary
index, referred to as the ‘social preference weights’
assigned to each statement in the dimensions. The
value of full health is assigned to value one (or state
11111, in EQ-‘5D’) from which reference is sought. EQ-
VAS index scores range from 0 to 100, least and best
health respectively. The patients mark, within the
range, his or her relevantly perceived state of health
[13].
Other PROMs used in England for joint replacement
include the condition-targeted Oxford Knee Scores
(OKS) and Oxford Hip Scores (OHS). The PROMs
contain twelve multiple choices, assigned later with
scores, about the patients state of mobility, pain, ease
of joint movement, ease of partaking normal chores
and activities. The scores in the PROM are such that
the less the scores the poorer the patient’s condition
with zero for greatest severity. For each multiple
choice, 4 is the greatest score for best patient
condition. Hence, the total score for every patient in
the PROM have a maximum limit of 48 for ideal patient
condition while zero indicates worst severity [14].
Postoperative Recovery Profile in condition-targeted
PROMs with recovery specific questions is used to
determine the quality of joint replacement procedures
in health facilities and person-centeredness of clinical
services [15]. This is common procedure for persons
with arthritis. The USA, Norway, Denmark, Sweden,
New Zealand, Canada and England operate 77-153 and
66-143 hip and knee replacement per 100 people in
prevalence rate. With advances in biomedical
operations and medication intended to shorten or
alleviate the post-operative recovery period especially
since recovery takes place in the vicinity patient’s
home, PROMs are significant and effective method of
evaluating these procedures on patients [16].
Traditionally, assessment of joint replacement were
assessed by drawing connections between different
intervention methods such as variant joint
replacement procedures. The types joint replacement
include prosthetics, implants, surgical techniques.
Relations of these types of joint replacements were
drawn to revision rates, complications and post-
operative medications. With increased impetus on the
use of PROMs, this evaluation is augmented thus
allowing for an improvement of healthcare services
[17]. While EQ-5D, EQ-VAS, OHS and OKS are
important instruments in PROMs, they do not
comprehensively provide adequate information
important of the requisite important aspects that
allow for quick recovery. Recovery-Specific
Instruments have been devised to bridge this gap.
Swedish healthcare PRP (Post-operative Recovery
Profile) PROMs on joint replacement patients has
comprehensive data on patient’s problems, medical
interventions and outcomes of treatments such that it
has gained global recognition [18]. The Swedish
methodologies of PROMs and their analytical tools are
being replicated across the developed world since they
include measurements on different groups of patients
and can be altered for different purposes in the variant
PROM areas [19]. The PRP has additionally
incorporated global-, dimensional- and item levels in
scoring not only for sole patients but more so for every
group of patients. The global score is significant in
deducting the recovery rate of a population-based
profile.
37
An embodiment of a PROM is one in Sweden that was
conducted on joint replacement (hip and knee)
operations patients whereby the PROM questionnaire
was provided the day before the procedure, three
days after the procedure and one month later after the
procedure. The peri-operative variables included sex,
surgical procedure, American Society of Anaes-
thesiologists’ (ASA) guided physical classification, age,
duration of surgery, length of postoperative stay,
blood loss and marital status [20]. PRP was included
into the PROM and 19 constructs collected included
physical functions and symptoms, psychological, social
and activity measures.
Response category for assessments, from which scores
would be assigned, included: none, mild, moderate,
and severe symptoms. Recovery profiles for every
individual and group on each item and dimension were
provided by the PRP. The 19 item responses account
for a detailed individual response profile over the
recovery dimensions and the item frequency
distributions reports on the item response profile of
the group [21]. Fully recovered score in the group
ideally would have indicator score of 19, 15-18
indicator sum for almost full recovered , 8-14 indicator
sum for partly recovered , 7 indicator score for slightly
recovered and below 7 not at all recovered.
Using methodological tools of frequency distribution
analysis, out of the 75 patients who voluntarily
participated in the PROMs assessment after
undergoing primary knee and hip replacement due to
osteoarthritis, 23 patients indicated the same level of
pain on both the 3 day and one month follow-up [22].
The remainder showed a decrease in pain after the
one month follow-up. Significance in RP values was
used to assess the systematic change in recovery of
groups. Individual variations within groups and
between groups can thereafter be scrutinized.
RESULTS
Besides pain, other score categories included muscle
weakness and re-establishment of everyday life. On
physical symptoms and function’s frequency
distribution, for three days the frequency for the none
assessment ranged between 62% and 7% while one
month later, 72% to 25% [23]. Systematic group
38
changes, unchanged assessments, individual
variability in all dimensions were analysed. For global
level assessments for day 3, 11(score for partly
recovered) was the median while 13(score for partly
recovered) was median after one month follow-up
[24].
This information was used to ascertain whether the
surgical intervention or rehabilitation in the joint
replacement procedures and therapy were
appropriate for individual patients or for groups of
patients [25]. The PROMs data was also used to
identify particular risks in particular groups
(categorized by demographics) associated with the hip
and knee replacements. While the analysis of the
PROMs indicated homogenous recovery changes in
the groups, certain assessments were unchanged for
both the 3day and one month assessment; muscle
weakness and pain.
However, great individual variations on the two
categories were found to result to this. Using this data,
Sweden was able to determine the best treatment and
therapy techniques to render to joint replacement
patients for a quick recovery [26]. It was also found out
that a standardized treatment method for groups that
exhibited great variations in individuals was not
necessarily the remedy to the situation. Extensive use
of PROMs in Sweden has allowed the country to
increase its knowledge on the best healthcare
practices hence an improvement in their healthcare
delivery and high score/ratings of their hospitals
internationally [27].
Based on the PROMs Swedish healthcare system is
able to establish expected recovery within junctures in
recover period. This can be sued to grade other
treatments as set-backs and gains with regards to the
expected outcome and therefore facilitate the overall
recovery and create awareness of the recovery
process. PROMs have also been used to enhance, as a
clinical tool, the manner of clinical relationship and
contact in follow-up visits between physicians, nurses
and their patients. In joint replacement, resumption
of normative daily activity and functionally capacity
were usually found to be unsatisfactory.
The level of satisfactions was greatly influenced by
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
pain, mental functioning and fulfilled expectations
regarding postoperative pain [28]. The psychological
dimension rated higher for those who concomitantly
scored 13 in physical functioning and pain. Longer
period assessment such as after 6 months have been
shown to record greater recovery scores. Nonetheless,
the Swedish HealthCare is keen on shortening the
recovery period for joint replacement thus the focus
of PROMs of short recovery periods. For long period
PROMs, categories of assessment such as Quality of
Life (QoL) and Health Related Quality of Life (HRQoL)
are incorporated [29].
These PROM scores by patients who visit variant
clinical and hospital facilities allow for the grading of
hospitals/clinics too. Using relevant and respective
methodological tools, scores from patients attended
in various hospitals/clinics can assist in the national
grading and scoring of hospitals. This initiates
competition for better healthcare provision
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9. Wiklund, I 2004, Assessment of patient-reported
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quality of life, Fundam Clin Pharmacol. 18(3):351-63.
10. Willke, RJ., Burke, LB & Erickson, P 2004, Measuring
concurrently improving the healthcare of a country.
Data has established that 70% of countries with
esteemed healthcare systems have national policies
on the use of PROMs in their HealthCare facilities.
CONCLUSION
Facilities that exhibit consistently low scores could be
sanctioned and enquiries instigated into their medical
practices. This allows for the monitoring of healthcare
[30]. PROMs therefore are ideal instruments for the
improvement of healthcare provision. They assist in
determining the treatment and medication that ideal
for patients in quick recovery mode. They create a
patient-centred healthcare system. Hospital
ranking/scoring on the other hand allow for
benchmarking of clinical performances thus generally
improving the provision of healthcare in a country
[31].
treatment impact: a review of patient-reported outcomes
and other efficacy endpoints in approved product labels,
Control Clin Trials. 25(6):535-52.
11. Health & Social Care Information Center, 2008, Monthly
Patient Reported Outcome Measures (PROMs) in
England.[www.chks.co.uk/index.php?id=24]
12. Clancy, C & Collins, FS 2010, Patient-Centered Outcomes
Research Institute. Sci Transl 2(37):37cm18
13. Keller RB 2003, Outcomes research in orthopedics. J Am
Acad Orthop Surg 1(2):122.
14. Novak EJ, Vail TP, Bozic KJ 2008, Advances in orthopedic
outcomes research. J Surg Orthop Adv 17(3):200.
15. Hawker G., et al. 2008, Health-related quality of life after
knee replacement. J Bone JointSurg Am 80(2):163.
16. Chang, CH 2007, Patient-reported outcomes
measurement and management with innovative
methodologies and technologies. Qual Life Res 16(Suppl
1):157.
17. Clancy, CM 2011, Commentary: precision science and
patient-centered care. Acad Med 86(6):667.
18. Clancy, CM & Eisenberg, JM 2008, Outcomes research:
measuring the end results of healthcare. Science
282(5387):245.
19. Rolfson, O 2010, Patient-reported outcome measures
39
and health-economic aspects of total hip arthroplasty.
Department Of Orthopaedics, Institute of Clinical Sciences.
Gothenburg: Sahlgrenska Academy, University of
Gothenburg. p. 60.
20. Dawson J, et al 2010, The routine use of patient reported
outcome measures in healthcare settings. BMJ 340:c186.
21. Wu AW, et al. 2010, Adding the patient perspective to
comparative effectiveness research. Health Aff (Millwood)
29(10):1863.
22. Dawson J, Fitzpatrick R, Carr A, Murray D 2006,
Questionnaire on the perceptions of patients about total hip
replacement. J BoneJoint Surg Br 78-B(2):185e90.
23. Field RE, Cronin MD, Singh PJ 2008, The Oxford hip
scores for primary and revision hip replacement. J Bone Joint
Surg Br 87(5):618e22.
24. Husted, H., Holm, G. & Jacobsen, S 2008, Predictors of
length of stay and patient satisfaction after hip and knee
replacement surgery. Fast-track experience in 712 patients.
Acta Orthopaedica 79 (2) 168–173.
25. Kärrholm, J 2010, The Swedish Hip Arthroplasty Register
(www.shpr.se). Acta Orthopaedica 81 (1) 3–4
26. Salmon, P., Hall, G.M., Peerbhoy, D., Shenkin, A. &
Parker, C 2001, Recovery from hip and knee arthroplasty:
40
Patients' perspective on pain, function, quality of life, and
well-being up to 6 months postoperatively. Archives of
Physical Medicine and Rehabilitation 82 (3) 360-366.
27. Knutson, K. & Robertsson, O 2010, The Swedish Knee
Arthroplasty Register (www.knee.se). The inside story. Acta
Orthopaedica 81 (1) 5–7.
28. Allvin, R., Ehnfors, M., Rawal, N., Svensson, E. & Idvall, E.
2009, Development of a questionnaire to measure patient-
reported postoperative recovery: content validity and intra-
patient reliability. Journal of Evaluation in Clinical Practice
15, 411-419
29. Jones, C.A., Beaupre, L.A., Johnston, D.W. & Suarez-
Almazor, M.E 2007, Total joint arthroplasties: current
concepts of patient outcomes after surgery. Rheumatic
Disease Clinics of North America 33 (1) 71-86.
30. Vissers, M.M., de Groot, I.B., Reijman, M., Bussmann,
J.B., Stam, H.J. & Verhaar, J.A 2010, Functional capacity and
actual daily activity do not contribute to patient satisfaction
after total knee arthroplasty. BMC Musculoskeletal
Disorders 11, 121
31. Chang RW, Pellisier JM, Hazen GB 2005, A cost-
effectiveness analysis of total hip arthroplasty for
osteoarthritis of the hip. JAMA 1996;275(11):858e65.
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

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

Physical effort – an underused preventable method in

colorectal cancer
Mihăiță Pătrășescu1,2, Petruț Nuță1, Raluca S. Costache1,2, Săndica Bucurică1,2, Bogdan Macadon1, Vasile
Balaban1,2, Andrada Popescu1,2, Roxana Călin1, Ioana Răduță1, Daniel Pantile1, Florentina Ioniță Radu1,3,
Mariana Jinga1,2

Abstract: Colorectal cancer prevalence is increasing worldwide. Modifiable risk factors are responsible
for almost 50 % of cases and this could imply a huge potential of preventability. Among these factors
the level of physical activity is of paramount importance. Physical activity has a positive impact on
health status in general and it decreases the prevalence of various cancers including colorectal cancer.
Physical activity decreases the prevalence of benign colorectal adenomas and it prolongs the disease
free interval after surgery in colorectal cancer, thus increasing survival. The mechanisms involved are
multiple: decreasing bowel transit time, regulating energy balance, decreasing peripheral insulin
resistance, decreasing hyperinsulinism, antiinflamatory effects, increasing vitamin D production.
Keywords: colorectal cancer, physical activity, obesity, lifestyle modifications

Physical activity is a major and potentialy have been published till

modifiable component of life style, which may be 2010 concerning the
able to highly influence the risk of main cancers. issue of physical activity
Hence, there are convincing evidence that an and CRC.[2] A metaana-
important benefit may be derived concerning risk lysis that included 21
reduction in endometrial cancer, colorectal studies stated a signifi-
cancer, breast cancer, prostate cancer, lung cant reduction of CRC
cancer and ovary cancer. It is estimated that in risk by 27% in the group
Europe in 2008 between 150000 and 300000 of subjects that per-
cases of cancer could have been prevented only formed vigurous physi-
by the way of maintaining a resonable level of cal activity as comparing 1Carol Davila University
physical effort in general population.[1] with the group of Central Emergency Military
Hospital, Bucharest
sedentary subjects (RR 2
A series of convincing observational data suggest Carol Davila University of
0.73, 95% CI 0.66- Medicine and Pharmacy,
that regular physical activity, be it ocupational Faculty of General
0.81).[3] The mechanism Medicine, Bucharest
type or recreational type, protects against
that may provide an 3Titu Maiorescu University,
colorectal cancer (CRC)[1,2]. Around 60 studies Bucharest
explanation for the

41
relative protection of physical effort is currently the risk of CRC regardless of the impact on BMI:
unknown. There are no interventional type this idea may imply that physical activity protects
studies published yet to support the role of against CRC by a mechanism independent of that
regular physical effort as preventive method in involved in resolution of obesity. The protective
CRC. effect of physical effort validates at distance. The
actual reduction of CRC risk is considerable only
In 2007 the results of a cohort study (Nurses’
after several years. In conclusion, the authors of
Health Study) has been published that enrolled
this study suggest that even minor physical effort
80,000 female subjects from 1986 with a 16 years
may derive benefit on CRC risk reduction. Several
follow-up. There have been diagnosed
mechanisms have been proposed. Thus, physical
approximately 500 cases of CRC. A multivariate
activity regulates energetic balance and
analysis that controlled the confounding factors
intervenes in reduction of hyperinsulinism and
represented by other risk factors for CRC
peripheral resistance to insulin. Physical activity
concluded that there was a proportionate
may intervene also through anti-inflammatory
reversed relationship between physical effort and
mechanisms. Moreover, the positive effects of
distal colonic cancer and, to a lesser extent, with
physical effort may also be explained by
proximal colonic cancer. Women situated in the
reduction of obesity in spite of the data that
highest percentile of recreational physical activity
demonstrated that physical activity may reduce
had a reduction of distal CRC risk by half as
the risk of CRC independent of the effect on
compared with women situated in the lowest
obesity. Another proposed mechanism involves
percentile (RR=0.54, 95% CI 0.34-0.84). Risk
accelerating the peristalsis which reduces the
reduction did not vary with body mass index
contact time between intraluminal carcinogens
(BMI), although former studies had suggested
and colonic mucosa. As a matter of fact, it is well
that physical activity had the greatest impact on
known data that physical active individuals are
CRC only in high BMI subjects. The level of
more prone to sun exposure for longer periods of
physical effort to produce prophylactic benefits
time which facilitates production of vitamin D
may be only minimal, as this study demonstrated.
that is associated with lessening the risk of
As such, even an hour of slight walking a week
CRC.[4]
may reduce the risk of CRC by 31% (RR=0.69, 95%
CI 0.45-1.03) as compared with women who do Figure 1: Mechanisms involved in protective effect of
not report any kind of physical activity. This physical effort on colorectal cancer risk
protective effect of slight walking reached a
plateau at 2 hours a week (RR 0.64, 95% CI 0.41-
1.00) as opposed to moderate and vigorous
physical effort that was characterized by very
clear dose-response relationship. The more alert
slight walking rendered greater protective effect
than slower slight walking (RR=0.43, 95% CI 0.17-
1.05). Furthermore, 4 hours a week of moderate/
vigorous physical effort may reduce the risk of An epidemiologic study published in 2008 (NIH-AARP
CRC by 44% comparing with 1 hour a week (RR= Diet and Health Study) shows interesting observations
0.56, 95% CI 0.33-0.94). Physical activity lessened regarding the periods of an individual life when the

42
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
physical effort has the utmost impact on the risk of
CRC. Thus, if the physical activity is performed in the
age group 15-30 years the impact on CRC risk
reduction will be minimal; on the other hand, if the
physical activity is performed in the age group 30-39
years or throughout the whole life of an individual the
reduction of CRC life-time risk will be maximal.[5]
Sedentarism is a globally important public health
issue, especially in developed countries, in women, in
old people and in low income individuals. Lack of
physical activity is responsible of the increase in
mortality rates especially from diabetes mellitus and
heart diseases. To a comparable extent physical
activity of moderate and vigorous intensity is
associated with certain benefits regarding health
status, including reduction of obesity risk,
cardiovascular risk, stroke risk, risk of some types of
cancers and decreasing in global mortality rate.
Physical activity increases the probability to cease
smoking, delays cognitive decline in old individuals,
alleviates the adverse effects of stress, anxiety and
depression. A study published in 2016 regarding the
issue of physical activity status in the group of more
than 50 years old individuals in USA the date are
worrisome: 27% do not report any kind of physical
activity outside working place in the last month; the
prevalence of inactivity increases with age, reaching
35.3% in age group after 75 years; sedentarism is more
prevalent in women then in men, in Afro-Americans
then in Caucasians. Also, the prevalence of inactivity is
decreasing with increasing in educational level and
with decreasing in BMI.[6]
Lack of physical activity is the main cause of CRC being
responsible of 14% of cases of CRC in USA; 12% of
cases may be attributable to western diet, 12% to lack
of daily administration of aspirin and 8% may be
related to a family history of CRC.[6]
Sedentarism, especially that kind related to spending
time in front of TV, is independently associated with
increasing CRC risk. Hence, if one spends 9 hours in
front of TV, as comparing with 3 hours or less, the risk
of CRC will rise significantly by a RR=1.61 (95% CI=1.14-
2.27).[5]
The relationship between physical activity, seden-
tarism and BMI is not to be changed even if one may
exclude the contribution of age, race, family history of
CRC, smoking and western diet.[6]
Several studies shows contradictory results concerning
the issue of rectal localization of CRC. Cancer
Prevention Study II indicates that moderate/vigorous
physical activity in men and in women reduces the risk
of rectal cancer by 30 %.[7] Many cohort studies did
not find any kind of association between physical
activity and rectal localization of CRC.[8,9]
A meta-analysis published in 2010, which included 20
studies on physical activity and colorectal benign
adenoma, concluded that there was 16% reduction of
the risk of these benign precursors of CRC if we
compared active population with less active
populations. Risk reduction was even more significant
if we took into consideration polyps bigger then 1cm
(31% risk reduction). It has been demonstrated in that
way that physical effort might decrease the risk of CRC
earlier in the stage of precursor lesions of oncogenic
process.[10]
The role of physical activity as a protection factor in
CRC is hardly known in general population. A study
developed in USA that included 2000 subjects showed
that only 15% of them are aware of this benefit of
physical activity.[6] One similar study from Europe that
included 21 countries indicated a 30% level of
knowledge concerning this topic.[11] Several studies
stated also that there was a close connection between
the level of information concerning prophylactic
benefits of physical effort in CRC and the increasing of
the motivational status to produce life style changes
that, in the end, will decrease the prevalence of
CRC.[12,13,14]
Physical exercises represent a form of human activity
that may benefit health more then it may inflict side
effects. The most common side effects are musculo-
skeletal injuries. The least common side effects
(sometimes more severe) are: cardiac arrhythmias,
heart arrest and myocardial infarction. Generally, we
may appreciate that the potential benefits of physical
exercises highly surpass the potential risks. Moreover,
it is considered that it is unnecessary to screen for
coronary diseases prior to initiating physical activity if
43
the subject was asymptomatic and included in the low In an observational study (unpublished data) that I
cardiovascular risk group. have conducted in 2016, concerning the topic of CRC
and its relationship with diabetes mellitus and other
One may consider mandatory that all healthy adult
risk factors an important conclusion has been drawn.
individuals to include in their life style moderate or
vigorous physical exercises. The majority of authors A multivariate analisys in which the most
agrees that the highest health benefits are provided by acknowledged CRC risk factors have been included
150 minutes a week of moderate physical activity or showed the statistical significance (p<0.05) have been
by 75 minutes a week of vigorous physical activity. reached for smoking and physical activity only. This
Nevertheless, adults that have a limited physical implies that by the way of increasing physical activity
activity capabilities should remain active because it levels in general populations and by giving up smoking
has been noticed that even if a modest amplitude of CRC „epidemics” could be fairly prevented.
physical effort is exercised regularly health benefits
will be significant. Table 1: Multivariate analysis of risk factors in CRC
Standard
Another epidemiologic studies suggest that physical Variabile Coeficient t Stat p
error
activity may influence not only the risk of CRC but also Age (years) 0.0014 0.0035 0.4087 0.68
it may prevent the recurence of CRC after curative BMI(Kg/m2) 0.0031 0.0055 0.5650 0.57
surgical treatment. All the data available resulted from Smoking 0.1273 0.0647 1.9658 0.05
observational type of studies; randomized and inter- Daytime
0.0150 0.0440 0.3404 0.73
ventional studies are not published. Nevertheless, nap (hours)
American Society of Oncology (ASCO) recently Physical
-0.1334 0.0601 -2.2181 0.02
recomended that the surviveours of CRC should activity

maintain an optimal weight, should perform daily

In conclusion, the preventable potential of CRC is high
physical exercises and should follow a healty diet.[14]
through the way of regular physical exercise and this
Futher on, there are some interesting results of a study
may represent a very approachable solution to
published in 2006 that included 832 patients suffering
decrease the global burden of the disease. It is very
from CRC stage III surgicaly treated and that followed
important to stress that the target of decreasing the
a program of chemotherapy. It has been demons-
prevalence of CRC by physical exercise does not
trated that moderate physical activity perfomed for at
necessarily imply an impact on obesity, the benefits on
least 300 minutes a week has increased the free
CRC being independent from the benefits on BMI. A
disease interval with 45% and has improved by 29-
good level of motivation in general population through
36% the mortality rate of any cause.[16] The benefits
health politics is mandatory because the changes in
have been dose dependent.
life-style (level of physical activity, diet and smoking)
are otherwise impossible to be reached.

References:
1. Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and
colon cancer prevention: a meta-analysis. Br J Cancer 2009;
100:611.
2. Boyle T, Keegel T, Bull F, et al. Physical activity and risks of
proximal and distal colon cancers: a systematic review and
meta-analysis. J Natl Cancer Inst 2012; 104:1548.
3. Christine M. Friedenreich, Heather K. Neilson, Brigid M.
Lynch. State of the epidemiological evidence on physical
activity and cancer prevention. Eur Journal Cancer 46 (2010)
2593-2606
4. Kathleen Y. Wolin, I-Min Lee, Graham A. Colditz, Robert J.
Glynn, Charles Fuchs and Edward Giovannucci. Leisure-time
physical activity patterns and risk of colon cancer in women.
Int. J. Cancer: 121, 2776–2781 (2007)
5. Regan A. Howard, D. Michal Freedman, Yikyung Park,
Albert Hollenbeck, Arthur Schatzkin, Michael F. Leitzmann.

44
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
Physical activity, sedentary behavior, and the risk of colon
and rectal cancer in the NIH-AARP Diet and Health Study.
Cancer Causes Control (2008) 19:939–953
6. Elliot J. Coups, Jennifer Hay, Jennifer S. Ford. Awareness
of the role of physical activity in colon cancer prevention.
Patient Education and Counseling 72 (2008) 246–251
7. ChaoA, ConnellCJ, Jacobs EJ et al (2004) Amount, type,
and timing of recreational physical activity in relation to
colon and rectal cancer in older adults: the Cancer
Prevention Study II Nutrition Cohort. Cancer Epidemiol
Biomarkers Prev 3:2187–2195
8. Friedenreich C, Norat T, Steindorf K et al (2006) Physical
activity and risk of colon and rectal cancers: The European
prospective investigation into cancer and nutrition. Cancer
Epidemiol Biomarkers Prev 15:2398–2407
9. Lee KJ, Inoue M, Otani T, Iwasaki M, Sasazuki S, Tsugane
S (2007) Physical activity and risk of colorectal cancer in
Japanese men and women: the Japan Public Health Cancer-
based prospective Study. Cancer Causes Control 18:199–209
10. KY Wolin, Y Yan and GA Colditz. Physical activity and risk
of colon adenoma: a meta-analysis. British Journal of Cancer
(2011) 104, 882 – 885
11. Keighley MR, O’Morain C, Giacosa A, Ashorn M,
Burroughs A, Crespi M, Delvaux M, Faivre J, Hagenmuller F,
Lamy V, Manger F, Mills HT, Neumann C, Nowak A, Pehrsson
A, Smits S, Spencer K, United European Gastroenterology
Federation Public Affairs Committee. Public awareness of
risk factors and screening for colorectal cancer in Europe. Eur
J Cancer Prev 2004;13:257–62.
12. Courneya KS, Hellsten L-AM. Cancer prevention as a
source of exercise motivation: an experimental test using
protection motivation theory. Psychol Health Med
2001;6:59–64.
13. Jalleh G, Donovan RJ, Slevin T, Dixon H. Efficacy of bowel
cancer appeals for promoting physical activity. Health
Promot J Austr 2005;16:107–9.
14. Meyerhardt JA, Mangu PB, Flynn PJ, et al. Follow-up
care, surveillance protocol, and secondary prevention
measures for survivors of colorectal cancer: American
Society of Clinical Oncology clinical practice guideline
endorsement. J Clin Oncol 2013; 31:4465.
15. Justin C. Brown , Andrea B. Troxel , Bonnie Ky , Nevena
Damjanov , Babette S. Zemel , Michael R. Rickels ,Andrew D.
Rhim, Anil K. Rustgi , Kerry S. Courneya , Kathryn H. Schmitz.
A randomized phase II dose–response exercise trial among
colon cancer survivors: Purpose, study design, methods, and
recruitment results. Contemporary Clinical Trials 47 (2016)
366–375
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Deborah A. Galuska, Ann O’Connor, Kurt J. Greenlund Janet
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36.
45
 Article received on March 28, 2018 and accepted for publishing on May 15, 2018.
ORIGINAL ARTICLES

The communication and promotion policies of the medical

organizations in the marketing of Romanian healthcare
services
Bogdan I. Coculescu1,2, Victor L. Purcărea3, Elena C. Coculescu4

Abstract: The interdisciplinarity of the marketing department is due to the application of concepts,
methods and marketing technics specific both to service and to social marketing. In addition to this
fact, the attempt of the social services to satisfy the patient’s needs places the health care domain at
the border between social and economic, between profit and non-profit orientation. However a lot of
the notions from the marketing field (competition, promotion, strategy, need, supply, cost etc.) acquire
new meaning when used for defining the rivalry between the distinct medical organizations, the
advance of the health care services, the development and implementation policies in medical
marketing, the increasingly acute demand for treatment, the use and the supply of health care services
as well as the cost that it requires..
Conclusion: These above described microscopy method can be used to distinguish between benign and
malignant thyroid nodules, based on different degree of the capsular collagen fibers orientation.
Keywords: communication policy, promotion policy, marketing mix strategy, Romanian healthcare
services

INTRODUCTION zations in order to attract new potential clients;

1 the health care market
Titu Maiorescu University,
Faculty of Medicine,
Bucharest
2Centre of Military Medical
Scientific Research, Ministry
of National Defence,
Bucharest
3Carol Davila University of
Medicine and Pharmacy,
Faculty of General
Medicine, Bucharest
4Carol Davila University of
Medicine and Pharmacy,
Faculty of Dental Medicine,
Bucharest
Medical organizations com-
munication policy towards
through constructive and
favorable relationships are
an important objective that
every health care provider
should promote. Primarily
communication strategies
target the following as-
pects:
- Promoting the service
offering of medical organi-
- Persuasion of the potential clients for the necessity
of purchasing these services by presenting the positive
advantages of the respective health care procedures.
Communications possess an important role in the
buying process, taking part both at the pre-sale and
sale, and also post sale stages [1-4].
DISCUSSION
Communication is a constituent of a great importance
in the marketing mix (product – cost – distribution –
development) aiming at establishing and maintaining
Corresponding author: Bogdan I. Coculescu MD, PhD
bogdancoculescu@yahoo.fr

46
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
a steady relationship with the patients. It represents
the tool with which an entity participates in the
informational exchange with the different business
field’s components, to inform about its presence, the
Figure 1: Communications and healthcare services marketing [5].
The instruments of the communicational mix are
based particularly on interpersonal communication,
yet at the same time on the adaptation and
enrichment of the classical techniques via the concept
of marketing integrated communication resulting in
complex communicational programs. The marketing
mix in the health care services sector includes as well
staff politics, represented by two segments which
must be approached differentially as follows: the
employees of the company providing services and the
consumers.
The principal methods and ways to communication,
that can be adopted by a medical organization in order
to orientate the patient in their referring to a certain
health care service or to build and reinforce a favo-
rable image of that sanitary unit on the market,
constitute the promotional mix of the medical
institution.
The achievement of an optimal promotional mix,
which satisfies the patients’ needs and fulfill the best
objectives of the promotional communication, is one
from the key points in obtaining the attributions
distinctive for a marketing specialist.
products and services it provides, to create a positive
attitude and to stimulate consumers to buy products
and services.
There are two ways by whom a medical organization
can communicate with its patients (Figure 1):
a. On the outside through:
 advertising
 promoting sales
 public relations
 direct marketing (inclusive online)
b. On the inside through the employed medical
personnel during the specific activities.
The advertising activity has clear purpose in preparing
the target public for favorable receiving of the medical
unit’s offer. Three types of marketing objectives are to
be distinguished from one another depending on their
purpose as follows: informing, convincing and
reminding. To advertise and broadcast the commercial
message the medical organization can make use of
different communicational channels: newspapers,
magazines, the press, printing materials (flyers,
brochures, catalogues), external publications
(billboards, posters, leaflets, stickers), internet, radio,
television etc. Through advertising activities the
medical organization succeeds in informing the
potential patients about its work and services with the
47
aim of influencing their decision for adherence to this
services.
The direct relationship between the medical staff and
the patients favors a particular manner of
communication: personal sale – the potential patients
can be notified and persuaded to subscribe for
services at the medical unit. Consequently the medical
contact personnel plays an important role for
increasing the sell’s volume in the medical system.
They must be very well prepared professionally and
respond promptly to the patients expectations.
Additionally the immediate connection with patients
represents the main way for informing them about the
benefits, offers, promotions, advantages, perfor-
mance conditions, health care services prices etc. of
the medical organization they belong.
A lot of the authors specify a clear distinction from the
concept of “team” and of “teamwork”. The “team”
concept is referring to persons who work together for
common purpose, while the “teamwork” concept – to
a certain environment from a larger organization,
which creates and sustain relations of trust, support,
respect, interdependence and collaboration.
It must be mentioned that in sanitary organizations –
particularly in the hospitals – team communication
possess an increasingly important role. A good team
communication, understanding the advantages,
disadvantages, “principles” of teamwork, contributes
to identifying the proper solutions to the inherent
problems. In multiple cases where it is necessary to
work as a team, encouragement and orientation of the
team members can improve the sanitary
organization’s results via: their motivation, use of the
team member’s ideas and personal capabilities,
acquiring support from their side, improving the
performance. Through guidance, the quality of health
employee’s performance can be made better, while
the tasks are accomplished properly by them.
Promoting is one of the forms of communication. The
difference between the two notions are made at the
level of the sent message. So that promoting to have
the desired effect, the messages received by the
patients must be clear and reflect what the
organization has to offer.
48
Promoting, as a variable from the marketing mix,
occupies place apart in the case of medical services,
because it is essential for the development and
maintenance of durable relations with the target
public. Marketing politics aims to inform the target
public as much as possible about the health activities
and the services offered by the respective medical
organization, but at the same time also for the
information received by them to have a positive
impact.
A particular case of promoting of medical organization
is represented by spreading the “mouth to mouth”
advertisement, from patient to patient, extremely
productive, as demonstrated fact in the practice of
health care service with results in growth of
consumers addressability in these services (“one
satisfied patient brings more patients”).
Client services in the field of health care relates to the
benefits offered to the patients – or the public in
general – further than the product itself, including its
nontechnical and nonclinical aspects. The connection
between client services and other elements of the
marketing mix is one of completion and support. The
efficient client services reduce the cost due to patients
and improves the access to health services [4-6].
CONCLUSIONS
Promoting sales imposes the use of all procedures and
stimulation techniques and increasing the sales of
medical services of the organization. If advertising has
a role in offering purchase motivation, conversely the
sell promotion has a role in the sells’ stimulating
process for the potential patients by the means of
consecrate methods in promoting sales, in the form of
promotional presents (watches, calendars, agendas,
pens, notebooks, umbrellas with inscription of the
medical organization etc.), with the aim of image
promoting on the target market.
Public relations have a part in setting trust relations
with the patients, ensuring protection, planning,
organizing and controlling the whole actions unfolded
by a medical organization for achieving its objectives.
The methods used in the activity of public relations for
obtaining the marketing goals (informing the patients
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
about the advantages of the organization, stimulating
the sales volume, keeping the investment in
promotional materials at minimal level) consists in
organizing events with scientific subject (congresses,
conferences), giving interviews, publishing brochures,
profile publications, promoting through press
conferences, participating in medical markets and
exhibitions etc. The coordination of a public relations
project with the other elements from the promotional
mix can be beneficial for the increase in prestige of the
medical organization.
The core of the marketing strategy in the field of
health care is presented by the quality of services,
quality which in its turn results from: precision of
performance, promptitude and professionalism of the
employees, kindness and politeness towards the
patients. Creation and implementation of a coherent
and productive medical marketing strategy as well as
References:
1 Kotler P., Keller K.L., Marketing management [in
Romanian], 5th Edition, Teora Publishing House, Bucharest,
Romania, 2008.
2 Coculescu B.I., Coculescu E.C., Radu A., Petrescu L.,
Purcărea V.L., Market policy as an innovative element of
marketing in the Romanian healthcare services - an
approach focused on the patient. Journal of Medicine and
Life, 2015, 8(4):440-443.
3 Coculescu B.I., Coculescu E.C., Purcărea V.L, Orientation to
the patient as marketing strategy in the Romanian public
healthcare system, Journal of Medicine and Life, 2016,
9(3):302-305.
defining the value system of a sanitary organization
consists a vital necessity for the organizations, whose
purpose is executing top health services.
In the field of health care services the marketing
strategy represents actually the attitude of the
sanitary organization towards the marketing
environment and simultaneously its behavior in regard
to its components.
Communication of the organization with the
marketing environment is an essential condition for
achievement of its activity objectives. The fulfilment of
the organization mission assumes concentrating
marketing efforts in the direction of achieving a
permanent and efficient communication with the
external surroundings, with the market and with the
patients.
4 Purcărea V.L., Coculescu B.I., Risk management in practice
by the revaluation laboratory methods and procedures
contained in the protocols work to reduce the number of
errors associated [in Romanian], “Carol Davila” University
Press, Bucharest, Romania, 2012.
5 Popa F., Purcărea T.V., Purcărea V.L., Rațiu M.P.,
Marketing of healthcare services [in Romanian], "Carol
Davila" University Press, Bucharest, 2007.
6 Purcărea V.L., Popa F., The medical system, in Ciurea A.V.,
Cooper C.L., Avram E., Management systems and health
organizations [in Romanian], "Carol Davila" University Press,
Bucharest, Romania, 2010.
49
 Article received on January 17, 2018 and accepted for publishing on March 15, 2018.
CLINICAL PRACTICE

Medical applications of the GC/MS method in the acute

intoxication with dimethoate – clinical case
Genica Caragea1, Mihail S. Tudosie2, Radu A. Macovei2,3, Ilenuţa L. Danescu3, Mihai Ionică1,4

Abstract: Mass spectrometry is a chemical analytical method of determining organic substances by

comparing their mass spectrum with mass spectra found in system libraries. In the case of biological
products, substances of interest, like organophosphorus compounds, must be separated and identified
for rapid and good medical measures (antidotism procedures) in acute intoxication case. A gas
chromatograph coupled with a Varian mass spectrometer (GC-MS), was used to develop the
application. The proposed objective is presenting the medical applicability in acute organophosphorus
compounds intoxication management of the GC/MS method (gas chromatography coupled with mass
spectrometry) as a separation and identification method for these compounds and their metabolites in
urine samples.
Keywords: dimethoate, GC/MS, urine, acute intoxication

INTRODUCTION both to limit their utilization and to control the

contamination of the environment.
Acute intoxications repre-
sent a worldwide problem The most efficient, but also most toxic substances
that tends to gain more utilized as pesticides are cholinesterase inhibitors
amplitude each year. (through reversible or irreversible mechanism). For
both mammals and insects, the major effect of these
Each intoxication presents
substances is the inhibiting of acetylcholinesterase
certain characteristics which
through the phosphorylation of the esterase site. The
stem from the degree of
signs of symptoms which characterize the acute
socio-economic develop-
intoxication are caused by the inhibition of this
ment of each country.
enzyme and the accumulation of acetylcholine. Some
1Military Medical
The organophosphorus com- of these substances possess a direct cholinergic
Research Center,
Bucharest, Romania pounds are mainly used to activity.[4]
2Carol Davila University fight pests, as an alternative
of Medicine and The absorption of organophosphorus compounds can
to chlorinated hydrocarbons,
Pharmacy, Bucharest be realized through three methods: inhalation,
3
Floreasca Clinical which persist much longer in
digestive and through the skin. One of their main
Emergency Hospital, the environment. Yet these
Bucharest, Romania characteristics is the fixation at hair level, where they
substances are very toxic for
4Polytechnic University, enter through the skin, thus representing a permanent
Bucharest, Romania
humans too.[6] Because of
source of intoxication. Through the inhalation way, the
this, measures were taken
intoxication is the most rapid. Through direct action on

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

the bulbar respiratory center (muscarinic phenome- represent severe threats to humans, animals and the
non) and the paralysis of respiratory musculature fauna.[2]
(nicotinic phenomenon), respiratory arrest occurs.
The dimethoate, patented and introduced in the 50s,
Organophosphorus compounds are rapidly absorbed
is a acetylcholinesterase inhibiting organo-phosphorus
through the skin or digestively in the thin intestine.
compound, it is not volatile, it is water soluble and it is
They bind well to the plasmatic proteins. High
not mobile in soil, where it degrades with a half-life of
concentrations can be attained in the body within
approximately 2-4 days, depending on the conditions.
hours.[7]
Dimethoate and omethoate urine levels reflect recent
Organophosphorus compounds represent a group of exposure.
compounds with liposolubility or hydrosolubility, with
Once having entered the body, organo-phosphorus
high distribution volume. They are rapidly distributed
compounds are metabolized to dialkylphosphates,
in the liver, lungs, kidneys, heart and brain but do not
which are eliminated through urine. Their
accumulate.
metabolizing takes place rapidly in the body and as
This type of organophosphorus compounds is such they don’t accumulate.
liposoluble, accumulating in the lexophile tissues of
Compounds such as parathion, malathion, phenthion,
the organism, being a source for metabolic conversion
chlorpyrifos, normally inactive, enter the body and
to very toxic compounds. Thus, the intermediate
transform at liver microsomal level, through oxidation,
syndrome can be explained (it appears between the 5th
into highly active compounds (paraoxon, malaoxon).
and 18th day from the intoxication). The toxicity of
Identification of these metabolites in the urine may be
these compounds is manifested through the direct
an indicator of exposure to organophosphorus
inhibition of cholinesterase, probably through direct
compounds and can be performed through a GC/MS
poly enzymatic inhibition.[7]
analytical method with an ion trap and electronic
The metabolizing of organophosphorus com-pounds ionization.
takes place rapidly in the body, and as such they do not
The dimethoate is rapidly metabolized, mainly
accumulate. Compounds such as parathion,
through the initial splitting of the C-N bond to obtain
malathion, phenthion, chlorpyrifos, normally inactive,
dimethoate carboxylic acid and, eventually, a number
upon entering the body they transform at liver
of tiophosphate and phosphate esters. The minor
microsomal level, through oxidation, in highly active
quantitative elimination way involves the oxidative
compounds (paraoxon, malaoxon).
metabolism to produce the oxygen analogue of
This transformation takes place under the action of dimethoate, omethoate. The parent compounds
paraoxonase. Their degradation takes place through represents 1-2% of the dose excreted in the urine.[5]
hydrolytic and oxidative ways, through liver and
kidney enzymes. The erythrocyte-origin cholineste- MATERIALS AND METHOD
rase remain blocked for the remainder of the red
The research was performed on a GC-MS Saturn 2000
blood cell’s life. Their regeneration takes place slowly
Varian system composed of gas chromatograph model
(0.5-1% per day), remaining below normal level for
Varian CP – 3800 and mass spectrometer Varian
over 3 months in severe intoxications.[8]
Saturn – 2000.
Organophosphorus compounds are eliminated
Establishing optimal working conditions and functional
through urine as such or as metabolites.
parameters for the development of a GC/MS method
In the current global situation, it is very probable that are important steps in the development of a GC/MS
these substances will be used in wars, conflicts, method for the separation and spectral identification
terrorist attacks. In such scenarios, they are used as of dimethoate in urine.
extremely toxic agents and thus continuously

51
ANALYTICAL CONDITIONS Mass spectrometer parameters
Manifold temperature = 800o C
GC – an instrument equipped with a ion trap detector;
Ion trap temperature = 1700o C
GC – gas-cromatograph has the role of taking in the
Ionization current = 20 µA
sample and separate the mixture of substances
Acceleration tension = 70 eV
composing it.
Working times
0 - 5 min – closed filament
GC/MS parameters
5 - 37 min acquisition in mass domain 50 - 450 amu.
Injector temperature: 300° C
Acquisition domain 50 – 400 amu
Carrier gas: He • Column flow: 1.2 ml/min
Segment setpoint
Separation time: 50 min
Scan time = 1 sec/scan
Ionization mode: electron impact (70eV)
Multiplier offset = 0 V
Ionization current: 20 μA
Emission current in FS 10 µA
Ionization temperature: 170° C
Ion threshold 1 count
Detection mode: full scan
Manifold temperature: 80° C
Scanning parameters for ions formed in the trap are
Ion trap temperature: 170° C
presented in Table 2.
Interface temperature GC-MS: 260° C
Table 2. Scanning parameters for ions formed in the trap.
The separation of the compounds was realized by the
Ionization Ionization
active layer of the DB-5MS capillary column (length 30 Low Mass High Mass
Storage Level Time Factor
(m/z) (m/z)
m, internal diameter 0.25 mm, film thickness 0.25 µm). (m/z) (%)
The optimal conditions for chromatographic 10 99 48.0 100
separation and detection were established following 100 249 48.0 100
the study on the compound’s retention time’s 250 399 48.0 100
dependency on the structures of the said substances. 400 650 48.0 100

The temperature program of the gas-chromatograph’s

column’s furnace is presented in Table 1.
Table 1: The column gas furnace temperature program.
Temperature (°C) Rate (°C/min) Hold (min)
140 0.00 1
290 5.00 19.00
MS – mass spectrometer – has the role of analysing
molecules that come out of the gas-chromatograph
through their unique mass spectre. Thus, the
molecules that come out of the GC can be identified by
the user. Mass spectrometry established the relative
abundance of ions resulted from the ionization
process of an organic molecule. The method is used in
chemical analyses, in the analysis of some quantum
processes or in the separation of certain chemical
elements. The determined mass represents the m/z
ratio (mass to charge) of the atom or group of atoms
from which the ions resulted.
Normally, the mass spectrometer operates in the
domain in which the analyzed substances will be
found. When coupling it with a gas-chromatograph,
substances no greater than 450 amu will be sent to
the mass spectrometer, as those with greater
molecular weight cannot be vaporized in the
chromatographic column.
Thus, the maximum acquisition domain will be 50 –
450 amu, as below 50 amu an acquisition is not typical,
since the atmosphere in the apparatus has a rich
spectre up to 44 amu.
The use of the full scan technique (FS) is very good,
since following the obtaining of the mass spectre, it
can be compared with mass spectres already existant
in dedicated spectral libraries. In this case though, the
duration of a ion’s analysis is of 4ms, in case it is used
as an acquisition time for a scan of 1 s.
Confirming the identity of the compounds relies on
comparing the mass specter and ratio of reference

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
ions’ abundance for each analyzed substance
identified in the sample with those of standards using
the mass specter library. To identify the obtained
specters, the following were used: Pfleger – Maurer –
Weber specter library (PMW), specialized for
compounds of interest in toxicology as well as specter
libraries NIST2000 and Wiley6. If a mass spectre
obtained from the sample cannot be compared with
mass spectres in specialize spectral libraries, the
identification of these compounds in biological
matrices would not be possible to perform.
RESULTS AND DISCUSSIONS
Dimethoate has moderate acute toxicity for mammals
(for example, DL50 in mice and rats is 150 and 400 mg/
kg of bodyweight) (IPCS, 1989). Omethoate is
approximately 10 times more toxic and a stronger
cholinesterase inhibitor than dimethoate. Dimethoate
is well distributed in the body’s tissue and metabolized
in the liver to omethoate (most probably through the
enzyme system of P450 cytochrome) which is then
quickly transformed into multiple dialkyl methyl
phosphate metabolites, which are eliminated in urine
within 1-2 days. Dimethoate is considered mutagenic,
but it is not teratogenic. [1,10].
In order to verify the developed methods, they were
applied on biological samples obtained from patients
in the ATI II Clinical Toxicology Section, patients
suspected of acute organophophorus compounds
intoxication. The urine (aprox. 25 ml) undergoes
liquid-liquid extraction procedures in order for the
sample to be analyzed through the GC/MS system. For
example, we present the medical applicability of this
method in the case of an acute dimethoate
intoxication.
The separation and identification of dimethoate or
Table 3: Specific ionic fragments and spectral lines for dimethoate
Spectral
Compound
line (m/z)
Dimethoate 157
C5H12NO3PS2 143
(M=229)
125
93
omethoate in urine corroborate with the enzymatic
activity determinations for serum pseudo-
cholinesterase and lead to the establishment of an
analytical diagnosis in case of an acute dimethoate
intoxication and the initiation of specific therapies for
this type of intoxication (such as antidotes).
Identifications are performed through the comparison
of the mass specter obtained through the analysis of
urinary extract samples with mass specters already
existent in the database. This specter is obtained
based on the molecular mass of the compound of
interest which, following fragmentation, gives birth to
specific spectral lines. These are shown in tables 3 and
4.
CASE REPORT
C.P., male, aged 19, no occupation
Admission reasons
- Coma
- Acute respiratory insufficiency
- Muscular fasciculation
APP – no significant case history
History – patient with no significant case history is
found by his parents in a coma with respiratory
dysfunctions and muscular fasciculation, symptoms
that follow the voluntary ingestion of an
organophosphorus pesticide. Near the young man,
the parents found an unlabeled bottle containing a
liquid with a smell particular to insecticides. They call
the ambulance and the young man is transported to
the Clinical Emergency Hospital.
In the Major Emergencies Department, the patient is
in a coma with severe dyspnea and muscular
fasciculation. The oropharyngeal secretions are
vacuumed and orotracheal intubation and Ruben
balloon ventilation are applied.
Chemical formula of ionic
fragment
– [M-72] - (CH3O)2PS.S+
– [M-86] - (CH3O)(HO)PS.S+
– [M-104]- (CH3O)2PS+
– [M-136]- (CH3O)2P+
53
 Figure 1: Mass spectre for dimethoate (Nist98 library)

Figure 2: Mass spectre for omethoate (Nist98 library)

Table 4: Specific ionic fragments and spectral lines for omethoate

Spectral Chemical formula of ionic
Compound
line (m/z) fragment
Omethoate 156 – [M-57] - CH3NCO
C5H12NO4PS 141 – [M-72] - (CH3O)2P=O.S+
(M=213)
126 – [M-87] - (CH3O)2(HS)P+
110 – [M-103] - (CH3O)2(HO)P+
109 – [M-104] - (CH3O)2P=O+
79 – [M-134] - (CH3O)(HO)P+

The determination of pseudocholinesterase activity Objective examination upon admission:

detects a high degree of inhibition of 0.5 UI/ml. A urine - Severe general condition;
sample is being taken for the toxicological examination - Reed IV coma; non-reactive;
and is sent to the Analytical Toxicology Laboratory. - Pale, sweaty skin;
The patient is hospitalized in the ATI Toxicology - Cyanotic extremities;
Section. - Miotic, equal pupils, with slow photomotor pupil

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

reflex; - Central sub-clavicle catheter

- Strong reflexes in all four members, with subintrant
muscular fasciculation;
- At pulmonary level, bronchial rales bilaterally
diffuse;
- Does not efficiently ventilate on IOT probe, so
mechanical ventilation is applied;
- Diarrhea;
- Arterial Tension = 80/60 mm Hg;
- Subfebrile (to = 37.5).
ECG upon admission records sinus bradycardia
(44/min) without conduction or repolarization.
The CT brain scan and lumbar puncture exclude a
vascular etiology of the coma.
The analytical toxicological GC/MS examination of the
urine:
Following the analysis of the urine, the total ion
chromatogram that is shown in Figure 3 was obtained.
In it, besides dimethoate, its metabolites can also be
identified.
The substances identified through the above GC/MS
method used for the urine analysis are shown in table
5.
The cardiopulmonary radiography detects a homo-
genous opacity situated in the inferior right pulmonary
field.
Therapeutic measures
Stabilization
- Vacuuming tracheobronchial secretions
- Support ventilation
- Nasogastric intubation; gastric lavage;
- Parenteral fluids
o glucose solution;
o Ringer solution;
o isotonic saline solution;
o Gelofusine;
Support therapy
- Specific antidote – atropine under clinical
surveillance
- Mucolytic – acetyl cysteine;
- Bronchodilators – miofilin;
- Antibiotherapy in combinations (penicilin G 1 milion
UI/6 hours + gentamicin 80 mg/day + metronidazol
500 mg/day);
- Plasma – 4 units/day, for 3 days and 2 units/day for
2 days;
- Monitoring vital functions;
- Monitoring pseudocholinesterase activity.
The applied therapeutic measures, respiratory and
general nursing are continued.
Clinical evolution
4 days from admission, the evolution is favorable; the
patient is conscious; he is taken off the mechanical
ventilation apparatus; he breathes spontaneously with
the intubation probe and is extubated. His oral cavity
is washed.
The cholinesterase activity is measured: 2.1 UI/ml.
The antibiotherapy is continued 3 days from the
extubation to solve his pulmonary affection.
The evolution is favorable. The patient is released 7
days from admission with no neurological damage.

Table 5: The substances identified in the urinary extract that was analyzed through the GC/MS method and their specific
spectral lines.
Compound MW EI fragment ions (m/z)
Dimethoate 229 87, 125, 93, 79, 229
Omethoate 214 156, 126, 110
Dimethoate M 230 93, 125, 198, 230
(HOOC-) ME
Phosphoditioic 172 93, 109, 125
acid – O,S,S
trimethyl ester

55
 Figure 3: Dimethoate and its metabolites – omethoate, dimethoate M (HOOC-) ME and the phosphoditioic acid – O,S,S
trimethyl ester. Omethoate mass specter.

CONCLUSIONS specialized libraries, making possible the identification

The GC-MS method is the only method that can
determine organophosphorus compounds in unknown
matrices for the quality control of water, the
environment and foods or to establish the analytical
diagnosis in case of contamination/intoxication with
organophosphorus compounds.
of these substances in unknown matrices.
To reduce the number of false positive or false
negative results, analytical procedures based on
precision, accuracy, detection limits, error source
identification are needed but also the expanding of
existent spectre databases.

The mass spectrometer can acquire data through A quick and correct analytical diagnosis influences the
various methods. In “full scan” method (FS), the mass quickness and correctness of specific therapy
spectre obtained through electron impact ionization measures that can be applied in such a context.
can be compared with mass spectres found in

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

References:

1. *** Food and Agriculture Organization/World Health 5. Kirkpatrick D (1995). 14C-Dimethoate: the biokinetics and
Organization (FAO/WHO). 4.10 Dimethoate, omethoate, and metabolism in the rat. DTF Doc No: ‘651-001’ [CHA; sub:
formothion (T**). In: Pesticide Residues in Food-1996. 12564, Ref: 3-1/Vol 3-2]
Report of the Joint Meeting of the FAO Panel of Experts on 6. Lewis R.A. Lewis’ Dictionary of Toxicology. CRC Lewis,
Pesticide Residues in Food and the Environment and the 1998.
WHO Core Assessment Group. FAO Plant Production and 7. Tudosie M., Macovei R.A., Ionică M. Corelaţii
Protection Paper, 140, 1997. Rome, 1997. 4/4/13 toxicocinetice şi toxicodinamice în intoxicaţia acută cu
2. Gupta R.C. Handbook of toxicology of chemical warfare compuşi organofosforici. Editura Universitară “Carol Davila”,
agents. Elselvier, 2009. Bucureşti 2014.
3. *** International Programme on Chemical Safety (IPCS). 8. Voicu V. Toxicologie Clinică. Editura Albatros, Bucuresti,
Environmental Health Criteria 90. Dimethoate [online]. 1997, 155 – 158.
1989. Available at URL: 9. http://www.inchem.org/documents/ehc/ehc/ehc90.htm
4. Ionică M., Macovei R.A., Dumitraşcu M., Costea V., 4/20/13
CarageaG., Forje M., Anghelescu G., Zamfir O. Increased the 10. Hassan A, Zayed SMAD, Bahig MRE. Metabolism of
sensitivity of optoelectronic methods in the identification of organophosphorus insecticides—XI. Metabolic fate of
reversible cholinesterase inhibitory substances. Smart dimethoate in the rat. Biochem Pharmacol
Applications & Technologies for Electronic engineering 1969;18(10):1419-38.
SATEE 2016, Alba Iulia.

57
 Article received on February 15, 2018 and accepted for publishing on May 21, 2018.
CLINICAL PRACTICE

Rare case of Stevens-Johnson-TEN overlap syndrome caused

by mycotoxins
Cristian Cobilinschi1, Radu C. Țincu2,3, Mihail S. Tudosie3, Zoie Ghiorghiu2, Radu A. Macovei2,3

Abstract: Mushroom poisoning is rarely associated with skin involvement. Stevens-Johnson syndrome
(SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous reactions, characterized
by extensive necrosis. SJS/TEN overlap includes patients with skin exfoliation between 10 to 30 percent
of the body surface area. We report the case of a patient that was assumed to have ingested one type
of toxic mushroom within the twelve hours prior to the appearance of skin lesions typical for SJS/TEN
overlap syndrome.

Keywords: Amatoxin, skin involvement, SJS/TEN overlap, MODS

INTRODUCTION cause of death in mushroom poisoned patients is

Amanitaphalloides, also called ʺthe death capʺ.[5-8]
Picking wild mushrooms is a
Toxic effects of Amanitaph. are determined by
very popular activity in
phallatoxins and amatoxins.[6,9] Phallatoxins are
European countries, there-
heptapeptides with severe toxic systemic effects that
fore mushroom poisoning is
cannot be absorbed from the digestive tract.[10]
a constant and serious
However these toxins can induce gastrointestinal
health issue [1-3]. More than
symptoms through lesions of the enterocytes .[1]
fifty species of toxic
1
Anesthesiology and mushrooms are known, α-amanitin, the most important amatoxin, is resistant
Intensive Care Unit which are usually very to all gastrointestinal fluids and after absorption it
Department, Clinical
Emergency Hospital, similar to edible mushrooms. mainly locates in the hepatocytes.[10,11] After
Bucharest [4,5] reaching the liver cells, α-amanitin binds DNA-
2 Anesthesiology and dependent ribonucleic acid (RNA) polymerase II, with
Intensive Care – The most severe cases of
Toxicology Unit high specificity, causing protein synthesis inhibi-
mushroom poisoning are
Department, Clinical tion.[11,12] Its toxic effects are also increased through
Emergency Hospital, mainly caused by ciclo-
Bucharest
the enterohepatic circulation of this toxin.[1,11]
peptides – toxins contained
3Carol Davila University
by Amanita mushrooms. Corresponding author: Cristian Cobilinschi, MD
of Medicine and
Pharmacy, Bucharest [2,5,6] The most frequent cob_rodion@yahoo.com

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
Histopathological results of these effects are initially
represented by nuclear lipid and carbohydrate
deposits and finally by hepatic centrolobular
necrosis.[1,12] α-amanitin also affects other
metabolically active tissues like the kidney or the
gastrointestinal tract.[7,12,13] No cases of skin
involvement secondary to Amanita ph. poisoning have
been reported so far except erythromelalgia – a
disease that is characterized by erythema and pain
especially in the extremities – that was sometimes
associated with some species of mushroom
intoxication, but never with Amanita ph.
Poisoning.[14,15]
Steven-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) are rare but highly severe disorders
that can affect patients of all ages.[16,17]
Caused by a variety of drugs, infections and rarely by
toxins, SJS and TEN are defined as a hypersensitive
cutaneous reaction that produces dermato-bullous
skin lesions.[16,18-20] Pathogenesis of these
conditions is controversial and involves genetic
susceptibility (haplotypes like HLA B*1502, HLA B12
etc.), immune cells (especially T lymphocytes CD 8+),
cytokines and mediators of cell death.[16,19,21]
Although initially was thought that SJS and TEN are
separate entities, today it is considered that they are
varying degrees of severity of the same disease.[22]
The difference between these two forms of disease is
represented by the percentage of the affected body
surface area (BSA) – SJS detachment of <10 % BSA and
TEN detachment of >30% BSA.[17,22]
Overlapping SJS/TEN includes cases with detachment
between 10-30% BSA.[22,23] Regardless of the size of
the affected area erythematous and macular lesions
may be associated.[17]
Apart from skin lesions, mucosal (respiratory,
gastrointestinal, urinary) and other organs (liver, lungs
and kidneys) involvement can occur.[20,24-26]
Despite numerous attempts of identifying an effective
curative therapy SJS/TEN has a mortality rate from 5
to 30%.[27]
Furthermore a variety of long-term sequelae can be
encountered in surviving patients.[24]
CASE PRESENTATION
We present the case of a 49 year old female patient
who was transferred to the Anesthesiology –
Toxicology – Intensive Care Unit of the Clinical
Emergency Hospital in Bucharest from a regional
Hospital Unit. She was suspected to have ingested a
sort of poisonous mushroom within the 12 hours prior
to admission. She presented to the emergency room
after mushroom consumption after picking them from
a local forest. During the night the patient presented
abdominal pain, nausea, vomiting and diarrhea, for
which she administered no treatment. In the morning
she decided to go to the emergency room, although
clinical signs became milder. Her medical records
revealed no pathological findings, except an untreated
dyslipidemia. Clinical examination revealed a
mediocre general condition, pale skin, gingivitis,
tachycardia and mild abdominal pain. Furthermore
she noticed appearance of cough and rhinorrhea in the
last two hours. After volume and electrolyte
rebalancing, she was transferred to our Department.
On admission the patient presented an altered general
state, she was conscious and feverish (38.6°C). Apart
from cough and rhinorrhea she also presented
dysphagia, myalgia and arthralgia especially in the
lower limbs. Physical examination revealed jaundice,
diffuse erythema on hands and feet, tachypnea,
tachycardia (HR=113bpm), hepatomegaly. Preliminary
laboratory results indicated hepatic cytolysis (ALAT =
9,412 U/L, ASAT = 6,720 U/L), hyperbilirubinemia (4
mg/dl), decreased serum potassium (3.1), elevated
creatinine level (2 mg/dl) and blood urea nitrogen
(BUN = 49.4 mg/dl). Electrocardiography showed no
abnormality, except the abovementioned tachycardia.
Superior digestive endoscopy indicated diffuse
erythematous lesions in the pharynx and esophagus.
Although according to the description of the ingested
mushroom we suspected an Amanita ph. poisoning,
rapid Meixner test could not be performed due to the
lack of gastric material when endoscopy was
performed. Therefore mushrooms leftovers from the
meal were sent to a specialized laboratory.
Considering the high suspicion of developing Steven-
Johnson syndrome and the liver insufficiency
59
secondary to mushroom poisoning, initial therapy
management was carefully selected. Oxygen therapy,
fluid replacement was initiated in combination with
gastric protection, antiemetic and diuretic therapy.
Vitamin supplementation, corticotherapy (prednisone
138 mg/day) and antioxidant therapy (N-acetyl-
cysteine 1,800 mg/day and alpha lipoic acid 900
mg/day) were also added. We performed continuous
digestive decontamination by administering 25 mg
mannitol p.o, 20 g lactulose and Ricinus communis oil
15 mg. Moreover activated charcoal administration
was started in order to interrupt mushroom toxins
enterohepatic recirculation.
Twelve hours after admission the patient presented
altered mental status, dyspnea, tachypnea and a
peripheral oxygen saturation of 80% under oxygen
mask. Because of that she was intubated and
mechanically ventilated. Despite volume controlled
ventilation hypoxemic index could not raise above
100. Furthermore over the erythematous areas of the
feet and hands atypical irregular lesions with darker
centers were observed. These lesions evolved within
the next twenty four hours to vesicles and bullae
(Nikolsky sign and Asboe-Hansen sign positive)
(Figures 1 and 2).

Figure 1

Figure 2

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

Figure 3

Skin lesions extended in the next few hours on both
forearms (Figure 3) and legs thus evaluating the
affected body surface, this case was classified as
Steven-Johnson – TEN overlap syndrome.
Gynecological exam also revealed vulvar bullae. In this
conditions SCORTEN score indicated a mortality risk of
58.3%.
Four days from admission Amanita ph. toxins were
identified in the laboratory.
Since Amanita ph. poisoning is not a specific cause of
Steven-Johnson syndrome, other causes were
thoroughly investigated.
Usually associated medication which is a trigger for
Steven-Johnson was excluded through detailed
anamnesis of the patient and her family. Viral and
bacterial causes like HIV, Cytomegalovirus or
Mycoplasma pneumonie were excluded after the PCR
and/or serological tests were negative.
Although liver insufficiency was remitted after one
week of treatment the evolution of the patient was
severe. Twelve days after admission the patient died
with multisystem organ failure.
DISCUSSION
Numerous studies are dedicated to the toxic effects of
mushroom poisoning. A considerable percentage of
fatal mushroom poisoning cases occur after ingestion
of Amanita ph.[1] Although amatoxins induce massive
liver cell necrosis, not all patients develop fatal acute
liver failure.[4]
Moreover, various treatment strategies proposed in
the literature decreased the mortality rates in these
patients.
Delayed onset of signs and the polymorphic symptoms
due to amatoxin poisoning may aggravate liver
toxicity, in the absence of early decontamination
treatment.[2] Besides liver failure, amatoxin was
associated with nephrotoxicity.[7] However there is no
report in the literature about the amatoxin’s toxic
effects on skin.
SJS/TEN is an acute severe mucocutaneous disease
caused by a variety of drugs, infections or malignant
comorbidities.[21] In the case presentation, the
patient did not receive any medication potentially
associated to SJS/TEN, neither in our unit nor in the
regional hospital. Moreover she was not on any
chronic treatment or suffered from any infectious or
malignant disease. However, several serological tests
were performed in order to exclude the most frequent
infectious causes of SJS/TEN.
SJS/TEN is often preceded by a prodrome
characterized by fever, headache and
pharyngitis.[16,17] In this case report after the
gastrointestinal phase of the amatoxin poisoning, the
patient developed rhinorrhea, malaise, dysphagia and
fever.
SJS/TEN may be associated with multisystem organ
failure.[16] In addition to the hepatic failure caused by
the amatoxin poisoning, soon after admission the

61
patient developed respiratory dysfunction, requiring
mechanical ventilation. Secondary to the respiratory
and hepatic dysfunction, neurological dysfunction
developed. Despite adequate volume repletion, cardio
circulatory dysfunction appeared requiring continuous
vasopressor therapy.
There are no recommendations regarding treatment
of the acute phase of SJS/TEN.[16] Considering that
there is no specific treatment for SJS/TEN, minimizing
the therapy with risk of aggravation of SJS/TEN was
tried and corticotherapy was initiated. Despite the
maximal supportive treatment and liver function
References:
1. Santi L, Maggioli C, Mastroroberto M, Tufoni M, Napoli
L, Caraceni P. Acute Liver Failure Caused by Amanita
phalloides Poisoning. 2012;2012:2–7.
2. Enjalbert F, Rapior S, Nouguier-Soulé J, Guillon S,
Amouroux N, Cabot C. Treatment of amatoxin poisoning: 20-
year retrospective analysis. J Toxicol Clin Toxicol.
2002;40(6):715–57.
3. Badsar A, Taramsari MR, Maafi AA, Rad MR, Chatrnour
G, Jahromi SK. Mushroom Poisoning in the Southwest Region
of the Caspian Sea , Iran : A Retrospective Study. 2013;7(20).
4. Escudie L, Francoz C, Vinel J, Moucari R, Cournot M,
Sauvanet A, et al. Amanita phalloides poisoning :
Reassessment of prognostic factors and indications for
emergency liver transplantation. 2007;46:466–73.
5. Berger KJ, Guss DA. Selected Topics : Toxicology
MYCOTOXINS REVISITED : PART I. 2005;28(1):53–62.
6. Vetter J. Toxins of Amanita phalloides. Toxicon.
1998;36(1):13–24.
7. Garcia J, Costa VM, Carvalho A, Baptista P, De PG,
Lourdes M De, et al. Amanita phalloides poisoning :
Mechanisms of toxicity and treatment. 2015;86:41–55.
8. Vendramin A, Brvar M. Toxicon Amanita muscaria and
Amanita pantherina poisoning : Two syndromes. Toxicon.
2014;90:269–72.
9. Yilmaz I, Kaya E, Aydin Z, Bayram R. Toxicon Clinical
importance of toxin concentration in Amanita verna
mushroom. Toxicon. Elsevier Ltd; 2014;87:68–75.
10. Walton J, Hallen-Adams H, Luo H. Ribosomal
biosynthesis of cyclic peptide toxins of Amanita mushrooms.
2011;72(2):181–204.
11. Letschert K, Faulstich H, Keller D, Keppler D. Molecular
62
improvement, the patient died from multisystem
organ failure.
CONCLUSIONS
From our knowledge this is the first case report on
Stevens-Johnson/TEN overlap syndrome induced by
mushroom poisoning. This case presentation aims to
highlight the polymorphic manifestations of severe
amatoxin intoxication as well the difficulties of
managing such a patient. Clinicians should be aware of
the systemic involvement in mushroom poisoning.
characterization and inhibition of amanitin uptake into
human hepatocytes. Toxicol Sci. 2006;91(1):140–9.
12. Smith MR, Davis RL. Mycetismus: a review.
2015;(October):1–6.
13. Kirchmair M, Carrilho P, Pfab R, Haberl B, Felgueiras J,
Carvalho F, et al. Amanita poisonings resulting in acute,
reversible renal failure: New cases, new toxic Amanita
mushrooms. Nephrol Dial Transplant. 2012;27(4):1380–6.
14. Latessa V. Erythromelalgia: A rare microvascular disease.
J Vasc Nurs. Society for Vascular Nursing, Inc.;
2010;28(2):67–71.
15. Saviuc P., Danel V., Moreau P., Claustre A., Ducluzeau R,
Carpentier P. Érythermalgie soudaine : cherchez le
champignon ! La Rev Médecine Interne. 2002;23(4):394–9.
16. Kohanim S, Polioura S, Saeed H, Akpek E, Amescua G,
Basu S, et al. Stevens-Johnson Syndrome / Toxic Epidermal
Necrolysis A Comprehensive Review and Guide to Therapy .
I . Systemic Disease. 2016;14(1):2–19.
17. Schwartz RA, Hon D, Edin F, Mcdonough PH, Lee BW.
Toxic epidermal necrolysis manifestations, etiology and
immunopathogenesis. J Am Dermatology. Elsevier Inc;
69(2):173.e1-173.e13.
18. Batra S. Serious cutaneous adverse reactions to
traditional Chinese medicines. Singapore Med J.
2006;47(7):647.
19. Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal
necrolysis ( Lyell ’ s disease ). Burns. Elsevier Ltd and
International Society of Burns Injuries; 2010;36(2):152–63.
20. Downey A, Jackson C, Harun N, Cooper A. Toxic
epidermal necrolysis : Review of pathogenesis and
management. J Am Dermatology. American Academy of
Dermatology, Inc.; 2012;66(6):995–1003.
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
21. Darlenski R, Kazandjieva J. Systemic drug reactions with
skin involvement : Stevens-Johnson syndrome , toxic
epidermal necrolysis , and DRESS. Clin Dermatol. Elsevier
Inc.; 2015;33(5):538–41.
22. Bastuji-Garin S. Clinical Classification of Cases of Toxic
Epidermal Necrolysis, Stevens-Johnson Syndrome, and
Erythema Multiforme. Arch Dermatol. American Medical
Association; 1993 Jan 1;129(1):92.
23. Barvaliya M, Sanmukhani J, Patel T, Paliwal N, Shah H,
Tripathi C. Drug-induced Stevens-Johnson syndrome (SJS),
toxic epidermal necrolysis (TEN), and SJS-TEN overlap: a
multicentric retrospective study. J Postgrad Med. 2011 Jan
1;57(2):115–9.
24. Saeed H, Mantagos IS, Chodosh J. Complications of
Stevens – Johnson syndrome beyond the eye and skin.
Burns. 2015;42(1):20–7.
25. Yamane Y, Matsukura S, Watanabe Y, Yamaguchi Y.
Allergology International Retrospective analysis of Stevens e
Johnson syndrome and toxic epidermal necrolysis in 87
Japanese patients e Treatment and outcome. Allergol Int.
Elsevier B.V; 2016;65(1):74–81.
26. Suwarsa O, Yuwita W, Dharmadji HP, Sutedja E. Stevens-
Johnson syndrome and toxic epidermal necrolysis in Dr.
Hasan Sadikin General Hospital Bandung, Indonesia from
2009–2013. Asia Pac Allergy. 2016;(6):43–7.
27. Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin
ME. Stevens-Johnson syndrome and toxic epidermal
necrolysis. Autoimmun Rev. 2008;7(8):598–605.
63
 Article received on October 10, 2017 and accepted for publishing on June 20, 2018.
CLINICAL PRACTICE

Uncommon giant sphenoidal tumor. Case report

R. Hainăroșie1,2, Irina Ioniță1,2, Cătălina Pietroșanu1,2, S. Pițuru1, Mura Hainăroșie1,2, V. Zainea1,2

Abstract: The authors will present a case report of a woman that presented a giant sphenoidal tumor
with endocranially extension and compression of the cerebral trunk. The patient was already presented
in a neurosurgical service where due to the tumor volume, the high-risk surgical elements involved was
sent to our ENT department to try to perform an endoscopic biopsy.
Using the endoscopic optical and mechanical ensemble the authors performed trans nasally a biopsy.
The histopathologic result was a surprise and was confirmed with three different immune-
histochemistry exams.

Keywords: sphenoidal tumor; hypophysis

INTRODUCTION result and based on that the patient will have a

Sphenoidal sinus is located in
the middle of the skull, and is
one of the most difficult
sinuses to be attacked.[1]
The surgical risk elements
are the internal carotid
artery, optic nerve; optic
chiasma; hypophysis and
skull-base.[2,3]
The tumors located in the
sphenoidal sinus are difficult
1Carol Davila University to access and due to the
of Medicine and vicinity of vital anatomical
Pharmacy, Bucharest
structures.
2Institute of
Phonoaudiology and A biopsy must be performed
Functional ENT surgery
“Prof. Dr. Dorin Hociotă”, to have a histopathological
Bucharest, Romania
treatment scheme.
In some cases, even biopsy’s hard to complete, and
high-risk factors are involved.[4,5]
The patient must be informed preoperatively about
the risk involved in taking the biopsy, why is necessary
to perform that biopsy and what are the risks of not
having a biopsy and treatment.
Multiple biopsies must be performed to have a
histopathologic result.
MATERIAL AND METHODS
We present a care, it was admitted a 52 years old
woman with the following symptoms: headache,
bilateral nasal obstruction, right abducens nerve
Corresponding author: Silviu Pițuru
piturus@yahoo.com

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

paralysis, right exophthalmia, and diplopia.
Anamnestic we have found out that the symptoms
started to develop six months ago gradually.
The patient was already consulted in a neurosurgical
department. It was performed a CT scan, and the
result was: expansive tumor which was located at, the
level of sphenoidal body, extending anterior to rhino
pharynx (nearly totally blocked) and posterior
intracranial, with emphasizing compression of the
cerebral trunk (pons and bulb).

Figure 1: CT scan exam expansive tumor which was located at the level of sphenoidal body, extending anterior to
rhino pharynx (nearly totally blocked) and posterior intracranial, with emphasizing compression of the cerebral trunk
(pons and bulb).
The intracranial fragment has T1 signal, suggesting intratumoral hemorrhage.
The cranian invasion extends to abducens nerves both sides.

The CT scan exam conclusion was: tumor located at
the level of the sphenoidal body, invading rhino
pharynx and breaking into posterior fossa compressing
cerebral trunk.
Possible diagnostic taken into account was chordoma,
sarcoma, primitive tumor of rhino pharynx invading
sphenoid sinus.
The patient was sent to our ENT department to be
performed a transnasal endoscopic biopsy to see the
histological nature of the tumor. Depending on the
histological nature of the tumor the skull base team
(neurosurgeon and ENT surgeon) will decide the best
treatment schema for the patient.
exam transnasally and transorally retrograde, where
we were able to see the tumor that destroys the
anterior and inferior wall of the sphenoid sinus,
protruding into the rhino pharynx that was blocked
near totally.
The surface of the tumor was smooth, and the mucosa
of the posterior wall of the rhino pharynx was not
destroyed, it was pushed from beneath. The tumor
had a rich vessels supply. The patient had a rhino
sinusitis secondary to the nasal obstruction produced
by the tumor.
We have started to prepare the patient for the
endoscopic trans nasally biopsy.

In our hospital first, we have performed a fiber optic

65
First, we have treated the rhino sinusitis with After one week we started to perform the biopsy
antibiotics, in steroids anti-inflammatory drugs and we under general anesthesia using both trans orally and
have cleaned the nasal fossa every day. We wanted to trans nasal corridor.
obtain a clean surgical field because of the
communication that will be created with the
endocranial cavity.

Figure 2: Optical and mechanical ensemble to Figure 4: Video contact endoscopy of the rhinopharynx.
endoscopically expose the rhinopharynx Locating a low vascular area

Figure 5: Targeted biopsy performed trans nasally

Figure 3: Video fiber optic trans orally exam. The tumor
block near totally the rhinopharynx

In our case, we did not discover any character of

First, we have performed a trans nasal video contact
endoscopy exam on the tumor. Video contact
endoscopy is an endoscopic technique that allows the
surgeon to study, after staining the tissue with
methylene blue, the desired tumoral area as an in vivo
histological exam. The surgeon can examine the
histological superficial epithelial layer, observing
histologic abnormalities and the vessels of tumors.
malignity at the superficial layer of the tumor, and we
have discovered rich areas of vessels that fed the
tumor.
We have started to gentle perform a targeted biopsy
from the tumor in an area where the vascular network
was limited because we wanted to prevent an
important hemorrhage.

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 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine

We have used cutting instruments because we did not CONCLUSION

want to perform traction maneuvers on a tumor that
In conclusion, trans nasal and trans oral corridor
can have adherence on the cerebral bulb and ponds.
provides the surgeon with a minimally invasive route
to preform biopsy and surgery.
RESULT AND DISCUTIONS
The use of video contact endoscopy helped the
We have obtained the bioptic material, and we have
surgeon to perform targeted biopsy from a low
aspirate an important quantity of liquid. We had no
vascular area and to observe that we are not dealing
CSF leak, we have packed the cavity with Gelfoam. The
with malignancy.
patient was packed for 48 hours.
We underline the role of the multidisciplinary
The evolution of the patient was good, and the
neurosurgical and ENT team. We have chosen a
headache ceased, right abducens nerve paralysis
minimal invasive surgery to minimize the surgical risks
started to reduce and disappear in 3 months.
(vascular and neurosurgical), and we have achieved an
The histopathological exam was a surprise, and it was uncommon histological finding that changed the
confirmed using three different labs and prognostic and the therapeutically route of the
immunochemistry tests. The sphenoidal tumor was a patient.
giant non-functionary pituitary adenoma.
Acknowledgement
The patient received medical and radiotherapy
All authors have contributed equally to this paper.
treatment after two months. The symptomatology
disappeared.

References:
1. Y.W. Lui, S.B. Dasari and R.J. Young, American Journal of
Neuroradiology April 2011, 32 (4) 617-626;
2. Dent JA, Rickhuss PK. Invasive pituitary adenoma
presenting with nasal obstruction. J. Laryngol Otol.
1989;103:605–9.
3. Levine H. The sphenoid sinus, the neglected nasal sinus.
Arch Otolaryngol 1978;104:585–87
4. Lee JC, Kao CH, Hsu CH, and Lin YS. Endoscopic
transsphenoidal vidian neurectomy. Eur Arch
Otorhinolaryngol. 268:851–856, 2011.
5. Unlu A, Meco C, Ugur HC, Comert A, Ozdemir M, Elhan
Endoscopic anatomy of sphenoid sinus for pituitary surgery,
A Clin Anat. 2008 Oct; 21(7):627-32

67
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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
rjmilmed@yahoo.com
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
 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine
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 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.
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 Romanian Journal of Military Medicine
New Series, Vol. CXXI, No 2/2018, August
ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126