vol. cxxi no. 2/2018 august military medicine · 2019-06-14 · vol. cxxi • no. 2/2018 • august...

• 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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Founded 1897 • New Series

Vol. CXXI • No. 2/2018 • August

REVISTA DE MEDICINĂ MILITARĂ

Military Medicine

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Editorial Board of Romanian Journal of Military Medicine

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

Honorary Editor Acad. Victor Voicu MD, PhD

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

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

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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

1

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

RJMM Romanian Journal of Military Medicine

2

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


3


5

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

Mirror Hall, with multiple

European implications...

Then, at Versailles in the

Grand Trianon Palace, a treaty

was signed on June 4, 1920

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".

EDITORIAL

Gral (R) Prof DAN MISCHIANU

Chief of Urology Clinic, Carol Davila Central Emergency

Military Hospital Faculty of General Medicine,

Carol Davila University of Medicine and Pharmacy,

Bucharest, Romania

6

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.

"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.

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.

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


7

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

8

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

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]


9

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.

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.

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

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


11

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

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

Normal biochemical reactions, increased exposure to

the environment, and higher levels of dietary xeno-

biotics result in the generation of reactive oxygen

species (ROS) and reactive nitrogen species (RNS). ROS

and RNS are responsible for the oxidative stress in

different pathophysiological conditions.

Cellular constituents of our body are altered in

oxidative stress conditions, resulting in various disease

states.

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 [1].

Free radicals are defined as “any chemical species

capable of independent existence that contains one or

more unpaired electrons”.

This unpaired electron(s)

usually gives a considerable

degree of reactivity to the free

radical.

An imbalance between oxi-

dants and antioxidants in

favor of the oxidants, poten-

tially leading to damage, has

been defined “oxidative

stress”.

It soon appeared that nitric

oxide (NO) plays a key role in

the physiological regulation of

the cardiovascular system,

since abnormalities in its

productions and/or bioavaila-

bility accompany or even

REVIEW ARTICLE

1 Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania

2 Sanador Hospital, Bucharest, Romania

Corresponding author: Assoc. Prof. Elena Rusu PhD

[email protected]

12

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

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


13

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 Ca2+ 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

14

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 H2O2 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

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.

References:

1. Kabel AM. Free radicals and antioxidants: role of enzymes and nutrition. World J. Nutrit. Health, 2014, 2 (3):35-38.


15

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.

16

Article received on February 09, 2018 and accepted for publishing on May 28, 2018.

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

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.

As professionals we are flooded with an information

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

REVIEW ARTICLE

1 Faculty of Dental Medicine, University of Medicine and Pharmacy

Carol Davila, Bucharest Corresponding author: Ana Maria C. Tancu MD, PhD

[email protected]


17

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,

18

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

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


19

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

20

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

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.

References:

1. Astarastoae V., Triff B.A., Essentialia in Bioetica, Cantes

Publishing, Iasi, 1998

2. Ahmad I., Risk management in clinical practice. Part 5. Ethical considerations for dental enhancement procedures,

British Dental Journal, 209:207-214, 2010

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,

Beauty or “Bucks’’?, Oral Health Group.com, 10/01/2010

8. Hancocks S., The Ethics of Cosmetics, British Dental

Journal, 211-11 Editorial, 2011

9. Jackson R.D., Judging Ethics Ethically, Journal of Esthetic & Restorative Dentistry-Journal Compilation Blackwell 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.


21

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

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,

transforming it and bypassing mistakes. The 20th

century met the expectations of those who wanted to

know this history by setting up the Institute of History

of Medicine in 1921 in Cluj. “More and more are those

who pretend to have a spiritual imitation in the past to

save the intellectual character of modern medicine.

This postulate translates practically into the

multiplication of medical-historical literature and

giving a growing importance to the history of

medicine.”[1] One of the first teachers to honor the

Romanian institute was the French Jules Guiart (1870-

1965) who taught for three years this subject. Those

who strongly supported him were Valeriu Bologa and

Emil Racoviţă. Guiart, fascinated by what he had

discovered on the Romanian realm, would also work

as an ethnographer, travelling intensively and

gathering various ethno-

graphic materials and

photos from all corners of

our country.

The Romanian physician

Valeriu Bologa (1892-1971)

is the exponent of a whole

caste: that of doctors

aware of the modeling

power of culture. He

dedicated himself to the

study of natural sciences

(at the University of Jena)

and, afterwards, he was

attracted to the medical

studies in Austria and Cluj.

The pride he felt for the art

REVIEW ARTICLE

1 Faculty of Medicine, Titu Maiorescu University, Bucharest

22

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

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


23

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

24

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

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


25

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

shared their opinions meant much for the later

developments of both.”[12]

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



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



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



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

26

Article received on March 25, 2018 and accepted for publishing on June 29 2018.

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

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.

Prevalence of dual diagnosis (substance use disorder

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

ORIGINAL ARTICLE

1 Carol Davila University Emergency Central Military Hospital, Bucharest


27

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

28

discontinued treatment and soon relapsed, so that a

new hospitalization was required. This time the

patient was stabilized on aripiprazole, but for the

maintenance phase the long acting injectable form of

aripiprazole 400 mg every 4 weeks was selected, in

order to diminish the risk of therapeutic non-

adherence.

The patient was also diagnosed during the current

psychotic episode with alcohol use disorder,

moderate, based on the DSM-5 criteria, admitting a

daily intake of 8 drinks, consisting mainly in beer and

wine for more than 12 months. Also, he is smoking 20

cigarettes daily, with a value of 10 pack-year.

Biochemistry panel reflected the liver damage, with

values for gamma-GT, GOT and GPT of 156 U/l, 70 U/l,

and 67 U/l, respectively. No abnormalities were

detected on his chest X-ray and abdominal ultrasound

exam (except for hepatic steatosis).

The psychological evaluation realized during the initial

visit for the third episode showed a 98 score on PANSS

[21], with high values on both positive and negative

sub-scales. CRDPSS [20] score was 17, based mainly

on hallucinations, delusions and abnormal

psychomotor behavior. AUDIT [22] score was 14,

reflecting a moderate risk of harm related to the

alcohol use, and the severity of nicotine dependence

was high, as supported by the FTND [23] score of 9.

GAF score at admission was 45, based on symptoms

severity and functional impairment, while the CGI-S

score was 5, which means a “markedly ill” clinical

status.

Therapeutic challenges analysis: This patient

presented a history of therapeutic non-adherence

which triggered two relapses. He was diagnosed with

two substance use disorders (alcohol and nicotine

dependence), which were not therapeutically

approached during his two previous psychotic

episodes, and this could be also a factor that may

contribute to relapse in schizophrenia [24]. There is a

lack of social and professional insertion in this case,

related to both positive and negative symptoms. The

patient lacks familial support and he discontinued

occupational therapy. Moreover, the metabolic profile

and the hepatic functional status were abnormal. All

these negative prognosis factors have been evaluated

by the case manager when the therapeutic strategy

was formulated. Aripiprazole was preferred because

of its good metabolic profile [25], and a long acting

injectable formula was selected because of the more

stable plasma concentrations and lower risk of

discontinuation. The patient received counselling for

his addictive behavior, and he participated in 4

individual sessions focused on smoking cessation and

alcohol use relapse prevention. Alcohol withdrawal

symptoms were mild-to-moderate and remitted after

B-vitamin therapy, parenteral rehydration, and oral

lorazepam 3 mg/day for 7 days, with gradual dose

reduction. Naltrexone, 50 mg/day, was initiated for

alcohol dependence after the withdrawal symptoms

remission, and nicotine replacement therapy was

suggested, but the patient refused. There are no data

reported about pharmacokinetic interactions between

aripiprazole and naltrexone in the literature, which

supports this therapeutic recommendation.

Follow-up visits: The patient was monitored for 4

months, using psychometric instruments, in order to

document psychotic symptoms, severity of addictions,

and overall clinical status evolution under treatment.

Global functioning improved once the psychotic

positive symptoms remitted, although the negative

symptoms persisted at a lower level of severity (as

reflected by PANSS and CRDPSS scores).

Table 1. Psychologic evaluations during the first patient’s

initial visit

Clinical scale Results

PANSS 98

CRDPSS 17

GAF 45

CGI-S 5

FTND 9

AUDIT- Interview Version 14

Alcohol use disorder had a favorable evolution and the

AUDIT scores diminished gradually, but the nicotine

dependence persisted and the mean number of

cigarettes increased with 25%, while the FTND score

increased with 10%. Biochemistry panel reflected an

improvement of the liver status after 4 months, with

values for gamma-GT, GOT and GPT of 56 U/l, 23 U/l,


29

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.

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

0

20

40

60

80

100

0 7 14 28 60 90 120

Sco

re

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

PANSS CRDPSS GAF CGI-S FTND AUDIT

30

admission was 60, based on symptoms severity and

functional impairment, while the CGI-S score was 4,

which means “moderately ill” clinical status. EuroQoL

(EQ-5D-5L) [27,28] visual analogic scale score was 67,

which seems to be correlated more with her

substance-related symptoms than with her psychotic

manifestations. Quality of life domains that seemed

more affected by her current status were

anxiety/depression (a score of 4) and usual activities (a

score of 3).

Her somatic status was good, with no abnormalities on

CBC or serum biochemistry panel. Also, her ECG and

chest X-ray didn’t suggest any abnormalities.

Therapeutic challenges analysis: This patient has a

history of adverse events to several antipsychotics

(haloperidol, amisulpride, olanzapine) which were

severe enough to grant changes in the antipsychotic

treatment. The patient received a new antipsychotic,

ziprasidone 160 mg/day, which has been associated

with low risk for hyperprolactinemia, weight gain, and

extrapyramidal syndrome [29]. A gradual switch was

preferred due to the different pharmacodynamic

profiles of risperidone and ziprasidone [29-31]. ECG

monitoring was initiated, and periodic measurement

of metabolic parameters was continued throughout

the duration of the antipsychotic therapy. The

presence of cannabis use disorder raises an important

question because there is no pharmacological

treatment with clear evidence of efficacy in patients

diagnosed with this disorder, while data about

psychotherapy effects are still debatable [32].

However, gabapentin and N-acetylcysteine have been

suggested as possible therapies [32], and gabapentin

was preferred in this case because of its positive effect

on anxiety and low risk of pharmacokinetic

interactions [33]. Nicotine replacement therapy with

nicotine patch 25 mg/16h for 8 weeks, followed by

gradual dose reduction, combined with psychological

counselling, was accepted by the patient.

Follow-up visits: The evolution of the psychotic

symptoms was favorable, as reflected in the PANSS (-

10%) and CRDPSS (-11%) scores. The overall

functionality increased significantly (+33%) compared

to baseline, and this improvement seems related to

the decrease in both FTND and CUDIT scores, with 71%

and 75%, respectively. Also, the quality of life

improved, both on the visual analogic scale (+17%),

and on its subscales (depression/anxiety -50% and

usual activities -33%). The Clinical Global Impression-

Severity improved with 50%, and the patient was

considered after 4 months “borderline mentally ill”.

Minimal QTc prolongation was detected on ECG after

4 months (+1.3%), but it didn’t reach the level of

significance (considered to be 460 msec in women,

after correction with Fredericia’s formula). No

metabolic abnormalities were detected during the

monitoring period, and the BMI decreased with 2.1%

compared to baseline.

Conclusion: Targeting the cannabis and nicotine use

disorders may improve the overall functionality and

patient’s quality of life, reducing further

schizophrenia-associated symptoms, like depression,

apathy, anhedonia or anxiety. In this case, the patient

was compliant to the therapeutic suggestions, and

participated in counselling sessions focused on

substance use relapse prevention, while being

adherent to the pharmacologic treatment. Her

evolution was favorable and the therapeutic switch

from risperidone to ziprasidone was well tolerated. No

pharmacokinetic interactions were anticipated

between the treatment for nicotine use disorder

(replacement therapy), cannabis use disorder

(gabapentin) and schizophrenia (ziprasidone).

Table 2. Psychologic evaluations during the second

patient’s initial visit


PANSS 69

CRDPSS 9

GAF 60

CGI-S 4

FTND 7

AUDIT – R 16

EuroQoL Visual analogic scale Mobility Self-care Usual activities Pain/discomfort Anxiety/depression

67 1 2 3 2 4


31

The third patient, S.G., was diagnosed for the first time

with acute psychotic disorder 3 months ago. Her

symptoms at hospital admission consisted in

psychomotor agitation, grandiose (“I am very

powerful, and I can make any wish come true, like

Santa Claus, only better”) and persecutory (“there is a

group of forces trying to kill me and take my powers”)

delusions, auditory and visual hallucinations (“I can

hear them talking about me and trying to make me feel

miserable… they are cursing me and telling lies about

me and my family”, “They are moving through the

light, I can see them… they are like some green

shadows”), disorganized behavior, and diminished

emotional expression. She was 27 years old when she

was first admitted in hospital, and her psychotic

symptoms had an insidious onset over at least 4

months. First, she was initiated on risperidone 6

mg/day, and her response was good, but discontinued

oral treatment because she had to take this drug twice

a day. The patient developed positive symptoms of

psychosis after one month of no treatment, and she

was readmitted in the Psychiatry Department. The

selected drug for clinical stabilization was risperidone

because of her previous good response. She was

informed that a long acting injectable form of this

antipsychotic exists, which requires administration

every two weeks. Also, she was informed that

paliperidone, the active metabolite of risperidone, has

two long acting injectable formulations, with

administration of one dose every 4 weeks, and after

stabilization, the drug may be administrated every 12

weeks. She agreed to be initiated on paliperidone long

acting after stabilization of acute symptoms.

The patient was smoking 30 cigarettes daily, with a

value of 9 pack-years. She fulfilled the DSM-5 criteria

for nicotine use disorder and accepted treatment for

this condition. She received nicotine replacement

therapy, but she declined the invitation to join a group

therapy focused on abstinence.

Her ECG was normal, as were chest X-ray, cerebral CT-

scan, CBC and serum biochemistry panel. The

toxicology exam was also negative.

Table 3. Psychologic evaluations during the third patient’s

initial visit


PANSS 88

CRDPSS 14

GAF 35

CGI-S 5

FTND 9

Therapeutic challenges analysis: This patient is still in

the early phase of disease, as her diagnosis of

schizophrenia was just established. She met the

necessary criteria for this diagnosis- time (more than 6

months including pre-hospitalization period of active

symptoms), clinical manifestations, functionality, and

differentials. The challenge is to select a treatment

0

20

40

60

80

100

0 7 14 28 60 90 120

Sco

re


PANSS CRDPSS GAF CGI-S

FTND CUDIT-R EuroQoL-VAS

32

regimen that could be more readily accepted by a

young and active person (she has to travel often

because she has contracts with different enterprises),

while targeting both schizophrenia and nicotine

addiction symptoms. One advantage in this case is the

insight of the patient and her willingness to continue

the treatment. She understood the therapeutic

options her psychiatrist presented, and she has chosen

the treatment which allows her less time for

administration and medication-supplying procedures

(visits to her GP, treating psychiatrist, and local

pharmacy). Therefore, paliperidone was considered

the most appropriate option for her, and after

stabilization with oral medication, she was switched

on paliperidone palmitate (PP1M) 100 mg monthly as

maintenance dose for 4 months, and paliperidone

palmitate (PP3M) 350 mg every 3 months after 4

months. Regarding her nicotine use disorder, she

received 25mg/16 h nicotine patches and nicotine

spray administered prn, in case of withdrawal

symptoms, with gradually dose reduction, and

termination after 3 months. The nicotine spray was

recommended because the patient is a heavy smoker,

and because she had no asthma, chronic sinusitis, or

other related diseases. Paliperidone is not a substrate

for CYP1A2, therefore its plasma concentrations are

not expected to be modified by cigarette smoking, in

case substance use disorder treatment fails.

Follow-up visits: The evolution of psychotic symptoms

was favorable, as reflected in the PANSS and CRDPSS

scores, which decreased with 40% and 65%,

respectively. The favorable trend maintained even

after switching on the long-acting formulae (PP1M and

PP3M). The slower rate of improvement after day 36

is related to the stabilization of the clinical status,

which is a condition for switching on long-acting

antipsychotic formula. The patient reported that she

could return to her job after 6 weeks of treatment and

her professional performances were fair. The cigarette

use declined during the first 4 weeks, but she admitted

she smoked during nicotine replacement therapy and

after its discontinuation. Therefore, after 11 months

her FTND score reflected a moderate dependence. She

refused a new trial of nicotine replacement therapy

and counselling sessions, as she states “smoking is not

a problem for me anymore… I’m only smoking when

I’m feeling nervous”. Her BMI increased with 3.5%

compared to baseline, but no significant alterations in

plasma lipids, blood glucose, hepatic enzymes or QTc

were reported.

CONCLUSIONS

In young patients who experience first episode of

psychosis establishing therapeutic relationship could

be a difficult challenge. Communication between the

psychiatrist and the patient is crucial in order to assure

an adequate level of therapeutic adherence. The

psychiatrist should consider the lifestyle of the patient,

her psychological resources and specific needs, and to

0

20

40

60

80

100

0 14 21 28 36 66 96 127 156 248 337

Sco

re


PANSS CRDPSS GAF CGI-S FTND


33

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].

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.

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9. Picciotto MR, Corrigall WA. Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci. 2002;22:3338–3341.

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11. Chen J, Bacanu SA, Yu H, et al. Genetic relationships between schizophrenia and nicotine dependence. Sci Rep 2016;6:25671.

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35

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

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

The questionnaire or interview used to gather

information is referred to as measures, tools or

instruments. Commonly, there are two types of PROM

questionnaires.

Generic PROMs, which are used to assess generally

across numerous diseases in a broad spectrum

perspective, and condition-targeted PROMs that are

developed for a particular medical condition [1].

This paper critically examines patient-reported

outcome measures (PROMs) and joint replacement

from a broad perspective.

METHODS

Most PROMs measure aspects such as Quality of Life

(QoL) that is fulfilment of needs and impact of

restrictions on emotional wellbeing, and drug side

effects. Others include symptoms/impairments that is

pain and depression, functioning during disability,

locomotion, daily living activities and personal care. In

addition, Health Related Quality of Life (HRQoL),

health status, general health experience and rating of

healthcare facilities and

operations [2].

Analysis of PROMs is

usually conducted using

approved analysis tools for

proper interpretation such

as Rasch analysis or confir-

matory factor analysis.

PROMs are often validated

using particular tools and

methodologies, such as

Linguistic validation for

population’s differences

and others to ensure that

they are effective in gathe-

ring relevant information.

Patient grouping too

ORIGINAL ARTICLES

1 Royal Stoke University Hospital, UK

36

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

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


37

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.

38

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

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


39

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

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].

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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.


41

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

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

modifiable component of life style, which may be

able to highly influence the risk of main cancers.

Hence, there are convincing evidence that an

important benefit may be derived concerning risk

reduction in endometrial cancer, colorectal

cancer, breast cancer, prostate cancer, lung

cancer and ovary cancer. It is estimated that in

Europe in 2008 between 150000 and 300000

cases of cancer could have been prevented only

by the way of maintaining a resonable level of

physical effort in general population.[1]

A series of convincing observational data suggest

that regular physical activity, be it ocupational

type or recreational type, protects against

colorectal cancer (CRC)[1,2]. Around 60 studies

have been published till

2010 concerning the

issue of physical activity

and CRC.[2] A metaana-

lysis that included 21

studies stated a signifi-

cant reduction of CRC

risk by 27% in the group

of subjects that per-

formed vigurous physi-

cal activity as comparing

with the group of

sedentary subjects (RR

0.73, 95% CI 0.66-

0.81).[3] The mechanism

that may provide an

explanation for the

ORIGINAL ARTICLES

1 Carol Davila University Central Emergency Military Hospital, Bucharest

2 Carol Davila University of Medicine and Pharmacy, Faculty of General Medicine, Bucharest

3 Titu Maiorescu University,

Bucharest

42

relative protection of physical effort is currently

unknown. There are no interventional type

studies published yet to support the role of

regular physical effort as preventive method in

CRC.

In 2007 the results of a cohort study (Nurses’

Health Study) has been published that enrolled

80,000 female subjects from 1986 with a 16 years

follow-up. There have been diagnosed

approximately 500 cases of CRC. A multivariate

analysis that controlled the confounding factors

represented by other risk factors for CRC

concluded that there was a proportionate

reversed relationship between physical effort and

distal colonic cancer and, to a lesser extent, with

proximal colonic cancer. Women situated in the

highest percentile of recreational physical activity

had a reduction of distal CRC risk by half as

compared with women situated in the lowest

percentile (RR=0.54, 95% CI 0.34-0.84). Risk

reduction did not vary with body mass index

(BMI), although former studies had suggested

that physical activity had the greatest impact on

CRC only in high BMI subjects. The level of

physical effort to produce prophylactic benefits

may be only minimal, as this study demonstrated.

As such, even an hour of slight walking a week

may reduce the risk of CRC by 31% (RR=0.69, 95%

CI 0.45-1.03) as compared with women who do

not report any kind of physical activity. This

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

CRC by 44% comparing with 1 hour a week (RR=

0.56, 95% CI 0.33-0.94). Physical activity lessened

the risk of CRC regardless of the impact on BMI:

this idea may imply that physical activity protects

against CRC by a mechanism independent of that

involved in resolution of obesity. The protective

effect of physical effort validates at distance. The

actual reduction of CRC risk is considerable only

after several years. In conclusion, the authors of

this study suggest that even minor physical effort

may derive benefit on CRC risk reduction. Several

mechanisms have been proposed. Thus, physical

activity regulates energetic balance and

intervenes in reduction of hyperinsulinism and

peripheral resistance to insulin. Physical activity

may intervene also through anti-inflammatory

mechanisms. Moreover, the positive effects of

physical effort may also be explained by

reduction of obesity in spite of the data that

demonstrated that physical activity may reduce

the risk of CRC independent of the effect on

obesity. Another proposed mechanism involves

accelerating the peristalsis which reduces the

contact time between intraluminal carcinogens

and colonic mucosa. As a matter of fact, it is well

known data that physical active individuals are

more prone to sun exposure for longer periods of

time which facilitates production of vitamin D

that is associated with lessening the risk of

CRC.[4]

Figure 1: Mechanisms involved in protective effect of physical effort on colorectal cancer risk

An epidemiologic study published in 2008 (NIH-AARP

Diet and Health Study) shows interesting observations

regarding the periods of an individual life when the


43

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

44

the subject was asymptomatic and included in the low

cardiovascular risk group.

One may consider mandatory that all healthy adult

individuals to include in their life style moderate or

vigorous physical exercises. The majority of authors

agrees that the highest health benefits are provided by

150 minutes a week of moderate physical activity or

by 75 minutes a week of vigorous physical activity.

Nevertheless, adults that have a limited physical

activity capabilities should remain active because it

has been noticed that even if a modest amplitude of

physical effort is exercised regularly health benefits

will be significant.

Another epidemiologic studies suggest that physical

activity may influence not only the risk of CRC but also

it may prevent the recurence of CRC after curative

surgical treatment. All the data available resulted from

observational type of studies; randomized and inter-

ventional studies are not published. Nevertheless,

American Society of Oncology (ASCO) recently

recomended that the surviveours of CRC should

maintain an optimal weight, should perform daily

physical exercises and should follow a healty diet.[14]

Futher on, there are some interesting results of a study

published in 2006 that included 832 patients suffering

from CRC stage III surgicaly treated and that followed

a program of chemotherapy. It has been demons-

trated that moderate physical activity perfomed for at

least 300 minutes a week has increased the free

disease interval with 45% and has improved by 29-

36% the mortality rate of any cause.[16] The benefits

have been dose dependent.

In an observational study (unpublished data) that I

have conducted in 2016, concerning the topic of CRC

and its relationship with diabetes mellitus and other

risk factors an important conclusion has been drawn.

A multivariate analisys in which the most

acknowledged CRC risk factors have been included

showed the statistical significance (p<0.05) have been

reached for smoking and physical activity only. This

implies that by the way of increasing physical activity

levels in general populations and by giving up smoking

CRC „epidemics” could be fairly prevented.

Table 1: Multivariate analysis of risk factors in CRC

Variabile Coeficient Standard

error t Stat p

Age (years) 0.0014 0.0035 0.4087 0.68

BMI(Kg/m2) 0.0031 0.0055 0.5650 0.57

Smoking 0.1273 0.0647 1.9658 0.05

Daytime nap (hours)

0.0150 0.0440 0.3404 0.73

Physical activity

-0.1334 0.0601 -2.2181 0.02

In conclusion, the preventable potential of CRC is high

through the way of regular physical exercise and this

may represent a very approachable solution to

decrease the global burden of the disease. It is very

important to stress that the target of decreasing the

prevalence of CRC by physical exercise does not

necessarily imply an impact on obesity, the benefits on

CRC being independent from the benefits on BMI. A

good level of motivation in general population through

health politics is mandatory because the changes in

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.


45

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

16. Kathleen B. Watson, Susan A. Carlson, Janelle P. Gunn,

Deborah A. Galuska, Ann O’Connor, Kurt J. Greenlund Janet

E. Fulton. US Department of Health and Human Services/

Centers for Disease Control and Prevention. Morbidity and

Mortality Weekly Report. September 16, 2016/Vol. 65/No.

36.

46

Article received on March 28, 2018 and accepted for publishing on May 15, 2018.

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

Medical organizations com-

munication policy towards

the health care market

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-

zations in order to attract new potential clients;

- 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

ORIGINAL ARTICLES

1 Titu Maiorescu University, Faculty of Medicine, Bucharest

2 Centre of Military Medical Scientific Research, Ministry of National Defence, Bucharest

3 Carol Davila University of Medicine and Pharmacy, Faculty of General Medicine, Bucharest

4 Carol Davila University of Medicine and Pharmacy, Faculty of Dental Medicine, Bucharest

Corresponding author: Bogdan I. Coculescu MD, PhD

[email protected]


47

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

products and services it provides, to create a positive

attitude and to stimulate consumers to buy products

and services.

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.

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

48

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.

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


49

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

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.

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.

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.

50

Article received on January 17, 2018 and accepted for publishing on March 15, 2018.

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

Acute intoxications repre-

sent a worldwide problem

that tends to gain more

amplitude each year.

Each intoxication presents

certain characteristics which

stem from the degree of

socio-economic develop-

ment of each country.

The organophosphorus com-

pounds are mainly used to

fight pests, as an alternative

to chlorinated hydrocarbons,

which persist much longer in

the environment. Yet these

substances are very toxic for

humans too.[6] Because of

this, measures were taken

both to limit their utilization and to control the

contamination of the environment.

The most efficient, but also most toxic substances

utilized as pesticides are cholinesterase inhibitors

(through reversible or irreversible mechanism). For

both mammals and insects, the major effect of these

substances is the inhibiting of acetylcholinesterase

through the phosphorylation of the esterase site. The

signs of symptoms which characterize the acute

intoxication are caused by the inhibition of this

enzyme and the accumulation of acetylcholine. Some

of these substances possess a direct cholinergic

activity.[4]

The absorption of organophosphorus compounds can

be realized through three methods: inhalation,

digestive and through the skin. One of their main

characteristics is the fixation at hair level, where they

enter through the skin, thus representing a permanent

source of intoxication. Through the inhalation way, the

intoxication is the most rapid. Through direct action on

CLINICAL PRACTICE

1 Military Medical Research Center, Bucharest, Romania

2 Carol Davila University of Medicine and Pharmacy, Bucharest

3 Floreasca Clinical Emergency Hospital, Bucharest, Romania

4 Polytechnic University, Bucharest, Romania


51

the bulbar respiratory center (muscarinic phenome-

non) and the paralysis of respiratory musculature

(nicotinic phenomenon), respiratory arrest occurs.

Organophosphorus compounds are rapidly absorbed

through the skin or digestively in the thin intestine.

They bind well to the plasmatic proteins. High

concentrations can be attained in the body within

hours.[7]

Organophosphorus compounds represent a group of

compounds with liposolubility or hydrosolubility, with

high distribution volume. They are rapidly distributed

in the liver, lungs, kidneys, heart and brain but do not

accumulate.

This type of organophosphorus compounds is

liposoluble, accumulating in the lexophile tissues of

the organism, being a source for metabolic conversion

to very toxic compounds. Thus, the intermediate

syndrome can be explained (it appears between the 5th

and 18th day from the intoxication). The toxicity of

these compounds is manifested through the direct

inhibition of cholinesterase, probably through direct

poly enzymatic inhibition.[7]

The metabolizing of organophosphorus com-pounds

takes place rapidly in the body, and as such they do not

accumulate. Compounds such as parathion,

malathion, phenthion, chlorpyrifos, normally inactive,

upon entering the body they transform at liver

microsomal level, through oxidation, in highly active

compounds (paraoxon, malaoxon).

This transformation takes place under the action of

paraoxonase. Their degradation takes place through

hydrolytic and oxidative ways, through liver and

kidney enzymes. The erythrocyte-origin cholineste-

rase remain blocked for the remainder of the red

blood cell’s life. Their regeneration takes place slowly

(0.5-1% per day), remaining below normal level for

over 3 months in severe intoxications.[8]

Organophosphorus compounds are eliminated

through urine as such or as metabolites.

In the current global situation, it is very probable that

these substances will be used in wars, conflicts,

terrorist attacks. In such scenarios, they are used as

extremely toxic agents and thus continuously

represent severe threats to humans, animals and the

fauna.[2]

The dimethoate, patented and introduced in the 50s,

is a acetylcholinesterase inhibiting organo-phosphorus

compound, it is not volatile, it is water soluble and it is

not mobile in soil, where it degrades with a half-life of

approximately 2-4 days, depending on the conditions.

Dimethoate and omethoate urine levels reflect recent

exposure.

Once having entered the body, organo-phosphorus

compounds are metabolized to dialkylphosphates,

which are eliminated through urine. Their

metabolizing takes place rapidly in the body and as

such they don’t accumulate.

Compounds such as parathion, malathion, phenthion,

chlorpyrifos, normally inactive, enter the body and

transform at liver microsomal level, through oxidation,

into highly active compounds (paraoxon, malaoxon).

Identification of these metabolites in the urine may be

an indicator of exposure to organophosphorus

compounds and can be performed through a GC/MS

analytical method with an ion trap and electronic

ionization.

The dimethoate is rapidly metabolized, mainly

through the initial splitting of the C-N bond to obtain

dimethoate carboxylic acid and, eventually, a number

of tiophosphate and phosphate esters. The minor

quantitative elimination way involves the oxidative

metabolism to produce the oxygen analogue of

dimethoate, omethoate. The parent compounds

represents 1-2% of the dose excreted in the urine.[5]

MATERIALS AND METHOD

The research was performed on a GC-MS Saturn 2000

Varian system composed of gas chromatograph model

Varian CP – 3800 and mass spectrometer Varian

Saturn – 2000.

Establishing optimal working conditions and functional

parameters for the development of a GC/MS method

are important steps in the development of a GC/MS

method for the separation and spectral identification

of dimethoate in urine.

52

ANALYTICAL CONDITIONS

GC – an instrument equipped with a ion trap detector;

GC – gas-cromatograph has the role of taking in the

sample and separate the mixture of substances

composing it.

GC/MS parameters

Injector temperature: 300° C

Carrier gas: He • Column flow: 1.2 ml/min

Separation time: 50 min

Ionization mode: electron impact (70eV)

Ionization current: 20 μA

Ionization temperature: 170° C

Detection mode: full scan

Manifold temperature: 80° C

Ion trap temperature: 170° C

Interface temperature GC-MS: 260° C

The separation of the compounds was realized by the

active layer of the DB-5MS capillary column (length 30

m, internal diameter 0.25 mm, film thickness 0.25 µm).

The optimal conditions for chromatographic

separation and detection were established following

the study on the compound’s retention time’s

dependency on the structures of the said substances.

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.

Mass spectrometer parameters

Manifold temperature = 800o C

Ion trap temperature = 1700o C

Ionization current = 20 µA

Acceleration tension = 70 eV

Working times

0 - 5 min – closed filament

5 - 37 min acquisition in mass domain 50 - 450 amu.

Acquisition domain 50 – 400 amu

Segment setpoint

Scan time = 1 sec/scan

Multiplier offset = 0 V

Emission current in FS 10 µA

Ion threshold 1 count

Scanning parameters for ions formed in the trap are

presented in Table 2.

Table 2. Scanning parameters for ions formed in the trap.

Low Mass (m/z)

High Mass (m/z)

Ionization Storage Level

(m/z)

Ionization Time Factor

(%)

10 99 48.0 100

100 249 48.0 100

250 399 48.0 100

400 650 48.0 100

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


53

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

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.

Table 3: Specific ionic fragments and spectral lines for dimethoate

Compound Spectral

line (m/z) Chemical formula of ionic

fragment

Dimethoate C5H12NO3PS2

(M=229)

157 – [M-72] - (CH3O)2PS.S+

143 – [M-86] - (CH3O)(HO)PS.S+

125 – [M-104]- (CH3O)2PS+

93 – [M-136]- (CH3O)2P+

54

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

Compound Spectral

line (m/z) Chemical formula of ionic

fragment

Omethoate C5H12NO4PS

(M=213)

156 – [M-57] - CH3NCO

141 – [M-72] - (CH3O)2P=O.S+

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

detects a high degree of inhibition of 0.5 UI/ml. A urine

sample is being taken for the toxicological examination

and is sent to the Analytical Toxicology Laboratory.

The patient is hospitalized in the ATI Toxicology

Section.

Objective examination upon admission:

- Severe general condition;

- Reed IV coma; non-reactive;

- Pale, sweaty skin;

- Cyanotic extremities;

- Miotic, equal pupils, with slow photomotor pupil


55

reflex;

- 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;

- Central sub-clavicle catheter

- 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 (HOOC-) ME

230 93, 125, 198, 230

Phosphoditioic acid – O,S,S trimethyl ester

172 93, 109, 125

56

Figure 3: Dimethoate and its metabolites – omethoate, dimethoate M (HOOC-) ME and the phosphoditioic acid – O,S,S

trimethyl ester. Omethoate mass specter.

CONCLUSIONS

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.

The mass spectrometer can acquire data through

various methods. In “full scan” method (FS), the mass

spectre obtained through electron impact ionization

can be compared with mass spectres found in

specialized libraries, making possible the identification

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.

A quick and correct analytical diagnosis influences the

quickness and correctness of specific therapy

measures that can be applied in such a context.


57

References:

1. *** Food and Agriculture Organization/World Health

Organization (FAO/WHO). 4.10 Dimethoate, omethoate, and

formothion (T**). In: Pesticide Residues in Food-1996.

Report of the Joint Meeting of the FAO Panel of Experts on

Pesticide Residues in Food and the Environment and the

WHO Core Assessment Group. FAO Plant Production and

Protection Paper, 140, 1997. Rome, 1997. 4/4/13

2. Gupta R.C. Handbook of toxicology of chemical warfare

agents. Elselvier, 2009.

3. *** International Programme on Chemical Safety (IPCS).

Environmental Health Criteria 90. Dimethoate [online].

1989. Available at URL:

4. Ionică M., Macovei R.A., Dumitraşcu M., Costea V.,

CarageaG., Forje M., Anghelescu G., Zamfir O. Increased the

sensitivity of optoelectronic methods in the identification of

reversible cholinesterase inhibitory substances. Smart

Applications & Technologies for Electronic engineering

SATEE 2016, Alba Iulia.

5. Kirkpatrick D (1995). 14C-Dimethoate: the biokinetics and

metabolism in the rat. DTF Doc No: ‘651-001’ [CHA; sub:

12564, Ref: 3-1/Vol 3-2]

6. Lewis R.A. Lewis’ Dictionary of Toxicology. CRC Lewis,

1998.

7. Tudosie M., Macovei R.A., Ionică M. Corelaţii

toxicocinetice şi toxicodinamice în intoxicaţia acută cu

compuşi organofosforici. Editura Universitară “Carol Davila”,

Bucureşti 2014.

8. Voicu V. Toxicologie Clinică. Editura Albatros, Bucuresti,

1997, 155 – 158.

9. http://www.inchem.org/documents/ehc/ehc/ehc90.htm

4/20/13

10. Hassan A, Zayed SMAD, Bahig MRE. Metabolism of

organophosphorus insecticides—XI. Metabolic fate of

dimethoate in the rat. Biochem Pharmacol

1969;18(10):1419-38.

58

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

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

Picking wild mushrooms is a

very popular activity in

European countries, there-

fore mushroom poisoning is

a constant and serious

health issue [1-3]. More than

fifty species of toxic

mushrooms are known,

which are usually very

similar to edible mushrooms.

[4,5]

The most severe cases of

mushroom poisoning are

mainly caused by ciclo-

peptides – toxins contained

by Amanita mushrooms.

[2,5,6] The most frequent

cause of death in mushroom poisoned patients is

Amanitaphalloides, also called ʺthe death capʺ.[5-8]

Toxic effects of Amanitaph. are determined by

phallatoxins and amatoxins.[6,9] Phallatoxins are

heptapeptides with severe toxic systemic effects that

cannot be absorbed from the digestive tract.[10]

However these toxins can induce gastrointestinal

symptoms through lesions of the enterocytes .[1]

α-amanitin, the most important amatoxin, is resistant

to all gastrointestinal fluids and after absorption it

mainly locates in the hepatocytes.[10,11] After

reaching the liver cells, α-amanitin binds DNA-

dependent ribonucleic acid (RNA) polymerase II, with

high specificity, causing protein synthesis inhibi-

tion.[11,12] Its toxic effects are also increased through

the enterohepatic circulation of this toxin.[1,11]

CLINICAL PRACTICE

1 Anesthesiology and Intensive Care Unit Department, Clinical Emergency Hospital, Bucharest

2 Anesthesiology and Intensive Care – Toxicology Unit Department, Clinical Emergency Hospital, Bucharest


Corresponding author: Cristian Cobilinschi, MD

[email protected]


59

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

60

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


61

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

62

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

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.

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).

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Sauvanet A, et al. Amanita phalloides poisoning :

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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.

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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.

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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.

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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.

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Carpentier P. Érythermalgie soudaine : cherchez le

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Basu S, et al. Stevens-Johnson Syndrome / Toxic Epidermal

Necrolysis A Comprehensive Review and Guide to Therapy .

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Toxic epidermal necrolysis manifestations, etiology and

immunopathogenesis. J Am Dermatology. Elsevier Inc;

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traditional Chinese medicines. Singapore Med J.

2006;47(7):647.

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necrolysis ( Lyell ’ s disease ). Burns. Elsevier Ltd and

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epidermal necrolysis : Review of pathogenesis and

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Article received on October 10, 2017 and accepted for publishing on June 20, 2018.

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

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

to access and due to the

vicinity of vital anatomical

structures.

A biopsy must be performed

to have a histopathological

result and based on that the patient will have a

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

CLINICAL PRACTICE


2 Institute of Phonoaudiology and Functional ENT surgery “Prof. Dr. Dorin Hociotă”,

Bucharest, Romania

Corresponding author: Silviu Pițuru

[email protected]


65

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.

In our hospital first, we have performed a fiber optic

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.

66

First, we have treated the rhino sinusitis with

antibiotics, in steroids anti-inflammatory drugs and we

have cleaned the nasal fossa every day. We wanted to

obtain a clean surgical field because of the

communication that will be created with the

endocranial cavity.

After one week we started to perform the biopsy

under general anesthesia using both trans orally and

trans nasal corridor.

Figure 2: Optical and mechanical ensemble to

endoscopically expose the rhinopharynx

Figure 3: Video fiber optic trans orally exam. The tumor

block near totally the rhinopharynx

Figure 4: Video contact endoscopy of the rhinopharynx.

Locating a low vascular area

Figure 5: Targeted biopsy performed trans nasally

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.

In our case, we did not discover any character of

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.


67

We have used cutting instruments because we did not

want to perform traction maneuvers on a tumor that

can have adherence on the cerebral bulb and ponds.

RESULT AND DISCUTIONS

We have obtained the bioptic material, and we have

aspirate an important quantity of liquid. We had no

CSF leak, we have packed the cavity with Gelfoam. The

patient was packed for 48 hours.

The evolution of the patient was good, and the

headache ceased, right abducens nerve paralysis

started to reduce and disappear in 3 months.

The histopathological exam was a surprise, and it was

confirmed using three different labs and

immunochemistry tests. The sphenoidal tumor was a

giant non-functionary pituitary adenoma.

The patient received medical and radiotherapy

treatment after two months. The symptomatology

disappeared.

CONCLUSION

In conclusion, trans nasal and trans oral corridor

provides the surgeon with a minimally invasive route

to preform biopsy and surgery.

The use of video contact endoscopy helped the

surgeon to perform targeted biopsy from a low

vascular area and to observe that we are not dealing

with malignancy.

We underline the role of the multidisciplinary

neurosurgical and ENT team. We have chosen a

minimal invasive surgery to minimize the surgical risks

(vascular and neurosurgical), and we have achieved an

uncommon histological finding that changed the

prognostic and the therapeutically route of the

patient.

Acknowledgement

All authors have contributed equally to this paper.

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

68

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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

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