Romanian Journal of Vol

Founded 1897 • New Series Romanian Journal of Vol. CXXI • No. 2/2018 • August Military Medicine

REVISTA DE MEDICINĂ MILITARĂ

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

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Editorial Board of Romanian Journal of Military Medicine Under the patronage 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 Associate Editor Mariana Jinga MD, PhD, MBA Redactors Raluca S. Costache MD, PhD, MBA – Bucharest Mihail S. Tudosie MD, PhD – Bucharest Editorial Assistants Ioana Oprea MD Cristina Solea Technical Secretary Oana Ciobanu Ionuț Olteanu Publisher Carol Davila University of Medicine and Pharmacy Publishing House

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

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

REDACTION

B-dul Eroii sanitari, Nr.8, Sector 5, București, Tel/fax 021/318.07.59, tel. 021/318.08.62/Int. 199; Email [email protected] Romanian Journal of Military Medicine (RJMM) is included in Romanian College of Physicians Medical Publications Index.

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

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

RJMM Founded 1897 • New Series Romanian Journal of Military Medicine 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

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

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

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

EDITORIAL

Brief notes about the Great War, Romanian military doctors and the Great Union

Dan Mischianu

Motto: “L’Histoire, c’est la rencontré d’une volonté et d’une Versailles in 1949 in the Gral (R) Prof DAN MISCHIANU évènement” – Charles de Gaulle, 1890-1970 Mirror Hall, with multiple Chief of Urology Clinic, Carol European implications... Davila Central Emergency This short notice, largely iatrohistoric, appear in the Military Hospital 100th year since the Great Union out of the desire to Then, at Versailles in the Faculty of General Medicine, know more about what has happened. Grand Trianon Palace, a treaty Carol Davila University of was signed on June 4, 1920 Medicine and Pharmacy, In Romania, there was a lot of talk about the First Bucharest, Romania between 16 allied states World War. The Germans remember this war under (including Romania) and the successor state of the the name of "der Erste Weltkrieg worde von 1914 bis Austro-Hungarian Empire. At the beginning of the war, 1918 in Europa, in Naken Osten, in Africa, Ostasien and Romania, a "very small country", in the form of "L", auf dez ozeanen gefurt". Obviously this first had 137,000 km2 and a population of 7.2 million conflagration was the army of "Zweiter Weltkrieg"! inhabitants, and after Trianon, it was reunited and The British preferred the denomination of the became „The Great Romania", with an area of 295,000 "European War" or, more correctly, they named it "the km2 and a nation of 18 million people. It is certainly Great War". why, in the collective mentality of a neighboring It appears that this name is slowly but surely nation, that this situation is perceived as unacceptable penetrating our literature, following "World War I" even after 100 years! which, referring to the title of this editorial only makes After the assassination of the crown Prince of Austria- us Romanians remind that we have also had a Small Hungary – Franz Ferdinand on June 28, 1914 the Union (1859), followed by the Great Union of 1918. actors, both big and small, began to enter the stage: It must be remembered that the Romanian literature Central Powers – Germany, Austria-Hungary, Turkey, between 1948-1989 wrote about the Great War in an Bulgaria and Antanta or the Triple Alliance, England, abbreviated manner, because of two reasons: the Russia followed by Italy, Romania, USA... Eastern neighbors had "turned history" – things did The Kingdom of Romania had passed through a recent, not happen as planned and the contribution and unforgettable experience for the army and especially participation of the Romanian Royalty to the final for the military doctors. In 1913, during the Second victory was extremely important but also very Balkan War, the Romanian troops that had easily embarrassing that it had to be silenced. entered the northern half of Bulgaria lost 1,600 lives The Great War began in Sarajevo in 1914 and ended at due to the cholera epidemic – a fearful "enemy".

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 He became Professor of Experimental Medicine at the station ". Faculty of Medicine in Bucharest at the age of 38 and Just after two years of "armed expectancy" war began, was appointed in 1908 as General Manager of the for Romania as well as for other nations, how all wars Health Service to "Effectively fight epidemics, set up start "suddenly and unprepared!". We do not insist in isolation hospitals and pavilions, rural infirmaries and geostrategic and political-economic details. We bacteriological laboratories". In the Bulgarian present only the result and brief considerations about campaign he successfully ordered the vaccination in an military doctors truly involved in the "Perpetual Drama epidemic environment, called and known as "the great of War". Romanian experience."

What Prof. Dr. Vasile Sârbu, a Templar Knight of He conducted the Civil Public Health and Military Romanian Surgery and Iatrohistory, presented with his Public Health Directorate during the Great War, a true known erudition a few months ago, is perfectly true: Ministry of Health, which allowed him to organize anti- "In this war, 400 military doctors died out of 2,800 choleric vaccination and fight against exanthematic participants." 2,400 health workers have also died out typhus, typhoid fever and smallpox – having the rank of 14,000 participants, as well as 14 pharmacists and of Col. Dr. of the Romanian Army. 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, In 1920, together with Nicolae Titulescu and Mihai founder of the Romanian School of Immunology and Ciucă, his student, participated, as the Romanian state Experimental Pathology, doctor of medicine with a delegate, at the Treaty of Trianon. He enjoyed a high thesis on the destruction of the vibrio cholera. The prestige, he had an important word to say, was even a subject of the thesis, supported in 1894, and its friend of French Prime Minister Georges Clemenceau, findings will prove useful in almost 20 years, as in the a distinguished neurologist... On April 1, 1921, as a novels of Alexandre Dumas. result of his unrelenting thought, effort, and

6 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine determination, he founded the "Serum and Vaccine The General Dr. Iacob Potarca (1866-1942), a graduate Institute", by royal decree, which will then bear its of the Bucharest Faculty of Medicine, specialized in name. general surgery in Paris, physician colonel in 1916, head physician of the First Army’s Corp, general in O tempora, o mores!... 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 medicine".[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 In 1911 the General Dr. Nicolae Vicol (1861-1936), as thought of the Great Union! Director of the Health Department of the Ministry of In August 1917, at Mărășești, there were "many other War, organizes two preparatory sanitary maneuvers doctors from the old country, young, learned able- around Bucharest that have proven to be beneficial in bodied: Victor Papilian, Titu Vasiliu, Odiseu Apostol, the future. In August 1916, when he signed the troops Grigore T. Popa, Constantin, Mihail Kerubach, and mobilization he followed the General Constantin many, many others”.[4] 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 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

Central Laboratory of Bacteriology of the Austro- Medical Clinic, dean of the new Faculty of Medicine in Hungarian Army. 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).

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 He was a graduate of the Faculty of Medicine in Hygiene of the Faculty of Medicine in Cluj, general Vienna, doctor of medicine, who established in secretary of the Social Protection Resort of the Carlsbad where he trained as an intern and Transylvanian Conducting Council and he also balneologist, later attracted to the political activity, organized the Transylvanian Medical Service. debuted in the Chamber of Budapest and the one who has read, on the 18th of October 1918 in the Hungarian I think it is worth mentioning the contribution of other Chamber, the Declaration of Self-Determination of the illustrious physicians to the Great Union just to Romanian People from Transylvania. He was a contradict Albert Camus, who said with cynicism: member of the ministry cabinet of Ion I.C. Brătianu, he "Forgetting is the first faculty of man!" 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] Iuliu Hatieganu (1885-1959) the first professor of a

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Our history, of the Romanian people, has implied over The unification of the Romanian states is the nation's the years a steady climb with a lot of difficulties. The greatest act, which configures and fully certifies our Great Union was accomplished in stages, all springing existence among other nations of the world. up from the ideal of unity of our nation, never forgotten.

References

1. Stoica Leontin – Serviciul Sanitar al Armatei Romane în europeană (1918-1940), Ed. Humanitas 1995 perioada 1918-1919, Teză de doctorat, Academia de Ştiinţe 4. Florea Marin – Medicii şi Marea Unire, Ed. Tipomur, 1993, a Moldovei, Institutul de Istorie şi Drept, Chişinău 2012 pg. 30 2. Sârbu Vasile - Participarea medicilor la Războiul de 5. Peter Ross Range – 1924, anul care l-a creat pe Hittler, Ed. Întregire a Neamului şi la Marea Unire din 1918 Litera, Bucureşti, 2018 3. Setlacec Dan – Medicina românească, medicină

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

Reactive nitrogen species and cardiovascular diseases

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

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

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

precede diseases such as hypertension, athero- disorders, and combined hyperlipidemias are more sclerosis and angiogenesis-associated disorders. severe. Cardiovascular disease is one of the major Cardiovascular disease (CVD) is the leading cause of causes of mortality and morbidity worldwide and the death in the United States and Europe and is poised to costs that involve handling this disorder are huge. The become the most significant health problem 2008 overall rate of death attributable to worldwide. cardiovascular disease was 244.8 per 100 000 individuals and this rate is critically growing [4]. Recent Free radicals are generated from either endogenous or evidence demonstrates that cardiovascular disorders exogenous sources. Endogenous free radicals are are usually associated with increased level of stress generated from immune cell activation, inflammation, hormones [5, 6]. mental stress, excessive exercise, ischemia, infection, cancer and aging. Exogenous free radicals result from Cardiovascular risks such as defects in angiogenesis/ air and water pollution, cigarette smoking, alcohol, vasculogenesis or vessel repair are major heavy metals, certain drugs (cyclosporine, tacrolimus), complications of coronary artery disease (CAD) which industrial solvents, cooking and radiation. are mostly seen in aged people. Similarly, CVD risks have also increased in women during pregnancy which ROS and RNS products can bring about reversible or is an important issue for management of their irreversible chemical changes (oxidation, nitrosylation cardiovascular health [7]. Conventional risk factors and nitrosation) in proteins, lipids, and DNA, resulting such as cigarette smoking, diabetes, hyperlipidemia, in diminished biochemical functions [2]. The greater and hypertension are absent in 15-20% of patients the amounts of ROS and RNS, the more extensive the with CVD. Atherosclerosis is the main cause of death chemical changes in these targets. ROS and RNS can in the world through causing ischemic heart disease. It induce adducts to DNA, leading to DNA fragmentation is peripheral arterial disease, most prevalent, morbid, [3]. and mortal disease. It is one of the most common Reactive nitrogen species (RNS) are free radicals which disorders among the elderly, because of depression are associated with the nitrogen atom: nitric oxide prevailed in the old age and rates of very high (NO), nitrogen dioxide (NO2) and peroxy-nitrite atherosclerosis. Atherosclerosis is characterized by (ONOO-). Reactive species are produced by regulate endothelial dysfunction, vascular inflammation, and enzyme such as nitric oxide synthase (NOS), and the buildup of lipids, cholesterol, calcium, and cellular isoforms of NADPH oxidase, or as by-products from debris within the intimae of the walls of large and not so well regulated sources, such as mithocondrial medium size arteries. electron-transport chain. Abnormal proliferation of vascular smooth muscle is Nitric oxide is a biatomic free radical containing an implicated in various pathological situations including unpaired electron. Until now have been described atherosclerotic lesions, restenosis after balloon three forms of NO, nitrosonium cation (NO+), nitric angioplasty, and vascular wall thickening in oxide (NO.), and nitroxyl anion (NO-) with nitrogen hypertension. NOS may play protective role by oxidation number +3, +2, and +1, respectively. NO can inhibiting proliferation of vascular smooth muscle cell react with oxygen free radical to form peroxynitrate [8]. For example, leiomyosarcoma, which is an (ONOO-). This last molecule is involved in protein aggressive mesenchymal tumor with differentiation oxidation reaction under physiological conditions. toward smooth muscle tissue, represents up to 9% of all primary malignant tumors. Some cases of CARDIOVASCULAR DISEASES leiomyosarcoma presumed to be infective Cardiovascular diseases are prevalent in human endocarditis [9]. population and most of them are related to diet but genetic lipid abnormalities such as hypercholeste- THE CHEMISTRY OF RNS rolemia, hypertriglyceridemia, HDL metabolism Nitric oxide (NO.) is a small molecule generated in

12 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine biological tissues by specific nitric oxide synthase and nNOS are upregulated in endothelial and muscle (NOS) which metabolizes arginine and citrulline with cells, respectively, leading to over-production of NO in the formation of NO. via a five electron oxidative the microvasculature and arteriolar dysfunction. reaction [10]. Nitric oxide synthase utilize L-arginine as Neuronal NOS is constitutively expressed in specific the substrate, and molecular oxygen and reduced neurons of the brain and its enzymatic activity is nicotinamide-adenine-dinucleotide phosphate – regulated by Ca+2 and calmodulin. This NOS isoform NADPH as co-substrat. has been identified also in the spinal cord, in the NO is involved in the regulation of cardiovascular sympathetic nerves, in epithelial cells of various motor tone, modulation of myocardial contractility, organs, in pancreatic islet cells, in the vascular smooth control of cell proliferation and inhibition of platelet muscle and in the skeletal muscle [14, 15]. activation, aggregation, and adhesion [11]. Endothelial NOS is mostly expressed in endothelial Hypertension is also associated with NO synthesis [12]. cells; Ca2+-activated calmodulin is important for the regulation of eNOS activity because Ca2+ induces the The enzyme nitric oxide synthase produce reactive binding of calmodulin to the enzyme. Endothelial NOS nitrogen species (RNS), such as nitric oxide (NO˙) from appears to be a homeostatic regulator of numerous arginine. essential cardiovascular functions and also controls . L-Arg + O2+ NADPH → NO + citruline the expression of genes involved in An inducible nitric oxide synthase (iNOS) is capable of atherogenesis. The blood vessel wall NO is mainly continuously producing large amount of NO˙, which produced from l-arginine by endothelial NOS. − − act as a O2˙ quencher. The NO˙ and O2˙ react together Nitric oxide as a key endothelial vasodilator also to produce peroxynitrite (ONOO−), a very strong directly affects metabolism by competing with oxidant, hence, each can modulate the effects of mithocondria for oxygen and consequently inhibiting − other. Although neither NO˙ nor O2˙ is a strong switching the metabolism to some other pathways. oxidant, peroxynitrite is a potent and versatile oxidant Also, some studies suggested that NO is implied in the that can attack a wide range of biological targets. response of Candida albicans species to the oxidative Peroxynitrites can interact with several cellular stress and also against some azoles drugs. Candida components and are implicated in NO signaling albicans is a commensal species of the human mechanisms involving protein modifications. gastrointestinal tract, in which it lives without adverse

− − effects on the host, but yeast-to-hypha transition has NO˙+ O2˙ → ONOO been associated with increased virulence, mucosal In aqueous aerobic solutions NO predominantly forms invasiveness and biofilm formation. Candidemia and - nitrite (NO2 ). In the presence of oxyhemoglobin and invasive candidiasis are frequently associated with oxymioglobin, NO is completely oxidized to nitrate high morbidity and high mortality rates [16]. - (NO3 ). Covalent interactions of NOS with cellular macromolecules are responsible for its many ANTIOXIDANTS AND DEFENSE MECHANISMS physiological and pathological effects. Protein containing iron and thiol groups are the major cellular Overproduction of ROS (arising either from target of NOS [13]. mitochondrial electron-transport chain or excessive stimulation of NADPH) results in oxidative stress, a There are three types of NOS, neuronal nitric oxide deleterious process that can be an important mediator synthase (nNOS), endothelial nitric oxide synthase of damage to cell structures, including lipids and (eNOS which plays a very important role in the membranes, proteins, and DNA. In contrast, beneficial vascular homeostasis) and inducible nitric oxide effects of ROS/RNS (e.g. superoxide radical and nitric synthase (iNOS; it is found in myocytes, macrophages oxide) occur at low/moderate concentrations and and ECs and is activated by immunological and involve physiological roles in cellular responses to inflammatory stimuli). Under septic conditions iNOS

noxia, as for example in defense against infectious natural antioxidants and the synthetic antioxidants. agents, in the function of a number of cellular signaling Vitamin C, vitamin A and plant phytochemicals like pathways, and the induction of a mitogenic response phenolics that inhibit the oxidation chain initiation and [2]. Cellular constituents of our body are altered in prevent chain propagation represented the second oxidative stress conditions, resulting in various disease line of defense. Vitamin A has a vital antioxidant states. The oxidative stress can be effectively contribution in protecting human LDL against copper neutralized by enhancing cellular defenses in the form stimulated oxidation. Lipid-soluble antioxidants such of antioxidants. Low levels of antioxidants have been as α-tocopherol localize mainly to membranes and associated with the heart disease and cancer. lipoproteins where they serve to limit lipid peroxidative damage. Vitamins E and C have been When ROS/RNS are generated in vivo, their actions are demonstrated to reduce the progression of opposed by intricate and coordinated antioxidant lines atherosclerosis. Vitamin E (α-tocopherol) is the most of defense systems. These include enzymatic and non- important lipid-soluble antioxidant and protects cell enzymatic antioxidants that keep in check ROS/RNS membranes against oxidation by reacting with the level and repair oxidative cellular damage. The lipid radicals produced in the lipid peroxidation chain antioxidant enzymes reduce the levels of lipid reaction and removing the free radical intermediates. hydroperoxide and H2O2, thus they are important in Phenolics are therefore an integral part of the diet, the prevention of lipid peroxidation and maintaining with significant amounts being reported in vegetables, the structure and function of cell membranes. fruits, teas and traditional plants. Epidemiological The major enzymes, constituting the first line of evidence indicates that consumption of fruit, defense, directly involved in the neutralization of vegetables and teas may reduce the risk of ROS/RNS are: superoxide dismutase (SOD), catalase cardiovascular disease and it is increasingly suggested (CAT) and glutathione peroxidase (GPx). SOD is a that this may due to their antioxidants that include ß- cytoplasmic and mitochondrial enzyme, which carotene, vitamin C, vitamin E and polyphenolics. accelerate the dismutation of superoxide. They are Dietary antioxidant phenolics may quench reactive present in almost all aerobic cells and in the oxygen and nitrogen species and, hence potentially extracellular fluids. They contain metal ions that can modify pathogenic mechanisms relevant to be copper, zinc, manganese or iron. In humans, the cardiovascular disease [18]. Vitamin C regenerates copper/zinc superoxide dismutase is present in the vitamin E in cell membranes in combination with cytosol, while manganese superoxide dismutase is glutathione or compounds capable of donating present in the mitochondria. CAT, an exclusively reducing equivalents. peroxisomal enzyme in most tissues, converts H2O2 to Low levels of antioxidants have been associated with water and O2. However, the most important H2O2- the heart disease and cancer. Antioxidants provide removing enzymes are the selenoprotein GPx protection against a number of disease processes such enzymes. GPx enzymes remove H2O2 by using it to as aging, allergies, algesia, arthritis, asthma, oxidize reduced glutathione (GSH) to oxidized atherosclerosis, autoimmune diseases, broncho- glutathione (GSSG). Glutathione reductase, a pulmonary dyspepsia, and cancer. The other disorders flavoprotein enzyme, regenerates GSH from GSSG, to which antioxidants provide protection are cataract, with NADPH as a source of reducing power. cerebral ischemia, diabetes mellitus, eczema, Glutathione peroxidase also catalyses the reduction of gastrointestinal inflammatory diseases, and genetic unstable hydroperoxides at the expense of GSH [17]. disorders. The nonenzymatic antioxidants are of two types, the

References:

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

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2. Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M et al. current state. Nutrition J. 2015, 15:71, doi.10.1186/s12937- Free radicals and antioxidants in normal physiological 016-1086-5 functions and human disease. Int J Biochem Cell Biol, 2007, 11. Napoli C., Paolisso G, Casamassimi A, Al-Omran M, 39 (1): 44-84. Barbieri M, Sommese L, Infante T, Ignarro LJ. Effects of nitric 3. Martin LJ. DNA damage and repair: relevance to oxide on cell proliferation: novel insights. J Am Coll Cardiol. mechanisms of neurodegeneration. J Neuropathol Exp 2013 Jul 9;62(2):89-95. Neurol. 2008; 67:377–387. 12. Misra MK., Sarwat M., Bhakuni P., Tuteja R., Tuteja N. 4. Roger V.L., Go A.S., Lloyd-Jones D.M., et al., AHA statistical Oxidative stress and ischemic myocardial syndromes. Med. - update heart disease and stroke statistics. Update Sci. Monit. 2009, 15(10): RA209-219 Circulation, 2012; 125, e2-e220 13. Ignarro Louis J. Nitric oxide: Biology and Pathobiology, 5. Vogelzangs N., Beekman A.T.F., Milaneschi Y., et al. Academis Press, 2000. Urinary cortisol and six-year risk of all-cause and 14. Forestermann U., Closs EI., Pollock JS., Nakane M., cardiovascular mortality, J. Clin. Endocrinol. Metabol. 2010, Schwarz P., Gath I., Kleinert H. Nitric oxide synthase 95(11):4959-64 isoenzyme, Characterization, purification, molecular cloning, 6. Manenskijn L., Van Kruysbergen R.G.M., De Jong F.H., et and functions. Hypertension, 1994, 23:1121-1131 al., Shift work at young age is associated with elevated long- 15. Forestermann U., Sessa WC. Nitric oxide synthase: term cortisol levels and body mass index, J.Clin. regulation and function. Eur Heart J., 2012, 33(7):829-837 Endocrinol.Metabol, 2011, 96(11):E1862-5 16. Rusu E, Sarbu I, Pelinescu D, Nedelcu I, Vassu T, 7. J. W. Rich-Edwards, A. Fraser, D. A. Lawlor, and J. M. Catov, Cristescu C, et all. Influence of associating nonsteroidal anti- “Pregnancy characteristics and women's future inflammatory drugs with antifungal compounds on viability cardiovascular health: an underused opportunity to improve of some Candida strains. Rev. Rom. de Boli Infectioase ISSN women's health?” Epidemiologic Reviews, 2014, 36,1: 57–70 1454-3389, 2014, vol. XVII nr.2:86-90 8. Loscalzo J, Vita AJ. Nitric oxide and the cardiovascular 17. Bahorun T., Soobrattee MA., Luximon-Ramma V., system. Spinger Science & Business Media, 2000. Arouma OI. Free radicals and antioxidants in cardiovascular 9. Jurcut R, Savu O, Popescu BA, Florian A, Herlea V, health and disease. Internet J Med Update, 2006, 1(2):25-41 Moldovan H, Ginghina C. Primary cardiac leiomyosarcoma. 18. Shahidi F, Wanasundara PKJPD. Phenolic antioxidants. When valvular disease becomes a vascular surgical Crit. Rev. Food. Sci. Nutr. 1992;32:67-103. emergency. Circulation, 2010, 121(21):e415-e418 10. Kurutas EB. The importance of antioxidants which play role n cellular response against oxidative nitrosative stress:

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

Ethical limits between aesthetic and cosmetic dentistry

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

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

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

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Prosthodontic terms, esthetic dentistry is defined as dental cosmetic, from an ethical point of view; (c) the part which studies beauty, creating harmonious esthetics, the reason for treatment and clinical results through prostheses, and ethics is a moral examination; (d) medical training, scientific publica- principle or a set of moral values of an individual or tions, patient information, consent. The search group of individuals, in our case – the ones involved in strategy was conducted using EBSCO Data Base the treatment (doctors, technicians). Cosmetic Dentistry & Oral Sciences Source with the aid of dentistry is not a term indexed by GPT, its definition Boolean Operators. The following keywords were being present in the Collins dictionary, like maneuvers combined: ethics, esthetic, and cosmetic dentistry. aimed to beautify without purpose or functional form. The search was limited to English peer reviewed The medical profession has ethical obligations [1] articles, full text and years limitation January 2000 - centered to prevent and treat diseases, in order to October 2015 academic journals. rehabilitate the dento-masticatory apparatus functionality, namely mastication, phonation, and the RESULTS patient's physiognomy. There was obtained a total of 1248 articles, including Questions related to dental esthetics are: What are the full text criteria, of which 580 articles were retained, ethical boundaries of the esthetic trends in dentistry? matching the search criteria requested. After applying Can anything be done from a medical standpoint for the search criteria 10 publications became relevant. the sake of obtaining an esthetic outcome? Are we Furthermore, there was done a manually electronic ready for this new challenge as physicians who took search on themed websites. In the end, 14 the Hippocratic Oath for the “primum non nocere” publications that included the search criteria were principle? Are we trained as trainers, academics, in selected. Among the issues raised by the retained order to educate students so that they become true publications, there were identified 4 axes of interest: professionals in esthetic dentistry? What are the limits 1. Dental esthetics as part of dentistry – boundaries. of esthetic dentistry and dental cosmetic, as a new term in our vocabulary? 2. Difference between esthetics and dental cosmetic from the ethics point of view. These are some of the questions that have led us to write this paper. This study is a literature one designed 3. Esthetics, as a reason for treatment and clinical to focus the current problems that modern dentistry is examination. facing in relation to esthetic requirements. The 4. Training the physicians, scientific publications, original aspect of this work is related to the definition informing the patient – consent. (both for patient and doctor) of these two terms, their character being a little bit confusing, also being DISCUSSION capable to lead to legal aspects, even malpractice. Dental Esthetics as Part of Dentistry – Boundaries MATERIAL AND METHOD At this point two issues detach themselves – A comprehensive literature study was completed in functionality and bias. As noted in the introduction, October 2015. There were selected publications in there is a definition of dental esthetics in the GPT, English, peer reviews, articles from academic however this is rather vague, making reference to publications, dated January 2000 to December 2015. “beauty, following the art’s rules and principles''. In There was obtained a total of 1248 articles, including dentistry, the therapeutic dental restorations are not full text criteria, of which 580 articles were retained, only esthetic, but they should primarily ensure the and after applying the selection criteria only 14 dento-masticatory apparatus and the dental occlusion publications remained. Identified as directions of functionality. For example, dental fillings can be done interest were: (a) dental esthetics as part of dentistry medically with physiognomic or non-physiognomic – boundaries; (b) the difference between esthetic and materials, both having advantages and disadvantages,

the dominant criteria for the physician must be based a good health state, respecting, of course, the dento- on clinical experience, choosing the optimal method of masticatory functions. So, we are talking about treatment in order to meet the basic medical principle, affected tissues, or with such potential. [4] “primum non nocere”. [2] Dental cosmetic seeks only embellishment, often The medical profession bases its treatment on clinical, without any consideration for functionality, interfering objectively examination of the patient. When with healthy tissues, without clinical impairment for regarding the esthetics dental problems, subjectivity beautifying intentions. Often, these maneuvers might occur; hence, the need to establish clear criteria, contradict even the esthetics concept – defined as both objective and subjective, for the examination in being an integration concept of beauty in natural dental esthetics. Indeed esthetic sense is not a proportions, with a humane dimension. Is it criterion for graduation from the Faculty of Dentistry; esthetically the completely unnatural pure white smile it has a great variability from person to person, from of an 80 years old lady? Is it not against the clinician to clinician, as well as from patient to physiological processes of aging teeth, with natural clinician. Given these difficulties related to the tooth staining due to time passage? Therefore, the subjective issues, it was suggested a hierarchy of the difference between cosmetic and esthetic dentistry esthetic aspects in dentistry, starting from basic must be properly ethically and medically esthetic rules where the smile’s coordinates comply to differentiated [5,6]. Moreover, some cosmetic the classical principles of the golden ratio, symmetry, maneuvers might damage a healthy dental tissue – for dental and dento-facial proportions, smooth line example when applying veneers, esthetic crowns, smiling. excessive grinding, applying adhesive – without pulp protection – can lead to tooth loss – defined as The next level is represented by the cultural and disfigurement, from the ethical point of view. [3] regional subjective aspects, for example in the United States the so-called Hollywood smile is a social One must respect, from the ethical point of view, the standard, the whiteness and perfect alignment of principle of minimally invasion; the so-called enamel teeth being associated with wealth, social and sacrifice on the altar of vanity [7, 8, 9] does not financial success. At last, the latest level is the so- correspond to the principles of medical ethics. On called virtual level – the one that a computer program long-term, the biological implications of the sets as ideal for the patient, from the esthetic point of maneuvers consequences that were performed only view. [3] for cosmetic purposes should be correctly assessed by practitioners. [10] Esthetic would mean beauty, form Is dental esthetics a part of the patient’s general and function – and cosmetic only beauty. [2] health state? Yes, it was clinically proven that the esthetic restoration brings an important psychological Esthetics, as a reason for treatment and clinical benefit to the patient. [3] examination

Difference between Esthetics and Dental Cosmetic As shown, although the boundary between esthetic from the Ethics Point of View and cosmetic maneuvers may seem “too fine” sometimes, the practitioner disposes of objective Within the last years, appearing the dental cosmetic criteria when deciding the treatment plan. [11] term, that was medically not registered otherwise, there have been many misunderstandings between Patients who address the dentist for solving the this term and the esthetic dentistry, both among esthetic problems divide into two categories – among patients and practitioners. these reasons are dental crowding, discoloration, unsightly tooth discoloration, missing teeth, multiple Traditionally, dental medicine as a medical specialty is teeth with coronal restorations. The patients’ reasons centered, ethically speaking, on the prophylaxis and may be esthetic ones, but after a properly conducted the treatment of the dental tissues in order to ensure clinical examination, the dentist will establish the

18 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine functional problems – occlusion problems, migration designed only to beautify, can be really dangerous, and others that, from an objective medical point of especially for young doctors who didn’t benefit from view, should be rehabilitated in order to restore the enough clinical experience and being pressured by morpho – functional, esthetic, masticatory and patients in order to obtain esthetic results, can guide phonetic balance. The dentist will decide the patient's their therapeutic conduct, based on good faith. [10] treatment plan, single or multidisciplinary In the modern age, consumer society pushes dentists orthodontics (teeth alignment through braces), to features, such as advertising, with the temptation conservative treatment (bleaching, esthetic for many dentists to promise spectacular results with restorations, and ceramic veneers), and dental a negative impact on the professionalism of the entire prosthetic (crowns coverage, dental implants). A profession [6], we must not forget the fundamental second category refers to patients without enough nature of our medical profession profile, namely the arguments – patients suffering from narcissism, professional doctor [13] and not the beautifying one. personality disorder, patients who can’t accept their In this context it is important, ethically speaking, the age. As in the first group, the dentist is the one that doctor-patient communication regarding the dental will make a “proper diagnose” considering the medical esthetic issues – the doctor is required in this type of history and clinical examination. treatment to inform the patient in order to receive his Patients with such presentation reasons will consent over long-term implications (especially in permanently be unsatisfied with the treatment younger patients). Communication must be made in outcome. Unlike the ones with consistent esthetical terms that the patient will be able to understand (not grounds that will be satisfied once the esthetic necessarily medical terms), assisted by pictures, problem is solved, for the second class the result will drawings, suggestive dental casts. It is also required to not be acceptable even if it has improved the esthetic present to the patient, where appropriate, one or aspect. [2] These are the most common candidates for more treatment alternatives, including the less dental cosmetic, for whom the “primum non nocere” esthetic alternative, before signing the informed principle must be respected from the ethical consent [3]. Esthetic dentistry requires less viewpoint. [10] accommodation, incorporates acceptable biologic technology for long-term survival, functions suitably, And not least, after the clinical examination, if the and mimics the pristine state of the natural dentition. dentist is in a doubtful situation, he should, according Cosmetic and esthetic dentistry are different in to "when in doubt, it is probably not ethical" [7] test definition, concept, and execution [14]. himself with "The Daughter Test" – Would I proceed with this intervention on my daughter? [8,12] CONCLUSIONS Training the physicians, scientific publications, As a result of this extensive literature study on a very informing the patient – consent actual dentistry issue – ethical considerations of Another important aspect is the dentists training, in esthetics and dental cosmetic, we came up with some addition to the fundamental principles of dental interesting conclusions intended to clarify the often esthetics already learned in college; the profession encountered confusion regarding these terms. Dental currently faces numerous specialty publications in Esthetics regroups several dental maneuvers, often which the so-called academic articles are praising interdisciplinary, aiming the morfo-functional rehabi- esthetic results obtained – the ethical aspect of the litation of the dento-masticatory apparatus, following presented cases being often questionable from the universal esthetic principles harmoniously integrated fairness of the dimension’s vertical occlusion point of into the overall health and harmony of the human view, occlusion stability and durability of these body as part of dentistry. Dental cosmetic is a set of restorations. Publishing some insufficiently and maneuvers that, although have a medical character, superficially documented cases – medically speaking, do not seek the reconstruction of the maxillary device

functionality, just have a beautifying character, implications, in order to be able to present to his intervening on healthy tissues without any patient all treatment alternatives and guide him to prophylactic role, often with disabling long-term choose the optimal treatment option for obtaining the implications. In terms of bioethics, the “primum non desired esthetic results within the ethical boundaries nocere” principle is not respected within these of this noble profession. The theme being new and the maneuvers. boundary between esthetics and cosmetic dentistry being quite subjective, no doubt that they still have to Therefore, it is important for the dentist to know the be studied, there are needed further studies and differences, the fundamental dental esthetic concepts, research that will clarify the differences between them in order to minimize the subjective component of the on an evidence-based scientific system. examination, to succeed the clinical examination with identification of the presentations reasons, to be Acknowledgements trained for all medium- and long-term treatment All authors had equal contribution in this paper elaboration.

References:

1. Astarastoae V., Triff B.A., Essentialia in Bioetica, Cantes Beauty or “Bucks’’?, Oral Health Group.com, 10/01/2010 Publishing, Iasi, 1998 8. Hancocks S., The Ethics of Cosmetics, British Dental 2. Ahmad I., Risk management in clinical practice. Part 5. Journal, 211-11 Editorial, 2011 Ethical considerations for dental enhancement procedures, 9. Jackson R.D., Judging Ethics Ethically, Journal of Esthetic British Dental Journal, 209:207-214, 2010 & Restorative Dentistry-Journal Compilation Blackwell 3.Liebler M., Devigus A., Randall R.C., Trevor Burke F.J., Munksgaard, 19:181-182, 2007 Pallesen U., Cerutti A., Putignano A., Clauchie D., Kanzler R., 10. Kelleher M., Ethical Issues, Dilemmas and Controversies Koskinen P., Skjerven H., Strand G.V., Vermaas R.W.A, Ehics in “Cosmetic” or Aesthetic Dentistry. A Personal Opinion, of Esthetic Dentistry, Quintessence International, 35:456- British Dental Journal, 212:365-367, 2012 465, 2004 11. Owsiany D.J, The Intersection of Dental Ethics and Law, 4. Williams J., FDI Dental Ethics Manual, ISBN 0-953 9261-5- Journal of the American college of Dentists, 75:47-54, 2008 X, 2007 12. Kelleher M., “The Daughter Test” in Esthetic or Cosmetic 5. Glick K., Cosmetic Dentistry is Still Dentistry, Journal Dentistry, Dental Update, Jan/Feb 2010 Canadian Dental Association, 66:88-91, 2000 13. Poonam et al, Ethics in Medicine and Dentistry: A Review, 6. Hussey D.L., Where is the Ethics in Aesthetic Dentistry, Indian Journal of Dental Sciences, 5:152-154, 2013 British Dental Journal, 192-6 Conference, 2002 14. Touyz LZ1, Raviv E, Harel-Raviv M. Cosmetic or esthetic 7. Faith K.E., The Ethics of Cosmetic Dentistry: Beneficence, dentistry? Quintessence Int. Apr;30(4):227-33,1999.

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

History of medicine on the border between philosophy and science

Mirela Radu 1

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

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

of healing practiced by the Romanians led him to lay the great Davila, our medicine goes from the the foundations of a new branch of science: the history assimilation phase to the one of creation, as more and of medicine. Between 1949-1971 he presided the more characteristically forms a Romanian medical International Society of Medicine History. Feeling that current. The old Transylvanian medical literature was the progress can only be heard through the knowledge represented equally well at the beginning – from the of the past, Bologa devoted many books to the facts of 16th century – by the works of the German doctors, the medicine in the past. One of the first important later with those of the Hungarians, finally from the papers signed by the Romanian physician focused on 18th century and with the first Romanian medical the special situation of the Hippocratic profession translations.”[2] practiced by the Transylvanian Romanian doctors who But Bologa was not the only one who fought for this had to face not only the lack of material means but new branch of medicine. He was helped in his efforts also the political repression: Contributions to the by the fellow surgeon Victor Gomoiu (1882-1960) who history of medicine in Transylvania (1927). Three years founded museums dedicated to the history of later, Bologa signed a second monograph, The medicine in Târgu-Jiu and Craiova. Gomoiu, in turn, Beginnings of Romanian Scientific Medicine for which published a monograph entitled From the History of he would receive in 1931 the V. Adamachi Prize of the Medicine and Romanian Medical Education (1923) and Romanian Academy. But until 1927, the physician during the interwar period he was elected president of signed only a studies with great historical significance, the International Society of Medicine History (1936). dedicated to some of the most diverse themes – from Gomoiu was also the one who signed the first History midwifery, to the forerunners of doctors, from of the Medical Press in Romania (1936), the work of ophthalmology to medical lexicology formation: collecting and organizing numerous medical papers Spells, old women and midwives today and the past and writings. But Gomoiu was not just an encyclopedic (1921); New data for Ioan Molnar (1925); About spirit. He also actively contributed to the struggle that Romanian Occultists (1925); Medicine in Moldavia doctors used to do with illnesses whose mortality (1925); Between physiology and medicine (1925); reaches worrying odds. Director of the Osteoarticular Romanian Medical Terminology of doctor I. Molnar Tuberculosis Sanatorium for Children in Techirghiol, (1926). eventually Gomoiu would practice surgery in Furthermore, Bologa dedicates himself to the Bucharest. His surgical work is quantified by the large construction and endowment of a museum dedicated number of innovative articles he has written, by to medical science in Romania. The Romanian scholar implementing the term solarectomy (resection of was particularly fond of two sections of the museum: lymph nodes), initiated the inguinal approach of Old Romanian Medicine and Medicine in the varicocele (Gomoiu-Phocas method). Intransigent Transylvanian past. The great importance he gave to character, Gomoiu was removed from academic the knowledge of the old times of the profession he education. His merit in the history of medicine is to revered could be felt from the appreciation with which insist on the Romanian contribution to the he emphasizes the importance of those early times, international folk medicine fund. This brought, at least but also the respect he had for his ancestors. For the historically, the Romanian medicine at the level of the reader of any age is visible the attachment and esteem other countries reducing the gap. A proof of his ideal that doctor Bologa carries to those who have done and his effort to bring medicine to the Western level medical pioneering work, especially in the are the three works published by the Romanian Transylvanian region: “From this rich Romanian physician in 1938: La Croix dans la Folclor medical medical library can be reconstituted the hard work of roumain, Histoire du Folclore medical en Roumanie the first gatherers of new roads in Romanian science. and Medicine in the Romanian folk prose. It is possible to see the influences from the outside, it Bologa also corresponded intensely with Mircea can be seen how gradually a Romanian medical Eliade, whom he intended to co-opt in his work at the terminology was formed, it can be noticed how, from

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Institute of Medical History. Eliade, despite the fact he perceives as a means of producing: “real services to had no necessary time for active participation in this the humanism of our age.”[5] Folk medicine is viewed approach, had a special esteem for the intellectual with reverence by Eliade because it represents the physician, as is also apparent from the lines written by immaterial and immutable connection with the the philosopher in an epistle addressed to the ancestors of the nation. Since 1926, Eliade physician-historian, a letter dated 23 October 1928: “I collaborated with Aldo Mieli, who was the publisher of testify that whenever I skim through your work and Archeion magazine, producing short studies of the meditate on the situation of the history of sciences in history of various sciences, medicine and folklore. our country – I am remorseful that I do not write more That's how Eliade got to correspond with Bologa. The often, warmer and harder, in the papers that are at my latter wanted to develop a collaboration with Miel's fingertips. I know that, personally, for the scientific Archeon by making contributions in the form of history studies I'm interested in – I have to thank you. articles devoted to Italian influences on Romanian Not to mention what others owe you, especially medicine. doctors and historians. The Institute makes For Eliade, the whole science represents, at least in the «environment» scientific history, we, isolated ones, initial phase, a single corpus. Subsequently, science can at most, make the atmosphere. If an association has specialized and subspecialized over time. What for such studies can be woken up, I always think that could bring back all these disparate fragments to one the courage of the achievements has been with the place would be the philological field. In fact, even production of the Cluj Institute.“[3] Even in India, Bologa was aware that his scientific approach was far Eliade maintains contact with the Romanian physician more philological. This is how one can explain the help for whom he does not hesitate to admit he has a great that he Bologa asked from the philosopher. Another cult of his extraordinary work of a huge volume: “The connection between the two, Bologa and Eliade, was passion of science – that is, the slow, precise, technical the scientific curiosity to study botany. As a small child, sorting of the material our culture provides us – is the Eliade devoted much energy to catching, studying, great temptation that brings me closer to you .” (Letter analyzing and cataloging various insects. At the age of dated 16.02.1930, Calcutta)[4] fourteen, Eliade published a study titled Silkworm’s The reason why Eliade particularly appreciated Bologa Enemy, under the pen name Eliade Gh. Mircea, which resides in the philosopher's aspiration to write a few showed the passion he has for insect biology. The stories on traditional Indian medicine branches. Eliade marvelous journey of the five beetles in the land of the admired the founder of medical history the ability to red ants-sketch of the novel – was written in the same synthesize the huge volume of works, objects and period. More the outline of a teenager fascinated by manuscripts. It was the systematization work that the world of gangs, behind the modest mise-en-place occupied the author of Religious History Treaty and is hiding a satire, an annoyance of the enemy (ants) by History of Religious Beliefs and Ideas all the time. At five elite bettles. It is a mockery of the human society the same time he was better equipped to understand reduced to the microcosm of insects. the enormous sacrifice of time and resources involved The step to science would come when Eliade in ordering, ranking, and organizing such amount of participated and won a contest that proposed the information. Frustrated by the huge volume of notes, literary approach of a scientific subject. The title of the contact with Bologa developed philosopher's essay (How I found the philosopher's stone) is an rationalization and ability to think more rigorously. epiphany of the future path that the teenager Eliade Eliade's interest in medicine crystallizes in 1936 when, would take. The essay written by a youngster seems to following a lecture held at an International Congress of have amazed the author himself when, over the years, History, Eliade publishes History of Medicine in he said, “How much I would like to be able to reread Romania. The affection borne by the philosopher of this story now, understand what that mysterious the religions to this new emerging branch stems from character revealed to me, what alchemical operations the support given to the history of medicine which he

he assisted! I had found the philosophical stone in my Renaissance humanism, but in the history of science - dream ... I could only understand, decades later, after understood as «any systematized knowledge» I read Jung, the meaning of this oniric symbolism!”[6] (Sarton), therefore more than «positive sciences».”[9] The short story, though a fantastic text loaded with Eliade, great admirer of George Sarton (1884-1956), supernatural, has as its starting point in Eliade's intuited in the Belgian chemist the innovative spirit. interest in chemistry and alchemy. Although he had Sarton embraced the history of science as a branch of promised Bologa that he would make his contribution gnoseology and aimed at linking science and to writing a history of Romanian medicine, Eliade's humanism to a comprehensive one: the philosophy of departure to India would break this momentum. science. Eliade was in the current with the theories of Though time did not allow him, for the young Eliade the American and hence the enthusiasm at the was trying to absorb the new information that was moment when a homologous branch was formed on crowded him, the philosopher gathers medical the Romanian realm. The only ones of sufficient material inspired by yoga practices and even offers to intellectual scope that Valeriu Bologa could count on write to the Romanian physician an article about were Mircea Eliade and Nicolae Iorga. Ayurvedic medicinal products, as we find out from a letter dated February 6, 1930: “I have a considerable If alchemy was the gate open to science, popular number of facts on pharmaceutical medicine and creation and ancestral healing practices were the magic in India, some of them astounding, such as those preamble of modern science. And Eliade felt this relating to vagus nerve control.”[7] correlation, especially as the prose was anchored in folklore: “In his writings, the folkloric elements For Eliade, alchemy is the gate open to an occult form intertwine with those of the history of religions or of practice. Alchemy is the first type of objective report ethnology. His stories take place in illo tempore, that leave leave, over the history of humanity, truly somewhere outside of physical time, and the scientific discoveries; a kind of ancestor of rational characters have supernatural powers, their existence knowledge. This preparatory, pseudo-scientific phase, enrolling in an eternal present, and the facts being the first attempt of structuring scientific knowledge predetermined in advance. Witches, queens, beautiful was the one that attracted Eliade from his youth women who make pact with the evil, curative herbs because of its esoteric character. In 1928 Eliade wrote and charm plants, here are some of the ingredients an article (Marcelin Berthelot and alchemy) dedicated with which Eliade sows his writings inspired by to a French chemist and biologist who imposed his folklore.”[10] name in the field of thermodynamics. Conscious of the enormous gap between Romanian and Western The pioneering work of building a frontier science in science at the beginning of the 20th century, Eliade our country like the history of science did not frighten sensed, from the philologist and philosopher point of Eliade. We find out from a letter addressed to Bologa view, the need to systematize the totality of that, on the contrary, ostentatiously, he protects this historiographical material in order to be saved from new branch of knowledge, although he is aware of the oblivion: “We cannot wait until Romanian science weight of action in a rebellious society to the new: “I reaches a European level to promote the validity of defend a science against the envy and imbecility of our historical-scientific studies. There is no discipline that intellectuals. I do not even think that our science will can be postponed.”[8] The philosopher's insight was to soon become popular. But it must not be ignored and, build a methodology in this vast field of history of above all, dishonored by the elite to which it is de jure medicine. The history of science would be appropriate, and de facto aimed at.”[11] with a takeover from a chemist and American historian What brought together a physician (Valeriu Bologa) Sarton, a new form of intellectual movement that and a philosopher (Mircea Eliade) were the folk would put man and science in the center: “Eliade traditions with application in medicine. Apparently understands a new interpretation or vision of man not two opposing personalities collaborated efficiently derived from philological studies (textual), as it was

24 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine and discovered the common denominator, the shared their opinions meant much for the later unspoken binder between a scholar spirit and a developments of both.”[12] metaphysical one, for “the research of Valeriu Bologa met the interests of Mircea Eliade and although they did not sign articles or books, the mere fact that they

References:

1. Valeriu Bologa, Wheat Grains, in Institute of History of 7. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas Medicine, Pharmacy and Folklor Medicine of Cluj, no. 6, June Publishing House 1999, Foreword and Care of the Edition by 1932, pp. 205-206 Mircea Handoca, p. 79 2. Valeriu Bologa, Wheat Grains, in Institute of History of 8. Mircea Eliade, History of Medicine in Romania in The Medicine, Pharmacy and Folklor Medicine of Cluj, no. 6, June Word, year IV, no. 1174, 30 July 1928, pp. 1-2 1932, pp. 218 9. Mac Linscott Ricketts, Romanian Roots of Mircea Eliade, 3. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas 1907-1945, vol. 1, Bucharest, Criterion Publishing House, Publishing House 1999, Foreword and Care of the Edition by 2004, p. 288 Mircea Handoca, p 76 10. Mihaela Gligor, Between philosophy and medicine. The 4. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas medical folklore in the vision of Mircea Eliade and Valeriu Publishing House 1999, Foreword and Care of the Edition by Bologa, Cluj University Press, 2014, p. 94 Mircea Handoca, p 78 11. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas 5. Mircea Eliade, History of Medicine in Romania in Journal Publishing House 1999, Foreword and Care of the Edition by of the Royal Foundation, no. 6, June 1936 Mircea Handoca, p. 85 6. Mircea Eliade, Memories, 1907-1960, 2nd Edition 12. Mihaela Gligor, Between philosophy and medicine. The medical folklore in the vision of Mircea Eliade and Valeriu Revision and Index by Mircea Handoca, Bucharest, Bologa, Cluj University Press, 2014, p. 138 Humanitas Publishing House, 1997, p. 63

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

Therapeutic management of schizophrenia and substance use disorders dual diagnosis – clinical vignettes

Octavian Vasiliu1

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

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

26 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine with an earlier onset of schizophrenia, more severe pharmacological explanation is that this agent has a forms of disorder, higher rates of relapse, and longer structural similarity with phencyclidine [18,19]. The hospitalizations [3-5]. Longitudinal studies report that risk of biperiden and orphenadrine abuse was cannabis use in childhood and adolescence doubles relatively small in a large database analysis [17]. the risk of psychosis onset later in life, which supports a causal role of this drug in the development of CLINICAL VIGNETTES schizophrenia [6]. Certain alleles of the type 1 cannabis The first patient, M.S., is a 29-year old male, diagnosed receptor gene (CNR1) may confer susceptibility to since 2015 with schizophrenia according to the DSM-5 schizophrenia [7]. criteria [20], currently at his third psychotic episode. Also, the overlap of nicotine dependence and He was hospitalized after he presented at the schizophrenia has been debated as a form of self- Emergency Department with delusions of persecution medication for schizophrenia-related cognitive and auditory hallucinations (“there are people who deficits, based on the fact that the nicotine receptors want me dead because of my soul, they want to collect activation increases the release of dopamine in my psychic energy”, “I can hear them through the cortical and subcortical areas [8,9]. Still, cigarette walls, day and night, they are plotting against me, and smoking decreases the bioavailability of many they are saying bad things about my family”, “They are psychotropics that are metabolized through the forcing me to do evil things, like cursing strangers with CYP450 1A2 isoenzymes and consequently may no reason”). These manifestations led to changes in his diminish the clinical effect of these drugs and delay the behavior, he became reclusive, didn’t go out of his patients recovery [10]. Multiple genes have been house for weeks and spoke with his family only by linked to both conditions, e.g. binding protein genes, phone, refusing to see them (“I can protect them if I’m protein modification genes, and energy production not seen with them”). He recently abandoned his job genes involved in cognitive functions and neuronal as a salesman and didn’t want to see her girlfriend plasticity [11]. anymore because of the belief that she was in cahoots with the persecutors who want him dead. Alcohol use disorder was found in 33.7% of patients diagnosed with schizophrenia or schizophreniform The pharmacological history in this case included disorder in the Epidemiologic Catchment Area study olanzapine 20 mg/day as the main treatment for his [12]. A dysregulation of the dopamine transmission first psychotic episode. After hospital discharge, he has been suggested as common neurological basis, but received the same antipsychotic for 8 months, then he shared genetic vulnerability factors have also been dropped out and relapsed after about 6 months. The investigated (e.g. KPNA3, or alcohol dehydrogenase overall clinical status during the second admission was variants) [13-16]. A review of the current evidence for similar to the first episode of psychosis, with common risk factors in alcohol use disorders and persecutory delusions and auditory hallucinations schizophrenia supports a highly polygenic model, with (both conversing and imperative voices) and induced rare penetrant alleles and frequent alleles with small defensive behavior- the patient refused to go out by effects [16]. himself because of the fear of being watched and plotted against. Olanzapine was re-initiated, but Patients diagnosed with schizophrenia tend to abuse shortly after this the patient was switched on anticholinergic drugs. These agents are often used for aripiprazole 30 mg/day due to concerns related to his the treatment of antipsychotic-induced extrapyra- metabolic status (240 mg/dl for the total cholesterol, midal symptoms, and a national database analysis 150 mg/dl for LDL-cholesterol, and 250 mg/dl for showed that patients with schizophrenia took 20 times triglycerides). The evolution was favorable during the more frequently antiparkinsonian agents than hospitalization and the patient was recommended to patients with Parkinson disease [17]. Trihexyphenidyl work in a controlled environment and to participate in abusers may claim this drug improve their daily occupational therapy. However, after 7 months he functioning and their affect, and a possible

discontinued treatment and soon relapsed, so that a by the case manager when the therapeutic strategy new hospitalization was required. This time the was formulated. Aripiprazole was preferred because patient was stabilized on aripiprazole, but for the of its good metabolic profile [25], and a long acting maintenance phase the long acting injectable form of injectable formula was selected because of the more aripiprazole 400 mg every 4 weeks was selected, in stable plasma concentrations and lower risk of order to diminish the risk of therapeutic non- discontinuation. The patient received counselling for adherence. his addictive behavior, and he participated in 4 individual sessions focused on smoking cessation and The patient was also diagnosed during the current alcohol use relapse prevention. Alcohol withdrawal psychotic episode with alcohol use disorder, symptoms were mild-to-moderate and remitted after moderate, based on the DSM-5 criteria, admitting a B-vitamin therapy, parenteral rehydration, and oral daily intake of 8 drinks, consisting mainly in beer and lorazepam 3 mg/day for 7 days, with gradual dose wine for more than 12 months. Also, he is smoking 20 reduction. Naltrexone, 50 mg/day, was initiated for cigarettes daily, with a value of 10 pack-year. alcohol dependence after the withdrawal symptoms Biochemistry panel reflected the liver damage, with remission, and nicotine replacement therapy was values for gamma-GT, GOT and GPT of 156 U/l, 70 U/l, suggested, but the patient refused. There are no data and 67 U/l, respectively. No abnormalities were reported about pharmacokinetic interactions between detected on his chest X-ray and abdominal ultrasound aripiprazole and naltrexone in the literature, which exam (except for hepatic steatosis). supports this therapeutic recommendation. The psychological evaluation realized during the initial Follow-up visits: The patient was monitored for 4 visit for the third episode showed a 98 score on PANSS months, using psychometric instruments, in order to [21], with high values on both positive and negative document psychotic symptoms, severity of addictions, sub-scales. CRDPSS [20] score was 17, based mainly and overall clinical status evolution under treatment. on hallucinations, delusions and abnormal Global functioning improved once the psychotic psychomotor behavior. AUDIT [22] score was 14, positive symptoms remitted, although the negative reflecting a moderate risk of harm related to the symptoms persisted at a lower level of severity (as alcohol use, and the severity of nicotine dependence reflected by PANSS and CRDPSS scores). was high, as supported by the FTND [23] score of 9. GAF score at admission was 45, based on symptoms Table 1. Psychologic evaluations during the first patient’s severity and functional impairment, while the CGI-S initial visit score was 5, which means a “markedly ill” clinical Clinical scale Results status. PANSS 98 Therapeutic challenges analysis: This patient CRDPSS 17 presented a history of therapeutic non-adherence GAF 45 which triggered two relapses. He was diagnosed with CGI-S 5 two substance use disorders (alcohol and nicotine FTND 9 dependence), which were not therapeutically AUDIT- Interview Version 14 approached during his two previous psychotic episodes, and this could be also a factor that may Alcohol use disorder had a favorable evolution and the contribute to relapse in schizophrenia [24]. There is a AUDIT scores diminished gradually, but the nicotine lack of social and professional insertion in this case, dependence persisted and the mean number of related to both positive and negative symptoms. The cigarettes increased with 25%, while the FTND score patient lacks familial support and he discontinued increased with 10%. Biochemistry panel reflected an occupational therapy. Moreover, the metabolic profile improvement of the liver status after 4 months, with and the hepatic functional status were abnormal. All values for gamma-GT, GOT and GPT of 56 U/l, 23 U/l, these negative prognosis factors have been evaluated

28 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine and 37 U/l, respectively, and the metabolic untreated or if the appropriate treatment is delayed. parameters improved, also: 190 mg/dl for the total In this particular case, naltrexone was efficient in the cholesterol, 120 mg/dl for LDL- cholesterol, and 170 treatment of alcohol use disorder, and the patient had mg/dl for triglycerides. also significant decrease of the psychotic symptoms. However, nicotine dependence could not be Conclusion: Addictive behaviors must be approached addressed pharmacologically because the patient as soon as possible by the case manager in patients refused, and he participated only in a few counseling with schizophrenia, because the risk of therapeutic sessions, which led to the persistence of his substance non-adherence, somatic complications, and reduced related condition. functionality is higher if these conditions are left

Fig.1. Evolution of the clinical variables during the first 4 months of treatment 100

Score 40

0 0 7 14 28 60 90 120

PANSS CRDPSS GAF CGI-S FTND AUDIT

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

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

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

Fig.2. Evolution of the clinical variables during the first 4 months of treatment 100

Score 40

0 0 7 14 28 60 90 120

PANSS CRDPSS GAF CGI-S FTND CUDIT-R EuroQoL-VAS

The third patient, S.G., was diagnosed for the first time stabilization, the drug may be administrated every 12 with acute psychotic disorder 3 months ago. Her weeks. She agreed to be initiated on paliperidone long symptoms at hospital admission consisted in acting after stabilization of acute symptoms. psychomotor agitation, grandiose (“I am very The patient was smoking 30 cigarettes daily, with a powerful, and I can make any wish come true, like value of 9 pack-years. She fulfilled the DSM-5 criteria Santa Claus, only better”) and persecutory (“there is a for nicotine use disorder and accepted treatment for group of forces trying to kill me and take my powers”) this condition. She received nicotine replacement delusions, auditory and visual hallucinations (“I can therapy, but she declined the invitation to join a group hear them talking about me and trying to make me feel therapy focused on abstinence. miserable… they are cursing me and telling lies about me and my family”, “They are moving through the Her ECG was normal, as were chest X-ray, cerebral CT- light, I can see them… they are like some green scan, CBC and serum biochemistry panel. The shadows”), disorganized behavior, and diminished toxicology exam was also negative. emotional expression. She was 27 years old when she was first admitted in hospital, and her psychotic Table 3. Psychologic evaluations during the third patient’s initial visit symptoms had an insidious onset over at least 4 Clinical scale Results months. First, she was initiated on risperidone 6 mg/day, and her response was good, but discontinued PANSS 88 oral treatment because she had to take this drug twice CRDPSS 14 a day. The patient developed positive symptoms of GAF 35 psychosis after one month of no treatment, and she CGI-S 5 was readmitted in the Psychiatry Department. The FTND 9 selected drug for clinical stabilization was risperidone because of her previous good response. She was Therapeutic challenges analysis: This patient is still in informed that a long acting injectable form of this the early phase of disease, as her diagnosis of antipsychotic exists, which requires administration schizophrenia was just established. She met the every two weeks. Also, she was informed that necessary criteria for this diagnosis- time (more than 6 paliperidone, the active metabolite of risperidone, has months including pre-hospitalization period of active two long acting injectable formulations, with symptoms), clinical manifestations, functionality, and administration of one dose every 4 weeks, and after differentials. The challenge is to select a treatment

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

Fig.3. Evolution of the clinical variables during the first 11 months of treatment 100

Score 40

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

PANSS CRDPSS GAF CGI-S FTND

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

32 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine formulate the most appropriate therapeutic strategy. Abreviations list In this case a long-acting formula of an atypical AUDIT = Alcohol Use Disorders Identification Test antipsychotic was preferred because of the active BMI = Body mass index lifestyle of the patient, and her expressed preference CBC = Complete blood count CGI-S = Clinical Global Impression- Severity for a treatment which could be easily administered. CRDPSS= Clinician-Rated Dimensions of Psychosis Symptoms The treatment for nicotine dependence has been a Severity challenge, as the patient did not quit completely CUDIT-R = Cannabis Use Disorders Identification Test – smoking, but only diminished it. Paliperidone could be Revised useful in patients who smoke because it is not EuroQoL 5D-3L= EuroGroup Quality of Life Scale metabolized through CYP1A2, and its plasma FTND = Fagerstrom Test for Nicotine Dependence concentrations remain stable even if this isoenzyme GAF = Global Assessment of Functioning gene is induced by the polycyclic aromatic PANSS = Positive and Negative Syndrome Scale hydrocarbons of the tobacco smoke [34]. 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.

References:

1. Schwartz MS, Wagner HR, Swanson JW, et al. The 9. Picciotto MR, Corrigall WA. Neuronal systems underlying effectiveness of antipsychotic medications in patients who behaviors related to nicotine addiction: neural circuits and use or avoid illicit substances: results from the CATIE trial. molecular genetics. J Neurosci. 2002;22:3338–3341. Schizophr Res 2008;100(1-3):39-52. 10. Theng YM, Wahab S, Wahab NA, et al. Schizophrenia 2. Mueller-Vahl KR, Emrich HM. Cannabis and schizophrenia: and nicotine dependence: What psychopharmacological towards a cannabinoid hypothesis of schizophrenia. Expert treatment options are available for the duo perturbations? Rev Neurother 2008;8(7):1037-48. Curr Drug Targets 2017; doi:10.2174/ 3. Foti DJ, Kotov R, Guey LT, Bromet EJ. Cannabis use and the 1389450118666171017163741. course of schizophrenia: 10-year follow-up after first 11. Chen J, Bacanu SA, Yu H, et al. Genetic relationships hospitalization. Am J Psychiatry 2010;167:987-993. between schizophrenia and nicotine dependence. Sci Rep 4. Weinstein A, Brickner O, Lerman H, et al. A study 2016;6:25671. investigating the acute dose-response effects of 13 mg and 12. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of 17 mg delta 9-tetrahydrocannabinol on cognitive-motor mental disorders with alcohol and other drug abuse: Results skills, subjective and autonomic measures in regular users of from the Epidemiologic Catchment Area (ECA) study. JAMA marijuana. J Psychopharmacol 2008;22:441-51. 1990;264:2511-18. 5. Lejoyeux M, Basquin A, Koch M, et al. Cannabis use and 13. Koob GF, Roberts AJ. Brain reward circuits in alcoholism. dependence among French schizophrenic inpatients. Front CNS Spectrums 1999;4:23-37. Psychiatry 2014;5:82. 14. Morris CP, Baune BT, Domschke K, et al. KPNA3 variation 6. Weiser M, Noy S. Interpreting the association between is associated with schizophrenia, major depression, opiate cannabis use and increased risk for schizophrenia. Dialogues dependence and alcohol dependence. Dis Markers Clin Neurosci 2005;7(1):81-85. 2012;33(4):163-170. 7. Ujike H, Takaki M, Nakata K, et al. CNR1, central 15. Zuo L, Wang KS, Zhang XY, et al. Association between cannabinoid receptor gene, associated with susceptibility to common alcohol dehydrogenase gene (ADH) variants and hebephrenic schizophrenia. Mol Psychiatry 2002;7(5):515-8. schizophrenia and autism. Human Genetics 2013;132:735- 8. Manzella F, Maloney SE, Taylor GT. Smoking in 43. schizophrenic patients: A critique of the self-medication 16. Wang K, LuoX, Zuo L. Genetic factors for alcohol hypothesis. World J Psychiatry 2015;5(1):35-46. dependence and schizophrenia: common and rare variants.

Austin J Drug Abuse Addict 2014;1(1):3. aripiprazole on metabolic profiles: comparison of patients 17. Gjerden P, Brammes JG, Slordal L. The use and potential treated with olanzapine to patients treated with olanzapine abuse of anticholinergic antiparkinson drugs in Norway: a to patients treated with other atypical antipsychotic drugs. pharmacoepidemiological study. Br J Clin Pharmacol Prog Neuropsychopharmacol Biol Psychiatry 2013;40:260-6. 2009;67(2):228-233. 26. Adamson SJ, Kay-Lambkin FJ, Baker AL, et al. An 18. Fisch RZ. Trihexyphenidyl abuse: therapeutic improved brief measure of cannabis misuse: the Cannabis implications for negative symptoms of schizophrenia? Acta Use Disorders Identification Test-Revised (CUDIT-R). Drug Psychiatrica Scandinavica 1987;75(1):91-94. Alcohol Depend 2010;110(1-2):137-43. 19. Nachkebia N, Mchedlidze O, Chkhartishvili E, et al. 27. Balestroni G, Bertolotti G. EuroQoL-5D (EQ-5D): an Effects of trihexyphenydil, the structural analog of instrument for measuring quality of life. Monaldi Arch Chest phencyclidine, on neocortical and hippocampal electrical Dis 2012;78(3):155-9 activity in sleep-waking cycle. Georgian Med News 28. van Reenen M, Janssen B. EQ-5D-5L User guide, 2015. 2009;(169):81-7. Accessed at https://euroqol.org/wp-content/uploads/2016/ 20. American Psychiatric Association. Diagnostic and 09/EQ-5D-5L_UserGuide_2015.pdf in 30/04/2018. Statistical Manual of Mental Disorders, 5th Washington DC, 29. Geodon- Summary of Product Characteristics. Accessed 2013. at https://www.accessdata.fda.gov/drugsatfda_docs/label/ 21. Kay SR, Fiszbein A, Opler LA. The Positive and Negative 2009/020825s035,020919s023lbl.pdf in 30/04/2018. Syndrome Scale (PANSS) for Schizophrenia. Schizophrenia 30. Risperidone – Summary of Product Characteristics. Bulletin 1987;13(2):261-276. Accessed at https://www.medicines.org.uk/emc/product/ 22. Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro M. 4547 in 30/04/2018. The Alcohol Use Disorders Identification Test : Guidelines for 31. Goodnick PJ. Ziprasidone: profile on safety. Expert Opin use in primary care, 2nd edition. Geneva, World Health Pharmacother 2001;2(10):1655-62. Organization, 2011. 32. Sherman BJ, McRae-Clark AL. Treatment of cannabis use 23. Pomerleau CS, Majchrezak MI, Pomerleau OF. Nicotine disorder: current science and future outlook. dependence and Fagerstrom Tolerance Questionnaire: a Pharmacotherapy 2016;36(5):511-535. brief review. J Substance Abuse 1989;1:471-7. 33. McLean MJ. Clinical pharmacokinetics of gabapentin. 24. Swofford CD, Kasckow JW, Scheller-Gilkey G, Inderbitzin Neurology 1994;44(Suppl.5):S17-22. LB. Substance use: a powerful predictor of relapse in 34. Hukkanen J, Jacob P III, Peng M, et al. Effect of nicotine schizophrenia. Schizophr Res 1996;20:145-151. on cytochrome P450 1A2 activity. Br J Clin Pharmacol 25. Wang LJ, Ree SC, Huang YS, et al. Adjunctive effects of 2011;72(5):836-838.

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

Patient reported outcome measures and joint replacement

Alexandra Sopu 1

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

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

should be reliable and conform to ideal scaling, as diabetes or arthritis [6]. The outcomes of a health development and psychometric standards. Examples procedure can be ascertained from the patient’s of renowned PROMs include the SF-36 Health Survey, perspective, through self-reported symptoms and EuroQol (EQ-5D), SF-12 Health Survey, Profile, Quality functional status, by comparing and determining the of Well-Being Scale, Health Utilities Index and differences in data between the pre-operative and Consumer Assessment of Healthcare Providers and post-operative PROMs. Systems (CAHPS) [3]. However, the PROMs are not compulsory for patients These are examples of generic PROMs. Ideal examples to fill. More so, consent from patients who participate of condition-targeted PROMs include Adult Asthma in the PROMs has to be sought before their data is Quality of Life Questionnaire (AQLQ), Seattle Angina used for analysis [7]. The patient’s identifiable Questionnaire (SAQ), Kidney Disease Quality of Life information is only used to electronically fetch for his Instrument, Epilepsy Surgery Inventory, National Eye or her National Health Number in government Institute Visual Functioning Questionnaire, Ankylosing database during analysis of PRO data. The rest of the Spondylitis Quality of Life questionnaire (ASQoL) and data is transferred to a database, such as the HES in Migraine Specific Quality of Life (MSQOL) [4]. England, from where the PRO analysis consequently occurs. Pre-operative and post-operative PROMs from With the advent of PROMs and the role they play in the same patients are identifiable in the dataset since medicine, individual countries such as England’s they possess similar serial numbers from which they National Health Service (NHS) have made it a are linked. After analysis, data in the HES is prerequisite for particular surgical operations to pseudonymised before it is made available to the provide non-compulsory PROMs before the procedure public for download for analysis and scrutiny and and following the procedure (ideally three months hospital/clinical scoring [8]. Other uses of PROMs after procedure); these include hip, knee and other include: allows managers and clinicians to benchmark joint replacements, hernia surgery and varicose vein their own performance with regards to others, they surgeries. are used for research purposes and draw relations to England used the PROMs to assess the effectiveness effectiveness and cost-effectiveness of health and effects of the surgeries on its national a patients procedures to care. It is also used to compare and deduced that the frequency of operations/ implications of presence and absence of the treatment surgeries should be maintained. Due to their efficiency or rather alternative treatment, searching for and importance in quality health service, PROMs are healthcare inequalities, and research on relationship updated monthly as a policy in most developed between pre-existing health and social conditions and countries. PROMs are currently used to grade health risk of deterioration after procedure. Other than the facilities with scores parameters according to patient anonymised data that is availed to the public for satisfaction. In England, HES (Hospital Episode scrutiny and further personalized analysis, PROMs can Statistics) use PROMs to rate hospital services across be availed to service providers of patient care through the state and their use are gaining impetus across the provider level extract only with patient’s approval. global health sector [5]. More so, extract service of particular requested data There is a general dataset that PROMs include in sub-subs by customers can be availed at an questionnaires; Generic and condition-specific administrative fee depending on complexity of the measures of self-reported health status. Patient- request [9]. identifiable information included in the PROMs, which There are variant methodologies in which PROMs are is used for relation purposes, is strictly not availed for used to score and rate health facilities. Some examples wider analysis, due to confidentiality. Additional of standardised PROMs that are analysed by specific questions inquiring into the patient’s health status methodologies include the five-dimensional descript- include whether they have antecedent conditions such tive system EQ-5DTM health questionnaire and the

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EuroQol Group’s visual analogue scale (EQ-VAS) [10]. condition while zero indicates worst severity [14]. Most PROMs used for joint replacement procedure, Postoperative Recovery Profile in condition-targeted such as hip and knee replacement, are condition- PROMs with recovery specific questions is used to targeted. Most common post-operative PROM determine the quality of joint replacement procedures questions include an inquiry into the patient’s health in health facilities and person-centeredness of clinical status after procedure such as their state of mobility services [15]. This is common procedure for persons or other operative complications.The EQ-5D is a with arthritis. The USA, Norway, Denmark, Sweden, simple, generic measure of health for clinical and New Zealand, Canada and England operate 77-153 and economic appraisal [11]. 66-143 hip and knee replacement per 100 people in The PROM with single indexing values for health prevalence rate. With advances in biomedical status and an unsophisticated descriptive profile is operations and medication intended to shorten or widely used in economic and clinical evaluation of alleviate the post-operative recovery period especially healthcare and in health surveys of populations. The since recovery takes place in the vicinity patient’s EQ-5D provided in joint replacements contains a home, PROMs are significant and effective method of descriptive system with issues on mobility, discomfort evaluating these procedures on patients [16]. /pain, self-care e.g. washing and dressing, anxiety and Traditionally, assessment of joint replacement were depression and normative activities e.g. work, assessed by drawing connections between different housework, study, family or leisure activities etc. Each intervention methods such as variant joint of these five dimensions has several level statements replacement procedures. The types joint replacement which the patients tick against the most appropriately include prosthetics, implants, surgical techniques. descriptive of his or her condition. Relations of these types of joint replacements were drawn to revision rates, complications and post- Each dimension has a score digit for each level operative medications. With increased impetus on the statement hence every patient has five string scores use of PROMs, this evaluation is augmented thus thence the connotation ‘5D’ [12]. Using a formula, the allowing for an improvement of healthcare services five string score are converted into a singular summary [17]. While EQ-5D, EQ-VAS, OHS and OKS are index, referred to as the ‘social preference weights’ important instruments in PROMs, they do not assigned to each statement in the dimensions. The comprehensively provide adequate information value of full health is assigned to value one (or state important of the requisite important aspects that 11111, in EQ-‘5D’) from which reference is sought. EQ- allow for quick recovery. Recovery-Specific VAS index scores range from 0 to 100, least and best Instruments have been devised to bridge this gap. health respectively. The patients mark, within the Swedish healthcare PRP (Post-operative Recovery range, his or her relevantly perceived state of health Profile) PROMs on joint replacement patients has [13]. comprehensive data on patient’s problems, medical Other PROMs used in England for joint replacement interventions and outcomes of treatments such that it include the condition-targeted Oxford Knee Scores has gained global recognition [18]. The Swedish (OKS) and Oxford Hip Scores (OHS). The PROMs methodologies of PROMs and their analytical tools are contain twelve multiple choices, assigned later with being replicated across the developed world since they scores, about the patients state of mobility, pain, ease include measurements on different groups of patients of joint movement, ease of partaking normal chores and can be altered for different purposes in the variant and activities. The scores in the PROM are such that PROM areas [19]. The PRP has additionally the less the scores the poorer the patient’s condition incorporated global-, dimensional- and item levels in with zero for greatest severity. For each multiple scoring not only for sole patients but more so for every choice, 4 is the greatest score for best patient group of patients. The global score is significant in condition. Hence, the total score for every patient in deducting the recovery rate of a population-based the PROM have a maximum limit of 48 for ideal patient profile.

An embodiment of a PROM is one in Sweden that was changes, unchanged assessments, individual conducted on joint replacement (hip and knee) variability in all dimensions were analysed. For global operations patients whereby the PROM questionnaire level assessments for day 3, 11(score for partly was provided the day before the procedure, three recovered) was the median while 13(score for partly days after the procedure and one month later after the recovered) was median after one month follow-up procedure. The peri-operative variables included sex, [24]. surgical procedure, American Society of Anaes- This information was used to ascertain whether the thesiologists’ (ASA) guided physical classification, age, surgical intervention or rehabilitation in the joint duration of surgery, length of postoperative stay, replacement procedures and therapy were blood loss and marital status [20]. PRP was included appropriate for individual patients or for groups of into the PROM and 19 constructs collected included patients [25]. The PROMs data was also used to physical functions and symptoms, psychological, social identify particular risks in particular groups and activity measures. (categorized by demographics) associated with the hip Response category for assessments, from which scores and knee replacements. While the analysis of the would be assigned, included: none, mild, moderate, PROMs indicated homogenous recovery changes in and severe symptoms. Recovery profiles for every the groups, certain assessments were unchanged for individual and group on each item and dimension were both the 3day and one month assessment; muscle provided by the PRP. The 19 item responses account weakness and pain. for a detailed individual response profile over the However, great individual variations on the two recovery dimensions and the item frequency categories were found to result to this. Using this data, distributions reports on the item response profile of Sweden was able to determine the best treatment and the group [21]. Fully recovered score in the group therapy techniques to render to joint replacement ideally would have indicator score of 19, 15-18 patients for a quick recovery [26]. It was also found out indicator sum for almost full recovered , 8-14 indicator that a standardized treatment method for groups that sum for partly recovered , 7 indicator score for slightly exhibited great variations in individuals was not recovered and below 7 not at all recovered. necessarily the remedy to the situation. Extensive use Using methodological tools of frequency distribution of PROMs in Sweden has allowed the country to analysis, out of the 75 patients who voluntarily increase its knowledge on the best healthcare participated in the PROMs assessment after practices hence an improvement in their healthcare undergoing primary knee and hip replacement due to delivery and high score/ratings of their hospitals osteoarthritis, 23 patients indicated the same level of internationally [27]. pain on both the 3 day and one month follow-up [22]. Based on the PROMs Swedish healthcare system is The remainder showed a decrease in pain after the able to establish expected recovery within junctures in one month follow-up. Significance in RP values was recover period. This can be sued to grade other used to assess the systematic change in recovery of treatments as set-backs and gains with regards to the groups. Individual variations within groups and expected outcome and therefore facilitate the overall between groups can thereafter be scrutinized. recovery and create awareness of the recovery process. PROMs have also been used to enhance, as a RESULTS clinical tool, the manner of clinical relationship and Besides pain, other score categories included muscle contact in follow-up visits between physicians, nurses weakness and re-establishment of everyday life. On and their patients. In joint replacement, resumption physical symptoms and function’s frequency of normative daily activity and functionally capacity distribution, for three days the frequency for the none were usually found to be unsatisfactory. assessment ranged between 62% and 7% while one The level of satisfactions was greatly influenced by month later, 72% to 25% [23]. Systematic group

38 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine pain, mental functioning and fulfilled expectations concurrently improving the healthcare of a country. regarding postoperative pain [28]. The psychological Data has established that 70% of countries with dimension rated higher for those who concomitantly esteemed healthcare systems have national policies scored 13 in physical functioning and pain. Longer on the use of PROMs in their HealthCare facilities. period assessment such as after 6 months have been shown to record greater recovery scores. Nonetheless, CONCLUSION the Swedish HealthCare is keen on shortening the Facilities that exhibit consistently low scores could be recovery period for joint replacement thus the focus sanctioned and enquiries instigated into their medical of PROMs of short recovery periods. For long period practices. This allows for the monitoring of healthcare PROMs, categories of assessment such as Quality of [30]. PROMs therefore are ideal instruments for the Life (QoL) and Health Related Quality of Life (HRQoL) improvement of healthcare provision. They assist in are incorporated [29]. determining the treatment and medication that ideal These PROM scores by patients who visit variant for patients in quick recovery mode. They create a clinical and hospital facilities allow for the grading of patient-centred healthcare system. Hospital hospitals/clinics too. Using relevant and respective ranking/scoring on the other hand allow for methodological tools, scores from patients attended benchmarking of clinical performances thus generally in various hospitals/clinics can assist in the national improving the provision of healthcare in a country grading and scoring of hospitals. This initiates [31]. competition for better healthcare provision

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1. Doward, LC & McKenna, SP 2004, Defining Patient- treatment impact: a review of patient-reported outcomes Reported Outcomes. Value in Health 7(S1): S4-S8. and other efficacy endpoints in approved product labels, 2. Fayers, P & Hays, RD 2005, Assessing Quality of Life in Control Clin Trials. 25(6):535-52. Clinical Trials: Methods and Practice. Oxford: Oxford 11. Health & Social Care Information Center, 2008, Monthly University Press. Patient Reported Outcome Measures (PROMs) in 3. Fung, CH & Hays, RD 2008, Prospects and challenges in England.[www.chks.co.uk/index.php?id=24] using patient-reported outcomes in clinical practice. Quality 12. Clancy, C & Collins, FS 2010, Patient-Centered Outcomes of Life Research 17: 1297-302 Research Institute. Sci Transl 2(37):37cm18 4. McKenna, SP & Doward, LC 2004, Integrating Patient- 13. Keller RB 2003, Outcomes research in orthopedics. J Am Reported Outcomes. Value in Health 7(S1): S9-S12. Acad Orthop Surg 1(2):122. 5. Kennedy, D 2010, CRF Designer. Canary Publications. 14. Novak EJ, Vail TP, Bozic KJ 2008, Advances in orthopedic 6. Tennant, A & McKenna, SP 2005, Conceptualizing and outcomes research. J Surg Orthop Adv 17(3):200. defining outcome. Br J Rheumatol 34:899-900. 15. Hawker G., et al. 2008, Health-related quality of life after 7. Kennedy, D.M., Stratford, P.W., Riddle, D.L., Hanna, S.E. knee replacement. J Bone JointSurg Am 80(2):163. & Gollish, J.D 2008, Assessing recovery and establishing 16. Chang, CH 2007, Patient-reported outcomes prognosis following total knee arthroplasty. Physical Therapy measurement and management with innovative 88 (1) 22-32. methodologies and technologies. Qual Life Res 16(Suppl 8. Valderas, JM & Alonso, J 2008, Patient reported outcome 1):157. measures: a model-based classification system for research 17. Clancy, CM 2011, Commentary: precision science and and clinical practice. Qual Life Res. 17: 1125-35. patient-centered care. Acad Med 86(6):667. 9. Wiklund, I 2004, Assessment of patient-reported 18. Clancy, CM & Eisenberg, JM 2008, Outcomes research: outcomes in clinical trials: the example of health-related measuring the end results of healthcare. Science quality of life, Fundam Clin Pharmacol. 18(3):351-63. 282(5387):245. 10. Willke, RJ., Burke, LB & Erickson, P 2004, Measuring 19. Rolfson, O 2010, Patient-reported outcome measures

and health-economic aspects of total hip arthroplasty. Patients' perspective on pain, function, quality of life, and Department Of Orthopaedics, Institute of Clinical Sciences. well-being up to 6 months postoperatively. Archives of Gothenburg: Sahlgrenska Academy, University of Physical Medicine and Rehabilitation 82 (3) 360-366. Gothenburg. p. 60. 27. Knutson, K. & Robertsson, O 2010, The Swedish Knee 20. Dawson J, et al 2010, The routine use of patient reported Arthroplasty Register (www.knee.se). The inside story. Acta outcome measures in healthcare settings. BMJ 340:c186. Orthopaedica 81 (1) 5–7. 21. Wu AW, et al. 2010, Adding the patient perspective to 28. Allvin, R., Ehnfors, M., Rawal, N., Svensson, E. & Idvall, E. comparative effectiveness research. Health Aff (Millwood) 2009, Development of a questionnaire to measure patient- 29(10):1863. reported postoperative recovery: content validity and intra- 22. Dawson J, Fitzpatrick R, Carr A, Murray D 2006, patient reliability. Journal of Evaluation in Clinical Practice Questionnaire on the perceptions of patients about total hip 15, 411-419 replacement. J BoneJoint Surg Br 78-B(2):185e90. 29. Jones, C.A., Beaupre, L.A., Johnston, D.W. & Suarez- 23. Field RE, Cronin MD, Singh PJ 2008, The Oxford hip Almazor, M.E 2007, Total joint arthroplasties: current scores for primary and revision hip replacement. J Bone Joint concepts of patient outcomes after surgery. Rheumatic Surg Br 87(5):618e22. Disease Clinics of North America 33 (1) 71-86. 24. Husted, H., Holm, G. & Jacobsen, S 2008, Predictors of 30. Vissers, M.M., de Groot, I.B., Reijman, M., Bussmann, length of stay and patient satisfaction after hip and knee J.B., Stam, H.J. & Verhaar, J.A 2010, Functional capacity and replacement surgery. Fast-track experience in 712 patients. actual daily activity do not contribute to patient satisfaction Acta Orthopaedica 79 (2) 168–173. after total knee arthroplasty. BMC Musculoskeletal Disorders 11, 121 25. Kärrholm, J 2010, The Swedish Hip Arthroplasty Register (www.shpr.se). Acta Orthopaedica 81 (1) 3–4 31. Chang RW, Pellisier JM, Hazen GB 2005, A cost- effectiveness analysis of total hip arthroplasty for 26. Salmon, P., Hall, G.M., Peerbhoy, D., Shenkin, A. & osteoarthritis of the hip. JAMA 1996;275(11):858e65. Parker, C 2001, Recovery from hip and knee arthroplasty:

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

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

Physical effort – an underused preventable method in colorectal cancer

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

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

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

relative protection of physical effort is currently the risk of CRC regardless of the impact on BMI: unknown. There are no interventional type this idea may imply that physical activity protects studies published yet to support the role of against CRC by a mechanism independent of that regular physical effort as preventive method in involved in resolution of obesity. The protective CRC. effect of physical effort validates at distance. The actual reduction of CRC risk is considerable only In 2007 the results of a cohort study (Nurses’ after several years. In conclusion, the authors of Health Study) has been published that enrolled this study suggest that even minor physical effort 80,000 female subjects from 1986 with a 16 years may derive benefit on CRC risk reduction. Several follow-up. There have been diagnosed mechanisms have been proposed. Thus, physical approximately 500 cases of CRC. A multivariate activity regulates energetic balance and analysis that controlled the confounding factors intervenes in reduction of hyperinsulinism and represented by other risk factors for CRC peripheral resistance to insulin. Physical activity concluded that there was a proportionate may intervene also through anti-inflammatory reversed relationship between physical effort and mechanisms. Moreover, the positive effects of distal colonic cancer and, to a lesser extent, with physical effort may also be explained by proximal colonic cancer. Women situated in the reduction of obesity in spite of the data that highest percentile of recreational physical activity demonstrated that physical activity may reduce had a reduction of distal CRC risk by half as the risk of CRC independent of the effect on compared with women situated in the lowest obesity. Another proposed mechanism involves percentile (RR=0.54, 95% CI 0.34-0.84). Risk accelerating the peristalsis which reduces the reduction did not vary with body mass index contact time between intraluminal carcinogens (BMI), although former studies had suggested and colonic mucosa. As a matter of fact, it is well that physical activity had the greatest impact on known data that physical active individuals are CRC only in high BMI subjects. The level of more prone to sun exposure for longer periods of physical effort to produce prophylactic benefits time which facilitates production of vitamin D may be only minimal, as this study demonstrated. that is associated with lessening the risk of As such, even an hour of slight walking a week CRC.[4] may reduce the risk of CRC by 31% (RR=0.69, 95%

CI 0.45-1.03) as compared with women who do Figure 1: Mechanisms involved in protective effect of not report any kind of physical activity. This physical effort on colorectal cancer risk protective effect of slight walking reached a plateau at 2 hours a week (RR 0.64, 95% CI 0.41- 1.00) as opposed to moderate and vigorous physical effort that was characterized by very clear dose-response relationship. The more alert slight walking rendered greater protective effect than slower slight walking (RR=0.43, 95% CI 0.17-

1.05). Furthermore, 4 hours a week of moderate/ vigorous physical effort may reduce the risk of An epidemiologic study published in 2008 (NIH-AARP CRC by 44% comparing with 1 hour a week (RR= Diet and Health Study) shows interesting observations 0.56, 95% CI 0.33-0.94). Physical activity lessened regarding the periods of an individual life when the

42 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine physical effort has the utmost impact on the risk of tarism and BMI is not to be changed even if one may CRC. Thus, if the physical activity is performed in the exclude the contribution of age, race, family history of age group 15-30 years the impact on CRC risk CRC, smoking and western diet.[6] reduction will be minimal; on the other hand, if the Several studies shows contradictory results concerning physical activity is performed in the age group 30-39 the issue of rectal localization of CRC. Cancer years or throughout the whole life of an individual the Prevention Study II indicates that moderate/vigorous reduction of CRC life-time risk will be maximal.[5] physical activity in men and in women reduces the risk Sedentarism is a globally important public health of rectal cancer by 30 %.[7] Many cohort studies did issue, especially in developed countries, in women, in not find any kind of association between physical old people and in low income individuals. Lack of activity and rectal localization of CRC.[8,9] physical activity is responsible of the increase in A meta-analysis published in 2010, which included 20 mortality rates especially from diabetes mellitus and studies on physical activity and colorectal benign heart diseases. To a comparable extent physical adenoma, concluded that there was 16% reduction of activity of moderate and vigorous intensity is the risk of these benign precursors of CRC if we associated with certain benefits regarding health compared active population with less active status, including reduction of obesity risk, populations. Risk reduction was even more significant cardiovascular risk, stroke risk, risk of some types of if we took into consideration polyps bigger then 1cm cancers and decreasing in global mortality rate. (31% risk reduction). It has been demonstrated in that Physical activity increases the probability to cease way that physical effort might decrease the risk of CRC smoking, delays cognitive decline in old individuals, earlier in the stage of precursor lesions of oncogenic alleviates the adverse effects of stress, anxiety and process.[10] depression. A study published in 2016 regarding the issue of physical activity status in the group of more The role of physical activity as a protection factor in than 50 years old individuals in USA the date are CRC is hardly known in general population. A study worrisome: 27% do not report any kind of physical developed in USA that included 2000 subjects showed activity outside working place in the last month; the that only 15% of them are aware of this benefit of prevalence of inactivity increases with age, reaching physical activity.[6] One similar study from Europe that 35.3% in age group after 75 years; sedentarism is more included 21 countries indicated a 30% level of prevalent in women then in men, in Afro-Americans knowledge concerning this topic.[11] Several studies then in Caucasians. Also, the prevalence of inactivity is stated also that there was a close connection between decreasing with increasing in educational level and the level of information concerning prophylactic with decreasing in BMI.[6] benefits of physical effort in CRC and the increasing of the motivational status to produce life style changes Lack of physical activity is the main cause of CRC being that, in the end, will decrease the prevalence of responsible of 14% of cases of CRC in USA; 12% of CRC.[12,13,14] cases may be attributable to western diet, 12% to lack of daily administration of aspirin and 8% may be Physical exercises represent a form of human activity related to a family history of CRC.[6] that may benefit health more then it may inflict side effects. The most common side effects are musculo- Sedentarism, especially that kind related to spending skeletal injuries. The least common side effects time in front of TV, is independently associated with (sometimes more severe) are: cardiac arrhythmias, increasing CRC risk. Hence, if one spends 9 hours in heart arrest and myocardial infarction. Generally, we front of TV, as comparing with 3 hours or less, the risk may appreciate that the potential benefits of physical of CRC will rise significantly by a RR=1.61 (95% CI=1.14- exercises highly surpass the potential risks. Moreover, 2.27).[5] it is considered that it is unnecessary to screen for The relationship between physical activity, seden- coronary diseases prior to initiating physical activity if

the subject was asymptomatic and included in the low In an observational study (unpublished data) that I cardiovascular risk group. have conducted in 2016, concerning the topic of CRC and its relationship with diabetes mellitus and other One may consider mandatory that all healthy adult risk factors an important conclusion has been drawn. individuals to include in their life style moderate or vigorous physical exercises. The majority of authors A multivariate analisys in which the most agrees that the highest health benefits are provided by acknowledged CRC risk factors have been included 150 minutes a week of moderate physical activity or showed the statistical significance (p<0.05) have been by 75 minutes a week of vigorous physical activity. reached for smoking and physical activity only. This Nevertheless, adults that have a limited physical implies that by the way of increasing physical activity activity capabilities should remain active because it levels in general populations and by giving up smoking has been noticed that even if a modest amplitude of CRC „epidemics” could be fairly prevented. physical effort is exercised regularly health benefits will be significant. Table 1: Multivariate analysis of risk factors in CRC Standard Variabile Coeficient t Stat p Another epidemiologic studies suggest that physical error activity may influence not only the risk of CRC but also Age (years) 0.0014 0.0035 0.4087 0.68 it may prevent the recurence of CRC after curative BMI(Kg/m2) 0.0031 0.0055 0.5650 0.57 surgical treatment. All the data available resulted from Smoking 0.1273 0.0647 1.9658 0.05 observational type of studies; randomized and inter- Daytime 0.0150 0.0440 0.3404 0.73 ventional studies are not published. Nevertheless, nap (hours) Physical American Society of Oncology (ASCO) recently -0.1334 0.0601 -2.2181 0.02 recomended that the surviveours of CRC should activity maintain an optimal weight, should perform daily In conclusion, the preventable potential of CRC is high physical exercises and should follow a healty diet.[14] through the way of regular physical exercise and this Futher on, there are some interesting results of a study may represent a very approachable solution to published in 2006 that included 832 patients suffering decrease the global burden of the disease. It is very from CRC stage III surgicaly treated and that followed important to stress that the target of decreasing the a program of chemotherapy. It has been demons- prevalence of CRC by physical exercise does not trated that moderate physical activity perfomed for at necessarily imply an impact on obesity, the benefits on least 300 minutes a week has increased the free CRC being independent from the benefits on BMI. A disease interval with 45% and has improved by 29- good level of motivation in general population through 36% the mortality rate of any cause.[16] The benefits health politics is mandatory because the changes in have been dose dependent. life-style (level of physical activity, diet and smoking) are otherwise impossible to be reached.

References:

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

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Physical activity, sedentary behavior, and the risk of colon risk factors and screening for colorectal cancer in Europe. Eur and rectal cancer in the NIH-AARP Diet and Health Study. J Cancer Prev 2004;13:257–62. Cancer Causes Control (2008) 19:939–953 12. Courneya KS, Hellsten L-AM. Cancer prevention as a 6. Elliot J. Coups, Jennifer Hay, Jennifer S. Ford. Awareness source of exercise motivation: an experimental test using of the role of physical activity in colon cancer prevention. protection motivation theory. Psychol Health Med Patient Education and Counseling 72 (2008) 246–251 2001;6:59–64. 7. ChaoA, ConnellCJ, Jacobs EJ et al (2004) Amount, type, 13. Jalleh G, Donovan RJ, Slevin T, Dixon H. Efficacy of bowel and timing of recreational physical activity in relation to cancer appeals for promoting physical activity. Health colon and rectal cancer in older adults: the Cancer Promot J Austr 2005;16:107–9. Prevention Study II Nutrition Cohort. Cancer Epidemiol 14. Meyerhardt JA, Mangu PB, Flynn PJ, et al. Follow-up Biomarkers Prev 3:2187–2195 care, surveillance protocol, and secondary prevention 8. Friedenreich C, Norat T, Steindorf K et al (2006) Physical measures for survivors of colorectal cancer: American activity and risk of colon and rectal cancers: The European Society of Clinical Oncology clinical practice guideline prospective investigation into cancer and nutrition. Cancer endorsement. J Clin Oncol 2013; 31:4465. Epidemiol Biomarkers Prev 15:2398–2407 15. Justin C. Brown , Andrea B. Troxel , Bonnie Ky , Nevena 9. Lee KJ, Inoue M, Otani T, Iwasaki M, Sasazuki S, Tsugane Damjanov , Babette S. Zemel , Michael R. Rickels ,Andrew D. S (2007) Physical activity and risk of colorectal cancer in Rhim, Anil K. Rustgi , Kerry S. Courneya , Kathryn H. Schmitz. Japanese men and women: the Japan Public Health Cancer- A randomized phase II dose–response exercise trial among based prospective Study. Cancer Causes Control 18:199–209 colon cancer survivors: Purpose, study design, methods, and 10. KY Wolin, Y Yan and GA Colditz. Physical activity and risk recruitment results. Contemporary Clinical Trials 47 (2016) of colon adenoma: a meta-analysis. British Journal of Cancer 366–375 (2011) 104, 882 – 885 16. Kathleen B. Watson, Susan A. Carlson, Janelle P. Gunn, 11. Keighley MR, O’Morain C, Giacosa A, Ashorn M, Deborah A. Galuska, Ann O’Connor, Kurt J. Greenlund Janet Burroughs A, Crespi M, Delvaux M, Faivre J, Hagenmuller F, E. Fulton. US Department of Health and Human Services/ Lamy V, Manger F, Mills HT, Neumann C, Nowak A, Pehrsson Centers for Disease Control and Prevention. Morbidity and A, Smits S, Spencer K, United European Gastroenterology Mortality Weekly Report. September 16, 2016/Vol. 65/No. Federation Public Affairs Committee. Public awareness of 36.

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

The communication and promotion policies of the medical organizations in the marketing of Romanian healthcare services

Bogdan I. Coculescu1,2, Victor L. Purcărea3, Elena C. Coculescu4

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

INTRODUCTION zations in order to attract new potential clients;

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

46 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine a steady relationship with the patients. It represents products and services it provides, to create a positive the tool with which an entity participates in the attitude and to stimulate consumers to buy products informational exchange with the different business and services. field’s components, to inform about its presence, the

Figure 1: Communications and healthcare services marketing [5].

The instruments of the communicational mix are There are two ways by whom a medical organization based particularly on interpersonal communication, can communicate with its patients (Figure 1): yet at the same time on the adaptation and a. On the outside through: enrichment of the classical techniques via the concept  advertising of marketing integrated communication resulting in  promoting sales complex communicational programs. The marketing  public relations mix in the health care services sector includes as well  direct marketing (inclusive online) staff politics, represented by two segments which must be approached differentially as follows: the b. On the inside through the employed medical employees of the company providing services and the personnel during the specific activities. consumers. The advertising activity has clear purpose in preparing The principal methods and ways to communication, the target public for favorable receiving of the medical that can be adopted by a medical organization in order unit’s offer. Three types of marketing objectives are to to orientate the patient in their referring to a certain be distinguished from one another depending on their health care service or to build and reinforce a favo- purpose as follows: informing, convincing and rable image of that sanitary unit on the market, reminding. To advertise and broadcast the commercial constitute the promotional mix of the medical message the medical organization can make use of institution. different communicational channels: newspapers, magazines, the press, printing materials (flyers, The achievement of an optimal promotional mix, brochures, catalogues), external publications which satisfies the patients’ needs and fulfill the best (billboards, posters, leaflets, stickers), internet, radio, objectives of the promotional communication, is one television etc. Through advertising activities the from the key points in obtaining the attributions medical organization succeeds in informing the distinctive for a marketing specialist. potential patients about its work and services with the

aim of influencing their decision for adherence to this Promoting, as a variable from the marketing mix, services. occupies place apart in the case of medical services, because it is essential for the development and The direct relationship between the medical staff and maintenance of durable relations with the target the patients favors a particular manner of public. Marketing politics aims to inform the target communication: personal sale – the potential patients public as much as possible about the health activities can be notified and persuaded to subscribe for and the services offered by the respective medical services at the medical unit. Consequently the medical organization, but at the same time also for the contact personnel plays an important role for information received by them to have a positive increasing the sell’s volume in the medical system. impact. They must be very well prepared professionally and respond promptly to the patients expectations. A particular case of promoting of medical organization Additionally the immediate connection with patients is represented by spreading the “mouth to mouth” represents the main way for informing them about the advertisement, from patient to patient, extremely benefits, offers, promotions, advantages, perfor- productive, as demonstrated fact in the practice of mance conditions, health care services prices etc. of health care service with results in growth of the medical organization they belong. consumers addressability in these services (“one satisfied patient brings more patients”). A lot of the authors specify a clear distinction from the concept of “team” and of “teamwork”. The “team” Client services in the field of health care relates to the concept is referring to persons who work together for benefits offered to the patients – or the public in common purpose, while the “teamwork” concept – to general – further than the product itself, including its a certain environment from a larger organization, nontechnical and nonclinical aspects. The connection which creates and sustain relations of trust, support, between client services and other elements of the respect, interdependence and collaboration. marketing mix is one of completion and support. The efficient client services reduce the cost due to patients It must be mentioned that in sanitary organizations – and improves the access to health services [4-6]. particularly in the hospitals – team communication possess an increasingly important role. A good team CONCLUSIONS communication, understanding the advantages, disadvantages, “principles” of teamwork, contributes Promoting sales imposes the use of all procedures and to identifying the proper solutions to the inherent stimulation techniques and increasing the sales of problems. In multiple cases where it is necessary to medical services of the organization. If advertising has work as a team, encouragement and orientation of the a role in offering purchase motivation, conversely the team members can improve the sanitary sell promotion has a role in the sells’ stimulating organization’s results via: their motivation, use of the process for the potential patients by the means of team member’s ideas and personal capabilities, consecrate methods in promoting sales, in the form of acquiring support from their side, improving the promotional presents (watches, calendars, agendas, performance. Through guidance, the quality of health pens, notebooks, umbrellas with inscription of the employee’s performance can be made better, while medical organization etc.), with the aim of image the tasks are accomplished properly by them. promoting on the target market.

Promoting is one of the forms of communication. The Public relations have a part in setting trust relations difference between the two notions are made at the with the patients, ensuring protection, planning, level of the sent message. So that promoting to have organizing and controlling the whole actions unfolded the desired effect, the messages received by the by a medical organization for achieving its objectives. patients must be clear and reflect what the The methods used in the activity of public relations for organization has to offer. obtaining the marketing goals (informing the patients

48 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine about the advantages of the organization, stimulating defining the value system of a sanitary organization the sales volume, keeping the investment in consists a vital necessity for the organizations, whose promotional materials at minimal level) consists in purpose is executing top health services. organizing events with scientific subject (congresses, In the field of health care services the marketing conferences), giving interviews, publishing brochures, strategy represents actually the attitude of the profile publications, promoting through press sanitary organization towards the marketing conferences, participating in medical markets and environment and simultaneously its behavior in regard exhibitions etc. The coordination of a public relations to its components. project with the other elements from the promotional mix can be beneficial for the increase in prestige of the Communication of the organization with the medical organization. marketing environment is an essential condition for achievement of its activity objectives. The fulfilment of The core of the marketing strategy in the field of the organization mission assumes concentrating health care is presented by the quality of services, marketing efforts in the direction of achieving a quality which in its turn results from: precision of permanent and efficient communication with the performance, promptitude and professionalism of the external surroundings, with the market and with the employees, kindness and politeness towards the patients. patients. Creation and implementation of a coherent and productive medical marketing strategy as well as

References:

1 Kotler P., Keller K.L., Marketing management [in 4 Purcărea V.L., Coculescu B.I., Risk management in practice Romanian], 5th Edition, Teora Publishing House, Bucharest, by the revaluation laboratory methods and procedures Romania, 2008. contained in the protocols work to reduce the number of errors associated [in Romanian], “Carol Davila” University 2 Coculescu B.I., Coculescu E.C., Radu A., Petrescu L., Press, Bucharest, Romania, 2012. Purcărea V.L., Market policy as an innovative element of marketing in the Romanian healthcare services - an 5 Popa F., Purcărea T.V., Purcărea V.L., Rațiu M.P., approach focused on the patient. Journal of Medicine and Marketing of healthcare services [in Romanian], "Carol Life, 2015, 8(4):440-443. Davila" University Press, Bucharest, 2007. 3 Coculescu B.I., Coculescu E.C., Purcărea V.L, Orientation to 6 Purcărea V.L., Popa F., The medical system, in Ciurea A.V., the patient as marketing strategy in the Romanian public Cooper C.L., Avram E., Management systems and health healthcare system, Journal of Medicine and Life, 2016, organizations [in Romanian], "Carol Davila" University Press, 9(3):302-305. Bucharest, Romania, 2010.

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

Medical applications of the GC/MS method in the acute intoxication with dimethoate – clinical case

Genica Caragea1, Mihail S. Tudosie2, Radu A. Macovei2,3, Ilenuţa L. Danescu3, Mihai Ionică1,4

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

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

50 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine the bulbar respiratory center (muscarinic phenome- represent severe threats to humans, animals and the non) and the paralysis of respiratory musculature fauna.[2] (nicotinic phenomenon), respiratory arrest occurs. The dimethoate, patented and introduced in the 50s, Organophosphorus compounds are rapidly absorbed is a acetylcholinesterase inhibiting organo-phosphorus through the skin or digestively in the thin intestine. compound, it is not volatile, it is water soluble and it is They bind well to the plasmatic proteins. High not mobile in soil, where it degrades with a half-life of concentrations can be attained in the body within approximately 2-4 days, depending on the conditions. hours.[7] Dimethoate and omethoate urine levels reflect recent Organophosphorus compounds represent a group of exposure. compounds with liposolubility or hydrosolubility, with Once having entered the body, organo-phosphorus high distribution volume. They are rapidly distributed compounds are metabolized to dialkylphosphates, in the liver, lungs, kidneys, heart and brain but do not which are eliminated through urine. Their accumulate. metabolizing takes place rapidly in the body and as This type of organophosphorus compounds is such they don’t accumulate. liposoluble, accumulating in the lexophile tissues of Compounds such as parathion, malathion, phenthion, the organism, being a source for metabolic conversion chlorpyrifos, normally inactive, enter the body and to very toxic compounds. Thus, the intermediate transform at liver microsomal level, through oxidation, syndrome can be explained (it appears between the 5th into highly active compounds (paraoxon, malaoxon). and 18th day from the intoxication). The toxicity of Identification of these metabolites in the urine may be these compounds is manifested through the direct an indicator of exposure to organophosphorus inhibition of cholinesterase, probably through direct compounds and can be performed through a GC/MS poly enzymatic inhibition.[7] analytical method with an ion trap and electronic The metabolizing of organophosphorus com-pounds ionization. takes place rapidly in the body, and as such they do not The dimethoate is rapidly metabolized, mainly accumulate. Compounds such as parathion, through the initial splitting of the C-N bond to obtain malathion, phenthion, chlorpyrifos, normally inactive, dimethoate carboxylic acid and, eventually, a number upon entering the body they transform at liver of tiophosphate and phosphate esters. The minor microsomal level, through oxidation, in highly active quantitative elimination way involves the oxidative compounds (paraoxon, malaoxon). metabolism to produce the oxygen analogue of This transformation takes place under the action of dimethoate, omethoate. The parent compounds paraoxonase. Their degradation takes place through represents 1-2% of the dose excreted in the urine.[5] hydrolytic and oxidative ways, through liver and kidney enzymes. The erythrocyte-origin cholineste- MATERIALS AND METHOD rase remain blocked for the remainder of the red The research was performed on a GC-MS Saturn 2000 blood cell’s life. Their regeneration takes place slowly Varian system composed of gas chromatograph model (0.5-1% per day), remaining below normal level for Varian CP – 3800 and mass spectrometer Varian over 3 months in severe intoxications.[8] Saturn – 2000. Organophosphorus compounds are eliminated Establishing optimal working conditions and functional through urine as such or as metabolites. parameters for the development of a GC/MS method In the current global situation, it is very probable that are important steps in the development of a GC/MS these substances will be used in wars, conflicts, method for the separation and spectral identification terrorist attacks. In such scenarios, they are used as of dimethoate in urine. extremely toxic agents and thus continuously

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

The temperature program of the gas-chromatograph’s Normally, the mass spectrometer operates in the column’s furnace is presented in Table 1. domain in which the analyzed substances will be found. When coupling it with a gas-chromatograph, Table 1: The column gas furnace temperature program. substances no greater than 450 amu will be sent to Temperature (°C) Rate (°C/min) Hold (min) the mass spectrometer, as those with greater 140 0.00 1 molecular weight cannot be vaporized in the 290 5.00 19.00 chromatographic column.

MS – mass spectrometer – has the role of analysing Thus, the maximum acquisition domain will be 50 – molecules that come out of the gas-chromatograph 450 amu, as below 50 amu an acquisition is not typical, through their unique mass spectre. Thus, the since the atmosphere in the apparatus has a rich molecules that come out of the GC can be identified by spectre up to 44 amu. the user. Mass spectrometry established the relative The use of the full scan technique (FS) is very good, abundance of ions resulted from the ionization since following the obtaining of the mass spectre, it process of an organic molecule. The method is used in can be compared with mass spectres already existant chemical analyses, in the analysis of some quantum in dedicated spectral libraries. In this case though, the processes or in the separation of certain chemical duration of a ion’s analysis is of 4ms, in case it is used elements. The determined mass represents the m/z as an acquisition time for a scan of 1 s. ratio (mass to charge) of the atom or group of atoms from which the ions resulted. Confirming the identity of the compounds relies on comparing the mass specter and ratio of reference

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

Table 3: Specific ionic fragments and spectral lines for dimethoate Spectral Chemical formula of ionic Compound line (m/z) fragment Dimethoate 157 – [M-72] - (CH3O)2PS.S+ C5H12NO3PS2 143 – [M-86] - (CH3O)(HO)PS.S+ (M=229) 125 – [M-104]- (CH3O)2PS+ 93 – [M-136]- (CH3O)2P+

Figure 1: Mass spectre for dimethoate (Nist98 library)

Figure 2: Mass spectre for omethoate (Nist98 library)

Table 4: Specific ionic fragments and spectral lines for omethoate Spectral Chemical formula of ionic Compound line (m/z) fragment Omethoate 156 – [M-57] - CH3NCO C5H12NO4PS 141 – [M-72] - (CH3O)2P=O.S+ (M=213) 126 – [M-87] - (CH3O)2(HS)P+ 110 – [M-103] - (CH3O)2(HO)P+ 109 – [M-104] - (CH3O)2P=O+ 79 – [M-134] - (CH3O)(HO)P+

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

54 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine reflex; - Central sub-clavicle catheter - Strong reflexes in all four members, with subintrant - Parenteral fluids muscular fasciculation; o glucose solution; - At pulmonary level, bronchial rales bilaterally o Ringer solution; diffuse; o isotonic saline solution; - Does not efficiently ventilate on IOT probe, so o Gelofusine; mechanical ventilation is applied; Support therapy - Diarrhea; - Specific antidote – atropine under clinical - Arterial Tension = 80/60 mm Hg; surveillance - Subfebrile (to = 37.5). - Mucolytic – acetyl cysteine; - Bronchodilators – miofilin; ECG upon admission records sinus bradycardia - Antibiotherapy in combinations (penicilin G 1 milion (44/min) without conduction or repolarization. UI/6 hours + gentamicin 80 mg/day + metronidazol The CT brain scan and lumbar puncture exclude a 500 mg/day); vascular etiology of the coma. - Plasma – 4 units/day, for 3 days and 2 units/day for The analytical toxicological GC/MS examination of the 2 days; urine: - Monitoring vital functions; - Monitoring pseudocholinesterase activity. Following the analysis of the urine, the total ion chromatogram that is shown in Figure 3 was obtained. The applied therapeutic measures, respiratory and In it, besides dimethoate, its metabolites can also be general nursing are continued. identified. Clinical evolution The substances identified through the above GC/MS 4 days from admission, the evolution is favorable; the method used for the urine analysis are shown in table patient is conscious; he is taken off the mechanical 5. ventilation apparatus; he breathes spontaneously with The cardiopulmonary radiography detects a homo- the intubation probe and is extubated. His oral cavity genous opacity situated in the inferior right pulmonary is washed. field. The cholinesterase activity is measured: 2.1 UI/ml.

Therapeutic measures The antibiotherapy is continued 3 days from the Stabilization extubation to solve his pulmonary affection. - Vacuuming tracheobronchial secretions The evolution is favorable. The patient is released 7 - Support ventilation days from admission with no neurological damage. - Nasogastric intubation; gastric lavage;

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

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

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

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

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References:

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

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

Rare case of Stevens-Johnson-TEN overlap syndrome caused by mycotoxins

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

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

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

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

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Histopathological results of these effects are initially CASE PRESENTATION represented by nuclear lipid and carbohydrate We present the case of a 49 year old female patient deposits and finally by hepatic centrolobular who was transferred to the Anesthesiology – necrosis.[1,12] α-amanitin also affects other Toxicology – Intensive Care Unit of the Clinical metabolically active tissues like the kidney or the Emergency Hospital in Bucharest from a regional gastrointestinal tract.[7,12,13] No cases of skin Hospital Unit. She was suspected to have ingested a involvement secondary to Amanita ph. poisoning have sort of poisonous mushroom within the 12 hours prior been reported so far except erythromelalgia – a to admission. She presented to the emergency room disease that is characterized by erythema and pain after mushroom consumption after picking them from especially in the extremities – that was sometimes a local forest. During the night the patient presented associated with some species of mushroom abdominal pain, nausea, vomiting and diarrhea, for intoxication, but never with Amanita ph. which she administered no treatment. In the morning Poisoning.[14,15] she decided to go to the emergency room, although Steven-Johnson syndrome (SJS) and toxic epidermal clinical signs became milder. Her medical records necrolysis (TEN) are rare but highly severe disorders revealed no pathological findings, except an untreated that can affect patients of all ages.[16,17] dyslipidemia. Clinical examination revealed a Caused by a variety of drugs, infections and rarely by mediocre general condition, pale skin, gingivitis, toxins, SJS and TEN are defined as a hypersensitive tachycardia and mild abdominal pain. Furthermore cutaneous reaction that produces dermato-bullous she noticed appearance of cough and rhinorrhea in the skin lesions.[16,18-20] Pathogenesis of these last two hours. After volume and electrolyte conditions is controversial and involves genetic rebalancing, she was transferred to our Department. susceptibility (haplotypes like HLA B*1502, HLA B12 On admission the patient presented an altered general etc.), immune cells (especially T lymphocytes CD 8+), state, she was conscious and feverish (38.6°C). Apart cytokines and mediators of cell death.[16,19,21] from cough and rhinorrhea she also presented Although initially was thought that SJS and TEN are dysphagia, myalgia and arthralgia especially in the separate entities, today it is considered that they are lower limbs. Physical examination revealed jaundice, varying degrees of severity of the same disease.[22] diffuse erythema on hands and feet, tachypnea, The difference between these two forms of disease is tachycardia (HR=113bpm), hepatomegaly. Preliminary represented by the percentage of the affected body laboratory results indicated hepatic cytolysis (ALAT = surface area (BSA) – SJS detachment of <10 % BSA and 9,412 U/L, ASAT = 6,720 U/L), hyperbilirubinemia (4 TEN detachment of >30% BSA.[17,22] mg/dl), decreased serum potassium (3.1), elevated creatinine level (2 mg/dl) and blood urea nitrogen Overlapping SJS/TEN includes cases with detachment (BUN = 49.4 mg/dl). Electrocardiography showed no between 10-30% BSA.[22,23] Regardless of the size of abnormality, except the abovementioned tachycardia. the affected area erythematous and macular lesions Superior digestive endoscopy indicated diffuse may be associated.[17] erythematous lesions in the pharynx and esophagus.

Apart from skin lesions, mucosal (respiratory, Although according to the description of the ingested gastrointestinal, urinary) and other organs (liver, lungs mushroom we suspected an Amanita ph. poisoning, and kidneys) involvement can occur.[20,24-26] rapid Meixner test could not be performed due to the Despite numerous attempts of identifying an effective lack of gastric material when endoscopy was curative therapy SJS/TEN has a mortality rate from 5 performed. Therefore mushrooms leftovers from the to 30%.[27] meal were sent to a specialized laboratory.

Furthermore a variety of long-term sequelae can be Considering the high suspicion of developing Steven- encountered in surviving patients.[24] Johnson syndrome and the liver insufficiency

secondary to mushroom poisoning, initial therapy Twelve hours after admission the patient presented management was carefully selected. Oxygen therapy, altered mental status, dyspnea, tachypnea and a fluid replacement was initiated in combination with peripheral oxygen saturation of 80% under oxygen gastric protection, antiemetic and diuretic therapy. mask. Because of that she was intubated and Vitamin supplementation, corticotherapy (prednisone mechanically ventilated. Despite volume controlled 138 mg/day) and antioxidant therapy (N-acetyl- ventilation hypoxemic index could not raise above cysteine 1,800 mg/day and alpha lipoic acid 900 100. Furthermore over the erythematous areas of the mg/day) were also added. We performed continuous feet and hands atypical irregular lesions with darker digestive decontamination by administering 25 mg centers were observed. These lesions evolved within mannitol p.o, 20 g lactulose and Ricinus communis oil the next twenty four hours to vesicles and bullae 15 mg. Moreover activated charcoal administration (Nikolsky sign and Asboe-Hansen sign positive) was started in order to interrupt mushroom toxins (Figures 1 and 2). enterohepatic recirculation.

Figure 1

Figure 2

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Figure 3

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

patient developed respiratory dysfunction, requiring improvement, the patient died from multisystem mechanical ventilation. Secondary to the respiratory organ failure. and hepatic dysfunction, neurological dysfunction developed. Despite adequate volume repletion, cardio CONCLUSIONS circulatory dysfunction appeared requiring continuous From our knowledge this is the first case report on vasopressor therapy. Stevens-Johnson/TEN overlap syndrome induced by There are no recommendations regarding treatment mushroom poisoning. This case presentation aims to of the acute phase of SJS/TEN.[16] Considering that highlight the polymorphic manifestations of severe there is no specific treatment for SJS/TEN, minimizing amatoxin intoxication as well the difficulties of the therapy with risk of aggravation of SJS/TEN was managing such a patient. Clinicians should be aware of tried and corticotherapy was initiated. Despite the the systemic involvement in mushroom poisoning. maximal supportive treatment and liver function

References:

1. Santi L, Maggioli C, Mastroroberto M, Tufoni M, Napoli characterization and inhibition of amanitin uptake into L, Caraceni P. Acute Liver Failure Caused by Amanita human hepatocytes. Toxicol Sci. 2006;91(1):140–9. phalloides Poisoning. 2012;2012:2–7. 12. Smith MR, Davis RL. Mycetismus: a review. 2. Enjalbert F, Rapior S, Nouguier-Soulé J, Guillon S, 2015;(October):1–6. Amouroux N, Cabot C. Treatment of amatoxin poisoning: 20- 13. Kirchmair M, Carrilho P, Pfab R, Haberl B, Felgueiras J, year retrospective analysis. J Toxicol Clin Toxicol. Carvalho F, et al. Amanita poisonings resulting in acute, 2002;40(6):715–57. reversible renal failure: New cases, new toxic Amanita 3. Badsar A, Taramsari MR, Maafi AA, Rad MR, Chatrnour mushrooms. Nephrol Dial Transplant. 2012;27(4):1380–6. G, Jahromi SK. Mushroom Poisoning in the Southwest Region 14. Latessa V. Erythromelalgia: A rare microvascular disease. of the Caspian Sea , Iran : A Retrospective Study. 2013;7(20). J Vasc Nurs. Society for Vascular Nursing, Inc.; 4. Escudie L, Francoz C, Vinel J, Moucari R, Cournot M, 2010;28(2):67–71. Sauvanet A, et al. Amanita phalloides poisoning : 15. Saviuc P., Danel V., Moreau P., Claustre A., Ducluzeau R, Reassessment of prognostic factors and indications for Carpentier P. Érythermalgie soudaine : cherchez le emergency liver transplantation. 2007;46:466–73. champignon ! La Rev Médecine Interne. 2002;23(4):394–9. 5. Berger KJ, Guss DA. Selected Topics : Toxicology 16. Kohanim S, Polioura S, Saeed H, Akpek E, Amescua G, MYCOTOXINS REVISITED : PART I. 2005;28(1):53–62. Basu S, et al. Stevens-Johnson Syndrome / Toxic Epidermal 6. Vetter J. Toxins of Amanita phalloides. Toxicon. Necrolysis A Comprehensive Review and Guide to Therapy . 1998;36(1):13–24. I . Systemic Disease. 2016;14(1):2–19. 7. Garcia J, Costa VM, Carvalho A, Baptista P, De PG, 17. Schwartz RA, Hon D, Edin F, Mcdonough PH, Lee BW. Lourdes M De, et al. Amanita phalloides poisoning : Toxic epidermal necrolysis manifestations, etiology and Mechanisms of toxicity and treatment. 2015;86:41–55. immunopathogenesis. J Am Dermatology. Elsevier Inc; 8. Vendramin A, Brvar M. Toxicon Amanita muscaria and 69(2):173.e1-173.e13. Amanita pantherina poisoning : Two syndromes. Toxicon. 18. Batra S. Serious cutaneous adverse reactions to 2014;90:269–72. traditional Chinese medicines. Singapore Med J. 9. Yilmaz I, Kaya E, Aydin Z, Bayram R. Toxicon Clinical 2006;47(7):647. importance of toxin concentration in Amanita verna 19. Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal mushroom. Toxicon. Elsevier Ltd; 2014;87:68–75. necrolysis ( Lyell ’ s disease ). Burns. Elsevier Ltd and 10. Walton J, Hallen-Adams H, Luo H. Ribosomal International Society of Burns Injuries; 2010;36(2):152–63. biosynthesis of cyclic peptide toxins of Amanita mushrooms. 20. Downey A, Jackson C, Harun N, Cooper A. Toxic 2011;72(2):181–204. epidermal necrolysis : Review of pathogenesis and 11. Letschert K, Faulstich H, Keller D, Keppler D. Molecular management. J Am Dermatology. American Academy of Dermatology, Inc.; 2012;66(6):995–1003.

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21. Darlenski R, Kazandjieva J. Systemic drug reactions with Stevens – Johnson syndrome beyond the eye and skin. skin involvement : Stevens-Johnson syndrome , toxic Burns. 2015;42(1):20–7. epidermal necrolysis , and DRESS. Clin Dermatol. Elsevier 25. Yamane Y, Matsukura S, Watanabe Y, Yamaguchi Y. Inc.; 2015;33(5):538–41. Allergology International Retrospective analysis of Stevens e 22. Bastuji-Garin S. Clinical Classification of Cases of Toxic Johnson syndrome and toxic epidermal necrolysis in 87 Epidermal Necrolysis, Stevens-Johnson Syndrome, and Japanese patients e Treatment and outcome. Allergol Int. Erythema Multiforme. Arch Dermatol. American Medical Elsevier B.V; 2016;65(1):74–81. Association; 1993 Jan 1;129(1):92. 26. Suwarsa O, Yuwita W, Dharmadji HP, Sutedja E. Stevens- 23. Barvaliya M, Sanmukhani J, Patel T, Paliwal N, Shah H, Johnson syndrome and toxic epidermal necrolysis in Dr. Tripathi C. Drug-induced Stevens-Johnson syndrome (SJS), Hasan Sadikin General Hospital Bandung, Indonesia from toxic epidermal necrolysis (TEN), and SJS-TEN overlap: a 2009–2013. Asia Pac Allergy. 2016;(6):43–7. multicentric retrospective study. J Postgrad Med. 2011 Jan 27. Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin 1;57(2):115–9. ME. Stevens-Johnson syndrome and toxic epidermal 24. Saeed H, Mantagos IS, Chodosh J. Complications of necrolysis. Autoimmun Rev. 2008;7(8):598–605.

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

Uncommon giant sphenoidal tumor. Case report

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

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

Keywords: sphenoidal tumor; hypophysis

INTRODUCTION result and based on that the patient will have a treatment scheme. Sphenoidal sinus is located in the middle of the skull, and is In some cases, even biopsy’s hard to complete, and one of the most difficult high-risk factors are involved.[4,5] sinuses to be attacked.[1] The patient must be informed preoperatively about The surgical risk elements the risk involved in taking the biopsy, why is necessary are the internal carotid to perform that biopsy and what are the risks of not artery, optic nerve; optic having a biopsy and treatment. chiasma; hypophysis and Multiple biopsies must be performed to have a skull-base.[2,3] histopathologic result. The tumors located in the sphenoidal sinus are difficult MATERIAL AND METHODS

1 Carol Davila University to access and due to the We present a care, it was admitted a 52 years old of Medicine and vicinity of vital anatomical woman with the following symptoms: headache, Pharmacy, Bucharest structures. 2 Institute of bilateral nasal obstruction, right abducens nerve Phonoaudiology and A biopsy must be performed Functional ENT surgery Corresponding author: Silviu Pițuru “Prof. Dr. Dorin Hociotă”, to have a histopathological [email protected] Bucharest, Romania

64 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine paralysis, right exophthalmia, and diplopia. result was: expansive tumor which was located at, the level of sphenoidal body, extending anterior to rhino Anamnestic we have found out that the symptoms pharynx (nearly totally blocked) and posterior started to develop six months ago gradually. intracranial, with emphasizing compression of the The patient was already consulted in a neurosurgical cerebral trunk (pons and bulb). department. It was performed a CT scan, and the

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

In our hospital first, we have performed a fiber optic

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

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

Figure 5: Targeted biopsy performed trans nasally Figure 3: Video fiber optic trans orally exam. The tumor block near totally the rhinopharynx

In our case, we did not discover any character of First, we have performed a trans nasal video contact malignity at the superficial layer of the tumor, and we endoscopy exam on the tumor. Video contact have discovered rich areas of vessels that fed the endoscopy is an endoscopic technique that allows the tumor. surgeon to study, after staining the tissue with methylene blue, the desired tumoral area as an in vivo We have started to gentle perform a targeted biopsy histological exam. The surgeon can examine the from the tumor in an area where the vascular network histological superficial epithelial layer, observing was limited because we wanted to prevent an histologic abnormalities and the vessels of tumors. important hemorrhage.

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

References:

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

ADMINISTRATIVE ISSUES

Guidelines for authors

Thank you for your interest in Romanian Journal of Military ETHICAL CONSIDERATIONS Medicine. Please read the complete Author Guidelines Principles for Publication of Research Involving Human carefully prior to submission, including the section on Subjects copyright. Manuscripts must contain a statement to the effect that all To ensure fast peer review and publication, manuscripts that human studies have been reviewed by the appropriate do not adhere to the following instructions will be returned ethics committee and have therefore been performed in to the corresponding author for technical revision before accordance with the ethical standards laid down in an undergoing peer review. appropriate version of the Declaration of Helsinki (as revised Note that submission implies that the content has not been in Brazil 2013), available at http://www.wma.net/ published or submitted for publication elsewhere except as en/30publications/10policies/b3/index.html. It should also a brief abstract in the proceedings of a scientific meeting or state clearly in the text that all persons gave their informed symposium. Once you have prepared your submission in consent prior to their inclusion in the study. Details that accordance with the Guidelines, manuscripts should be might disclose the identity of the subjects under the study submitted online at [email protected]. should be omitted. Photographs need to be cropped We look forward to your submission. sufficiently to prevent human subjects being recognized (or an eye bar should be used). EDITORIAL AND CONTENT CONSIDERATIONS Registration of Clinical Trials Aims and Scope We strongly recommend, as a condition of consideration for Romanian Journal of Military Medicine (RJMM) is the official publication, registration in a public trials registry. Trials journal of the Romanian Association of Military Physicians register at or before the onset of patient enrolment. This and Pharmacists. The Journal publishes peer-reviewed policy applies to any clinical trial. We define a clinical trial as original papers, reviews, meta-analyses and systematic any research project that prospectively assigns human reviews, and editorials concerned with clinical practice and subjects to intervention or comparison groups to study the research in the fields of medicine. cause-and-effect relationship between a medical Papers cover the medical, surgical, radiological, pathological, intervention and a health outcome. Studies designed for biochemical, physiological, ethical and historical aspects of other purposes, such as to study pharmacokinetics or major the subject areas. toxicity (e.g., phase 1 trials) are exempt. Clinical trials are afforded expedited publication if deemed We do not advocate one particular registry, but registration suitable. RJMM also deals with the basic sciences and with a registry that meets the following minimum criteria: experimental work, particularly that with a clear relevance (1) Accessible to the public at no charge; to disease mechanisms and new therapies. Case reports and (2) Searchable by standard, electronic (Internet-based) letters to the Editor will not be considered for publication. methods; Editorial Review and Acceptance (3) Open to all prospective registrants free of charge or at The acceptance criteria for all papers and reviews are based minimal cost; on the quality and originality of the research and its clinical (4) Validates registered information; and scientific significance to our readership. All manuscripts (5) Identifies trials with a unique number; and are peer reviewed under the direction of an Editor. The (6) includes information on the investigator(s), research Editor reserves the right to refuse any material for review question or hypothesis, methodology, intervention and that does not conform to the submission guidelines detailed comparisons, eligibility criteria, primary and secondary throughout this document, including ethical issues, outcomes measured, date of registration, anticipated or completion of an Exclusive License Form and stipulations as actual start date, anticipated or actual date of last follow-up, to length. target number of subjects, status (anticipated, ongoing or closed) and funding source(s). Plagiarism Detection The journal employs a plagiarism detection system. By submitting your manuscript to this journal you accept that

68 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine your manuscript may be screened for plagiarism against the Education and Imaging Coordinating Editors. The format previously published works. of the Images pages involves two parts, each of which will Committee on Publication Ethics occupy up to one journal page. In part 1, a case will be The journal subscribes to the principles of the Committee on described briefly, including a summary of the presentation, Publication Ethics (COPE). clinical features and key laboratory results. One to two key images will then be presented. It is helpful to the reader if MANUSCRIPT CATEGORIES AND SPECIFICATIONS the author responds to questions that follow from the All articles, with the exception of Editorials, must contain an images of the case, such as ‘What is your diagnosis? What abstract of no more than 250 words. Abstracts for original are the features indicated on the CT scan? What is the articles should be formatted into subheadings, as detailed differential diagnosis?’ Part 2 will briefly describe the below. Titles must not be longer than 120 characters imaging features, particularly those that lead to diagnosis or (including spaces). which are critical for management. Differential diagnosis Editorials should be mentioned. It will be useful to include either These are invited by the Editor-in-Chief or their delegated further images or pathological details that validate the editor, and should be a brief review of the subject imaging diagnosis. Occasionally, presentation of analogous concerned, with reference to and commentary about one or cases or related images from a similar case might be more articles published in the same issue of RJMM. Editorials appropriate. Please include between one and three are generally 1200–1500 words, may contain one table or references to definitive studies and appropriate reviews of figure and cite up to 15 references, including the source the subject. The format of the Images page involves a brief article [this should be cited as Military Med. Today (year); background to and description of the disorder of interest (vol): [this issue]. together with two figures of high quality. Colored Review Articles photographs are encouraged. The submission may take the RJMM welcomes reviews of important topics across the form of a case report or may illustrate particular features scientific basis of medicine, and advances in clinical practice. from more than one patient. Most published reviews are in response to editorial invitation, including thematically related “mini-series” of MANUSCRIPT PREPARATION reviews. Authors considering submitting a review for RJMM Style are advised to canvas their possible review with the Editor- Manuscripts should follow the style of the Vancouver in-Chief or a colleague editor; this avoids early rejection if agreement detailed in the International Committee of the subject matter is not deemed a high priority for the Medical Journal Editors’ revised ‘Uniform Requirements for Journal at the time of submission. Reviews are limited to Manuscripts Submitted to Biomedical Journals: Writing and 3500–5000 words, with an abstract of up to 250 words and Editing for Biomedical Publication’, as presented at up to 75 references and 3–7 figures or tables. http://www.ICMJE.org/. Meta-Analyses or Systematic Reviews Spelling. The journal uses US spelling and authors should RJMM particularly welcomes submission of Meta-Analyses therefore follow the latest edition of the Merriam-Webster’s and Systematic Reviews, which underpin evidence-based Collegiate Dictionary. medicine. Guidelines for preparation of Meta-Analysis and Units. All measurements must be given in SI units as outlined Systematic Reviews are similar to other reviews, and articles in the latest edition of Units, Symbols and Abbreviations: A are subject to the usual peer review process. Meta-Analyses Guide for Biological and Medical Editors and Authors (Royal and Systematic Reviews have a word limit of 3500–5000 Society of Medicine Press, London). words, with an abstract of up to 250 words and up to 75 Abbreviations should be used sparingly and only where they references and 3–7 figures or tables. ease the reader’s task by reducing repetition of long Original Articles (including clinical trials) technical terms. Initially use the word in full, followed by the RJMM welcomes original articles concerned with clinical abbreviation in parentheses. Thereafter use the practice and research in the fields of medicine. Papers can abbreviation. cover the medical, surgical, radiological, pathological, Trade names should not be used. Drugs should be referred biochemical, physiological, ethical and/or historical aspects to by their generic names, rather than brand names. of the subject areas. Clinical trials are afforded expedited Parts of the Manuscript publication if deemed suitable. RJMM also deals with the The manuscript should be submitted in separate files: title basic sciences and experimental work, particularly that with page; main text file; figures. a clear relevance to disease mechanisms and new therapies. Title page Original articles are limited to 3000 words, with an abstract The title page should contain (i) a short informative title that of up to 250 words and up to 50 references and 3–7 figures contains the major key words. The title should not contain and tables. abbreviations; (ii) the full names of the authors (if possible, Education and Imaging not more than 5 authors per title); (iii) the author's The Editors welcome contributions to the Education and institutional affiliations at which the work was carried out; Imaging section. The purpose is to present imaging for the (iv) the full postal and email address, plus telephone evaluation of unusual features of common conditions or number, of the author to whom correspondence about the diagnosis of unusual cases. Contributions will be reviewed by manuscript should be sent; (v) disclosure statement; and (vi)

acknowledgements. The present address of any author, if in press (with the name of the publication known) may be different from that where the work was carried out, should numbered and listed; abstracts and letters to the editor may be supplied in a footnote. be cited, but they must be less than 3 years old and identified Disclosure statement as such. Refer to only in the text, in parentheses, other The source of financial grants and other funding should be material (manuscripts submitted, unpublished data, acknowledged, including a frank declaration of the authors’ personal communications, and the like) as in the following industrial links and affiliations. In the case of clinical trials or example: (Chercheur X, unpublished data). If the owner of any article describing use of a commercial device, the unpublished data or personal communication is not an therapeutic substance or food must state whether there are author of the manuscript under review, a signed statement any potential conflicts of interest for each of the authors: is required verifying the accuracy of the attributed failure to make such a statement may jeopardize the article information and agreement to its publication. Use Index being sent out for peer-review. Medicus as the style guide for references and other journal Acknowledgments abbreviations. List all authors up to six, using six and "et al." The contribution of colleagues or institutions should also be when the number is greater than six. acknowledged. Thanks to anonymous reviewers are not Tables allowed. Tables should be self-contained and complement, but not Main text duplicate, information contained in the text. Number tables As papers are double-blind peer reviewed the main text file consecutively in the text in Arabic numerals. Type tables on should not include any information that might identify the a separate page with the legend above. Legends should be authors. The main text of the manuscript should be concise but comprehensive – the table, legend and presented in the following order: (i) abstract and key words, footnotes must be understandable without reference to the (ii) text, (iii) references, (iv) tables (each table complete with text. Vertical lines should not be used to separate columns. title and footnotes), (vii) figure legends. Figures and Column headings should be brief, with units of measurement supporting information should be submitted as separate in parentheses; all abbreviations must be defined in files. Footnotes to the text are not allowed and any such footnotes. Footnote symbols: †, ‡, §, ¶ should be used (in material should be incorporated into the text as that order) and *, **, *** should be reserved for P-values. parenthetical matter. Statistical measures such as SD or SEM should be identified Abstract and keywords in the headings. Original articles must have a structured abstract that states Figure legends in 250 words or less the purpose, basic procedures, main Type figure legends on a separate page. Legends should be findings and principal conclusions of the study. Divide the concise but comprehensive – the figure and its legend must abstract with the headings: Background and Aim, Methods, be understandable without reference to the text. Include Results, Conclusions. The abstracts of reviews need not be definitions of any symbols used and define/explain all structured. The abstract should not contain abbreviations or abbreviations and units of measurement Indicate the stains references. Three to five keywords should be supplied below used in histopathology. Identify statistical measures of the abstract and should be taken from those recommended variation, such as standard deviation and standard error of by the US National Library of Medicine’s Medical Subject the mean. Headings (MeSH) browser—(http://www.nlm.nih.gov/ Figures mesh/meshhome.html). All illustrations (line drawings and photographs) are Text classified as figures. Figures should be numbered using Authors should use subheadings to divide the sections of Arabic numerals, and cited in consecutive order in the text. their manuscript: Introduction, Methods, Results, Discussion Each figure should be supplied as a separate file, with the Acknowledgments and References. figure number incorporated in the file name. References Preparation of Electronic Figures for Publication: Although The Vancouver system of referencing should be used. In the low quality images are adequate for review purposes, text, references should be cited using superscript Arabic publication requires high quality images to prevent the final numerals in the order in which they appear. If cited only in product being blurred or fuzzy. tables or figure legends, number them according to the first SUBMISSION REQUIREMENTS identification of the table or figure in the text. In the Manuscripts should be submitted online at reference list, the references should be numbered and listed [email protected] in order of appearance in the text. Cite the names of all A cover letter containing an authorship statement should be authors when there are six or less; when seven or more list included. the first three followed by et al. Names of journals should be The cover letter should include a statement covering each of abbreviated in the style used in MEDLINE. Reference to the following areas: unpublished data and personal communications should 1. Confirmation that all authors have contributed to and appear in the text only. agreed on the content of the manuscript, and the respective References should be listed in the following form: roles of each author. Number references in the order cited as Arabic numerals in 2. Confirmation that the manuscript has not been published parentheses on the line. Only literature that is published or

70 Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine previously, in any language, in whole or in part, and is not PUBLICATION PROCESS AFTER ACCEPTANCE currently under consideration elsewhere. Accepted papers will be passed to production team for 3. A statement outlining how ethical clearance has been publication. The author identified as the formal obtained for the research, particularly in relation to studies corresponding author for the paper will receive an email, involving human subjects, and animal experimentation. The being asked to complete an electronic license agreement on institutional ethics committees approving this research must behalf of all authors on the paper. comply with acceptable international standards (such as the Accepted Articles Declaration of Helsinki) and this must be stated. The accepted ‘in press’ manuscripts are published online 4. For research involving pharmacological agents, devices or very soon after acceptance, prior to copy-editing or medical technology, a clear Conflict of Interest statement in typesetting. Accepted Articles are published online a few relation to any funding from or pecuniary interests in days after final acceptance, appear in PDF format only, are companies that could be perceived as a potential conflict of given a Digital Object Identifier (DOI), which allows them to interest in the outcome of the research. be cited and tracked. After print publication, the DOI 5. For clinical trials, that these have been registered in a remains valid and can continue to be used to cite and access publically accessible database. the article. Given that copyright licensing is a condition of If the above items are not included in the cover letter, publication, a completed copyright form is required before a manuscripts cannot be sent for review. manuscript can be processed as an Accepted Article. Please also note that the cover letter does not require a Proofs detailed or lengthy description of the content or structure of Once the paper has been typeset, the corresponding author the manuscript itself. will receive an e-mail alert containing instructions on how to Two Word-files need to be included upon submission: A title provide proof corrections to the article. It is therefore page file and a main text file that includes all parts of the text essential that a working e-mail address is provided for the in the sequence indicated in the section 'Parts of the corresponding author. Proofs should be corrected carefully; manuscript', including tables and figure legends but the responsibility for detecting errors lies with the author. excluding figures which should be supplied separately. The proof should be checked, and approval to publish the The main text file should be prepared using Microsoft Word, article should be emailed to the Publisher by the date doubled-spaced. The top, bottom and side margins should indicated; otherwise, it may be signed off on by the Editor or be 30 mm. All pages should be numbered consecutively in held over to the next issue. the top right-hand corner, beginning with the first page of Offprint the main text file. A PDF reprint of the article will be supplied free of charge to Each figure should be supplied as a separate file, with the the corresponding author. Additional printed offprint may figure number incorporated in the file name. For submission, be ordered for a fee. low-resolution figures saved as .jpg or .bmp files should be COPYRIGHT, LICENSING AND ONLINE OPEN uploaded, for ease of transmission during the review Details are on the Copyright Agreement Form that must be process. Upon acceptance of the article, high-resolution completed and signed when the Article is accepted. figures (at least 300 d.p.i.) saved as .eps or .tif files will be required.

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