Romanian Journal of Military Medicine

0 downloads 0 Views 2MB Size Report
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. Honorary Editor. Acad. ...... materials, both having advantages and disadvantages, ...
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

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

www.revistamedicinamilitara.ro

Editorial Board of Romanian Journal of Military Medicine Under the patronage

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) Cris S. Constantinescu (UK) Daniel Dănilă (USA) Mihai Moldovan (Denmark) Ioan Opriș (USA)

Gerard Roul (France) Erwin Santo (Israel) Adrian Săftoiu (Denmark) Ioanel Sinescu (Romania)

C. Ionescu Târgovişte (Romania) Radu Ţuţuian (Switzerland) Shyam Varadarajulu (USA) Peter Vilmann (Denmark) Victor Voicu (Romania)

Gabriel Constantinescu (Bucharest) Dan Corneci (Bucharest) Raluca S. Costache (Bucharest) Dragoș Cuzino (Bucharest) Mircea Diculescu (Bucharest) Cosmin Dobrin (Bucharest) Silviu Dumitrescu (Bucharest) Carmen G. Fierbințeanu (Bucharest) Cristian Gheorghe (Bucharest) Liana S. Gheorghe (Bucharest) Mihai E. Hinescu (Bucharest) Ruxandra Jurcuț (Bucharest)

Viorel Jinga (Bucharest) Ovidiu Nicodin (Bucharest) Tudor Nicolaie (Bucharest) Bogdan A. Popescu (Bucharest) Emilian A. Ranetti (Bucharest) Corneliu Romanițan (Bucharest) Carmen A. Sîrbu (Bucharest) Ion Țintoiu (Bucharest) Sorin G. Țiplica (Bucharest) Daniel Vasile (Bucharest) Dragoş Vinereanu (Bucharest)

Scientific Publishing Committee Adrian Barbilian (Bucharest) Anda Băicuş (Bucharest) Cristian Băicuş (Bucharest) Andra Bălănescu (Bucharest) Mircea Beuran (Bucharest) Ovidiu Bratu (Bucharest) Daciana Brănișteanu (Iași) Dragoș Bumbăcea (Bucharest) Marian Burcea (Bucharest) Sofia Colesca (Bucharest) Dumitru Constantin Dulcan (Bucharest)

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. www.revistamedicinamilitara.ro

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

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

RJMM Romanian Journal of Military Medicine

Founded 1897 • New Series

Vol. CXXI • No. 2/2018 • August

Edited by the Romanian Association of Military Physicians and Pharmacists.

Contents EDITORIAL Dan Mischianu

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

5

REVIEW ARTICLE Gabriel Gorecki, Elena Rusu, Horaţiu Moldovan, Ioan S. Tudorache

 Reactive nitrogen species and cardiovascular diseases

11

Marina Melescanu Imre, Elena Preoteasa, Ana Maria C. Tancu, Cristina T. Preoteasa, Mihaela Pantea, Paula Perlea

 Ethical limits between aesthetic and cosmetic dentistry

16

Mirela Radu

 History of medicine on the border between philosophy and science

21

ORIGINAL ARTICLES Octavian Vasiliu

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

26

Alexandra Șopu

 Patient reported outcome measures and joint replacement

35

Mihăiță Pătrășescu, Petruț Nuță, Raluca S. Costache, Săndica Bucurică, Bogdan Macadon, Vasile Balaban, Andrada Popescu, Roxana Călin, Ioana Răduță, Daniel Pantile, Florentina Ioniță Radu, Mariana Jinga

 Physical effort – an underused preventable method in colorectal cancer

41

Bogdan I. Coculescu, Victor L. Purcărea, Elena C. Coculescu

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

46

CLINICAL PRACTICE Genica Caragea, Mihail S. Tudosie, Radu A. Macovei, Ilenuţa L. Dănescu, Mihai Ionică

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

50

Cristian Cobilinschi, Radu C. Țincu, Mihail S. Tudosie, Zoie Ghiorghiu, Radu A. Macovei

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

58

1

R. Hainăroșie, Irina Ioniță, Cătălina Pietroșanu, S. Pițuru, Mura Hainăroșie, V. Zainea

 Uncommon giant sphenoidal tumor. Case report ADMINISTRATIVE ISSUES Guidelines for authors

2

64 68

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

3

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

EDITORIAL

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

Motto: “L’Histoire, c’est la rencontré d’une volonté et d’une évènement” – Charles de Gaulle, 1890-1970

This short notice, largely iatrohistoric, appear in the 100th year since the Great Union out of the desire to know more about what has happened. In Romania, there was a lot of talk about the First World War. The Germans remember this war under the name of "der Erste Weltkrieg worde von 1914 bis 1918 in Europa, in Naken Osten, in Africa, Ostasien and auf dez ozeanen gefurt". Obviously this first conflagration was the army of "Zweiter Weltkrieg"! The British preferred the denomination of the "European War" or, more correctly, they named it "the Great War". It appears that this name is slowly but surely penetrating our literature, following "World War I" which, referring to the title of this editorial only makes us Romanians remind that we have also had a Small Union (1859), followed by the Great Union of 1918. It must be remembered that the Romanian literature between 1948-1989 wrote about the Great War in an abbreviated manner, because of two reasons: the Eastern neighbors had "turned history" – things did not happen as planned and the contribution and participation of the Romanian Royalty to the final victory was extremely important but also very embarrassing that it had to be silenced. The Great War began in Sarajevo in 1914 and ended at

Versailles in 1949 in the Mirror Hall, with multiple European implications...

Gral (R) Prof DAN MISCHIANU

Chief of Urology Clinic, Carol Davila Central Emergency Military Hospital Faculty of General Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

Then, at Versailles in the Grand Trianon Palace, a treaty was signed on June 4, 1920 between 16 allied states (including Romania) and the successor state of the Austro-Hungarian Empire. At the beginning of the war, Romania, a "very small country", in the form of "L", had 137,000 km2 and a population of 7.2 million inhabitants, and after Trianon, it was reunited and became „The Great Romania", with an area of 295,000 km2 and a nation of 18 million people. It is certainly why, in the collective mentality of a neighboring nation, that this situation is perceived as unacceptable even after 100 years! After the assassination of the crown Prince of AustriaHungary – Franz Ferdinand on June 28, 1914 the actors, both big and small, began to enter the stage: Central Powers – Germany, Austria-Hungary, Turkey, Bulgaria and Antanta or the Triple Alliance, England, Russia followed by Italy, Romania, USA... The Kingdom of Romania had passed through a recent, unforgettable experience for the army and especially for the military doctors. In 1913, during the Second Balkan War, the Romanian troops that had easily entered the northern half of Bulgaria lost 1,600 lives due to the cholera epidemic – a fearful "enemy".

5

Evidently, the accusations have risen, obviously committees for dysfunctions research have been named, obviously the responsible military doctors – Constantin Papilian (1852-1917) and Senator G-ral (r) Prof. Dr. Athanase Demosthen (1846-1925) informed I.C. Bratianu – Prime Minister and Minister of War about all this. Certainly, the two years of neutrality have chosen better and more efficient organizational lines, as "stage sanitation, semi-hospital evacuation, evacuation hospitals, auxiliary hospitals, and infirmary station ". Just after two years of "armed expectancy" war began, for Romania as well as for other nations, how all wars start "suddenly and unprepared!". We do not insist in geostrategic and political-economic details. We present only the result and brief considerations about military doctors truly involved in the "Perpetual Drama of War". What Prof. Dr. Vasile Sârbu, a Templar Knight of Romanian Surgery and Iatrohistory, presented with his known erudition a few months ago, is perfectly true: "In this war, 400 military doctors died out of 2,800 participants." 2,400 health workers have also died out of 14,000 participants, as well as 14 pharmacists and 20 students of the Military Health Institute. These numbers do not say much. If we compare them with the other "weapons", we will be surprised to learn that this group of people is on the 2nd place after the infantry, which made King Ferdinand to offer them the right to wear the "combatant weapon" badge.

He became Professor of Experimental Medicine at the Faculty of Medicine in Bucharest at the age of 38 and was appointed in 1908 as General Manager of the Health Service to "Effectively fight epidemics, set up isolation hospitals and pavilions, rural infirmaries and bacteriological laboratories". In the Bulgarian campaign he successfully ordered the vaccination in an epidemic environment, called and known as "the great Romanian experience." He conducted the Civil Public Health and Military Public Health Directorate during the Great War, a true Ministry of Health, which allowed him to organize anticholeric vaccination and fight against exanthematic typhus, typhoid fever and smallpox – having the rank of Col. Dr. of the Romanian Army.

"This was the result!..." Among the personalities, the first name to be quoted with gratitude and piety is that of Prof. Dr. Ion Cantacuzino – Jean Cantacuzen for the French, descendant of Byzantine emperors, a medical school creator, graduate of the French medical school, born in 1863 in Bucharest, student of Ilia Mecinikov, founder of the Romanian School of Immunology and Experimental Pathology, doctor of medicine with a thesis on the destruction of the vibrio cholera. The subject of the thesis, supported in 1894, and its findings will prove useful in almost 20 years, as in the novels of Alexandre Dumas.

6

In 1920, together with Nicolae Titulescu and Mihai Ciucă, his student, participated, as the Romanian state delegate, at the Treaty of Trianon. He enjoyed a high prestige, he had an important word to say, was even a friend of French Prime Minister Georges Clemenceau, a distinguished neurologist... On April 1, 1921, as a result of his unrelenting thought, effort, and

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine determination, he founded the "Serum and Vaccine Institute", by royal decree, which will then bear its name. O tempora, o mores!...

In 1911 the General Dr. Nicolae Vicol (1861-1936), as Director of the Health Department of the Ministry of War, organizes two preparatory sanitary maneuvers around Bucharest that have proven to be beneficial in the future. In August 1916, when he signed the troops mobilization he followed the General Constantin Prezan – the head of the General Headquarters, unfortunately not having total decision-making power and being obliged to listen to the Minister Constantin Angelescu. Since February 1917, when the Public Health Directorate was founded, led by the supreme authority in the field – Colonel Prof Dr Ion Cantacuzino, he starts a great collaboration with him.

The General Dr. Iacob Potarca (1866-1942), a graduate of the Bucharest Faculty of Medicine, specialized in general surgery in Paris, physician colonel in 1916, head physician of the First Army’s Corp, general in 1917, then Sanitary Inspector of the First Army – who fought in the Mărăști-Mărășești sector, was not only an illustrious military physician in the war. In 1924 he becomes General Inspector of the Army's Sanitary Service, but it is worth mentioning that he is the first Romanian surgeon to have operated the esophagus, having other remarkable surgical researches quoted by Professor Dan Setlacec in his formidable monograph "Romanian Medicine, European 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 thought of the Great Union! In August 1917, at Mărășești, there were "many other doctors from the old country, young, learned ablebodied: Victor Papilian, Titu Vasiliu, Odiseu Apostol, Grigore T. Popa, Constantin, Mihail Kerubach, and many, many others”.[4]

The name Col (r) Prof. Iacob Iacobovici (1879-1959) is worth mentioning from the beginning, not only for being the founder of the Surgery School in Cluj, after the Great Union and of the first Emergency Hospital in Romania, the one in Bucharest, but also an involved participant in the Bulgarian campaign and the commander of the 7th Evacuation Hospital of the Second Army in Bacau in 1917. Professor Iuliu Moldovan (1882-1966) attended the Faculty of Medicine in Vienna and Prague, and then, what a few know (4), he worked as a military doctor at the Department of Dermatovenerology and at the

7

Central Laboratory of Bacteriology of the AustroHungarian Army.

Medical Clinic, dean of the new Faculty of Medicine in Cluj, "Magnificus rector", precursor, visionary, called the "Hippocrates of the Romanians", was also a participant in the Great National Assembly in AlbaIulia. 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 AlbaIulia. Between 1919 and 1920, he became the professor of the Department of Hygiene and Social Hygiene of the Faculty of Medicine in Cluj, general secretary of the Social Protection Resort of the Transylvanian Conducting Council and he also organized the Transylvanian Medical Service. I think it is worth mentioning the contribution of other illustrious physicians to the Great Union just to contradict Albert Camus, who said with cynicism: "Forgetting is the first faculty of man!"

He was a graduate of the Faculty of Medicine in Vienna, doctor of medicine, who established in Carlsbad where he trained as an intern and balneologist, later attracted to the political activity, debuted in the Chamber of Budapest and the one who has read, on the 18th of October 1918 in the Hungarian Chamber, the Declaration of Self-Determination of the Romanian People from Transylvania. He was a member of the ministry cabinet of Ion I.C. Brătianu, he also joined the Peace Conference delegation in Paris and formed and led the first Government of the United Romania. When Romania was finally united, things seemed to be on an upward trend. The Romanian military doctors, as well as the civilian physicians, great personalities or unknown remarkable people, have fulfilled their duty. Regarding "The Map of Great Romania in 1924" we have only one comment: the year 1924 was the year in which, in Germany, the ideology of Nazism has started to blossom.[5]

Iuliu Hatieganu (1885-1959) the first professor of a

8

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

Our history, of the Romanian people, has implied over the years a steady climb with a lot of difficulties. The Great Union was accomplished in stages, all springing up from the ideal of unity of our nation, never forgotten.

The unification of the Romanian states is the nation's greatest act, which configures and fully certifies our existence among other nations of the world.

References 1. Stoica Leontin – Serviciul Sanitar al Armatei Romane în perioada 1918-1919, Teză de doctorat, Academia de Ştiinţe a Moldovei, Institutul de Istorie şi Drept, Chişinău 2012

europeană (1918-1940), Ed. Humanitas 1995

2. Sârbu Vasile - Participarea medicilor la Războiul de Întregire a Neamului şi la Marea Unire din 1918

5. Peter Ross Range – 1924, anul care l-a creat pe Hittler, Ed. Litera, Bucureşti, 2018

3. Setlacec

Dan



Medicina

românească,

4. Florea Marin – Medicii şi Marea Unire, Ed. Tipomur, 1993, pg. 30

medicină

9

10

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

REVIEW ARTICLE

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

Reactive nitrogen species and cardiovascular diseases Gabriel Gorecki1, Elena Rusu1, Horaţiu Moldovan1,2, Ioan S. Tudorache1

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

INTRODUCTION Normal biochemical reactions, increased exposure to the environment, and higher levels of dietary xenobiotics result in the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS are responsible for the oxidative stress in different pathophysiological conditions. Cellular constituents of our body are altered in oxidative stress conditions, resulting in various disease states. Oxidative stress plays a major part in the development of chronic and degenerative diseases such as cancer, arthritis, aging, autoimmune disorders, cardiovascular and neurodegenerative diseases [1]. Free radicals are defined as “any chemical species Corresponding author: Assoc. Prof. Elena Rusu PhD [email protected]

capable of independent existence that contains one or more unpaired electrons”. This unpaired electron(s) usually gives a considerable degree of reactivity to the free radical. An imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage, has been defined “oxidative stress”. It soon appeared that nitric oxide (NO) plays a key role in the physiological regulation of the cardiovascular system, since abnormalities in its productions and/or bioavailability accompany or even

1

Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania 2

Sanador Hospital, Bucharest, Romania

11

precede diseases such as hypertension, atherosclerosis and angiogenesis-associated disorders. Cardiovascular disease (CVD) is the leading cause of death in the United States and Europe and is poised to become the most significant health problem worldwide. Free radicals are generated from either endogenous or exogenous sources. Endogenous free radicals are generated from immune cell activation, inflammation, mental stress, excessive exercise, ischemia, infection, cancer and aging. Exogenous free radicals result from air and water pollution, cigarette smoking, alcohol, heavy metals, certain drugs (cyclosporine, tacrolimus), industrial solvents, cooking and radiation. ROS and RNS products can bring about reversible or irreversible chemical changes (oxidation, nitrosylation and nitrosation) in proteins, lipids, and DNA, resulting in diminished biochemical functions [2]. The greater the amounts of ROS and RNS, the more extensive the chemical changes in these targets. ROS and RNS can induce adducts to DNA, leading to DNA fragmentation [3]. Reactive nitrogen species (RNS) are free radicals which are associated with the nitrogen atom: nitric oxide (NO), nitrogen dioxide (NO2) and peroxy-nitrite (ONOO-). Reactive species are produced by regulate enzyme such as nitric oxide synthase (NOS), and isoforms of NADPH oxidase, or as by-products from not so well regulated sources, such as mithocondrial electron-transport chain. Nitric oxide is a biatomic free radical containing an unpaired electron. Until now have been described three forms of NO, nitrosonium cation (NO+), nitric oxide (NO.), and nitroxyl anion (NO-) with nitrogen oxidation number +3, +2, and +1, respectively. NO can react with oxygen free radical to form peroxynitrate (ONOO-). This last molecule is involved in protein oxidation reaction under physiological conditions.

CARDIOVASCULAR DISEASES Cardiovascular diseases are prevalent in human population and most of them are related to diet but genetic lipid abnormalities such as hypercholesterolemia, hypertriglyceridemia, HDL metabolism

12

disorders, and combined hyperlipidemias are more severe. Cardiovascular disease is one of the major causes of mortality and morbidity worldwide and the costs that involve handling this disorder are huge. The 2008 overall rate of death attributable to cardiovascular disease was 244.8 per 100 000 individuals and this rate is critically growing [4]. Recent evidence demonstrates that cardiovascular disorders are usually associated with increased level of stress hormones [5, 6]. Cardiovascular risks such as defects in angiogenesis/ vasculogenesis or vessel repair are major complications of coronary artery disease (CAD) which are mostly seen in aged people. Similarly, CVD risks have also increased in women during pregnancy which is an important issue for management of their cardiovascular health [7]. Conventional risk factors such as cigarette smoking, diabetes, hyperlipidemia, and hypertension are absent in 15-20% of patients with CVD. Atherosclerosis is the main cause of death in the world through causing ischemic heart disease. It is peripheral arterial disease, most prevalent, morbid, and mortal disease. It is one of the most common disorders among the elderly, because of depression prevailed in the old age and rates of very high atherosclerosis. Atherosclerosis is characterized by endothelial dysfunction, vascular inflammation, and the buildup of lipids, cholesterol, calcium, and cellular debris within the intimae of the walls of large and medium size arteries. Abnormal proliferation of vascular smooth muscle is implicated in various pathological situations including atherosclerotic lesions, restenosis after balloon angioplasty, and vascular wall thickening in hypertension. NOS may play protective role by inhibiting proliferation of vascular smooth muscle cell [8]. For example, leiomyosarcoma, which is an aggressive mesenchymal tumor with differentiation toward smooth muscle tissue, represents up to 9% of all primary malignant tumors. Some cases of leiomyosarcoma presumed to be infective endocarditis [9].

THE CHEMISTRY OF RNS Nitric oxide (NO.) is a small molecule generated in

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine biological tissues by specific nitric oxide synthase (NOS) which metabolizes arginine and citrulline with the formation of NO. via a five electron oxidative reaction [10]. Nitric oxide synthase utilize L-arginine as the substrate, and molecular oxygen and reduced nicotinamide-adenine-dinucleotide phosphate – NADPH as co-substrat. NO is involved in the regulation of cardiovascular motor tone, modulation of myocardial contractility, control of cell proliferation and inhibition of platelet activation, aggregation, and adhesion [11]. Hypertension is also associated with NO synthesis [12]. The enzyme nitric oxide synthase produce reactive nitrogen species (RNS), such as nitric oxide (NO˙) from arginine. L-Arg + O2+ NADPH → NO. + citruline An inducible nitric oxide synthase (iNOS) is capable of continuously producing large amount of NO˙, which act as a O2˙−quencher. The NO˙ and O2˙− react together to produce peroxynitrite (ONOO−), a very strong oxidant, hence, each can modulate the effects of other. Although neither NO˙ nor O2˙− is a strong oxidant, peroxynitrite is a potent and versatile oxidant that can attack a wide range of biological targets. Peroxynitrites can interact with several cellular components and are implicated in NO signaling mechanisms involving protein modifications. NO˙+ O2˙− → ONOO− In aqueous aerobic solutions NO predominantly forms nitrite (NO2-). In the presence of oxyhemoglobin and oxymioglobin, NO is completely oxidized to nitrate (NO3-). Covalent interactions of NOS with cellular macromolecules are responsible for its many physiological and pathological effects. Protein containing iron and thiol groups are the major cellular target of NOS [13]. There are three types of NOS, neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS which plays a very important role in the vascular homeostasis) and inducible nitric oxide synthase (iNOS; it is found in myocytes, macrophages and ECs and is activated by immunological and inflammatory stimuli). Under septic conditions iNOS

and nNOS are upregulated in endothelial and muscle cells, respectively, leading to over-production of NO in the microvasculature and arteriolar dysfunction. Neuronal NOS is constitutively expressed in specific neurons of the brain and its enzymatic activity is regulated by Ca+2 and calmodulin. This NOS isoform has been identified also in the spinal cord, in the sympathetic nerves, in epithelial cells of various organs, in pancreatic islet cells, in the vascular smooth muscle and in the skeletal muscle [14, 15]. Endothelial NOS is mostly expressed in endothelial cells; Ca2+-activated calmodulin is important for the regulation of eNOS activity because Ca 2+ induces the binding of calmodulin to the enzyme. Endothelial NOS appears to be a homeostatic regulator of numerous essential cardiovascular functions and also controls the expression of genes involved in atherogenesis. The blood vessel wall NO is mainly produced from l-arginine by endothelial NOS. Nitric oxide as a key endothelial vasodilator also directly affects metabolism by competing with mithocondria for oxygen and consequently inhibiting switching the metabolism to some other pathways. Also, some studies suggested that NO is implied in the response of Candida albicans species to the oxidative stress and also against some azoles drugs. Candida albicans is a commensal species of the human gastrointestinal tract, in which it lives without adverse effects on the host, but yeast-to-hypha transition has been associated with increased virulence, mucosal invasiveness and biofilm formation. Candidemia and invasive candidiasis are frequently associated with high morbidity and high mortality rates [16].

ANTIOXIDANTS AND DEFENSE MECHANISMS Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NADPH) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to

13

noxia, as for example in defense against infectious agents, in the function of a number of cellular signaling pathways, and the induction of a mitogenic response [2]. Cellular constituents of our body are altered in oxidative stress conditions, resulting in various disease states. The oxidative stress can be effectively neutralized by enhancing cellular defenses in the form of antioxidants. Low levels of antioxidants have been associated with the heart disease and cancer. When ROS/RNS are generated in vivo, their actions are opposed by intricate and coordinated antioxidant lines of defense systems. These include enzymatic and nonenzymatic antioxidants that keep in check ROS/RNS level and repair oxidative cellular damage. The antioxidant enzymes reduce the levels of lipid hydroperoxide and H2O2, thus they are important in the prevention of lipid peroxidation and maintaining the structure and function of cell membranes. The major enzymes, constituting the first line of defense, directly involved in the neutralization of ROS/RNS are: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). SOD is a cytoplasmic and mitochondrial enzyme, which accelerate the dismutation of superoxide. They are present in almost all aerobic cells and in the extracellular fluids. They contain metal ions that can be copper, zinc, manganese or iron. In humans, the copper/zinc superoxide dismutase is present in the cytosol, while manganese superoxide dismutase is present in the mitochondria. CAT, an exclusively peroxisomal enzyme in most tissues, converts H2O2 to water and O2. However, the most important H2O2removing enzymes are the selenoprotein GPx enzymes. GPx enzymes remove H 2O2 by using it to oxidize reduced glutathione (GSH) to oxidized glutathione (GSSG). Glutathione reductase, a flavoprotein enzyme, regenerates GSH from GSSG, with NADPH as a source of reducing power. Glutathione peroxidase also catalyses the reduction of unstable hydroperoxides at the expense of GSH [17].

natural antioxidants and the synthetic antioxidants. Vitamin C, vitamin A and plant phytochemicals like phenolics that inhibit the oxidation chain initiation and prevent chain propagation represented the second line of defense. Vitamin A has a vital antioxidant contribution in protecting human LDL against copper stimulated oxidation. Lipid-soluble antioxidants such as α-tocopherol localize mainly to membranes and lipoproteins where they serve to limit lipid peroxidative damage. Vitamins E and C have been demonstrated to reduce the progression of atherosclerosis. Vitamin E (α-tocopherol) is the most important lipid-soluble antioxidant and protects cell membranes against oxidation by reacting with the lipid radicals produced in the lipid peroxidation chain reaction and removing the free radical intermediates. Phenolics are therefore an integral part of the diet, with significant amounts being reported in vegetables, fruits, teas and traditional plants. Epidemiological evidence indicates that consumption of fruit, vegetables and teas may reduce the risk of cardiovascular disease and it is increasingly suggested that this may due to their antioxidants that include ßcarotene, vitamin C, vitamin E and polyphenolics. Dietary antioxidant phenolics may quench reactive oxygen and nitrogen species and, hence potentially modify pathogenic mechanisms relevant to cardiovascular disease [18]. Vitamin C regenerates vitamin E in cell membranes in combination with glutathione or compounds capable of donating reducing equivalents. Low levels of antioxidants have been associated with the heart disease and cancer. Antioxidants provide protection against a number of disease processes such as aging, allergies, algesia, arthritis, asthma, atherosclerosis, autoimmune diseases, bronchopulmonary dyspepsia, and cancer. The other disorders to which antioxidants provide protection are cataract, cerebral ischemia, diabetes mellitus, eczema, gastrointestinal inflammatory diseases, and genetic disorders.

The nonenzymatic antioxidants are of two types, the

References: 1. Kabel AM. Free radicals and antioxidants: role of enzymes

14

and nutrition. World J. Nutrit. Health, 2014, 2 (3):35-38.

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine 2. Valko M, Leibfritz D, Moncol J, Cronin M, Mazur M et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol, 2007, 39 (1): 44-84. 3. Martin LJ. DNA damage and repair: relevance to mechanisms of neurodegeneration. J Neuropathol Exp Neurol. 2008; 67:377–387. 4. Roger V.L., Go A.S., Lloyd-Jones D.M., et al., AHA statistical - update heart disease and stroke statistics. Update Circulation, 2012; 125, e2-e220 5. Vogelzangs N., Beekman A.T.F., Milaneschi Y., et al. Urinary cortisol and six-year risk of all-cause and cardiovascular mortality, J. Clin. Endocrinol. Metabol. 2010, 95(11):4959-64 6. Manenskijn L., Van Kruysbergen R.G.M., De Jong F.H., et al., Shift work at young age is associated with elevated longterm cortisol levels and body mass index, J.Clin. Endocrinol.Metabol, 2011, 96(11):E1862-5 7. J. W. Rich-Edwards, A. Fraser, D. A. Lawlor, and J. M. Catov, “Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health?” Epidemiologic Reviews, 2014, 36,1: 57–70 8. Loscalzo J, Vita AJ. Nitric oxide and the cardiovascular system. Spinger Science & Business Media, 2000. 9. Jurcut R, Savu O, Popescu BA, Florian A, Herlea V, Moldovan H, Ginghina C. Primary cardiac leiomyosarcoma. When valvular disease becomes a vascular surgical emergency. Circulation, 2010, 121(21):e415-e418

current state. Nutrition J. 2015, 15:71, doi.10.1186/s12937016-1086-5 11. Napoli C., Paolisso G, Casamassimi A, Al-Omran M, Barbieri M, Sommese L, Infante T, Ignarro LJ. Effects of nitric oxide on cell proliferation: novel insights. J Am Coll Cardiol. 2013 Jul 9;62(2):89-95. 12. Misra MK., Sarwat M., Bhakuni P., Tuteja R., Tuteja N. Oxidative stress and ischemic myocardial syndromes. Med. Sci. Monit. 2009, 15(10): RA209-219 13. Ignarro Louis J. Nitric oxide: Biology and Pathobiology, Academis Press, 2000. 14. Forestermann U., Closs EI., Pollock JS., Nakane M., Schwarz P., Gath I., Kleinert H. Nitric oxide synthase isoenzyme, Characterization, purification, molecular cloning, and functions. Hypertension, 1994, 23:1121-1131 15. Forestermann U., Sessa WC. Nitric oxide synthase: regulation and function. Eur Heart J., 2012, 33(7):829-837 16. Rusu E, Sarbu I, Pelinescu D, Nedelcu I, Vassu T, Cristescu C, et all. Influence of associating nonsteroidal antiinflammatory drugs with antifungal compounds on viability of some Candida strains. Rev. Rom. de Boli Infectioase ISSN 1454-3389, 2014, vol. XVII nr.2:86-90 17. Bahorun T., Soobrattee MA., Luximon-Ramma V., Arouma OI. Free radicals and antioxidants in cardiovascular health and disease. Internet J Med Update, 2006, 1(2):25-41 18. Shahidi F, Wanasundara PKJPD. Phenolic antioxidants. Crit. Rev. Food. Sci. Nutr. 1992;32:67-103.

10. Kurutas EB. The importance of antioxidants which play role n cellular response against oxidative nitrosative stress:

15

REVIEW ARTICLE

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

Ethical limits between aesthetic and cosmetic dentistry Marina Melescanu Imre1, Elena Preoteasa1, Ana Maria C. Tancu1, Cristina T. Preoteasa1, Mihaela Pantea1, Paula Perlea1

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

INTRODUCTION Nowadays, more and more frequently, within dental, practical or training activities, we are dealing with matters related to esthetics. Patients often require esthetic restorations without being able to specify most of the time, what exactly they would like. Students show an increasing interest in esthetic dentistry aspects. 1 Faculty

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

16

As professionals we are flooded with an information influx both through scientific publications and dental materials producers, with a dental esthetics value. After the implant, esthetics is the “new trend” in dental medicine as a natural consequence of the development of modern society. Esthetic concerns existed since forever, from the first protagonist of scientific esthetics Pythagoras, who defined the “golden ratio”, combined with dynamic symmetry discovered in 1920 by Jay Hambridge and Sir D’Arcy Thompson who explained how natural beauty can be quantified and how it can be reproduced in art, architecture and other crafts. For dentistry, as terminology, in the Glossary of Corresponding author: Ana Maria C. Tancu MD, PhD [email protected]

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine Prosthodontic terms, esthetic dentistry is defined as the part which studies beauty, creating harmonious results through prostheses, and ethics is a moral principle or a set of moral values of an individual or group of individuals, in our case – the ones involved in the treatment (doctors, technicians). Cosmetic dentistry is not a term indexed by GPT, its definition being present in the Collins dictionary, like maneuvers aimed to beautify without purpose or functional form. The medical profession has ethical obligations [1] centered to prevent and treat diseases, in order to rehabilitate the dento-masticatory apparatus functionality, namely mastication, phonation, and the patient's physiognomy. Questions related to dental esthetics are: What are the ethical boundaries of the esthetic trends in dentistry? Can anything be done from a medical standpoint for the sake of obtaining an esthetic outcome? Are we ready for this new challenge as physicians who took the Hippocratic Oath for the “primum non nocere” principle? Are we trained as trainers, academics, in order to educate students so that they become true professionals in esthetic dentistry? What are the limits of esthetic dentistry and dental cosmetic, as a new term in our vocabulary? These are some of the questions that have led us to write this paper. This study is a literature one designed to focus the current problems that modern dentistry is facing in relation to esthetic requirements. The original aspect of this work is related to the definition (both for patient and doctor) of these two terms, their character being a little bit confusing, also being capable to lead to legal aspects, even malpractice.

dental cosmetic, from an ethical point of view; (c) esthetics, the reason for treatment and clinical examination; (d) medical training, scientific publications, patient information, consent. The search strategy was conducted using EBSCO Data Base Dentistry & Oral Sciences Source with the aid of Boolean Operators. The following keywords were combined: ethics, esthetic, and cosmetic dentistry. The search was limited to English peer reviewed articles, full text and years limitation January 2000 October 2015 academic journals.

RESULTS There was obtained a total of 1248 articles, including full text criteria, of which 580 articles were retained, matching the search criteria requested. After applying the search criteria 10 publications became relevant. Furthermore, there was done a manually electronic search on themed websites. In the end, 14 publications that included the search criteria were selected.
Among the issues raised by the retained publications, there were identified 4 axes of interest: 1. Dental esthetics as part of dentistry – boundaries. 
 2. Difference between esthetics and dental cosmetic from the ethics point of 
view. 
 3. Esthetics, as a reason for treatment and clinical examination. 
 4. Training the physicians, scientific publications, informing the patient – consent.

DISCUSSION Dental Esthetics as Part of Dentistry – Boundaries

MATERIAL AND METHOD A comprehensive literature study was completed in October 2015. There were selected publications in English, peer reviews, articles from academic publications, dated January 2000 to December 2015. There was obtained a total of 1248 articles, including full text criteria, of which 580 articles were retained, and after applying the selection criteria only 14 publications remained. Identified as directions of interest were: (a) dental esthetics as part of dentistry – boundaries; (b) the difference between esthetic and

At this point two issues detach themselves – functionality and bias. As noted in the introduction, there is a definition of dental esthetics in the GPT, however this is rather vague, making reference to “beauty, following the art’s rules and principles''. In dentistry, the therapeutic dental restorations are not only esthetic, but they should primarily ensure the dento-masticatory apparatus and the dental occlusion functionality. For example, dental fillings can be done medically with physiognomic or non-physiognomic materials, both having advantages and disadvantages,

17

the dominant criteria for the physician must be based on clinical experience, choosing the optimal method of treatment in order to meet the basic medical principle, “primum non nocere”. [2] The medical profession bases its treatment on clinical, objectively examination of the patient. When regarding the esthetics dental problems, subjectivity might occur; hence, the need to establish clear criteria, both objective and subjective, for the examination in dental esthetics. Indeed esthetic sense is not a criterion for graduation from the Faculty of Dentistry; it has a great variability from person to person, from clinician to clinician, as well as from patient to clinician. Given these difficulties related to the subjective issues, it was suggested a hierarchy of the esthetic aspects in dentistry, starting from basic esthetic rules where the smile’s coordinates comply to the classical principles of the golden ratio, symmetry, dental and dento-facial proportions, smooth line smiling. The next level is represented by the cultural and regional subjective aspects, for example in the United States the so-called Hollywood smile is a social standard, the whiteness and perfect alignment of teeth being associated with wealth, social and financial success. At last, the latest level is the socalled virtual level – the one that a computer program sets as ideal for the patient, from the esthetic point of view. [3] Is dental esthetics a part of the patient’s general health state? Yes, it was clinically proven that the esthetic restoration brings an important psychological benefit to the patient. [3] Difference between Esthetics and Dental Cosmetic from the Ethics Point of View Within the last years, appearing the dental cosmetic term, that was medically not registered otherwise, there have been many misunderstandings between this term and the esthetic dentistry, both among patients and practitioners. Traditionally, dental medicine as a medical specialty is centered, ethically speaking, on the prophylaxis and the treatment of the dental tissues in order to ensure

18

a good health state, respecting, of course, the dentomasticatory functions. So, we are talking about affected tissues, or with such potential. [4] Dental cosmetic seeks only embellishment, often without any consideration for functionality, interfering with healthy tissues, without clinical impairment for beautifying intentions. Often, these maneuvers contradict even the esthetics concept – defined as being an integration concept of beauty in natural proportions, with a humane dimension. Is it esthetically the completely unnatural pure white smile of an 80 years old lady? Is it not against the physiological processes of aging teeth, with natural tooth staining due to time passage? Therefore, the difference between cosmetic and esthetic dentistry must be properly ethically and medically differentiated [5,6]. Moreover, some cosmetic maneuvers might damage a healthy dental tissue – for example when applying veneers, esthetic crowns, excessive grinding, applying adhesive – without pulp protection – can lead to tooth loss – defined as disfigurement, from the ethical point of view. [3] One must respect, from the ethical point of view, the principle of minimally invasion; the so-called enamel sacrifice on the altar of vanity [7, 8, 9] does not correspond to the principles of medical ethics. On long-term, the biological implications of the maneuvers consequences that were performed only for cosmetic purposes should be correctly assessed by practitioners. [10] Esthetic would mean beauty, form and function – and cosmetic only beauty. [2] Esthetics, as a reason for treatment and clinical examination As shown, although the boundary between esthetic and cosmetic maneuvers may seem “too fine” sometimes, the practitioner disposes of objective criteria when deciding the treatment plan. [11] Patients who address the dentist for solving the esthetic problems divide into two categories – among these reasons are dental crowding, discoloration, unsightly tooth discoloration, missing teeth, multiple teeth with coronal restorations. The patients’ reasons may be esthetic ones, but after a properly conducted clinical examination, the dentist will establish the

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine functional problems – occlusion problems, migration and others that, from an objective medical point of view, should be rehabilitated in order to restore the morpho – functional, esthetic, masticatory and phonetic balance. The dentist will decide the patient's treatment plan, single or multidisciplinary orthodontics (teeth alignment through braces), conservative treatment (bleaching, esthetic restorations, and ceramic veneers), and dental prosthetic (crowns coverage, dental implants). A second category refers to patients without enough arguments – patients suffering from narcissism, personality disorder, patients who can’t accept their age. As in the first group, the dentist is the one that will make a “proper diagnose” considering the medical history and clinical examination. Patients with such presentation reasons will permanently be unsatisfied with the treatment outcome. Unlike the ones with consistent esthetical grounds that will be satisfied once the esthetic problem is solved, for the second class the result will not be acceptable even if it has improved the esthetic aspect. [2] These are the most common candidates for dental cosmetic, for whom the “primum non nocere” principle must be respected from the ethical viewpoint. [10] And not least, after the clinical examination, if the dentist is in a doubtful situation, he should, according to "when in doubt, it is probably not ethical" [7] test himself with "The Daughter Test" – Would I proceed with this intervention on my daughter? [8,12] Training the physicians, scientific publications, informing the patient – consent Another important aspect is the dentists training, in addition to the fundamental principles of dental esthetics already learned in college; the profession currently faces numerous specialty publications in which the so-called academic articles are praising esthetic results obtained – the ethical aspect of the presented cases being often questionable from the fairness of the dimension’s vertical occlusion point of view, occlusion stability and durability of these restorations. Publishing some insufficiently and superficially documented cases – medically speaking,

designed only to beautify, can be really dangerous, especially for young doctors who didn’t benefit from enough clinical experience and being pressured by patients in order to obtain esthetic results, can guide their therapeutic conduct, based on good faith. [10] In the modern age, consumer society pushes dentists to features, such as advertising, with the temptation for many dentists to promise spectacular results with a negative impact on the professionalism of the entire profession [6], we must not forget the fundamental nature of our medical profession profile, namely the professional doctor [13] and not the beautifying one. In this context it is important, ethically speaking, the doctor-patient communication regarding the dental esthetic issues – the doctor is required in this type of treatment to inform the patient in order to receive his consent over long-term implications (especially in younger patients). Communication must be made in terms that the patient will be able to understand (not necessarily medical terms), assisted by pictures, drawings, suggestive dental casts. It is also required to present to the patient, where appropriate, one or more treatment alternatives, including the less esthetic alternative, before signing the informed consent [3]. Esthetic dentistry requires less accommodation, incorporates acceptable biologic technology for long-term survival, functions suitably, and mimics the pristine state of the natural dentition. Cosmetic and esthetic dentistry are different in definition, concept, and execution [14].

CONCLUSIONS As a result of this extensive literature study on a very actual dentistry issue – ethical considerations of esthetics and dental cosmetic, we came up with some interesting conclusions intended to clarify the often encountered confusion regarding these terms. Dental Esthetics regroups several dental maneuvers, often interdisciplinary, aiming the morfo-functional rehabilitation of the dento-masticatory apparatus, following universal esthetic principles harmoniously integrated into the overall health and harmony of the human body as part of dentistry. Dental cosmetic is a set of maneuvers that, although have a medical character, do not seek the reconstruction of the maxillary device

19

functionality, just have a beautifying character, intervening on healthy tissues without any prophylactic role, often with disabling long-term implications. In terms of bioethics, the “primum non nocere” principle is not respected within these maneuvers. Therefore, it is important for the dentist to know the differences, the fundamental dental esthetic concepts, in order to minimize the subjective component of the examination, to succeed the clinical examination with identification of the presentations reasons, to be trained for all medium- and long-term treatment

implications, in order to be able to present to his patient all treatment alternatives and guide him to choose the optimal treatment option for obtaining the desired esthetic results within the ethical boundaries of this noble profession. The theme being new and the boundary between esthetics and cosmetic dentistry being quite subjective, no doubt that they still have to be studied, there are needed further studies and research that will clarify the differences between them on an evidence-based scientific system. Acknowledgements All authors had equal contribution in this paper elaboration.

References: 1. Astarastoae V., Triff B.A., Essentialia in Bioetica, Cantes Publishing, Iasi, 1998 
 2. Ahmad I., Risk management in clinical practice. Part 5. Ethical considerations for dental enhancement procedures, British Dental Journal, 209:207-214, 2010 
 3.Liebler M., Devigus A., Randall R.C., Trevor Burke F.J., Pallesen U., Cerutti A., Putignano A., Clauchie D., Kanzler R., Koskinen P., Skjerven H., Strand G.V., Vermaas R.W.A, Ehics of Esthetic Dentistry, Quintessence International, 35:456465, 2004 4. Williams J., FDI Dental Ethics Manual, ISBN 0-953 9261-5X, 2007 5. Glick K., Cosmetic Dentistry is Still Dentistry, Journal Canadian Dental Association, 66:88-91, 2000 6. Hussey D.L., Where is the Ethics in Aesthetic Dentistry, British Dental Journal, 192-6 Conference, 2002 7. Faith K.E., The Ethics of Cosmetic Dentistry: Beneficence,

20

Beauty or “Bucks’’?, Oral Health Group.com, 10/01/2010 
 8. Hancocks S., The Ethics of Cosmetics, British Dental Journal, 211-11 Editorial, 2011 
 9. Jackson R.D., Judging Ethics Ethically, Journal of Esthetic & Restorative Dentistry-Journal Compilation Blackwell Munksgaard, 19:181-182, 2007 10. Kelleher M., Ethical Issues, Dilemmas and Controversies in “Cosmetic” or Aesthetic Dentistry. A Personal Opinion, British Dental Journal, 212:365-367, 2012 
 11. Owsiany D.J, The Intersection of Dental Ethics and Law, Journal of the American college of Dentists, 75:47-54, 2008 12. Kelleher M., “The Daughter Test” in Esthetic or Cosmetic Dentistry, Dental Update, Jan/Feb 2010 
 13. Poonam et al, Ethics in Medicine and Dentistry: A Review, Indian Journal of Dental Sciences, 5:152-154, 2013 14. Touyz LZ1, Raviv E, Harel-Raviv M. Cosmetic or esthetic dentistry? Quintessence Int. Apr;30(4):227-33,1999.

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

REVIEW ARTICLE

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

History of medicine on the border between philosophy and science Mirela Radu 1

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

The new involves acknowledging the past, transforming it and bypassing mistakes. The 20th century met the expectations of those who wanted to know this history by setting up the Institute of History of Medicine in 1921 in Cluj. “More and more are those who pretend to have a spiritual imitation in the past to save the intellectual character of modern medicine. This postulate translates practically into the multiplication of medical-historical literature and giving a growing importance to the history of medicine.”[1] One of the first teachers to honor the Romanian institute was the French Jules Guiart (18701965) who taught for three years this subject. Those who strongly supported him were Valeriu Bologa and Emil Racoviţă. Guiart, fascinated by what he had discovered on the Romanian realm, would also work as an ethnographer, travelling intensively and

gathering various ethnographic materials and photos from all corners of our country. The Romanian physician Valeriu Bologa (1892-1971) is the exponent of a whole caste: that of doctors aware of the modeling power of culture. He dedicated himself to the study of natural sciences (at the University of Jena) and, afterwards, he was attracted to the medical studies in Austria and Cluj. The pride he felt for the art

1

Faculty of Medicine, Titu Maiorescu University, Bucharest

21

of healing practiced by the Romanians led him to lay the foundations of a new branch of science: the history of medicine. Between 1949-1971 he presided the International Society of Medicine History. Feeling that the progress can only be heard through the knowledge of the past, Bologa devoted many books to the facts of the medicine in the past. One of the first important papers signed by the Romanian physician focused on the special situation of the Hippocratic profession practiced by the Transylvanian Romanian doctors who had to face not only the lack of material means but also the political repression: Contributions to the history of medicine in Transylvania (1927). Three years later, Bologa signed a second monograph, The Beginnings of Romanian Scientific Medicine for which he would receive in 1931 the V. Adamachi Prize of the Romanian Academy. But until 1927, the physician signed only a studies with great historical significance, dedicated to some of the most diverse themes – from midwifery, to the forerunners of doctors, from ophthalmology to medical lexicology formation: Spells, old women and midwives today and the past (1921); New data for Ioan Molnar (1925); About Romanian Occultists (1925); Medicine in Moldavia (1925); Between physiology and medicine (1925); Romanian Medical Terminology of doctor I. Molnar (1926). Furthermore, Bologa dedicates himself to the construction and endowment of a museum dedicated to medical science in Romania. The Romanian scholar was particularly fond of two sections of the museum: Old Romanian Medicine and Medicine in the Transylvanian past. The great importance he gave to the knowledge of the old times of the profession he revered could be felt from the appreciation with which he emphasizes the importance of those early times, but also the respect he had for his ancestors. For the reader of any age is visible the attachment and esteem that doctor Bologa carries to those who have done medical pioneering work, especially in the Transylvanian region: “From this rich Romanian medical library can be reconstituted the hard work of the first gatherers of new roads in Romanian science. It is possible to see the influences from the outside, it can be seen how gradually a Romanian medical terminology was formed, it can be noticed how, from

22

the great Davila, our medicine goes from the assimilation phase to the one of creation, as more and more characteristically forms a Romanian medical current. The old Transylvanian medical literature was represented equally well at the beginning – from the 16th century – by the works of the German doctors, later with those of the Hungarians, finally from the 18th century and with the first Romanian medical translations.”[2] But Bologa was not the only one who fought for this new branch of medicine. He was helped in his efforts by the fellow surgeon Victor Gomoiu (1882-1960) who founded museums dedicated to the history of medicine in Târgu-Jiu and Craiova. Gomoiu, in turn, published a monograph entitled From the History of Medicine and Romanian Medical Education (1923) and during the interwar period he was elected president of the International Society of Medicine History (1936). Gomoiu was also the one who signed the first History of the Medical Press in Romania (1936), the work of collecting and organizing numerous medical papers and writings. But Gomoiu was not just an encyclopedic spirit. He also actively contributed to the struggle that doctors used to do with illnesses whose mortality reaches worrying odds. Director of the Osteoarticular Tuberculosis Sanatorium for Children in Techirghiol, eventually Gomoiu would practice surgery in Bucharest. His surgical work is quantified by the large number of innovative articles he has written, by implementing the term solarectomy (resection of lymph nodes), initiated the inguinal approach of varicocele (Gomoiu-Phocas method). Intransigent character, Gomoiu was removed from academic education. His merit in the history of medicine is to insist on the Romanian contribution to the international folk medicine fund. This brought, at least historically, the Romanian medicine at the level of the other countries reducing the gap. A proof of his ideal and his effort to bring medicine to the Western level are the three works published by the Romanian physician in 1938: La Croix dans la Folclor medical roumain, Histoire du Folclore medical en Roumanie and Medicine in the Romanian folk prose. Bologa also corresponded intensely with Mircea Eliade, whom he intended to co-opt in his work at the

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine Institute of Medical History. Eliade, despite the fact he had no necessary time for active participation in this approach, had a special esteem for the intellectual physician, as is also apparent from the lines written by the philosopher in an epistle addressed to the physician-historian, a letter dated 23 October 1928: “I testify that whenever I skim through your work and meditate on the situation of the history of sciences in our country – I am remorseful that I do not write more often, warmer and harder, in the papers that are at my fingertips. I know that, personally, for the scientific history studies I'm interested in – I have to thank you. Not to mention what others owe you, especially doctors and historians. The Institute makes «environment» scientific history, we, isolated ones, can at most, make the atmosphere. If an association for such studies can be woken up, I always think that the courage of the achievements has been with the production of the Cluj Institute.“[3] Even in India, Eliade maintains contact with the Romanian physician for whom he does not hesitate to admit he has a great cult of his extraordinary work of a huge volume: “The passion of science – that is, the slow, precise, technical sorting of the material our culture provides us – is the great temptation that brings me closer to you .” (Letter dated 16.02.1930, Calcutta)[4] The reason why Eliade particularly appreciated Bologa resides in the philosopher's aspiration to write a few stories on traditional Indian medicine branches. Eliade admired the founder of medical history the ability to synthesize the huge volume of works, objects and manuscripts. It was the systematization work that occupied the author of Religious History Treaty and History of Religious Beliefs and Ideas all the time. At the same time he was better equipped to understand the enormous sacrifice of time and resources involved in ordering, ranking, and organizing such amount of information. Frustrated by the huge volume of notes, contact with Bologa developed philosopher's rationalization and ability to think more rigorously. Eliade's interest in medicine crystallizes in 1936 when, following a lecture held at an International Congress of History, Eliade publishes History of Medicine in Romania. The affection borne by the philosopher of the religions to this new emerging branch stems from the support given to the history of medicine which he

perceives as a means of producing: “real services to the humanism of our age.”[5] Folk medicine is viewed with reverence by Eliade because it represents the immaterial and immutable connection with the ancestors of the nation. Since 1926, Eliade collaborated with Aldo Mieli, who was the publisher of Archeion magazine, producing short studies of the history of various sciences, medicine and folklore. That's how Eliade got to correspond with Bologa. The latter wanted to develop a collaboration with Miel's Archeon by making contributions in the form of articles devoted to Italian influences on Romanian medicine. For Eliade, the whole science represents, at least in the initial phase, a single corpus. Subsequently, science has specialized and subspecialized over time. What could bring back all these disparate fragments to one place would be the philological field. In fact, even Bologa was aware that his scientific approach was far more philological. This is how one can explain the help that he Bologa asked from the philosopher. Another connection between the two, Bologa and Eliade, was the scientific curiosity to study botany. As a small child, Eliade devoted much energy to catching, studying, analyzing and cataloging various insects. At the age of fourteen, Eliade published a study titled Silkworm’s Enemy, under the pen name Eliade Gh. Mircea, which showed the passion he has for insect biology. The marvelous journey of the five beetles in the land of the red ants-sketch of the novel – was written in the same period. More the outline of a teenager fascinated by the world of gangs, behind the modest mise-en-place is hiding a satire, an annoyance of the enemy (ants) by five elite bettles. It is a mockery of the human society reduced to the microcosm of insects. The step to science would come when Eliade participated and won a contest that proposed the literary approach of a scientific subject. The title of the essay (How I found the philosopher's stone) is an epiphany of the future path that the teenager Eliade would take. The essay written by a youngster seems to have amazed the author himself when, over the years, he said, “How much I would like to be able to reread this story now, understand what that mysterious character revealed to me, what alchemical operations

23

he assisted! I had found the philosophical stone in my dream ... I could only understand, decades later, after I read Jung, the meaning of this oniric symbolism!”[6] The short story, though a fantastic text loaded with supernatural, has as its starting point in Eliade's interest in chemistry and alchemy. Although he had promised Bologa that he would make his contribution to writing a history of Romanian medicine, Eliade's departure to India would break this momentum. Though time did not allow him, for the young Eliade was trying to absorb the new information that was crowded him, the philosopher gathers medical material inspired by yoga practices and even offers to write to the Romanian physician an article about Ayurvedic medicinal products, as we find out from a letter dated February 6, 1930: “I have a considerable number of facts on pharmaceutical medicine and magic in India, some of them astounding, such as those relating to vagus nerve control.”[7] For Eliade, alchemy is the gate open to an occult form of practice. Alchemy is the first type of objective report that leave leave, over the history of humanity, truly scientific discoveries; a kind of ancestor of rational knowledge. This preparatory, pseudo-scientific phase, the first attempt of structuring scientific knowledge was the one that attracted Eliade from his youth because of its esoteric character. In 1928 Eliade wrote an article (Marcelin Berthelot and alchemy) dedicated to a French chemist and biologist who imposed his name in the field of thermodynamics. Conscious of the enormous gap between Romanian and Western science at the beginning of the 20th century, Eliade sensed, from the philologist and philosopher point of view, the need to systematize the totality of historiographical material in order to be saved from oblivion: “We cannot wait until Romanian science reaches a European level to promote the validity of historical-scientific studies. There is no discipline that can be postponed.”[8] The philosopher's insight was to build a methodology in this vast field of history of medicine. The history of science would be appropriate, with a takeover from a chemist and American historian Sarton, a new form of intellectual movement that would put man and science in the center: “Eliade understands a new interpretation or vision of man not derived from philological studies (textual), as it was

24

Renaissance humanism, but in the history of science understood as «any systematized knowledge» (Sarton), therefore more than «positive sciences».”[9] Eliade, great admirer of George Sarton (1884-1956), intuited in the Belgian chemist the innovative spirit. Sarton embraced the history of science as a branch of gnoseology and aimed at linking science and humanism to a comprehensive one: the philosophy of science. Eliade was in the current with the theories of the American and hence the enthusiasm at the moment when a homologous branch was formed on the Romanian realm. The only ones of sufficient intellectual scope that Valeriu Bologa could count on were Mircea Eliade and Nicolae Iorga. If alchemy was the gate open to science, popular creation and ancestral healing practices were the preamble of modern science. And Eliade felt this correlation, especially as the prose was anchored in folklore: “In his writings, the folkloric elements intertwine with those of the history of religions or ethnology. His stories take place in illo tempore, somewhere outside of physical time, and the characters have supernatural powers, their existence enrolling in an eternal present, and the facts being predetermined in advance. Witches, queens, beautiful women who make pact with the evil, curative herbs and charm plants, here are some of the ingredients with which Eliade sows his writings inspired by folklore.”[10] The pioneering work of building a frontier science in our country like the history of science did not frighten Eliade. We find out from a letter addressed to Bologa that, on the contrary, ostentatiously, he protects this new branch of knowledge, although he is aware of the weight of action in a rebellious society to the new: “I defend a science against the envy and imbecility of our intellectuals. I do not even think that our science will soon become popular. But it must not be ignored and, above all, dishonored by the elite to which it is de jure and de facto aimed at.”[11] What brought together a physician (Valeriu Bologa) and a philosopher (Mircea Eliade) were the folk traditions with application in medicine. Apparently two opposing personalities collaborated efficiently

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine and discovered the common denominator, the unspoken binder between a scholar spirit and a metaphysical one, for “the research of Valeriu Bologa met the interests of Mircea Eliade and although they did not sign articles or books, the mere fact that they

shared their opinions meant much for the later developments of both.”[12]

References: 1. Valeriu Bologa, Wheat Grains, in Institute of History of Medicine, Pharmacy and Folklor Medicine of Cluj, no. 6, June 1932, pp. 205-206

7. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas Publishing House 1999, Foreword and Care of the Edition by Mircea Handoca, p. 79

2. Valeriu Bologa, Wheat Grains, in Institute of History of Medicine, Pharmacy and Folklor Medicine of Cluj, no. 6, June 1932, pp. 218

8. Mircea Eliade, History of Medicine in Romania in The Word, year IV, no. 1174, 30 July 1928, pp. 1-2

3. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas Publishing House 1999, Foreword and Care of the Edition by Mircea Handoca, p 76 4. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas Publishing House 1999, Foreword and Care of the Edition by Mircea Handoca, p 78 5. Mircea Eliade, History of Medicine in Romania in Journal of the Royal Foundation, no. 6, June 1936 6. Mircea Eliade, Memories, 1907-1960, 2nd Edition Revision and Index by Mircea Handoca, Bucharest, Humanitas Publishing House, 1997, p. 63

9. Mac Linscott Ricketts, Romanian Roots of Mircea Eliade, 1907-1945, vol. 1, Bucharest, Criterion Publishing House, 2004, p. 288 10. Mihaela Gligor, Between philosophy and medicine. The medical folklore in the vision of Mircea Eliade and Valeriu Bologa, Cluj University Press, 2014, p. 94 11. Mircea Eliade, Correspondence A-H, vol. 1, Humanitas Publishing House 1999, Foreword and Care of the Edition by Mircea Handoca, p. 85 12. Mihaela Gligor, Between philosophy and medicine. The medical folklore in the vision of Mircea Eliade and Valeriu Bologa, Cluj University Press, 2014, p. 138

25

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

ORIGINAL ARTICLE

Therapeutic management of schizophrenia and substance use disorders dual diagnosis – clinical vignettes Octavian Vasiliu1

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

BACKGROUND

1

Carol Davila University Emergency Central Military Hospital, Bucharest

26

Substance-related disorders are very common throughout the course of schizophrenia, and this phenomenon is responsible for poorer quality of life, higher impairment of daily functioning, lower rate of treatment response, lower therapeutic adherence, leading to a worse prognosis in these patients.

Prevalence of dual diagnosis (substance use disorder and psychotic disorders) ranges from 10 to 70% in a large-scale trial for schizophrenia [1]. Many hypotheses about the link between cannabis use and schizophrenia are still tested, cannabis being considered an independent risk factor for psychosis and a variable that may worsen prognosis in schizophrenia patients [2]. A cannabinoid hypothesis of schizophrenia has been suggested, based on the observed alteration of endocannabinoid system (abnormalities in cannabinoid type 1 receptor binding properties and modified levels of anandamide in the cerebrospinal fluid) [2]. Cannabis use was associated

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine with an earlier onset of schizophrenia, more severe forms of disorder, higher rates of relapse, and longer hospitalizations [3-5]. Longitudinal studies report that cannabis use in childhood and adolescence doubles the risk of psychosis onset later in life, which supports a causal role of this drug in the development of schizophrenia [6]. Certain alleles of the type 1 cannabis receptor gene (CNR1) may confer susceptibility to schizophrenia [7]. Also, the overlap of nicotine dependence and schizophrenia has been debated as a form of selfmedication for schizophrenia-related cognitive deficits, based on the fact that the nicotine receptors activation increases the release of dopamine in cortical and subcortical areas [8,9]. Still, cigarette smoking decreases the bioavailability of many psychotropics that are metabolized through the CYP450 1A2 isoenzymes and consequently may diminish the clinical effect of these drugs and delay the patients recovery [10]. Multiple genes have been linked to both conditions, e.g. binding protein genes, protein modification genes, and energy production genes involved in cognitive functions and neuronal plasticity [11]. Alcohol use disorder was found in 33.7% of patients diagnosed with schizophrenia or schizophreniform disorder in the Epidemiologic Catchment Area study [12]. A dysregulation of the dopamine transmission has been suggested as common neurological basis, but shared genetic vulnerability factors have also been investigated (e.g. KPNA3, or alcohol dehydrogenase variants) [13-16]. A review of the current evidence for common risk factors in alcohol use disorders and schizophrenia supports a highly polygenic model, with rare penetrant alleles and frequent alleles with small effects [16]. Patients diagnosed with schizophrenia tend to abuse anticholinergic drugs. These agents are often used for the treatment of antipsychotic-induced extrapyramidal symptoms, and a national database analysis showed that patients with schizophrenia took 20 times more frequently antiparkinsonian agents than patients with Parkinson disease [17]. Trihexyphenidyl abusers may claim this drug improve their daily functioning and their affect, and a possible

pharmacological explanation is that this agent has a structural similarity with phencyclidine [18,19]. The risk of biperiden and orphenadrine abuse was relatively small in a large database analysis [17].

CLINICAL VIGNETTES The first patient, M.S., is a 29-year old male, diagnosed since 2015 with schizophrenia according to the DSM-5 criteria [20], currently at his third psychotic episode. He was hospitalized after he presented at the Emergency Department with delusions of persecution and auditory hallucinations (“there are people who want me dead because of my soul, they want to collect my psychic energy”, “I can hear them through the walls, day and night, they are plotting against me, and they are saying bad things about my family”, “They are forcing me to do evil things, like cursing strangers with no reason”). These manifestations led to changes in his behavior, he became reclusive, didn’t go out of his house for weeks and spoke with his family only by phone, refusing to see them (“I can protect them if I’m not seen with them”). He recently abandoned his job as a salesman and didn’t want to see her girlfriend anymore because of the belief that she was in cahoots with the persecutors who want him dead. The pharmacological history in this case included olanzapine 20 mg/day as the main treatment for his first psychotic episode. After hospital discharge, he received the same antipsychotic for 8 months, then he dropped out and relapsed after about 6 months. The overall clinical status during the second admission was similar to the first episode of psychosis, with persecutory delusions and auditory hallucinations (both conversing and imperative voices) and induced defensive behavior- the patient refused to go out by himself because of the fear of being watched and plotted against. Olanzapine was re-initiated, but shortly after this the patient was switched on aripiprazole 30 mg/day due to concerns related to his metabolic status (240 mg/dl for the total cholesterol, 150 mg/dl for LDL-cholesterol, and 250 mg/dl for triglycerides). The evolution was favorable during the hospitalization and the patient was recommended to work in a controlled environment and to participate in occupational therapy. However, after 7 months he

27

discontinued treatment and soon relapsed, so that a new hospitalization was required. This time the patient was stabilized on aripiprazole, but for the maintenance phase the long acting injectable form of aripiprazole 400 mg every 4 weeks was selected, in order to diminish the risk of therapeutic nonadherence. The patient was also diagnosed during the current psychotic episode with alcohol use disorder, moderate, based on the DSM-5 criteria, admitting a daily intake of 8 drinks, consisting mainly in beer and wine for more than 12 months. Also, he is smoking 20 cigarettes daily, with a value of 10 pack-year. Biochemistry panel reflected the liver damage, with values for gamma-GT, GOT and GPT of 156 U/l, 70 U/l, and 67 U/l, respectively. No abnormalities were detected on his chest X-ray and abdominal ultrasound exam (except for hepatic steatosis). The psychological evaluation realized during the initial visit for the third episode showed a 98 score on PANSS [21], with high values on both positive and negative sub-scales. CRDPSS [20] score was 17, based mainly on hallucinations, delusions and abnormal psychomotor behavior. AUDIT [22] score was 14, reflecting a moderate risk of harm related to the alcohol use, and the severity of nicotine dependence was high, as supported by the FTND [23] score of 9. GAF score at admission was 45, based on symptoms severity and functional impairment, while the CGI-S score was 5, which means a “markedly ill” clinical status. Therapeutic challenges analysis: This patient presented a history of therapeutic non-adherence which triggered two relapses. He was diagnosed with two substance use disorders (alcohol and nicotine dependence), which were not therapeutically approached during his two previous psychotic episodes, and this could be also a factor that may contribute to relapse in schizophrenia [24]. There is a lack of social and professional insertion in this case, related to both positive and negative symptoms. The patient lacks familial support and he discontinued occupational therapy. Moreover, the metabolic profile and the hepatic functional status were abnormal. All these negative prognosis factors have been evaluated

28

by the case manager when the therapeutic strategy was formulated. Aripiprazole was preferred because of its good metabolic profile [25], and a long acting injectable formula was selected because of the more stable plasma concentrations and lower risk of discontinuation. The patient received counselling for his addictive behavior, and he participated in 4 individual sessions focused on smoking cessation and alcohol use relapse prevention. Alcohol withdrawal symptoms were mild-to-moderate and remitted after B-vitamin therapy, parenteral rehydration, and oral lorazepam 3 mg/day for 7 days, with gradual dose reduction. Naltrexone, 50 mg/day, was initiated for alcohol dependence after the withdrawal symptoms remission, and nicotine replacement therapy was suggested, but the patient refused. There are no data reported about pharmacokinetic interactions between aripiprazole and naltrexone in the literature, which supports this therapeutic recommendation. Follow-up visits: The patient was monitored for 4 months, using psychometric instruments, in order to document psychotic symptoms, severity of addictions, and overall clinical status evolution under treatment. Global functioning improved once the psychotic positive symptoms remitted, although the negative symptoms persisted at a lower level of severity (as reflected by PANSS and CRDPSS scores). Table 1. Psychologic evaluations during the first patient’s initial visit Clinical scale

Results

PANSS

98

CRDPSS

17

GAF

45

CGI-S

5

FTND

9

AUDIT- Interview Version

14

Alcohol use disorder had a favorable evolution and the AUDIT scores diminished gradually, but the nicotine dependence persisted and the mean number of cigarettes increased with 25%, while the FTND score increased with 10%. Biochemistry panel reflected an improvement of the liver status after 4 months, with values for gamma-GT, GOT and GPT of 56 U/l, 23 U/l,

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine and 37 U/l, respectively, and the metabolic parameters improved, also: 190 mg/dl for the total cholesterol, 120 mg/dl for LDL- cholesterol, and 170 mg/dl for triglycerides. Conclusion: Addictive behaviors must be approached as soon as possible by the case manager in patients with schizophrenia, because the risk of therapeutic non-adherence, somatic complications, and reduced functionality is higher if these conditions are left

untreated or if the appropriate treatment is delayed. In this particular case, naltrexone was efficient in the treatment of alcohol use disorder, and the patient had also significant decrease of the psychotic symptoms. However, nicotine dependence could not be addressed pharmacologically because the patient refused, and he participated only in a few counseling sessions, which led to the persistence of his substance related condition.

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

Score

80 60 40 20 0 0 PANSS

7 CRDPSS

14

28 GAF

The second patient, E.D., is a 30-year old female, diagnosed with schizophrenia for 6 years, currently in a partial remission, who presented to her psychiatrist asking for a therapeutic change because of galactorrhea and irregular periods. She attributed these symptoms to risperidone, which was initiated by the psychiatrist during her latest psychotic relapse, about 3 months ago. This patient had 4 psychotic episodes since the onset of her disease at age of 22 and received for her first episode haloperidol 15 mg/day for 2 months, followed by amisulpride 800 mg/day for 10 months; for her second episode, she was treated with olanzapine 15 mg/day, for 16 months; during her third episode she received haloperidol 20 mg/day for the acute phase, and again olanzapine 15 mg/day for an indefinite period of time, and for the last episode she received risperidone 6 mg/day maintenance dose. Changes in the antipsychotic regimen were determined by adverse events- extrapyramidal symptoms during

60 CGI-S

90 FTND

120 AUDIT

haloperidol treatment, hyperprolactinemia during amisulpride administration, and weight gain during olanzapine therapy. This patient presented also criteria for nicotine and cannabis use disorder, both of moderate severity, according to the DSM-5 criteria. She was on cannabis for more than 2 years, with very few short periods of abstinence, and regarding nicotine use she admitted she was smoking 15 cigarettes daily for at least 8 years. She admitted she did not recognized cannabis addiction in front of her psychiatrist until the current visit. She was never offered nicotine replacement therapy or any other type of treatment targeting nicotine dependence. The psychological evaluation during her third episode sh owed a PANSS score of 69, with low values on both positive and negative sub-scales. CUDIT-R [26] score was 16, supporting severe cannabis dependence, and the severity of nicotine dependence was high, as reflected by the FTND score of 7. GAF score at

29

admission was 60, based on symptoms severity and functional impairment, while the CGI-S score was 4, which means “moderately ill” clinical status. EuroQoL (EQ-5D-5L) [27,28] visual analogic scale score was 67, which seems to be correlated more with her substance-related symptoms than with her psychotic manifestations. Quality of life domains that seemed more affected by her current status were anxiety/depression (a score of 4) and usual activities (a score of 3). Her somatic status was good, with no abnormalities on CBC or serum biochemistry panel. Also, her ECG and chest X-ray didn’t suggest any abnormalities. Therapeutic challenges analysis: This patient has a history of adverse events to several antipsychotics (haloperidol, amisulpride, olanzapine) which were severe enough to grant changes in the antipsychotic treatment. The patient received a new antipsychotic, ziprasidone 160 mg/day, which has been associated with low risk for hyperprolactinemia, weight gain, and extrapyramidal syndrome [29]. A gradual switch was preferred due to the different pharmacodynamic profiles of risperidone and ziprasidone [29-31]. ECG monitoring was initiated, and periodic measurement of metabolic parameters was continued throughout the duration of the antipsychotic therapy. The presence of cannabis use disorder raises an important question because there is no pharmacological treatment with clear evidence of efficacy in patients diagnosed with this disorder, while data about psychotherapy effects are still debatable [32]. However, gabapentin and N-acetylcysteine have been suggested as possible therapies [32], and gabapentin was preferred in this case because of its positive effect on anxiety and low risk of pharmacokinetic interactions [33]. Nicotine replacement therapy with nicotine patch 25 mg/16h for 8 weeks, followed by gradual dose reduction, combined with psychological counselling, was accepted by the patient. Follow-up visits: The evolution of the psychotic symptoms was favorable, as reflected in the PANSS (10%) and CRDPSS (-11%) scores. The overall functionality increased significantly (+33%) compared to baseline, and this improvement seems related to the decrease in both FTND and CUDIT scores, with 71%

30

and 75%, respectively. Also, the quality of life improved, both on the visual analogic scale (+17%), and on its subscales (depression/anxiety -50% and usual activities -33%). The Clinical Global ImpressionSeverity improved with 50%, and the patient was considered after 4 months “borderline mentally ill”. Minimal QTc prolongation was detected on ECG after 4 months (+1.3%), but it didn’t reach the level of significance (considered to be 460 msec in women, after correction with Fredericia’s formula). No metabolic abnormalities were detected during the monitoring period, and the BMI decreased with 2.1% compared to baseline. Conclusion: Targeting the cannabis and nicotine use disorders may improve the overall functionality and patient’s quality of life, reducing further schizophrenia-associated symptoms, like depression, apathy, anhedonia or anxiety. In this case, the patient was compliant to the therapeutic suggestions, and participated in counselling sessions focused on substance use relapse prevention, while being adherent to the pharmacologic treatment. Her evolution was favorable and the therapeutic switch from risperidone to ziprasidone was well tolerated. No pharmacokinetic interactions were anticipated between the treatment for nicotine use disorder (replacement therapy), cannabis use disorder (gabapentin) and schizophrenia (ziprasidone). Table 2. Psychologic evaluations during the second patient’s initial visit Clinical scale

Results

PANSS

69

CRDPSS

9

GAF

60

CGI-S

4

FTND

7

AUDIT – R

16

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

67 1 2 3 2 4

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

80 60 40 20 0 0

7

14

28

60

PANSS

CRDPSS

GAF

FTND

CUDIT-R

EuroQoL-VAS

The third patient, S.G., was diagnosed for the first time with acute psychotic disorder 3 months ago. Her symptoms at hospital admission consisted in psychomotor agitation, grandiose (“I am very powerful, and I can make any wish come true, like Santa Claus, only better”) and persecutory (“there is a group of forces trying to kill me and take my powers”) delusions, auditory and visual hallucinations (“I can hear them talking about me and trying to make me feel miserable… they are cursing me and telling lies about me and my family”, “They are moving through the light, I can see them… they are like some green shadows”), disorganized behavior, and diminished emotional expression. She was 27 years old when she was first admitted in hospital, and her psychotic symptoms had an insidious onset over at least 4 months. First, she was initiated on risperidone 6 mg/day, and her response was good, but discontinued oral treatment because she had to take this drug twice a day. The patient developed positive symptoms of psychosis after one month of no treatment, and she was readmitted in the Psychiatry Department. The selected drug for clinical stabilization was risperidone because of her previous good response. She was informed that a long acting injectable form of this antipsychotic exists, which requires administration every two weeks. Also, she was informed that paliperidone, the active metabolite of risperidone, has two long acting injectable formulations, with administration of one dose every 4 weeks, and after

90

120

CGI-S

stabilization, the drug may be administrated every 12 weeks. She agreed to be initiated on paliperidone long acting after stabilization of acute symptoms. The patient was smoking 30 cigarettes daily, with a value of 9 pack-years. She fulfilled the DSM-5 criteria for nicotine use disorder and accepted treatment for this condition. She received nicotine replacement therapy, but she declined the invitation to join a group therapy focused on abstinence. Her ECG was normal, as were chest X-ray, cerebral CTscan, CBC and serum biochemistry panel. The toxicology exam was also negative. Table 3. Psychologic evaluations during the third patient’s initial visit Clinical scale

Results

PANSS

88

CRDPSS

14

GAF

35

CGI-S

5

FTND

9

Therapeutic challenges analysis: This patient is still in the early phase of disease, as her diagnosis of schizophrenia was just established. She met the necessary criteria for this diagnosis- time (more than 6 months including pre-hospitalization period of active symptoms), clinical manifestations, functionality, and differentials. The challenge is to select a treatment

31

regimen that could be more readily accepted by a young and active person (she has to travel often because she has contracts with different enterprises), while targeting both schizophrenia and nicotine addiction symptoms. One advantage in this case is the insight of the patient and her willingness to continue the treatment. She understood the therapeutic options her psychiatrist presented, and she has chosen the treatment which allows her less time for administration and medication-supplying procedures (visits to her GP, treating psychiatrist, and local pharmacy). Therefore, paliperidone was considered the most appropriate option for her, and after stabilization with oral medication, she was switched on paliperidone palmitate (PP1M) 100 mg monthly as maintenance dose for 4 months, and paliperidone palmitate (PP3M) 350 mg every 3 months after 4 months. Regarding her nicotine use disorder, she received 25mg/16 h nicotine patches and nicotine spray administered prn, in case of withdrawal symptoms, with gradually dose reduction, and termination after 3 months. The nicotine spray was recommended because the patient is a heavy smoker, and because she had no asthma, chronic sinusitis, or other related diseases. Paliperidone is not a substrate for CYP1A2, therefore its plasma concentrations are

not expected to be modified by cigarette smoking, in case substance use disorder treatment fails. Follow-up visits: The evolution of psychotic symptoms was favorable, as reflected in the PANSS and CRDPSS scores, which decreased with 40% and 65%, respectively. The favorable trend maintained even after switching on the long-acting formulae (PP1M and PP3M). The slower rate of improvement after day 36 is related to the stabilization of the clinical status, which is a condition for switching on long-acting antipsychotic formula. The patient reported that she could return to her job after 6 weeks of treatment and her professional performances were fair. The cigarette use declined during the first 4 weeks, but she admitted she smoked during nicotine replacement therapy and after its discontinuation. Therefore, after 11 months her FTND score reflected a moderate dependence. She refused a new trial of nicotine replacement therapy and counselling sessions, as she states “smoking is not a problem for me anymore… I’m only smoking when I’m feeling nervous”. Her BMI increased with 3.5% compared to baseline, but no significant alterations in plasma lipids, blood glucose, hepatic enzymes or QTc were reported.

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

Score

80 60 40 20 0 0

14 PANSS

21

28

36

CRDPSS

CONCLUSIONS In young patients who experience first episode of psychosis establishing therapeutic relationship could be a difficult challenge. Communication between the

32

66 GAF

96

127 CGI-S

156

248

337

FTND

psychiatrist and the patient is crucial in order to assure an adequate level of therapeutic adherence. The psychiatrist should consider the lifestyle of the patient, her psychological resources and specific needs, and to

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine formulate the most appropriate therapeutic strategy. In this case a long-acting formula of an atypical antipsychotic was preferred because of the active lifestyle of the patient, and her expressed preference for a treatment which could be easily administered. The treatment for nicotine dependence has been a challenge, as the patient did not quit completely smoking, but only diminished it. Paliperidone could be useful in patients who smoke because it is not metabolized through CYP1A2, and its plasma concentrations remain stable even if this isoenzyme gene is induced by the polycyclic aromatic hydrocarbons of the tobacco smoke [34].

Abreviations list AUDIT = Alcohol Use Disorders Identification Test BMI = Body mass index CBC = Complete blood count CGI-S = Clinical Global Impression- Severity CRDPSS= Clinician-Rated Dimensions of Psychosis Symptoms Severity CUDIT-R = Cannabis Use Disorders Identification Test – Revised EuroQoL 5D-3L= EuroGroup Quality of Life Scale FTND = Fagerstrom Test for Nicotine Dependence GAF = Global Assessment of Functioning PANSS = Positive and Negative Syndrome Scale PP1M = paliperidone palmitate with monthly administration PP3M = paliperidone palmitate administered every 3 months prn = pro re nata Disclaimer The author was speaker for Servier, Eli Lilly and BristolMyers, 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 effectiveness of antipsychotic medications in patients who use or avoid illicit substances: results from the CATIE trial. Schizophr Res 2008;100(1-3):39-52. 2. Mueller-Vahl KR, Emrich HM. Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother 2008;8(7):1037-48. 3. Foti DJ, Kotov R, Guey LT, Bromet EJ. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalization. Am J Psychiatry 2010;167:987-993. 4. Weinstein A, Brickner O, Lerman H, et al. A study investigating the acute dose-response effects of 13 mg and 17 mg delta 9-tetrahydrocannabinol on cognitive-motor skills, subjective and autonomic measures in regular users of marijuana. J Psychopharmacol 2008;22:441-51. 5. Lejoyeux M, Basquin A, Koch M, et al. Cannabis use and dependence among French schizophrenic inpatients. Front Psychiatry 2014;5:82. 6. Weiser M, Noy S. Interpreting the association between cannabis use and increased risk for schizophrenia. Dialogues Clin Neurosci 2005;7(1):81-85. 7. Ujike H, Takaki M, Nakata K, et al. CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 2002;7(5):515-8. 8. Manzella F, Maloney SE, Taylor GT. Smoking in schizophrenic patients: A critique of the self-medication hypothesis. World J Psychiatry 2015;5(1):35-46.

9. Picciotto MR, Corrigall WA. Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci. 2002;22:3338–3341. 10. Theng YM, Wahab S, Wahab NA, et al. Schizophrenia and nicotine dependence: What psychopharmacological treatment options are available for the duo perturbations? Curr Drug Targets 2017; doi:10.2174/ 1389450118666171017163741. 11. Chen J, Bacanu SA, Yu H, et al. Genetic relationships between schizophrenia and nicotine dependence. Sci Rep 2016;6:25671. 12. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: Results from the Epidemiologic Catchment Area (ECA) study. JAMA 1990;264:2511-18. 13. Koob GF, Roberts AJ. Brain reward circuits in alcoholism. CNS Spectrums 1999;4:23-37. 14. Morris CP, Baune BT, Domschke K, et al. KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence. Dis Markers 2012;33(4):163-170. 15. Zuo L, Wang KS, Zhang XY, et al. Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism. Human Genetics 2013;132:73543. 16. Wang K, LuoX, Zuo L. Genetic factors for alcohol dependence and schizophrenia: common and rare variants.

33

Austin J Drug Abuse Addict 2014;1(1):3. 17. Gjerden P, Brammes JG, Slordal L. The use and potential abuse of anticholinergic antiparkinson drugs in Norway: a pharmacoepidemiological study. Br J Clin Pharmacol 2009;67(2):228-233. 18. Fisch RZ. Trihexyphenidyl abuse: therapeutic implications for negative symptoms of schizophrenia? Acta Psychiatrica Scandinavica 1987;75(1):91-94. 19. Nachkebia N, Mchedlidze O, Effects of trihexyphenydil, the phencyclidine, on neocortical and activity in sleep-waking cycle. 2009;(169):81-7.

Chkhartishvili E, et al. structural analog of hippocampal electrical Georgian Med News

20. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Washington DC, 2013. 21. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for Schizophrenia. Schizophrenia Bulletin 1987;13(2):261-276. 22. Babor TF, Higgins-Biddle JC, Saunders JB, Monteiro M. The Alcohol Use Disorders Identification Test : Guidelines for use in primary care, 2nd edition. Geneva, World Health Organization, 2011. 23. Pomerleau CS, Majchrezak MI, Pomerleau OF. Nicotine dependence and Fagerstrom Tolerance Questionnaire: a brief review. J Substance Abuse 1989;1:471-7. 24. Swofford CD, Kasckow JW, Scheller-Gilkey G, Inderbitzin LB. Substance use: a powerful predictor of relapse in schizophrenia. Schizophr Res 1996;20:145-151. 25. Wang LJ, Ree SC, Huang YS, et al. Adjunctive effects of

34

aripiprazole on metabolic profiles: comparison of patients treated with olanzapine to patients treated with olanzapine to patients treated with other atypical antipsychotic drugs. Prog Neuropsychopharmacol Biol Psychiatry 2013;40:260-6. 26. Adamson SJ, Kay-Lambkin FJ, Baker AL, et al. An improved brief measure of cannabis misuse: the Cannabis Use Disorders Identification Test-Revised (CUDIT-R). Drug Alcohol Depend 2010;110(1-2):137-43. 27. Balestroni G, Bertolotti G. EuroQoL-5D (EQ-5D): an instrument for measuring quality of life. Monaldi Arch Chest Dis 2012;78(3):155-9 28. van Reenen M, Janssen B. EQ-5D-5L User guide, 2015. Accessed at https://euroqol.org/wp-content/uploads/2016/ 09/EQ-5D-5L_UserGuide_2015.pdf in 30/04/2018. 29. Geodon- Summary of Product Characteristics. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/ 2009/020825s035,020919s023lbl.pdf in 30/04/2018. 30. Risperidone – Summary of Product Characteristics. Accessed at https://www.medicines.org.uk/emc/product/ 4547 in 30/04/2018. 31. Goodnick PJ. Ziprasidone: profile on safety. Expert Opin Pharmacother 2001;2(10):1655-62. 32. Sherman BJ, McRae-Clark AL. Treatment of cannabis use disorder: current science and future outlook. Pharmacotherapy 2016;36(5):511-535. 33. McLean MJ. Clinical pharmacokinetics of gabapentin. Neurology 1994;44(Suppl.5):S17-22. 34. Hukkanen J, Jacob P III, Peng M, et al. Effect of nicotine on cytochrome P450 1A2 activity. Br J Clin Pharmacol 2011;72(5):836-838.

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

ORIGINAL ARTICLES

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

Patient reported outcome measures and joint replacement Alexandra Sopu 1

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

OBJECTIVE The questionnaire or interview used to gather information is referred to as measures, tools or instruments. Commonly, there are two types of PROM questionnaires. Generic PROMs, which are used to assess generally across numerous diseases in a broad spectrum perspective, and condition-targeted PROMs that are developed for a particular medical condition [1]. This paper critically examines patient-reported outcome measures (PROMs) and joint replacement from a broad perspective.

METHODS Most PROMs measure aspects such as Quality of Life (QoL) that is fulfilment of needs and impact of restrictions on emotional wellbeing, and drug side effects. Others include symptoms/impairments that is pain and depression, functioning during disability,

locomotion, daily living activities and personal care. In addition, Health Related Quality of Life (HRQoL), health status, general health experience and rating of healthcare facilities and operations [2]. Analysis of PROMs is usually conducted using approved analysis tools for proper interpretation such as Rasch analysis or confirmatory factor analysis. PROMs are often validated using particular tools and methodologies, such as Linguistic validation for population’s differences and others to ensure that they are effective in gathering relevant information. Patient grouping too

1

Royal Stoke University Hospital, UK

35

should be reliable and conform to ideal scaling, development and psychometric standards. Examples of renowned PROMs include the SF-36 Health Survey, EuroQol (EQ-5D), SF-12 Health Survey, Profile, Quality of Well-Being Scale, Health Utilities Index and Consumer Assessment of Healthcare Providers and Systems (CAHPS) [3]. These are examples of generic PROMs. Ideal examples of condition-targeted PROMs include Adult Asthma Quality of Life Questionnaire (AQLQ), Seattle Angina Questionnaire (SAQ), Kidney Disease Quality of Life Instrument, Epilepsy Surgery Inventory, National Eye Institute Visual Functioning Questionnaire, Ankylosing Spondylitis Quality of Life questionnaire (ASQoL) and Migraine Specific Quality of Life (MSQOL) [4]. With the advent of PROMs and the role they play in medicine, individual countries such as England’s National Health Service (NHS) have made it a prerequisite for particular surgical operations to provide non-compulsory PROMs before the procedure and following the procedure (ideally three months after procedure); these include hip, knee and other joint replacements, hernia surgery and varicose vein surgeries. England used the PROMs to assess the effectiveness and effects of the surgeries on its national a patients and deduced that the frequency of operations/ surgeries should be maintained. Due to their efficiency and importance in quality health service, PROMs are updated monthly as a policy in most developed countries. PROMs are currently used to grade health facilities with scores parameters according to patient satisfaction. In England, HES (Hospital Episode Statistics) use PROMs to rate hospital services across the state and their use are gaining impetus across the global health sector [5]. There is a general dataset that PROMs include in questionnaires; Generic and condition-specific measures of self-reported health status. Patientidentifiable information included in the PROMs, which is used for relation purposes, is strictly not availed for wider analysis, due to confidentiality. Additional questions inquiring into the patient’s health status include whether they have antecedent conditions such

36

as diabetes or arthritis [6]. The outcomes of a health procedure can be ascertained from the patient’s perspective, through self-reported symptoms and functional status, by comparing and determining the differences in data between the pre-operative and post-operative PROMs. However, the PROMs are not compulsory for patients to fill. More so, consent from patients who participate in the PROMs has to be sought before their data is used for analysis [7]. The patient’s identifiable information is only used to electronically fetch for his or her National Health Number in government database during analysis of PRO data. The rest of the data is transferred to a database, such as the HES in England, from where the PRO analysis consequently occurs. Pre-operative and post-operative PROMs from the same patients are identifiable in the dataset since they possess similar serial numbers from which they are linked. After analysis, data in the HES is pseudonymised before it is made available to the public for download for analysis and scrutiny and hospital/clinical scoring [8]. Other uses of PROMs include: allows managers and clinicians to benchmark their own performance with regards to others, they are used for research purposes and draw relations to effectiveness and cost-effectiveness of health procedures to care. It is also used to compare implications of presence and absence of the treatment or rather alternative treatment, searching for healthcare inequalities, and research on relationship between pre-existing health and social conditions and risk of deterioration after procedure. Other than the anonymised data that is availed to the public for scrutiny and further personalized analysis, PROMs can be availed to service providers of patient care through provider level extract only with patient’s approval. More so, extract service of particular requested data sub-subs by customers can be availed at an administrative fee depending on complexity of the request [9]. There are variant methodologies in which PROMs are used to score and rate health facilities. Some examples of standardised PROMs that are analysed by specific methodologies include the five-dimensional descripttive system EQ-5DTM health questionnaire and the

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine EuroQol Group’s visual analogue scale (EQ-VAS) [10]. Most PROMs used for joint replacement procedure, such as hip and knee replacement, are conditiontargeted. Most common post-operative PROM questions include an inquiry into the patient’s health status after procedure such as their state of mobility or other operative complications.The EQ-5D is a simple, generic measure of health for clinical and economic appraisal [11]. The PROM with single indexing values for health status and an unsophisticated descriptive profile is widely used in economic and clinical evaluation of healthcare and in health surveys of populations. The EQ-5D provided in joint replacements contains a descriptive system with issues on mobility, discomfort /pain, self-care e.g. washing and dressing, anxiety and depression and normative activities e.g. work, housework, study, family or leisure activities etc. Each of these five dimensions has several level statements which the patients tick against the most appropriately descriptive of his or her condition. Each dimension has a score digit for each level statement hence every patient has five string scores thence the connotation ‘5D’ [12]. Using a formula, the five string score are converted into a singular summary index, referred to as the ‘social preference weights’ assigned to each statement in the dimensions. The value of full health is assigned to value one (or state 11111, in EQ-‘5D’) from which reference is sought. EQVAS index scores range from 0 to 100, least and best health respectively. The patients mark, within the range, his or her relevantly perceived state of health [13]. Other PROMs used in England for joint replacement include the condition-targeted Oxford Knee Scores (OKS) and Oxford Hip Scores (OHS). The PROMs contain twelve multiple choices, assigned later with scores, about the patients state of mobility, pain, ease of joint movement, ease of partaking normal chores and activities. The scores in the PROM are such that the less the scores the poorer the patient’s condition with zero for greatest severity. For each multiple choice, 4 is the greatest score for best patient condition. Hence, the total score for every patient in the PROM have a maximum limit of 48 for ideal patient

condition while zero indicates worst severity [14]. Postoperative Recovery Profile in condition-targeted PROMs with recovery specific questions is used to determine the quality of joint replacement procedures in health facilities and person-centeredness of clinical services [15]. This is common procedure for persons with arthritis. The USA, Norway, Denmark, Sweden, New Zealand, Canada and England operate 77-153 and 66-143 hip and knee replacement per 100 people in prevalence rate. With advances in biomedical operations and medication intended to shorten or alleviate the post-operative recovery period especially since recovery takes place in the vicinity patient’s home, PROMs are significant and effective method of evaluating these procedures on patients [16]. Traditionally, assessment of joint replacement were assessed by drawing connections between different intervention methods such as variant joint replacement procedures. The types joint replacement include prosthetics, implants, surgical techniques. Relations of these types of joint replacements were drawn to revision rates, complications and postoperative medications. With increased impetus on the use of PROMs, this evaluation is augmented thus allowing for an improvement of healthcare services [17]. While EQ-5D, EQ-VAS, OHS and OKS are important instruments in PROMs, they do not comprehensively provide adequate information important of the requisite important aspects that allow for quick recovery. Recovery-Specific Instruments have been devised to bridge this gap. Swedish healthcare PRP (Post-operative Recovery Profile) PROMs on joint replacement patients has comprehensive data on patient’s problems, medical interventions and outcomes of treatments such that it has gained global recognition [18]. The Swedish methodologies of PROMs and their analytical tools are being replicated across the developed world since they include measurements on different groups of patients and can be altered for different purposes in the variant PROM areas [19]. The PRP has additionally incorporated global-, dimensional- and item levels in scoring not only for sole patients but more so for every group of patients. The global score is significant in deducting the recovery rate of a population-based profile.

37

An embodiment of a PROM is one in Sweden that was conducted on joint replacement (hip and knee) operations patients whereby the PROM questionnaire was provided the day before the procedure, three days after the procedure and one month later after the procedure. The peri-operative variables included sex, surgical procedure, American Society of Anaesthesiologists’ (ASA) guided physical classification, age, duration of surgery, length of postoperative stay, blood loss and marital status [20]. PRP was included into the PROM and 19 constructs collected included physical functions and symptoms, psychological, social and activity measures. Response category for assessments, from which scores would be assigned, included: none, mild, moderate, and severe symptoms. Recovery profiles for every individual and group on each item and dimension were provided by the PRP. The 19 item responses account for a detailed individual response profile over the recovery dimensions and the item frequency distributions reports on the item response profile of the group [21]. Fully recovered score in the group ideally would have indicator score of 19, 15-18 indicator sum for almost full recovered , 8-14 indicator sum for partly recovered , 7 indicator score for slightly recovered and below 7 not at all recovered. Using methodological tools of frequency distribution analysis, out of the 75 patients who voluntarily participated in the PROMs assessment after undergoing primary knee and hip replacement due to osteoarthritis, 23 patients indicated the same level of pain on both the 3 day and one month follow-up [22]. The remainder showed a decrease in pain after the one month follow-up. Significance in RP values was used to assess the systematic change in recovery of groups. Individual variations within groups and between groups can thereafter be scrutinized.

RESULTS Besides pain, other score categories included muscle weakness and re-establishment of everyday life. On physical symptoms and function’s frequency distribution, for three days the frequency for the none assessment ranged between 62% and 7% while one month later, 72% to 25% [23]. Systematic group

38

changes, unchanged assessments, individual variability in all dimensions were analysed. For global level assessments for day 3, 11(score for partly recovered) was the median while 13(score for partly recovered) was median after one month follow-up [24]. This information was used to ascertain whether the surgical intervention or rehabilitation in the joint replacement procedures and therapy were appropriate for individual patients or for groups of patients [25]. The PROMs data was also used to identify particular risks in particular groups (categorized by demographics) associated with the hip and knee replacements. While the analysis of the PROMs indicated homogenous recovery changes in the groups, certain assessments were unchanged for both the 3day and one month assessment; muscle weakness and pain. However, great individual variations on the two categories were found to result to this. Using this data, Sweden was able to determine the best treatment and therapy techniques to render to joint replacement patients for a quick recovery [26]. It was also found out that a standardized treatment method for groups that exhibited great variations in individuals was not necessarily the remedy to the situation. Extensive use of PROMs in Sweden has allowed the country to increase its knowledge on the best healthcare practices hence an improvement in their healthcare delivery and high score/ratings of their hospitals internationally [27]. Based on the PROMs Swedish healthcare system is able to establish expected recovery within junctures in recover period. This can be sued to grade other treatments as set-backs and gains with regards to the expected outcome and therefore facilitate the overall recovery and create awareness of the recovery process. PROMs have also been used to enhance, as a clinical tool, the manner of clinical relationship and contact in follow-up visits between physicians, nurses and their patients. In joint replacement, resumption of normative daily activity and functionally capacity were usually found to be unsatisfactory. The level of satisfactions was greatly influenced by

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine pain, mental functioning and fulfilled expectations regarding postoperative pain [28]. The psychological dimension rated higher for those who concomitantly scored 13 in physical functioning and pain. Longer period assessment such as after 6 months have been shown to record greater recovery scores. Nonetheless, the Swedish HealthCare is keen on shortening the recovery period for joint replacement thus the focus of PROMs of short recovery periods. For long period PROMs, categories of assessment such as Quality of Life (QoL) and Health Related Quality of Life (HRQoL) are incorporated [29]. These PROM scores by patients who visit variant clinical and hospital facilities allow for the grading of hospitals/clinics too. Using relevant and respective methodological tools, scores from patients attended in various hospitals/clinics can assist in the national grading and scoring of hospitals. This initiates competition for better healthcare provision

concurrently improving the healthcare of a country. Data has established that 70% of countries with esteemed healthcare systems have national policies on the use of PROMs in their HealthCare facilities.

CONCLUSION Facilities that exhibit consistently low scores could be sanctioned and enquiries instigated into their medical practices. This allows for the monitoring of healthcare [30]. PROMs therefore are ideal instruments for the improvement of healthcare provision. They assist in determining the treatment and medication that ideal for patients in quick recovery mode. They create a patient-centred healthcare system. Hospital ranking/scoring on the other hand allow for benchmarking of clinical performances thus generally improving the provision of healthcare in a country [31].

References: 1. Doward, LC & McKenna, SP 2004, Defining PatientReported Outcomes. Value in Health 7(S1): S4-S8. 2. Fayers, P & Hays, RD 2005, Assessing Quality of Life in Clinical Trials: Methods and Practice. Oxford: Oxford University Press. 3. Fung, CH & Hays, RD 2008, Prospects and challenges in using patient-reported outcomes in clinical practice. Quality of Life Research 17: 1297-302

treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels, Control Clin Trials. 25(6):535-52. 11. Health & Social Care Information Center, 2008, Monthly Patient Reported Outcome Measures (PROMs) in England.[www.chks.co.uk/index.php?id=24] 12. Clancy, C & Collins, FS 2010, Patient-Centered Outcomes Research Institute. Sci Transl 2(37):37cm18

4. McKenna, SP & Doward, LC 2004, Integrating PatientReported Outcomes. Value in Health 7(S1): S9-S12.

13. Keller RB 2003, Outcomes research in orthopedics. J Am 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 outcomes research. J Surg Orthop Adv 17(3):200.

6. Tennant, A & McKenna, SP 2005, Conceptualizing and defining outcome. Br J Rheumatol 34:899-900. 7. Kennedy, D.M., Stratford, P.W., Riddle, D.L., Hanna, S.E. & Gollish, J.D 2008, Assessing recovery and establishing prognosis following total knee arthroplasty. Physical Therapy 88 (1) 22-32. 8. Valderas, JM & Alonso, J 2008, Patient reported outcome measures: a model-based classification system for research and clinical practice. Qual Life Res. 17: 1125-35.

15. Hawker G., et al. 2008, Health-related quality of life after knee replacement. J Bone JointSurg Am 80(2):163. 16. Chang, CH 2007, Patient-reported outcomes measurement and management with innovative methodologies and technologies. Qual Life Res 16(Suppl 1):157. 17. Clancy, CM 2011, Commentary: precision science and patient-centered care. Acad Med 86(6):667.

9. Wiklund, I 2004, Assessment of patient-reported outcomes in clinical trials: the example of health-related quality of life, Fundam Clin Pharmacol. 18(3):351-63.

18. Clancy, CM & Eisenberg, JM 2008, Outcomes research: measuring the end results of healthcare. Science 282(5387):245.

10. Willke, RJ., Burke, LB & Erickson, P 2004, Measuring

19. Rolfson, O 2010, Patient-reported outcome measures

39

and health-economic aspects of total hip arthroplasty. Department Of Orthopaedics, Institute of Clinical Sciences. Gothenburg: Sahlgrenska Academy, University of Gothenburg. p. 60. 20. Dawson J, et al 2010, The routine use of patient reported outcome measures in healthcare settings. BMJ 340:c186. 21. Wu AW, et al. 2010, Adding the patient perspective to comparative effectiveness research. Health Aff (Millwood) 29(10):1863. 22. Dawson J, Fitzpatrick R, Carr A, Murray D 2006, Questionnaire on the perceptions of patients about total hip replacement. J BoneJoint Surg Br 78-B(2):185e90. 23. Field RE, Cronin MD, Singh PJ 2008, The Oxford hip scores for primary and revision hip replacement. J Bone Joint Surg Br 87(5):618e22. 24. Husted, H., Holm, G. & Jacobsen, S 2008, Predictors of length of stay and patient satisfaction after hip and knee replacement surgery. Fast-track experience in 712 patients. Acta Orthopaedica 79 (2) 168–173. 25. Kärrholm, J 2010, The Swedish Hip Arthroplasty Register (www.shpr.se). Acta Orthopaedica 81 (1) 3–4 26. Salmon, P., Hall, G.M., Peerbhoy, D., Shenkin, A. & Parker, C 2001, Recovery from hip and knee arthroplasty:

40

Patients' perspective on pain, function, quality of life, and well-being up to 6 months postoperatively. Archives of Physical Medicine and Rehabilitation 82 (3) 360-366. 27. Knutson, K. & Robertsson, O 2010, The Swedish Knee Arthroplasty Register (www.knee.se). The inside story. Acta Orthopaedica 81 (1) 5–7. 28. Allvin, R., Ehnfors, M., Rawal, N., Svensson, E. & Idvall, E. 2009, Development of a questionnaire to measure patientreported postoperative recovery: content validity and intrapatient reliability. Journal of Evaluation in Clinical Practice 15, 411-419 29. Jones, C.A., Beaupre, L.A., Johnston, D.W. & SuarezAlmazor, M.E 2007, Total joint arthroplasties: current concepts of patient outcomes after surgery. Rheumatic Disease Clinics of North America 33 (1) 71-86. 30. Vissers, M.M., de Groot, I.B., Reijman, M., Bussmann, J.B., Stam, H.J. & Verhaar, J.A 2010, Functional capacity and actual daily activity do not contribute to patient satisfaction after total knee arthroplasty. BMC Musculoskeletal Disorders 11, 121 31. Chang RW, Pellisier JM, Hazen GB 2005, A costeffectiveness analysis of total hip arthroplasty for osteoarthritis of the hip. JAMA 1996;275(11):858e65.

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

ORIGINAL ARTICLES

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

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

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

Physical activity is a major and potentialy modifiable component of life style, which may be able to highly influence the risk of main cancers. Hence, there are convincing evidence that an important benefit may be derived concerning risk reduction in endometrial cancer, colorectal cancer, breast cancer, prostate cancer, lung cancer and ovary cancer. It is estimated that in Europe in 2008 between 150000 and 300000 cases of cancer could have been prevented only by the way of maintaining a resonable level of physical effort in general population.[1] A series of convincing observational data suggest that regular physical activity, be it ocupational type or recreational type, protects against colorectal cancer (CRC)[1,2]. Around 60 studies

have been published till 2010 concerning the issue of physical activity and CRC.[2] A metaanalysis that included 21 studies stated a significant reduction of CRC risk by 27% in the group of subjects that performed vigurous physical activity as comparing with the group of sedentary subjects (RR 0.73, 95% CI 0.660.81).[3] The mechanism that may provide an explanation for the

1

Carol Davila University Central Emergency Military Hospital, Bucharest 2

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

Titu Maiorescu University, Bucharest

41

relative protection of physical effort is currently unknown. There are no interventional type studies published yet to support the role of regular physical effort as preventive method in CRC. In 2007 the results of a cohort study (Nurses’ Health Study) has been published that enrolled 80,000 female subjects from 1986 with a 16 years follow-up. There have been diagnosed approximately 500 cases of CRC. A multivariate analysis that controlled the confounding factors represented by other risk factors for CRC concluded that there was a proportionate reversed relationship between physical effort and distal colonic cancer and, to a lesser extent, with proximal colonic cancer. Women situated in the highest percentile of recreational physical activity had a reduction of distal CRC risk by half as compared with women situated in the lowest percentile (RR=0.54, 95% CI 0.34-0.84). Risk reduction did not vary with body mass index (BMI), although former studies had suggested that physical activity had the greatest impact on CRC only in high BMI subjects. The level of physical effort to produce prophylactic benefits may be only minimal, as this study demonstrated. As such, even an hour of slight walking a week may reduce the risk of CRC by 31% (RR=0.69, 95% CI 0.45-1.03) as compared with women who do not report any kind of physical activity. This protective effect of slight walking reached a plateau at 2 hours a week (RR 0.64, 95% CI 0.411.00) 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 0.171.05). Furthermore, 4 hours a week of moderate/ vigorous physical effort may reduce the risk of CRC by 44% comparing with 1 hour a week (RR= 0.56, 95% CI 0.33-0.94). Physical activity lessened

42

the risk of CRC regardless of the impact on BMI: this idea may imply that physical activity protects against CRC by a mechanism independent of that involved in resolution of obesity. The protective effect of physical effort validates at distance. The actual reduction of CRC risk is considerable only after several years. In conclusion, the authors of this study suggest that even minor physical effort may derive benefit on CRC risk reduction. Several mechanisms have been proposed. Thus, physical activity regulates energetic balance and intervenes in reduction of hyperinsulinism and peripheral resistance to insulin. Physical activity may intervene also through anti-inflammatory mechanisms. Moreover, the positive effects of physical effort may also be explained by reduction of obesity in spite of the data that demonstrated that physical activity may reduce the risk of CRC independent of the effect on obesity. Another proposed mechanism involves accelerating the peristalsis which reduces the contact time between intraluminal carcinogens and colonic mucosa. As a matter of fact, it is well known data that physical active individuals are more prone to sun exposure for longer periods of time which facilitates production of vitamin D that is associated with lessening the risk of CRC.[4] Figure 1: Mechanisms involved in protective effect of physical effort on colorectal cancer risk

An epidemiologic study published in 2008 (NIH-AARP Diet and Health Study) shows interesting observations regarding the periods of an individual life when the

Vol. CXXI • No. 2/2018 • August • Romanian Journal of Military Medicine physical effort has the utmost impact on the risk of CRC. Thus, if the physical activity is performed in the age group 15-30 years the impact on CRC risk reduction will be minimal; on the other hand, if the physical activity is performed in the age group 30-39 years or throughout the whole life of an individual the reduction of CRC life-time risk will be maximal.[5] Sedentarism is a globally important public health issue, especially in developed countries, in women, in old people and in low income individuals. Lack of physical activity is responsible of the increase in mortality rates especially from diabetes mellitus and heart diseases. To a comparable extent physical activity of moderate and vigorous intensity is associated with certain benefits regarding health status, including reduction of obesity risk, cardiovascular risk, stroke risk, risk of some types of cancers and decreasing in global mortality rate. Physical activity increases the probability to cease smoking, delays cognitive decline in old individuals, alleviates the adverse effects of stress, anxiety and depression. A study published in 2016 regarding the issue of physical activity status in the group of more than 50 years old individuals in USA the date are worrisome: 27% do not report any kind of physical activity outside working place in the last month; the prevalence of inactivity increases with age, reaching 35.3% in age group after 75 years; sedentarism is more prevalent in women then in men, in Afro-Americans then in Caucasians. Also, the prevalence of inactivity is decreasing with increasing in educational level and with decreasing in BMI.[6] Lack of physical activity is the main cause of CRC being responsible of 14% of cases of CRC in USA; 12% of cases may be attributable to western diet, 12% to lack of daily administration of aspirin and 8% may be related to a family history of CRC.[6] Sedentarism, especially that kind related to spending time in front of TV, is independently associated with increasing CRC risk. Hence, if one spends 9 hours in front of TV, as comparing with 3 hours or less, the risk of CRC will rise significantly by a RR=1.61 (95% CI=1.142.27).[5] The relationship between physical activity, seden-

tarism and BMI is not to be changed even if one may exclude the contribution of age, race, family history of CRC, smoking and western diet.[6] Several studies shows contradictory results concerning the issue of rectal localization of CRC. Cancer Prevention Study II indicates that moderate/vigorous physical activity in men and in women reduces the risk of rectal cancer by 30 %.[7] Many cohort studies did not find any kind of association between physical activity and rectal localization of CRC.[8,9] A meta-analysis published in 2010, which included 20 studies on physical activity and colorectal benign adenoma, concluded that there was 16% reduction of the risk of these benign precursors of CRC if we compared active population with less active populations. Risk reduction was even more significant if we took into consideration polyps bigger then 1cm (31% risk reduction). It has been demonstrated in that way that physical effort might decrease the risk of CRC earlier in the stage of precursor lesions of oncogenic process.[10] The role of physical activity as a protection factor in CRC is hardly known in general population. A study developed in USA that included 2000 subjects showed that only 15% of them are aware of this benefit of physical activity.[6] One similar study from Europe that included 21 countries indicated a 30% level of knowledge concerning this topic.[11] Several studies stated also that there was a close connection between the level of information concerning prophylactic benefits of physical effort in CRC and the increasing of the motivational status to produce life style changes that, in the end, will decrease the prevalence of CRC.[12,13,14] Physical exercises represent a form of human activity that may benefit health more then it may inflict side effects. The most common side effects are musculoskeletal injuries. The least common side effects (sometimes more severe) are: cardiac arrhythmias, heart arrest and myocardial infarction. Generally, we may appreciate that the potential benefits of physical exercises highly surpass the potential risks. Moreover, it is considered that it is unnecessary to screen for coronary diseases prior to initiating physical activity if

43

the subject was asymptomatic and included in the low cardiovascular risk group. One may consider mandatory that all healthy adult individuals to include in their life style moderate or vigorous physical exercises. The majority of authors agrees that the highest health benefits are provided by 150 minutes a week of moderate physical activity or by 75 minutes a week of vigorous physical activity. Nevertheless, adults that have a limited physical activity capabilities should remain active because it has been noticed that even if a modest amplitude of physical effort is exercised regularly health benefits will be significant. Another epidemiologic studies suggest that physical activity may influence not only the risk of CRC but also it may prevent the recurence of CRC after curative surgical treatment. All the data available resulted from observational type of studies; randomized and interventional studies are not published. Nevertheless, American Society of Oncology (ASCO) recently recomended that the surviveours of CRC should maintain an optimal weight, should perform daily physical exercises and should follow a healty diet.[14] Futher on, there are some interesting results of a study published in 2006 that included 832 patients suffering from CRC stage III surgicaly treated and that followed a program of chemotherapy. It has been demonstrated that moderate physical activity perfomed for at least 300 minutes a week has increased the free disease interval with 45% and has improved by 2936% the mortality rate of any cause.[16] The benefits have been dose dependent.

In an observational study (unpublished data) that I have conducted in 2016, concerning the topic of CRC and its relationship with diabetes mellitus and other risk factors an important conclusion has been drawn. A multivariate analisys in which the most acknowledged CRC risk factors have been included showed the statistical significance (p