Founded 1897 • New Series Romanian Journal of Vol. CXXI • No. 3/2018 • December Military Medicine
REVISTA DE MEDICINĂ MILITARĂ
• The history of military medicine in the last 100 years • Complications of systemic lupus erythematosus: A review • Heart failure with preserved ejection fraction: A review • Gut microbiota – new insight in colorectal cancer pathogenesis • Diagnosis and management of cases with deep infiltrating endometriosis affecting the urinary tract • The strategic importance of vaccination for national defense and security • The role of metatarsophalangeal joint arthroscopy in hallux rigidus treatment: technique and early results • Women’s facial attractiveness nowadays – results from analysis of public figures • The semi-centenary of a prestigious medical unit: Military-Medical Research Center • Black hairy tongue due to antibiotic intake • Atypical case of achalasia
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Editorial Board of Romanian Journal of Military Medicine Under the patronage Romanian Association of Military Physicians and Pharmacists Carol Davila University of Medicine and Pharmacy, Bucharest, Romania Honorary Editor Acad. Victor Voicu MD, PhD Editors-in-Chief Florentina Ioniță Radu MD, PhD, MBA Dan Mischianu MD, PhD Executive Editors Daniel O. Costache MD, PhD, MBA Victor L. Purcărea PhD, MBA Associate Editor Mariana Jinga MD, PhD, MBA Redactors Raluca S. Costache MD, PhD, MBA – Bucharest Mihail S. Tudosie MD, PhD – Bucharest Editorial Assistants Ioana Oprea MD Cristina Solea Technical Secretary Oana Ciobanu Ionuț Olteanu Publisher Carol Davila University of Medicine and Pharmacy Publishing House
International Editorial Board Natan Børnstein (Israel) Gerard Roul (France) C. Ionescu Târgovişte (Romania) Cris S. Constantinescu (UK) Erwin Santo (Israel) Radu Ţuţuian (Switzerland) Daniel Dănilă (USA) Adrian Săftoiu (Denmark) Shyam Varadarajulu (USA) Mihai Moldovan (Denmark) Ioanel Sinescu (Romania) Peter Vilmann (Denmark) Ioan Opriș (USA) Victor Voicu (Romania)
Scientific Publishing Committee Adrian Barbilian (Bucharest) Gabriel Constantinescu (Bucharest) Viorel Jinga (Bucharest) Anda Băicuş (Bucharest) Dan Corneci (Bucharest) Ovidiu Nicodin (Bucharest) Cristian Băicuş (Bucharest) Raluca S. Costache (Bucharest) Tudor Nicolaie (Bucharest) Andra Bălănescu (Bucharest) Dragoș Cuzino (Bucharest) Bogdan A. Popescu (Bucharest) Mircea Beuran (Bucharest) Mircea Diculescu (Bucharest) Emilian A. Ranetti (Bucharest) Ovidiu Bratu (Bucharest) Cosmin Dobrin (Bucharest) Corneliu Romanițan (Bucharest) Daciana Brănișteanu (Iași) Silviu Dumitrescu (Bucharest) Carmen A. Sîrbu (Bucharest) Dragoș Bumbăcea (Bucharest) Carmen G. Fierbințeanu (Bucharest) Ion Țintoiu (Bucharest) Marian Burcea (Bucharest) Cristian Gheorghe (Bucharest) Sorin G. Țiplica (Bucharest) Sofia Colesca (Bucharest) Liana S. Gheorghe (Bucharest) Daniel Vasile (Bucharest) Dumitru Constantin Dulcan (Bucharest) Mihai E. Hinescu (Bucharest) Dragoş Vinereanu (Bucharest) Ruxandra Jurcuț (Bucharest)
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Romanian Journal of Military Medicine, New Series, vol. CXXI, No 3/2018, December ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126
Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine
RJMM Founded 1897 • New Series Romanian Journal of Military Medicine Vol. CXXI • No. 3/2018 • December Edited by the Romanian Association of Military Physicians and Pharmacists.
Contents
EDITORIAL Paul Oprea The history of military medicine in the last 100 years 5 REVIEW ARTICLE Georgiana Iftimie, Anca Pantea Stoian, Bogdan Socea, Ion Motofei, Dragoș Marcu, Raluca S. Costache, Camelia Diaconu Complications of systemic lupus erythematosus: A review 9 Ruxandra N. Horodinschi, Anca Pantea Stoian, Dragoș Marcu, Raluca S. Costache, Camelia Diaconu Heart failure with preserved ejection fraction: A review 16 Mihăiță Pătrășescu, Petruț Nuță, Raluca S. Costache, Săndica Bucurică, Bogdan Macadon, Vasile Balaban, Andrada Popescu, Roxana Călin, Florentina Ioniță Radu, Mariana Jinga Gut microbiota – new insight in colorectal cancer pathogenesis 26 ORIGINAL ARTICLES C.B. Coroleucă, C. Berceanu, L. Brîndușe, D. Marcu, C.A. Coroleucă, Elvira Brătilă Diagnosis and management of cases with deep infiltrating endometriosis affecting the urinary tract 31 Viorel Ordeanu The strategic importance of vaccination for national defense and security 38 Ieronim O. Crișan The role of metatarsophalangeal joint arthroscopy in hallux rigidus treatment: technique and early results 45 Cristina T. Preoteasa, Sabina Iordache, Marina Imre, Paula Perlea, Ana Maria C. Tancu, Elena Preoteasa Women’s facial attractiveness nowadays – results from analysis of public figures 52 Viorel Ordeanu The semi-centenary of a prestigious medical unit: Military-Medical Research Center 57 CLINICAL PRACTICE Cătălina E. Lavric, Silviu V. Dumitrescu Black hairy tongue due to antibiotic intake 61 Andreea Grigore, Bianca Săndulescu, Alexandra Lulache, Andrada Popescu, Săndica Bucurică, Mihai Șotcan, Florina Vasilescu, Petruț Nuță, Mariana Jinga, Florentina Ioniță Radu, Daniel O. Costache, Raluca S. Costache Atypical case of achalasia 63
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ADMINISTRATIVE ISSUES Guidelines for authors 68
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Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine
EDITORIAL
The history of military medicine in the last 100 years xxx
Paul Oprea
The begining of the medical military service in first military hospitals were Gral Brig PAUL OPREA Romania is related to the set up of the public set up in addition to those in Chief of Romanian Army institutions with military regime: gendarmerie and Bucharest, the period Medical Directorate military subunits (pedestrians and riders), military between 1880 and 1900 being a period of massive firefighters, whose purpose was to provide sanitary construction. services. In addition to the Central Military Hospital in Due to the different evolution of Romanian regions, Bucharest, hospitals were built in Craiova, Piteşti, the history of military-medical structures was Galaţi, Focsani and the hospital from Iaşi was resized. different. Fortunately for the Romanian people, the beginning of the 20th century found the Romanian Army at a good The unification of the Romanian Principalities under level of organization, endowment and with enough the ruler Alexandru Ioan Cuza - modernist and good staff. administrator - was an important leap in the development of the medical assistance structures of In the Armed Forces, the medical service has the armies, with the increase, diversification and developed to a great extent: there are specialists in specialization of the military units. It is the time when surgery, internal medicine, dermatology, laboratory, battalion infirmaries grow in size, the number of etc. Hospitalization conditions are modern, both in the stationary beds for officers and troop’s increases, medical departments and in laboratories, the latter more doctors are employed and therapeutic methods being managed by well-trained medical staff. In this are diversified. period, there is a rise of military-medical professors, some of which turned out to be excellent specialists, The arrival of King Carol I, one of the founders of role models for the next generations. modern Romania, in the country, has generated progress and development of the medical-military With the general physician Carol Davila, the first network. command (planning / administration / coordination) structure of the Army's medical service appears. He is After the conquest of Romania's state independence, the first chief in the history of the current Medical the development of the institutions of the new state Directorate. under the leadership of Carol I and of a political class of liberal and nationalist orientation recorded a Having central activity as support, medical structures - momentum not yet encountered. Consequently, the infirmaries, hospitals - are standardized as structure,
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organization chart and endowment. as well as the therapeutic resources and the means of diagnostics diversified, the imaging (Rx) developed The period 1914-1916 until Romania's entry into war consistently. In these twenty years, hospitals in provided a partial modernization of the Army. Entry Romania (including the military ones) evolved, into World War I was an act of courage and sacrifice developed, offering diagnostic and treatment for all the services of the Army. The medical service methods similar to those available in Western Europe. was well prepared and managed to provide comprehensive health care in the operations theatres. Romanian medical education has matured through the Unfortunately, the Army's sanitary material conditions activity of the Medical Faculties in Bucharest, Cluj- were not at an appropriate level, making it possible for Napoca, Timisoara and Iasi, generating a plethora of the outbreak of typhus epidemic, which has ravaged high-performance medical practitioners and thousands of lives among the Army's military. The pharmacists (some of the world's recognition intervention of the medical service, benefiting from personalities). the consistent support of volunteer women, The interwar evolution of international relations that coordinated by the new queen of Romania, eventually gradually brought Romania to Hitler's Germany led to juggled the epidemic, improving the level of the conclusion of the assistance protocol on the healthcare insurance - especially in terms of providing military line between Germany and Romania. Due to care for the wounded and sick. the offensive actions in particular, the functioning of The victorious outbreak of war and the creation of the the medical service has been rethought in order to Romanian national state - Great Romania - allying ensure the triage and saving of life in the battlefield, in Transylvania, Basarabia and Bucovina - is the greatest the conditions of multiple victims, tactical and moment in our history. However, the Romanian strategic medical evacuation, ensuring the continuity military continued military operations aimed at of medical care along the hospital network imposing order and compelling Hungary to accept the (rehabilitation of wounded / sick military personnel so Versailles peace treaty. that it could be used again in combat), storage of functional and reserve stocks, use of blood transfusion On the occasion of the reintegration, the Army's (for the first time in history). medical care network has expanded accordingly, including hospitals from Timisoara, Sibiu, Brasov, Cluj- During the years 1940-1945, Romanian military Napoca, Oradea, Cernauti and Chisinau. The newly medical network (both internal military hospitals and established military units organized unit and garrison civil ones, as well as campus military hospitals) were infirmaries. One of the Army's sanitary warehouses tested. The Romanian sanitary trains, used as modern was organized in an old artillery unit, in Sebes, in means of medical evacuation - during the First World addition to the one in Bucharest. War, demonstrated the logistic capacity held by the Romanian Army, allowing the strategic medical After the great global conflagration of 1914-1918, the evacuation to be carried out by placing combat actions principles and norms of organization and functioning far away from the country. of the campus hospitals (mobile and fixed - of the inner area) organized in school buildings, mansions, The period 1945-1950 represented, in addition to the administrative buildings, etc. - were established. introduction of Russian communism dogma in the During the war, campus hospitals provided medical country, a period of radical transformation of the Army services to save the lives of the wounded and sick and, implicitly, of its medical service. There has been a military. general and dramatic regression by the exclusion from military physicians of leading personalities, who were The interwar period was a period of development of considered counterrevolutionary and irredentist. the Armed Forces medical network not only in These people were replaced by less prepared and numerical / quantitative but also qualitative terms: the competent, but "healthy" staff, unable to provide medical units / departments and medical specialties,
6 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine proper quality of the military-medical activities. The that work in management and medical planning performance of the entire Romanian education structures and provide medical care within unit system decreased consistently, therefore there was a infirmaries and campus hospitals. decrease in the quality of the medical-military However, the responsibility of relations with the education as well. medical education system from the Western Europe, After the 1960, the number and size of the military which was evolved and emancipated by arbitrary units increased by reorganizing the Army of the restrictions, generated a period of regress in the Romanian People's Republic (the beginning of the Cold performance of medical service. The provision of War between Western Capitalist Europe and Eastern medical logistics was poor by reducing the import of European Communist Europe). medical devices: the only medical devices factory (ITM Bucharest) and several other medicine factories The number of unit infirmaries and company hospitals provided mediocre quality goods for the requirements increased and the number of military hospitals was of medical service. However, at the level of decided, as follows: Bucharest Military Hospital, Cluj- infrastructure, progress was made by building new Napoca Military Hospital, Craiova Military Hospital, structures and setting up medical services, diversifying Constanta Military Hospital, Focşani Military Hospital, the range of medical services by introducing new Galati Military Hospital, Iasi Military Hospital, Oradea medical specialties in the surgical field (cardiovascular Military Hospital (transferred to the Ministry for surgery, thoracic-pulmonary surgery, neurosurgery, Internal Affairs after 1989), Pitesti Military Hospital, maxillofacial surgery, orthopedics, urological surgery, Sibiu Military Hospital, Timisoara Military Hospital. gynecological surgery and pediatrics surgery) but also Military dispensaries were organized in big garissons: in the field of internal medicine (neurology, psychiatry, Bucharest (became CMDTA Acad. Ştefan Milcu), cardiology, pulmonology, gastroenterology and Bacău, Braila, Buzău, Ploieşti, Targoviste, Caracal, Alba hematology, endocrinology and nutritional diseases, Iulia and others. At Sebeş the central sanitary storage geriatrics, obstetrics, etc.). center was reorganized, as well as the pharmaceutical After 1989, the medical-military system went through storage center in Bucharest. The Center for Preventive a regression, between the years 1990-1995, generated Medicine and the Armed Forces Transfusion Center by deficiencies in planning, budgeting and supply, but were set up within the Central Military Hospital in that was outreached. Since 1994, medical-military Bucharest. education has started in an institutional framework In view of the new concept of reaction to weapons of again, within the Medical and Military Institute from mass destruction (microbiological, chemical, Bucharest (with two sections: one in Bucharest at radiological and nuclear means), the Army's Medical- Carol Davila University of Medicine and Pharmacy and Military Scientific Research Center was established in the other in Targu Mures - University of Medicine and 1970-1978. Also, in 1975, the Faculty of Military Pharmacy). Although the number of trainees is much Medicine was established. lower than the generations prior to 1989, tradition After 1960 - with the improvement of the political and continues. social situation in the country, the access to education In accordance to the other institutions of the of all young people and the organization of a fair Romanian State, the Army registered a reduction of promotion system are also present within the Armed budgets and investments in the military field between Forces medical system, thus creating the premises for 1990 and 2000. Military units were reduced in number a series of excellent professionals: doctors and and size progressively. Military medicine from the pharmacists. level of different forces also declined.
The school of sanitary petty officers was founded in Military hospital units registered a real progress in the 1966 in Focsani. It prepares the sanitary petty officers years 1997-2000 through the modernization of
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medical devices (centralized purchase of medical imbalance in the Army's medical network: each goods worth US $ 114 million). This strategic hospital evolved separately - depending on the period budgetary allocation has allowed the development of of medical services in which it was located, the a network of military hospitals providing superior performance of the medical staff, the management quality medical services which managed to impose at and organizational skills of the different managers, national level. lack of vision and involvement at the level of the Medical Directorate, etc. The reorganization of the Romanian Armed Forces during the period 2000-2005, which anticipated the The foundation of the Health Insurance House of the entry into the North Atlantic Alliance, generated a Army, Public Order, National Security and Judicial regress in the Army's medical system by giving up the Authority was a saving and integrative action in the Military Hospital from Oradea to the Ministry of national health system, establishing a favorable Internal Affairs, the retreat of many excellent doctors attitude towards maintaining the quality of services, (introduction of mandatory retirement at the age of 55 fulfilling the accreditation standards, implementation - age corresponding to top performance in the medical of systematic management, providing for hygiene and career), abolition of the campus hospitals network, sanitary-veterinary conditions of operation, ensuring infirmary of large units, etc. respect for patients' rights and life security, etc.
Medical-military scientific research is reduced because From 2017, the Romanian Army benefits from a of inadequate budgets (a trend at national level), budget allocation of 2% of GDP. This financial support suspending the production of antidotes and salts used has enabled the Medical Directorate of the Ministry of in CBRN interventions - implemented from 1978-1980. National Defense to develop several projects in line with the major medical insurance objectives of the Gradually, from 2007 to 2010, the specialized human Army: resources were fewer and fewer, some of the causes were: low addressability of admission to the military 1. Modernizing medical and military education and system, migration of work force to the West, lack of training; vision at the level of the Medical Directorate regarding 2. Standardization of medical structures (mobile and the future of the military medical system, legislative fixed); modifications in the health field, etc. 3. Providing operational medical support - according In 2008 there is an unfortunate event: the reduction of to the training needs, resilience forces functioning and military functions at the level of military hospitals. This defense of the territory in times of crisis and war; event associated with the transition to the self- financing system of military hospitals (public hospital 4. Ensure medical logistics of forces and territory in quality) and defense funding gap - generated a major case of peace (crisis) and war.
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Article received on September 30, 2018 and accepted for publishing on November 1, 2018. REVIEW ARTICLE
Complications of systemic lupus erythematosus: A review
Georgiana Iftimie1, Anca Pantea Stoian2, Bogdan Socea1,3, Ion Motofei1,3, Dragoș Marcu1,4, Raluca S. Costache1,5, Camelia Diaconu1,6
Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune condition, which often evolves with severe complications. In SLE, autoantibodies appear, with systemic inflammation and multiple tissue destructions. SLE is the most common form of lupus and is considered more severe than other forms. SLE can affect many parts of the body, including the kidneys, heart, lungs, brain, blood, and skin. Symptoms vary among patients. SLE can follow an unpredictable pattern of remissions (symptoms improve) and flares (symptoms worsen). Renal involvement is one of the most severe complications in SLE patients. The process of depositing the immune complexes in the kidneys could lead to the appearance of lupus nephritis. If the treatment is early and treat-to-target, it can change the course of the renal disease. Keywords: systemic lupus erythematosus, renal complications, target treatment
INTRODUCTION decades, probably due to the 1 University of Medicine development of diagnostic and Pharmacy „Carol Systemic lupus erythematosus (SLE) is a complex Davila”, Bucharest, methods. [2] Romania autoimmune condition, characterized by an 2 University of Medicine exaggerated activity of the immune system, which ETIOLOGY OF SLE and Pharmacy “Carol often evolves with severe complications. In SLE, Davila”, Department of The etiology of SLE includes Diabetes and Nutrition, autoantibodies appear, with inflammation and Bucharest, Romania multiple tissue destructions. genetic, environmental, hor- 3 St. Pantelimon Hospital, monal and immune factors, Department of General EPIDEMIOLOGY OF SLE which have a strong impor- Surgery, Bucharest, Romania tance in triggering the disease. SLE is a disease that appears particularly in young 4 Urology Department, Central University people, aged between 15 and 45 years, mainly young Genetic factors plays an Emergency Military women. 10-15 times more women than men have SLE. important role in triggering Hospital, Bucharest, Romania The black population is more commonly affected by SLE. The monozygotic twins` 5 Gastroenterology the disease, 2-3 times more than the white population, disease risk is about 57% Department, Central and develop more aggressive forms [1]. The incidence higher compared to hetero- University Emergency zygote twins’ risk.[3] Military Hospital, of the disease has increased significantly over the last Bucharest, Romania The existence of genetic 6 Clinical Emergency Corresponding author: Camelia Diaconu PhD Hospital of Bucharest, susceptibility is also supported [email protected] Bucharest, Romania
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by the presence of other autoimmune diseases, such Other types of antibodies are: anti-Chromatin; as autoimmune thyro-iditis, hemolytic anemia, antibodies to RNA structures and ribonucleoproteins; idiopathic thrombocytopenic purpura [4,5]. SLE is anti Smith antibodies, only described in SLE; associated with a multigenic determinism. The antiprotetic P ribosomal antibodies.[14] correlation with the major histocompatibility complex Autoantibodies in SLE participate in lesions of various (MHC) on the short arm of the chromosome 6 has a organs through the formation of immune complexes particular importance in the development of the (by immune response of type III) or by the direct action autoimmune processes in SLE [6]. Clinical studies have of these antibodies (by type II cytotoxic reaction) [15]. demonstrated the association of certain haplotypes of Pathogenic alterations can be secondary to deposition HLA DR (DR2 and DR3), DQ (DQ6), B8, components of of circulating immune complexes, but also the the complement system (C2 and C4) with various formation in situ of immune complexes, especially at clinical and immunological manifestations. Other renal, cutaneous, vascular, nervous system level, genes, like C1q, the Fcγ receptor gene may be causing inflammatory phenomena because of involved. activation of the complement system.[16] The environmental factors involved in the SLE are: Lupus has different forms: systemic, cutaneous, drug- ultraviolet rays (UV), that can trigger the autoimmune induced, and neonatal. processes, justifying the occurrence or exacerbation of clinical manifestations after exposure to sun; both The systemic form is the most severe and complex, viral and bacterial infections: antibodies anti Epstein- leading to kidney, heart, lung, brain, blood and skin Barr virus are present in the serum of SLE patients; complications. Symptoms vary among patients. SLE bacterial triggers (bacterial DNA, membrane lipopoly- can follow an unpredictable pattern of remissions saccharides, endotoxins) were described as factors (symptoms improve) and flares (symptoms worsen). that can induce an exaggerated immune response; Cutaneous lupus is a form of lupus that involves only medications that may cause SLE or "lupus-like" the skin and causes rashes. These rashes may appear phenomena: hydralazine, procainamide, isoniazide, anywhere, but are usually found on the face, neck, and chlorpromazine, methyldopa, penicillamine, scalp. When the cutaneous lesions had an atypical minocycline, TNF alpha inhibitors, alpha-interferon; localization, a differential diagnosis is needed [17-19]. other possible environmental factors: nutritional, This type of lupus usually does not involve the internal vitamin D deficiency, smoking.[7-10] organs, but a number of patients living with cutaneous Hormonal factors: the increased prevalence of the lupus will develop systemic lupus. disease in women is supported by increased levels of Drug-induced lupus can occur after the intake of high estrogen and prolactin. Dihydroepiandrosterone has doses of certain drugs. The symptoms are similar to low values in SLE patients.[11] Birth control and systemic lupus, but usually disappear when the drug is substitution therapy hormone increases the risk of stopped or can manifest six months to one year. The developing SLE in the women with a certain genetic antinuclear antibody (ANA) test may remain positive susceptibility.[12] for years.
Immune factors. Lymphocytes T and B, monocytes, Neonatal lupus is present in newborns of a woman macrophages and neutrophils have increased with lupus or another autoimmune disease. This production of autoantibodies in SLE patients.[13] The condition can cause skin rashes, anemia or liver formation of autoantibodies has a central role in the complications. Symptoms usually disappear after a appearance of SLE complications. The main antibodies few months and do not cause permanent damage. are antinuclear antibodies (ANA). Anti-DNA antibodies Some babies with neonatal lupus can be born with a (Ac anti-ADNdc) are the most specific for diagnosis, severe heart defect.[18] being correlated with disease’ activity. Anti-histone antibodies are associated with drug-induced SLE.
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COMPLICATIONS OF SLE Gastrointestinal complications may vary from mesenteric vasculitis or intestinal obstruction SLE is a complex, multifactorial and polymorphic syndromes to peritonitis, pancreatitis or inflammatory disease that may lead to severe complications. bowel syndromes [32,33]. The most common Muscular complications. Muscular pain, commonly symptoms are abdominal pain, nausea, anorexia, and encountered in many diseases, may occur frequently vomiting [34,35]. Hepatomegaly and hepatic enzyme in SLE patients with progressive evolution and it can elevations are found in 30% of patients, hepatorenal often lead to a misdiagnose [20,21]. It is often located syndrome can appear [36], and Budd Chiari syndrome in the scapular-humeral belt and symptoms like may also be associated with the presence of myalgia and muscle weakness often appear.[19] antiphospholipid antibodies.[37-39] Finally, franc myositis is associated with the increase in Neuro-psihiatric complications are the least serum muscle enzymes, aminotranspherases or understood complications. They may involve either creatine kinase levels.[22] The pain is, in many cases, the central nervous system, causing aseptic very severe an requires multimodal treatment. meningitis, seizures, anxiety syndrome, psychosis, or Osteoarticular complications. Arthritis in SLE the peripheral nervous system, with myasthenia resembles that of rheumatoid arthritis, symmetrically gravis, mononeuritis, autonomic neuropathy or affecting the small joints of the hands. In the case of polyneuropathy. Endothelial dysfunction may be SLE, arthritis is non-erosive. A special form of SLE responsible for the passage of autoantibodies to the arthritis is Jaccoud arthropathy, with deformations nervous system and the occurrence of the lesions.[40] “swan neckline” type. When erosive arthritis occurs in Renal complications are one of the most serious SLE, it is called rhupus. Osteoporosis can occur complications in SLE patients [41-43]. The process of frequently in SLE patients and is directly related to the depositing the immune complexes in the kidneys could high risk of fractures [23]. The surgical management of lead to the appearance of lupus nephritis.[44] The these fractures is complicated, especially due to bone classification of ISN RPS 2004 of lupus nephritis is fragility, needing limited periosteum stripping in order universally accepted: to prevent further damage of the bone [24]. Osteoporosis can also be associated with the adverse . Class I: Minimal mesangial lupus nephritis, with effects of cortisone therapy in these patients. normal glomeruli by microscopic evaluation, but mesangial immune deposits at immunofluorescence. Cardio-vascular complications. The most common are . Class II: Mesangial proliferative nephritis, with pericarditis, which may range from asymptomatic to mesangial hyperplasia at the optical microscope, but accumulation of moderate fluid, and myocarditis, with mesangial immune deposits on immunofluorescence. global hypokinesia at echocardiography.[25] A typical . Class III: Focal proliferative nephritis, involving less lesion that may occur in SLE patients is Libman-Sacks than half of the glomeruli, with or without mesangial verrucous endocarditis, with thickening of the mitral involvement. Subgroups: IIIA (active lesions); IIIA/C and aortic valve [26-28]. The presence of (active and chronic lesions); IIIC (inactive lesions). antiphospholipid antibodies appears to be directly . Class IV: Diffuse proliferative nephritis, involving related to valvular damage.[29] more than half of the glomeruli. Pulmonary complications. Pleural effusion is the most . Class V: Membranous nephritis. common, is bilateral, and associated with the presence . Class VI: Sclerotic nephritis with no active lesions. of antinuclear antibodies. In patients with SLE, Other less common forms of lupus renal disease impairment may be at the level of parenchyma, with include interstitial nephritis, drug-induced and lupus pneumonia or alveolar hemorrhage, or at the vascular disease, when the renal vessels are pulmonary vessels level, with pulmonary affected.[40,44,45] hypertension.[30,31] Paraclinical, the parameters evaluated are: 24-h
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proteinuria, with values above 0.5 g/24 h; active thrombosis, renal infarction, renal artery stenosis or urinary sediment with diffractional red blood cells and malignant arterial hypertension.[56] APS nephropathy cell cylinders; serum creatinine above the upper limit was found to be statistically correlated with arterial of the laboratory, low creatinine clearance, low thrombosis, fetal loss, and the presence of lupus complement and high titer of double-stranded DNA anticoagulant. These characteristics seem to be linked antibodies.[46] to an increased prevalence of hypertension, raised serum creatinine, and interstitial renal fibrosis.[57] Usually, about 25–50% of lupus patients have abnormalities of the renal function, starting early or The therapy of renal disease in SLE is a challenge for during the evolution of the disease. The renal the practitioner. An early and targeted intervention complications seem to be discovered in the first three can influence the disease’ course. The mortality of SLE years after the diagnosis of SLE.[47,48] Regarding the decreased considerably after the introduction of ethnic origin, different studies revealed that renal cyclophosphamide as the major weapon against lupus impairment is significantly worse in black subjects than nephritis, the renal disease no longer impairing the in white patients with lupus nephritis.[49-51] survival rates of these patients. The results of a recent study sustain the role of combined therapy with Proteinuria is considered to be the essential piece in intravenous pulses of cyclophosphamide and the lupus nephritis structure. In a review on lupus methylprednisolone in the improvement of lupus nephritis, proteinuria was reported in 100% of nephritis [58,59]. However, the long-term use of patients, with nephrotic syndrome in 45–65%.[47] cyclophosphamide can cause major side effects, such Microscopic hematuria was found in about 80% of as bone marrow suppression, hemorrhagic cystitis [60- patients during the disease course.[46] 63], gonadal toxicity and, eventually, the development A recent retrospective study, exploring the of neoplastic disorders or can complicate some determinants of earlier renal disease in patients with surgical procedures [64-66], with subsequent SLE, found that features like young age, non-European infections.[67-70] On the other hand, studies have origin and male sex have a great impact on the disease very good results on long-term remission rates and the [52]. Approximately 10–15% of patients with lupus ability to achieve a second remission with currently nephritis, despite treatment, progress to end-stage recommended intravenous cyclophosphamide renal failure.[49] Features predictive of end-stage regimens. Concerning the new therapeutic options renal disease in patients with severe lupus nephritis [71,72], it seems that biological agents, such as included higher baseline serum creatinine level and blockers of other co-stimulatory pathways (for failure to obtain remission, with increased level of example, CTLA4-Ig), monoclonal antibody against potassium, which can lead to arrhythmic events53. In CD20, anticomplement (anti-C5b) and anti-cytokine this stage of disease evolution, the anesthetic risk for treatment, induction of T and B cell tolerance, and this patients is high, being necessary a strictly hormonotherapy, could be involved in the perioperative management in order to prevent further management of lupus nephritis, but these therapies complications.[54] still have no sustainable evidence.[73-75] Anti-phospholipidic syndrome (APS) is a disorder associated with recurrent arterial or venous CONCLUSIONS thrombotic events and pregnancy morbidity, along SLE is an autoimmune disease in which self-tolerance with the presence of antiphospholipid antibodies is lost, with polymorphic manifestations that (anticardiolipin antibodies and/or lupus anticoagulant) represent a real challenge, both for diagnosis and for [55]. Renal disease in APS is characterized by treatment. SLE often involves severe complication in interstitial tubular or glomerular injury due to the various systems of the body, causing a decrease in obstruction of the vessels. Renal manifestations the patient’s quality of life. Renal impairment is one of include thrombotic microangiopathy, renal vein the most serious complications and could lead to end-
12 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine stage renal failure. Lately, the focus is on early Acknowledgements diagnosis and targeted-treatment for the good There are no conflict of interest. management of these patients. All authors had equal contribution in this paper elaboration.
References:
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Article received on September 30, 2018 and accepted for publishing on October 28, 2018. REVIEW ARTICLE
Heart failure with preserved ejection fraction: A review
Ruxandra N. Horodinschi1, Anca Pantea Stoian2, Dragoș Marcu1,3, Raluca S. Costache1,4, Camelia Diaconu1,5
Abstract: Heart failure is the final stage of evolution of a large number of cardiovascular diseases and represents a health problem worldwide, due to increased prevalence of cardiovascular diseases. The patients with heart failure with preserved ejection fraction (HFpEF) represent about a half of the patients with heart failure and the prevalence of HFpEF is on the rise. HFpEF is mainly a disease of the elderly patients, who have numerous cardiovascular diseases – hypertension, myocardial ischaemia, atrial fibrillation, valvular disease, and also non-cardiovascular comorbidities, such as obesity, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, and obstructive sleep apnoea. HFpEF is more prevalent in women than in men, but women have a better prognosis than men. The pathophysiological changes that appear in HFpEF are: ventricular stiffening, cardiomyocite hypertrophy and hypercontractility, myocardial fibrosis and inflammation, which lead to abnormal diastolic function with delayed relaxation and inappropriate filling, in the presence of a normal systolic function of the left ventricle. The diagnosis of HFpEF is based on clinical, echocardiographic and biological criteria. In contrast to HFrEF, there is no effective treatment for HFpEF. The treatment of HFpEF includes diuretics for clinical improvement and treatment of comorbidities. The prognosis of patients with HFpEF is similar with those with HFrEF. Currently, the main objectives of the treatment in patients with HFpEF are to improve clinical status and decrease hospitalizations. Further studies are needed to establish an effective treatment to increase survival in these patients. Therefore, HFpEF continues to be a challenge for clinicians regarding the optimal therapy.. Keywords: heart failure with preserved ejection fraction, diastolic dysfunction, 1 University of Medicine myocardial fibrosis, natriuretic peptides and Pharmacy „Carol Davila”, Bucharest, Romania 2 University of Medicine and Pharmacy “Carol Davila”, Department of INTRODUCTION diseases, after successful treatment of their Diabetes and Nutrition, conditions. Bucharest, Romania Heart failure is the final 3 Urology Department, stage of evolution of a large The most frequent causes of heart failure are: Central University number of cardiovascular myocardial ischaemia, valvular diseases, arrhythmias, Emergency Military Hospital, Bucharest, diseases. Heart failure is a atrio-ventricular conduction disorders, myocarditis, Romania major health problem pericarditis. Often, heart failure has more than one 4 Gastroenterology worldwide, due to cause. It is extremely important to determine the Department, Central University Emergency increased prevalence of aetiology of heart failure in order to establish the Military Hospital, cardiovascular diseases specific therapeutic options (for exemple to reduce Bucharest, Romania and prolonged survival of 5 Clinical Emergency Hospital of Bucharest, some categories of patients Corresponding author: Camelia Diaconu PhD Bucharest, Romania with cardiovascular [email protected]
16 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine heart rate in tachyarrhythmias, to replace a valve in mainly a disease of the elderly, who associate valvular disease, revascularization of the coronary numerous cardiovascular and non-cardiovascular arteries in patients with myocardial ischaemia, etc.) comorbidities [9]. [1]. HFpEF is more prevalent in women than in men, with Currently, heart failure is classified into heart failure a ratio women to men of 2:1, explained by the with reduced ejection fraction (less than 40%) - different sex cardiomyocite remodeling pattern in HFrEF,mid-range ejection fraction (between 40-49%) – women than men [10,11]. In men, the eccentric left HFmrEF, and preserved ejection fraction (≥ 50%) – ventricle remodeling is more frequent, while in HFpEF1. HFmrEF is a new category of heart failure, first women the concentric remodeling is more frequent, introduced in the classification of heart failure in 2016, as a response to aortic stenosis or hypertension [10]. in the European Society of Cardiology Guidelines [1]. Due to the concentric remodeling, women have a smaller left ventricle cavity and an increased wall HFmrEF is usually studied in trials along with HFpEF, so thickness, with less collagen deposition [10]. in this paper we will use the terminology of HFpEF, Consequently, women have a better contractility and including both entities. Until now, the majority of ejection fraction of the left ventricle, with the clinical trials regarding the treatment of heart failure predominance of HFpEF. Women with HFpEF are more have focused on patients with HFrEF. While in the case likely to be obese, hypertensive or to have renal of HFrEF, it had been proven that the treatment can disease or diabetes mellitus, while men are more likely reduce both morbidity and mortality, in the case of to have coronary artery disease, atrial fibrillation, HFpEF there is no drug which can reduce mortality or chronic obstructive pulmonary disease, anemia [12]. morbidity. This is why HfpEF is more challenging for Even if HFpEF is more common in women, they have a the clinician regarding the diagnosis and treatment. better prognosis, with a rate of hospitalization with Patients with HfpEF associate many comorbidities, 20% less than men and a lower risk of cardiovascular such as hypertension, diabetes mellitus, vascular and non-cardiovascular events. [12] disease, atrial fibrillation, metabolic syndrome, chronic kidney disease, which complicate even more RISK FACTORS the evolution of HFpEF and increase the risk of Traditional cardiovascular risk factors, such as mortality. smoking, obesity, diabetes mellitus, hypertension, precede the onset of both heart failure with reduced PREVALENCE OF HFpEF and preserved ejection fraction, but there are specific In the last years, the prevalence of HfpEF increased, risk factors for each of them. While male sex, because of the demographic changes and the changes myocardial infarction, left bundle branch block or high in the risk factors prevalence, such as the increasing potassium level represent major risk factors for HFrEF, prevalence of hypertension, atrial fibrillation and the risk factors for HFpEF are female sex, higher diabetes mellitus that are all risk factors for HFpEF [2]. systolic blood pressure, right bundle branch block and HFpEF currently affects more than 7 million people in atrial fibrillation [13-15]. Europe and is the only cardiovascular condition that Hypertension is common in patients with HFpEF and has increasing incidence and prevalence [3]. The increases the risk of developing heart failure. The increasing prevalence of HfpEF can also be a result of optimal treatment of hypertension improves diastolic the changes in clinicians’ awareness over time and of filling, leads to the regression of left ventricular the fact that the diagnostic methods have evolved hypertrophy and may reduce the progression of heart during the last decades. failure. The patients with HFpEF represent about a half or even Atrial fibrillation (AF) and HFpEF are related, and each more of the patients with heart failure and the of the diseases predisposes to the other. AF occur in prevalence of HFpEF is on the rise [4-8]. HFpEF is
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approximately two thirds of the patients with HFpEF associates also elevated filling pressures, especially and contribute to the progression of the illness, due to during physical exercise. High filling pressures are the uncontrolled ventricular rates and the loss of atrial considered the primordial cause of dyspnea and contraction and its contribution to the left ventricle exercise intolerance [21]. The abnormalities filling, leading to a shorter filling time and diastolic encountered in HFpEF include delayed relaxation, dysfunction of the left ventricle [16]. When present stiffening of the myocardium and inappropriate filling together, HFpEF and AF lead to a worse outcome than dynamics. each condition separately [17]. Patients with HFpEF The changes that occur in the cardiomyocites are the and AF have a higher risk of stroke and mortality. All key to understand the dysfunction that appears in patients with HFpEF and AF should receive an oral HFpEF and consequently to discover a specific anticoagulant and should have a good control of the treatment. An important element is cardiac ventricular rate. hypertrophy. The extent of hypertrophy is a major Myocardial ischemia may contribute to HFpEF, too, by predictor for HFpEF outcome. Other elements that altering the diastolic filling. Significant coronary artery contribute to HFpEF are fibrosis, left ventricle filling disease is present in more than half of the patients pressure, left ventricle end-diastolic volume, systemic with HFpEF. Patients with HFpEF and myocardial inflammation, and metabolic disorders [22]. ischemia have a greater risk of ventricular dysfunction HFrEF is characterized by a diminished contractile and mortality than those without myocardial ischemia. response of the cardiomyocite, reduced availability of Coronary revascularization can improve the prognosis calcium activator and inadequate storage of calcium in of patients with HFpEF and myocardial ischemia. the sarcoplasmic reticulum [22]. Knowing these Regarding patients with diabetes mellitus, particularly mechanisms, HFrEF may benefit of a specific patients with insulin-dependent diabetes mellitus treatment which acts at the level of renin-angiotensin- have an increased risk to develop major adverse aldosterone system and beta-adrenergic receptors. cardiovascular events, including cardiovascular The treatment for HFrEF is ineffective in HFpEF, mortality, hospitalization for heart failure, non-fatal because of the different pathophysiological myocardial infarction, non-fatal non-hemorrhagic mechanisms. stroke, aborted cardiac arrest. Therefore, patients In the case of HFpEF, there are no animal models, with HFpEF and diabetes have a worse quality of life which is a major problem to a complete understanding and poorer outcomes than those without diabetes of the pathophysiological mechanisms, in order to mellitus. establish a specific therapy. Comorbidities such as obesity, diabetes mellitus, A study published in June 2018 suggests a new theory chronic kidney disease, anemia, chronic obstructive regarding HFpEF: hypertrophic cardiomyocytes pulmonary disease, and obstructive sleep apnea are develop also hyperfunction and elevated availability of related to the worsening of heart function in HFpEF. systolic calcium activator [23]. In vivo, it is present a The treatment of these comorbidities improves the diastolic dysfunction and in vitro, hypercontractility of prognosis of heart failure and reduces mortality [18- the cardiomyocytes. The researchers also noticed 20]. discrete, focal areas of fibrosis and in vivo, propensity to arrhythmias, caused by the instability of the calcium PATHOPHYSIOLOGY OF HEART FAILURE WITH from the sarcoplasmic reticulum, and sudden death PRESERVED EJECTION FRACTION [23]. Apparently, the hypercontractility due to the HFpEF is characterized by a normal systolic function, increase of the L-type calcium channel density is but abnormal diastolic function, with inappropriate responsible for the normal systolic function [23]. On filling of the left ventricle in the presence of normal the other hand, the high level of calcium limits the pressure, initially. In more advanced stages, it relaxation and promotes the stiffness of the ventricle
18 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine walls. It was noticed also a deficit in cardiomyocytes, mellitus, may contribute to the proinflammatory state which leads to the compensatory hypertrophy of [27]. Several proinflammatory cytokines are increased surviving myocytes [23]. Therefore, when failure in HFpEF, such as interleukin-6, tumor necrosis factor occurs, diastolic dysfunction is predominant, but α, pentraxin 3 and soluble ST2 [27]. These patients ejection fraction is preserved and end-diastolic have systemic inflammation and endothelial volume is normal. There have been also observed the dysfunction, caused by the elevated expression of hypertrophy of the cardiomyocytes, the stiffness of vascular cell adhesion molecules: VCAM-1, E-selectin, the ventricle walls and focal interstitial fibrosis. reactive oxygen species (ROS) [20]. The high level of ROS leads to the reduction of nitric oxide and Arrhythmias can occur in HFpEF and they are related consequently aggravates cardiomyocyte stiffness, with the high levels of operational calcium, which hypertrophy and fibrosis [20,26]. confer instability, and with spontaneous release of calcium from the sarcoplasmic reticulum during DIAGNOSIS OF HFpEF diastole. Arrhythmias increase the risk of sudden cardiac death [23]. Heart failure can be initially suspected based on clinical criteria. For a definite diagnosis, it is mandatory Myocardial fibrosis contributes to diastolic to perform an echocardiography. dysfunction. Patients with HFpEF have a profibrotic state. Fibrosis is organized in focal areas, observed At echocardiography, the ejection fraction of the left especially near the interventricular septum. Fibrosis ventricle, the thickness of the ventricular walls, the increases the stiffness of the walls. Collagen type I and cavities’ geometry and dimensions, the associated III are elevated in HFpEF, collagenase and pathologies, such as valvular stenosis or insufficiency, metalloproteinase-1 are reduced, but tissue inhibitor are evaluated. of matrix metalloproteinase-1 is increased, changes The clinical and paraclinical elements necessary for the which contribute to fibrosis [23]. In tissue biopsy of diagnosis of HFpEF/HFmrEF are: patients with HFpEF, inflammatory cells have been also found. Hypertrophy is related to a diminished . The presence of symptoms and signs of heart population of cardiomyocytes at an early-stage of failure. growth. Hypercontractility predisposes to . A left ventricle ejection fraction ≥ 50% for HFpEF cardiomyocytes rupture and substitution with fibrotic and 40-49% for HFmrEF. tissue. Consequently, the integrity of the cardiac . Increased levels of natriuretic peptides: BNP > 35 muscle is affected by focal fibrosis and the change of pg/mL; NT-proBNP > 125 pg/mL. the ventricle geometry. In time, as the failure . Objective elements of structural and/or functional progresses, the diastolic function is totally disorders of the heart as a possible cause for the compromised, but the systolic function, measured by clinical presentation. the ejection fraction, is conserved [23]. . If the diagnosis is uncertain, a stress test or invasive measurement of increased left ventricle filling Ventricular stiffening is associated with vascular pressure may be necessary [1]. stiffening in HFpEF. Vascular stiffening increases with age and is related to hypertension, chronic kidney The specific symptoms of heart failure are disease, diabetes mellitus and obesity [24-26]. breathlessness at variable degrees of effort or at rest Vascular stiffening requires increased cardiac output and exercise intolerance. Dyspnea interferes with the to fill the rigid arteries that contributes to ventricular daily activities and impairs the quality of life. On stiffening. Thus, ventricular-vascular stiffening is a physical examination, patients with heart failure have common association in patients with HFpEF. pulmonary crackles, bilateral ankle edema, jugular venous dilatation, laterally displaced apical beat. Inflammation has an important role in HFpEF. Comorbidities, such as renal disease, diabetes Echocardiography is the conclusive method for the
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diagnosis of heart failure. The left ventricle ejection On the other hand, atrial fibrillation can be a mark of fraction (LVEF) is the most important parameter used HFpEF. Patients with HFpEF and atrial fibrillation may to determine the systolic function of the left ventricle have more advanced heart failure than those with and a powerful predictor of death in patients with HFpEF and sinus rhythm [1]. reduced ejection fraction [27]. LVEF is an important Biomarkers measured with highly specific and predictor for fatal and nonfatal cardiovascular events sensitive assay play an important role in the diagnosis in patients with heart failure, including heart failure- of heart failure and its risk stratification [27]. The Brain related death, sudden cardiac death, hospitalization, Natriuretic Peptide (BNP) is higher in patients with myocardial infarction, especially in patients with HFpEF than in patients without heart failure, but lower reduced ejection fraction [28]. A 10% reduction of the than in patients with HFrEF [28]. BNP is associated with ejection fraction is associated with a 39% higher risk of diastolic left ventricle walls stress and pressure. cardiovascular mortality [27]. Biomarkers of extracellular matrix and fibrosis (soluble In patients with HFpEF, echocardiography reveals a ST2, galectin-3, type I procollagen C-terminal pro- normal or near-normal ejection fraction and peptide, type I and II collagen amino-terminal pro- inadequate diastolic relaxation and left ventricle peptide, collagen telopeptides, matrix metallo- filling. proteinases – MMP-1, MMP-2, MMP-8, MMP-9, tissue inhibitor of metalloproteinases – TIMP-1, TIMP-4, The structural elements of HFpEF are the left atrial osteopontin) can be increased in patients with HFpEF volume index > 34 mL/m2, a left ventricular mass index [6]. Renal biomarkers, such as cystatin C and urinary ≥ 115 g/m2 for males and ≥ 95 g/m2 for females [1]. albumin, and cardiac troponins are also elevated6. All The diastolic dysfunction has 3 stages that can be these biomarkers may sustain the diagnosis of HFpEF, evaluated by echocardiography. The first stage is but have a poor prognostic role and, excepting delayed relaxation, with an E/A ratio under 0.8, natriuretic peptides, cannot be used to guide the deceleration time of E wave > 200 ms, E/e’ medium treatment [6]. The natriuretic peptides values are ratio less than 8. The second stage is pseudonormal related to the severity of the disease, therefore higher function, with E/A ratio between 0.8 and 1.5, levels of natriuretic peptides are linked with more deceleration time of E wave between 160 ms and 200 advanced HFpEF [6]. ms, E/e’ medium ratio between 9 and 12. The last stage is the restrictive pattern, with E/A ratio more TREATMENT OF HFpEF than 2, deceleration time of E wave less than 160 ms, There is no specific or effective treatment for patients E/e’ medium ratio more than 13 [28]. with HFpEF, in order to reduce the mortality rate [29]. If echocardiography at rest is inconclusive, the In clinical practice, fewer patients with HFpEF appear diastolic stress test, using a semi-supine bicycle to to receive beta-blockers, diuretics, angiotensin- measure the pulmonary artery pressures and cardiac converting enzyme inhibitors, angiotension receptor output changes with exercise, may be necessary [1]. blockers and aldosterone antagonists than patients Another paraclinical test is invasive measurement of with HFrEF and if they receive these drugs, it may be the filling pressures – the pulmonary capillary wedge to treat comorbidities, such as hypertension, coronary pressure ≥ 15 mmHg, left ventricular end-diastolic artery disease, atrial fibrillation [29,30]. pressure ≥ 16 mmHg [1]. Renin-angiotensin-aldosterone system blockers have In the presence of atrial fibrillation, the been studied in patients with HFpEF, due to their echocardiographic diagnosis of HFpEF is more difficult, effects on hypertension, fluid retention and fibrosis. because the left atrial volume index is higher, the Also, beta-adrenergic blockers were studied due to functional parameters of diastolic disorder are not their effects of prolonging diastole and increasing the well established. Also, the values of natriuretic filling time of the left ventricle. Despite their well- peptides are higher in patients with atrial fibrillation. known benefits in patients with HFrEF, in those with
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HFpEF beta blockers offer only a modest symptomatic bradycardia or chronotropic incompetence and improvement and do not reduce mortality [31,32]. neither in patients with restrictive type of diastolic Some studies revealed a decreased hospitalization disorder, because filling occurs early and rapidly in rate with angiotensin converting enzyme inhibitors/ these patients and decreasing heart rate would angiotensin receptors blockers [6]. The study „The worsen cardiac output even more [6]. Effects of Candesartan in Patients with Heart Failure Introduction of device therapy was a great progress for and Preserved Left-Ventricular Ejection Fraction” patients with HFrEF, with pacemakers, implantable concluded that patients with HfpEF who received cardioverter defibrillators, and resynchronization candesartan had fewer hospitalizations for therapy. In patients with HFpEF, asynchrony is rarer decompensated heart failure compared with placebo, than in HFrEF, thus device therapy has no applicability but without influence on the mortality rate [6]. in HFpEF [6]. Probably, renin-angiotensin-aldosterone-system does not have such an important role in HFpEF as in HFrEF, No treatment has yet been found to diminish this is why its blockers have much less benefits [6]. morbidity and mortality in patients with HFpEF and HFmrEF. An important objective of the treatment in The use of aldosterone antagonists was also tested in these patients is to improve symptoms and the quality HFpEF. The results of the study ALDO-DHF, published of life. Diuretics are prescribed to reduce pulmonary in 2013, showed an improvement of the diastolic and systemic congestion signs and symptoms. As function, but no improvement was noticed in the mentioned before, aldosterone antagonists and beta- maximal exercise capacity, clinical symptoms and blockers do not improve symptoms in patients with quality of life [6]. The TOPCAT study, whose results HFpEF, only a relative improvement in NYHA class with have been published in 2014, also did not achieve its candesartan was observed [1]. primary outcomes – cardiovascular mortality or aborted cardiac arrest, only a small decline in Regarding hospital admission, patients with HFpEFin hospitalization rate has been observed [6,33]. sinus rhythm may benefit from the use of nebivolol, spironolactone and candesartan, which decrease Sildenafil, a phosphodiesterase-5 inhibitor, was tested hospital admission1. For patients who associate atrial in RELAX study and showed no advantage on mortality fibrillation, beta-blockers are ineffective and digoxin or symptomatic relief [6]. has not yet been studied [1]. Statins can be prescribed in patients with HFpEF and Arterial hypertension should be carefully treated in have shown a significant impact on survival, due to patients with HFpEF/HFmrEF, who have often systolic their pleomorphic anti-inflammatory effects [6]. arterial hypertension. The antihypertensive drugs Considering the lack of results on mortality rate with recommended are diuretics, angiotensin-converting beta-blockers use, ivabradine was also studied. enzyme inhibitors, angiotensin receptor blockers and Ivabradine slows the sinus node rate, but does not aldosterone antagonists [1]. Beta-blockers appear to affect contractility and peripheral vasculature, in be less effective [1]. contrast to beta-adrenergic blockers [6]. Studies on The specific therapy for comorbidities is also mice revealed an improvement in the left ventricle important, for example losing weight in obese function and lowering of aortic stiffness and fibrosis patients, oral anticoagulants for atrial fibrillation or after four weeks of therapy with ivabradine [6]. A other arrhythmias, medical and/or interventional clinical trial, including 61 patients with HFpEF, has treatment for coronary artery disease, treatment of found an improvement in exercise capacity and diabetes mellitus, preferably with metformin [1], renal decreased exercise-induced E/e’ ratio, which disease treatment [34-37], treatment of anemia, represents diastolic pressure index, with ivabradine chronic obstructive pulmonary disease and versus placebo [6]. No side effects appeared. obstructive sleep apnea. Ivabradine cannot be used in patients with
21
The most challenging situation is the treatment of non-cardiovascular events [12]. Women have an HFpEF when different kinds of surgical procedures are overall better prognosis than men [12]. The prognosis required [38-40]. Either is abdominal surgery [41-44] is modified by the presence of atrial fibrillation, stable or pelvic interventions [45-47], in males [48-51] or angina pectoris, and renal disease in both sexes [12]. females procedures [52-55], the management of these comorbidities involves complex treatment strategies CONCLUSIONS from surgeons, cardiologists or anesthesiologist. Patients with heart failure with preserved/mid-range Thus, the management of HFpEF includes diuretics, ejection fraction represent approximately a half of the which reduce systemic congestion and improve the patients with heart failure. filling pressure of the left ventricle, and treatment of The diagnosis of HfpEF is based on clinical signs and comorbidities, which improves considerably the symptoms, echocardiography, natriuretic peptides clinical outcome [56]. levels and stress tests or invasive measurement of filling pressures and left ventricular end-diastolic PROGNOSIS OF PATIENTS WITH HFpEF pressure, if necessary. Overall, the prognosis of patients with HFpEF is similar Overall, the prognosis of patients with HFpEF is similar with those with HfrEF [57]. Patients with HFpEF have with those with HFrEF, with the difference that in more frequent a non-cardiovascular cause of death or these patients the death of non-cardiovascular cause hospitalization, in contrast to the patients with HFrEF, is more common, in contrast to the patients with who have commonly a cardiovascular cause for HFrEF, in whom the cardiovascular death is more hospitalization or death [1]. Renal involvement in frequent. patients with HF is a redutable complication, especially in patients with increased blood pressure [58-61]. There has not yet been found a specific therapy for HFpEF that may reduce morbidity and mortality, in The left ventricle hypertrophy and elevated left contrast to HFrEF. The main objective of the treatment ventricle filling pressure correlate with hospital- in patients with HFpEF is to improve clinical status and lizations for heart failure [62,63]. Recurrent decrease hospitalizations. hospitalizations are as frequent in HFpEF as in HFrEF and are associated with higher mortality rate [62]. Further studies are needed to establish an effective treatment, to increase survival in these patients. In There are sex-related differences between the risk conclusion, HFpEF continues to be a challenge for factors for HFpEF. Hypertension, obesity and renal clinicians regarding the optimal treatment. disease are more common in women, while ischemia, atrial fibrillation, chronic obstructive pulmonary Acknowledgements disease and anemia are more frequent in males [12]. There are no conflict of interest. Women have a 20% lower risk of hospital admission All authors had equal contribution in this paper elaboration. than men, and also a lower risk of cardiovascular and
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Article received on August 31, 2018 and accepted for publishing on October 26, 2018. REVIEW ARTICLE
Gut microbiota – new insight in colorectal cancer pathogenesis
Mihăiță Pătrășescu1,2, Petruț Nuță1, Raluca S. Costache1,2, Săndica Bucurică1,2, Bogdan Macadon1, Vasile Balaban1,2, Andrada Popescu1,2, Roxana Călin1, Florentina Ioniță Radu1,3, Mariana Jinga1,2
Abstract: Gut microbiota is a superorganism involved in homeostasis and in pathogenesis. Microbiota composition is influenced by several factors such as: type of birth (cesarean or natural), role of age, role of diet. Pathological consequences of certain type of diet (especially western type of diet) may, in fact, be mediated by gut microbiota alteration. Also few studies have investigated the issue of gut microbiota composition in patients suffering of colorectal cancer, several reports notice relevant differences. Certain pathogenic bacteria in gut microbiota have been extensively studied in relation to their role in colorectal cancer. Thus, Fusobacterium nucleatum, which is abundant in colorectal cancer patient’s colon, may initiate the progression from adenoma to adenocarcinoma. A suggested pattern of oncogenesis in colorectal cancer may be represented by this: dysbiosis-inflammation-oncogenesis. A metanalysis that has been published in 2006 concluded a protective role of probiotics in colorectal cancer and in colonic adenoma. Keywords: colorectal cancer, gut microbiota, probiotics
Human gut harbors a complex that contains a 100 fold richer genome than human and abundant microbial commu- genome [1]. As a matter of fact we may acknowledge nity which is symbiotically linked the existence of a true superorganism whose with host organism and plays a implications in physiology and pathology of human major role in maintaining the body are continuously revealed by a great pool of homeostasis by the way of scientific data. fulfilling various functions such as: Microbiota composition is influenced by several limiting the number of intra- factors such as: type of birth (cesarean or natural), role 1 Carol Davila University luminal pathogens, functionnal of age, role of diet. Emergency Central optimization of immunity system, Military Hospital, Bucharest and important contribution to Pathological consequences of certain type of diet 2 Carol Davila University maintaining energy balance. (especially western type of diet) may, in fact, be of Medicine and mediated by gut microbiota changing [2]. Pharmacy, Faculty of It is estimated that there are General Medicine, around 1,014 microorganisms in It has been noticed that there are significant differ- Bucharest rences between European children that eat a western 3 Titu Maiorescu the colon (mostly bacteria) which University, Faculty of is 10 fold above the number of diet and African children that eat rural diet rich in Medicine, Bucharest eukaryote cell of human body and vegetal fibers and poor in meat, as concerning the
26 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine composition of gut microbiota. microbiota such as: E. Coli, B. fragilis, S. Gallolyticus (former S. bovis particularly associated with CRC) Firmicutes genera is prevalent in European children [8,9,10,11] and Bacteroidetes genera is depleted as opposed to African children in whom the ratio is reversed [3]. The Also it is obvious that there is a change in CRC patients real significance of those changes is to be better gut microbiota composition, it is not clear if those defined in the near future. Medical literature is changes are already present before the diagnosis of abundant in information on this topic, especially about CRC suggesting a role of risk factor or those changes the composition of microbiota in various pathological reflect the consequences of the disease. situations, but the studies published are mostly animal From another point of view, the CRC risk factors studies and the implications in understanding of modify gut microbiota and may elicit the oncogenic pathological mechanisms and in medical practice are process by this route. Several studies have indicated ill defined. that a meat diet, by the way of microbiota composition The role of gut microbiota played in certain alteration, may play an important role in oncogenesis inflammatory ailments (such as inflammatory bowel [12,13]. diseases – IBD) is well known [1]. Important practical Obesity is a major risk factor in CRC. Many studies consequences may be derived from these data: stool showed a certain pattern of gut microbiota change in transplant and probiotics treatment [4]. Chronic local obese subjects, in animal as well as in human studies inflammation is a risk factor for colorectal cancer [14,15]. Gut bacteria have an impact on peripheral (CRC). As a matter of fact patients suffering from IBD resistance to insulin, systemic inflammatory status and have a yearly risk of CRC of 1% after 10 years from the on systemic adiposity by the way of interaction with onset of inflammatory disease [4]. It is an answered intestinal epithelial cells. Those interactions are very question as to what extent the composition of gut complex and mutually beneficial. Thus, gut bacteria microbiota is implicated in CRC susceptibility. metabolize various nutrients such as digest-resistant Also a few studies have investigated the issue of gut carbohydrates which results in production of short microbiota composition in patients suffering of CRC chain fatty acids (mainly butyrate). Gut epithelial cells [1], several reports notice relevant differences. For uses as a main source of energy those fatty acids. instance, a study indicated an increased prevalence of Moreover, butyrate may be involved in anti-oncologic Bacteroidetes and Prevotella genera than in general effects [16]. Backend noticed, in a mice study, that population [5]. Another study which investigated germ-free subjects experienced a 60% increase in bacterial populations on the surface of colonic mucosa adiposity and a significant increase in peripheral as opposed to luminal bacteria showed that there was resistance to insulin after 14 days from stool an abundance of Faecalibacterium and Dorea species transplant performed from lean mice, in spite of a in patients suffering of adenomatous colonic polyps as restrictive diet. Stool transplant from obese mice opposed to those without polyps [6]. elicits an even greater increase in total fat mass, which may render a reasonable demonstration about the Certain pathogenic bacteria in gut microbiota have role played by microbiota in obesity and this may been extensively studied in relation to their role in further suggest a role in colonic oncogenesis [15]. CRC. Thus, Fusobacterium nucleatum, which is abundant in CRC patients’ colon, may initiate the A suggested pattern of oncogenesis in CRC may be progression from adenoma to adenocarcinoma [7]. represented by this: dysbiosis – inflammation – Rubinstein showed that the species of Fusobacterium oncogenesis. Alteration of gut microbiota (dysbiosis), which produced the virulence factor FadA stimulated as a response to an unidentified trigger, has been epithelial cell proliferation, promoted inflammation studied in animal experimental models with regard to and initiated oncogenesis [8]. Similar studies have collective or individual role of bacteria in development been published about other components of gut of inflammation and CRC [17]. The pathogenic
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mechanism is still unclear but we may appreciate an probiotics against oncogenesis of colonic tumors. involvement of certain receptors of innate immune Hence, the induction of apoptosis could be seen as a system responsible for microbial detection [18]. phenomenon of oncologic screening [23].
Indirect data on the topic of gut microbiota in CRC are In spite of all these experimental data from animal derived from the acknowledged protective role of models that indicate the fact that probiotics have the probiotics. The term of probiotics has been used for potential to stop the development of CRC, systematic several decades but World Health Organization has studies to show the same benefits in humans are very issued a definition only in 2001: „ live microorganisms limited. In a human study about the prophylactic effect that render health benefits when they are of Lactobacillus casei in CRC the conclusion was that administered in proper doses” [19]. Lactic bacteria and two years of continuous administration significantly Bifidobacteria are among the most known types of reduced the incidence of CRC as compared to control probiotics. A metanalysis that has been published in group [24]. Recently, in a cohort study that included 2006 concluded a protective role of probiotics in CRC 45000 subjects over a period of 12 years it has been and in colonic adenoma [20]. The authors of this noticed that large daily amounts of yoghurt reduced metanalysis suggested a cautious use of these data as the incidence of CRC, suggesting a major prophylactic the interventional type of studies were still not enough benefit from long term administration of joghurt to render an unequivoque positive answer. [25,26]. Future clinical studies should consider, also, the standardization of probiotics composition, as well Recently, Faecalibacterium prausnitzii, a commensal as the control of diet, time and frequency of probiotics bacterium in gut microbiota that has anti- administration. They should identify the proper inflammatory properties, has also been indicated as a biomarkers that may allow monitor of long term probiotic to decrease the risk of CRC [21]. effects. Mechanisms engaged by probiotics in the process of In conclusion, a large and significant pool of data oncogenesis are multiple: cell cycle influences, oxygen indicates a major role of gut microbiota in CRC reactive species, apoptosis, specific bacterial enzymes, oncogenesis as well as in CRC prophylaxis. The influences on human host metabolome [1]. Probiotics majority of studies are, still, animal studies. Those and have an important contribution to the development of the few human studies are, never the less, highly mucosal associated immune system as it modulates suggestive. Unfortunately, we do not know the unspecific inflammatory response and it dampens definition of „normal” composition of gut microbiota, down mucosal inflammation. Probiotics exert also yet. The mechanisms that link dysbiosis and CRC are certain effects on dendritic cell, colonic epithelial cells, complex and are related to local and systemic chronic lamina propria T cells, thus having an impact on inflammation. Some of the modifiable risk factors in adaptive immune system. Perdigon noticed in a mice CRC (obesity, diabetes mellitus, and western type of study, that joghurt (rich in lactic bacteria) hampered diet) may act, also, through alteration of gut the growth of colonic tumors which had been microbiota. The prophylactic role of probiotics may previously induced by mice exposure to 1,2 render a powerful mean to significantly reduce the dimetilhidralazine [22]. Urbanska reached a similar incidence of CRC in the future. conclusion in another mice study. He showed that yoghurt might reduce the volume of the tumor. Acknowledgements Induction of apoptosis may be credited as a major There are no conflict of interest. mechanism that mediates the beneficial effects of
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1. Yuanmin Zhu a, T. Michelle Luo c, Christian Jobin b, Nutr. 137 (Suppl. 1) (2007) S175–182 Howard A. Young, Gut microbiota and probiotics in colon 15. M.C. Collado, E. Isolauri, K. Laitinen, S. Salminen, Effect tumorigenesis, Cancer Letters 309 (2011) 119–12 of mother’s weight on infant’s microbiota acquisition, 2. William B. Whitman William, David C. Coleman, William composition, and activity during early infancy: a prospective J. Wiebe, Prokaryotes: the unseen majority, Proc. Natl. Acad. follow-up study initiated in early pregnancy, Am. J. Clin. Nutr. Sci. USA 95(1998) 6578–6583 92 (2010) 1023–1030 3. C. De Filippo, D. Cavalieri, M. Di Paola, M. Ramazzotti, 16. F. Bäckhed, H. Ding, T. Wang, L.V. Hooper, G.Y. Koh, A. J.B. Poullet, S. Massart, S. Collini, G. Pieraccini, P. Lionetti, Nagy, C.F. Semenkovich, J.I. 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Microbial dysbiosis in colorectal cancer (CCR) patients, PLoS Sartor, Bifidobacterium animalis causes extensive duodenitis One 6 (2011) and mild colonic inflammation in monoassociated 6. X.J. Shen, J.F. Rawls, T. Randall, L. Burcal, C.N. Mpande, interleukin-10-deficient mice, Inflamm. Bowel Dis. 15 (2009) N. Jenkins, B. Jovov, Z. Abdo, R.S. Sandler, T.O. Keku, 1022–1031 Molecular characterization of mucosal adherent bacteria 19. G.Y. Chen, M.H. Shaw, G. Redondo, G. Núñez, The innate and associations with colorectal adenomas, Gut Microbes 1 immune receptor Nod1 protects the intestine from (2010) 138–147 inflammation-induced tumorigenesis, Cancer Res. 68 (2008) 7. Bashir A, Miskeen AY, Bhat A, Fazili KM, Ganai BA. 10060–10067 Fusobacterium nucleatum: an emerging bug in colorectal 20. Report of a Joint FAO/WHO Expert Consultation on tumorigenesis. Eur J Cancer Prev 2015 Evaluation of Health and Nutritional Properties of Probiotics 8. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW. in Food Including Powder Milk with Live Lactic Acid Bacteria. Fusobacterium nucleatum promotes colorectal Health and Nutritional Properties of Probiotics in Food carcinogenesis by modulating E-cadherin/b-catenin including Powder Milk with Live Lactic Acid Bacteria, October signalling via its FadAadhesin. Cell Host Microbe 2013 2001. 9. Sears CL, Geis AL, Housseau F. Bacteroides fragilis 21. G. Capurso, M. Marignani, G. Delle Fave, Probiotics and subverts mucosal biology: from symbiont to colon the incidence of colorectal cancer: when evidence is not carcinogenesis. J Clin Invest 2014 evident, Dig. Liver Dis. 38(Suppl. 2) (2006) S277–S282 10. Boleij A, Hechenbleikner EM, Goodwin AC, Badani R, 22. Miquel S, Martín R, Bridonneau C, Robert V, Sokol H, Stein EM, Lazarev MG, et al. The Bacteroides fragilis toxin Bermúdez-Humar an LG, et al. 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consumption and risk of colorectal cancer in the italian EPIC cohort, Int. J. Cancer, 2011
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Article received on September 30, 2018 and accepted for publishing on November 2 2018. ORIGINAL ARTICLE
Diagnosis and management of cases with deep infiltrating endometriosis affecting the urinary tract
C.B. Coroleucă1, C. Berceanu2, L. Brindușe3, D. Marcu4, C.A. Coroleucă1, Elvira Brătilă1
Abstract: Objective: The goal of this paper is to present the management of cases of deep endometriosis that affects the bladder, the ureters and the kidney. Materials and method: In this review we analyzed the sensitivity and specificity of imaging techniques for diagnosing deep infiltrating endometriosis, the optimal surgical technique and the surgical approach. Results: In patients with pelvic endometriosis in advanced stages the urinary tract is frequently involved. Preoperative work-up of patients with deep infiltrating endometriosis is aimed at evaluating the extension of the lesions in order to assess the complexity of the intervention and to choose the optimal approach. Conclusions: Laparoscopic and robotic management of these cases are good therapeutic alternatives. Ultrasound, sonovaginography with gel and MRI are useful imaging techniques for evaluating patients with deep infiltrating endometriois. The surgical management of patients with deep infiltrating endometriosis that involves the urinary tract consists of partial bladder resections, ureterolysis, ureteral resection and anastomosis and ureteral reimplantation.. Keywords: bladder endometriosis, deep infiltrating endometriosis, ureterolysis
INTRODUCTION infiltrating endometriosis. 1 Department of Obstetrics and Gynecology, “Carol Endometriosis is a benign pathology of the female Secondary bladder endometriosis Davila” University of reproductive tract, characterized by the presence of is represented by lesions that Medicine and Pharmacy, Bucharest, Romania, “Prof. endometrial glands or stroma outside the uterine have occurred iatrogenically after Dr.Panait Sârbu” Clinical cavity [1]. The presence of endometrial tissue at the pelvic surgery, caesarean section Hospital of Obstetrics and Gynecology level of the bladder will be stimulated during the or hysterectomy [4,5]. 2 University of Medicine menstrual cycle. In response to the cyclical stimulation The distribution of the lesions is and Pharmacy, Craiova of hormones throughout the menstrual cycle, some multifocal, affecting the bladder 3 “Carol Davila” University patients may even present with cyclic hematuria [2,3]. of Medicine and Pharmacy, trigone and dome from the Bucharest, Romania, Bladder endometriosis can be defined as “primary” or serosa to the mucosa [6,7]. Department of Public Health and Management “secondary”. Primary bladder endometriosis is The ectopic endometrial tissue is 4 Department of Urology, represented by lesions associated with deep subjected to stimulation during Central Emergency University Military Hospital, the normal cycle creating “Carol Davila” University of Corresponding author: Elvira Brătilă hormonal changes that result in Medicine and Pharmacy, [email protected] Bucharest, Romania
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bleeding, inflammation and adhesions [8]. The two investigations based on the presenting symptoms. main manifestations of this disease are chronic pelvic Imaging diagnosis pain of varying intensity and infertility [9,10]. Ultrasonography is the first line imaging investigation Table 1: The prevalence of urinary tract endometriosis [11] used in the work-up for patients with endometriosis. Kidney 4 % of all urinary tract locations The bladder and the kidneys can be evaluated using Ureter 9 % of all urinary tract locations transvaginal and abdominal ultrasound. The patient’s Bladder 85 % of all urinary tract locations bladder should be in semirepletion for a correct Urethra 2 % of all urinary tract locations evaluation. (Figure 1) Prevalence 0,3 – 12 % of all cases of endometriosis Figure 1: Vesical endometriosis DIAGNOSIS
The diagnosis of bladder endometriosis is based on the presence of ectopic endometrial glands and stroma located at the level of the detrusor muscle. Patients presenting with bladder endometriosis often present nonspecific urinary symptoms. In some cases, patients will present with dysuria, urgency to void, frequent micturition and abdominal pain [12,13]. The main aspect that dominates the clinical picture is exacerbation of these symptoms during the menstrual period [14]. Due to the fact that the symptomatology of bladder endometriosisis is nonspecific, many women will not seek medical attention in the first few Abdominal ultrasound can be used in cases of years. The symptomatology can vary depending on the suspected lesions of the bladder, abdominal wall and site and the dimension of the lesion [15]. The various umbilical endometriosis [29]. During the initial work- degrees of abdominal or pelvic pain associated with up of a patient with deep infiltrating endometriois, an bladder endometriosis will not prompt patients to abdominal ultrasound must be performed to evaluate seek additional work-up for this syndrome [16]. Thus, the impact on the ureters and kidneys. Endometriotic an average of 6 years will pass from the onset of the lesions can affect the ureter extrinsically or symptomatology to the diagnosis of endometriosis intrinsically. This can have an impact on the kidney [17]. causing hydronephrosis or ureterohydronephrosis. Any other causes of ureteral extrinsec compression Urinary tract endometriosis can present with a non- must be excluded [30-33]. If surgical excision of the specific symptomatology [18-20]. The presence of lesions is not performed this may affect the kidney endometrial tissue at the level of ureteral orifices can leading to loss of function [19-25]. produce hydronephrosis, with subsequent renal failure [21,22]. If the ureteral obstruction is acute, the There are some authors that suggest that ureteral symptoms may mimic a renal colic that requires a form endometriosis should be suspected in all cases of deep of drainage [23-25].In chronic urinary obstruction, the infiltrating endometriosis [34]. lumbar pain can be absent and the renal insufficiency Sonovaginography with ultrasound gel is a useful could appear like arterial hypertension, due to a bad diagnostic option in cases with deep infiltrating regulation of blood pressure, thus involving the delay endometriosis. This method is useful for identifying of a right treatment [26-28]. The medical history and endometriotic lesions in the posterior compartiment accurate identification of the patient’s symptoms can as well as in the anterior compartment. An acoustic guide the clinician in choosing the correct imaging window is created by introducing 20 ml of ultrasound
32 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine gel into the vagina. The technique initially used saline (transvaginal ultrasound – TVS sonovaginography with solution [35]. Using this technique, we observed a high gel – SVG) – Table 2. diagnostic accuracy for the following locations
Table 2. The diagnostic accuracy for transvaginal ultrasound and sonovaginography with gel in the anterior and posterior compartiment [36]. Endometriotic lesion Ultrasound Sensitivity Specificity PPV NPV Ovaries TVS 94.8 % 95.6 % 92.5 % 94 % SVG 95.5 % 97 % 92.6 % 93 % Urinary bladder TVS 65.5 % 98.6 % 66.6 % 98.5 % SVG 67 % 97 % 98 % 98 % Utero-sacral ligaments TVS 69.7 % 95 % 84.2 % 87 % SVG 78.5 % 96 % 89 % 91 % Vagina TVS 58.5 % 99 % 94.3 % 95.4 % SVG 79 % 99 % 92 % 96 % Recto-vaginal septum TVS 64.8 % 99.4 % 81.5 % 97.8 % SVG 94 % 97 % 82 % 93.5 % Pouch of Douglas TVS 81.5 % 99 % 95 % 97 % SVG 81 % 98 % 91 % 97 % Recto-sigmoid TVS 91 % 97 % 95 % 96 % SVG 94 % 95.5 % 91 % 97.2 %
In the anterior compartment the transvaginal kidney being affected by hydronephrosis, the patient’s ultrasound and sonovaginography with gel have a desire and contraindications for the treatment [41,42]. similar sensitivity and specificity (80.1 % vs 81.2 % and The imunohistochemical aspects of patients treated 97.1% vs 97%). However, the positive predictive value with progesterone can be useful in choosing the is in favour of the latter (79.5 % vs 95.3 %). In cases of optimal medical treatment after the surgical with deep infiltrating endometriosis the association intervention [43,44]. The expression of the anti- between magnetic resonance imaging and computer apoptotic markers (Bcl-2), cell proliferation markers tomography- based virtual colonoscopy has a (Ki-67), estrogen and progesterone receptors offers sensitivity of 98.36 % for nodule identification. The anexplanation for the different outcomes after association of these two investigations allows a medical treatment for patients with endometriosis superior mapping of the endometriotic lesions at the [45,46]. level of the posterior compartment. This aspect is Surgical treatment important in the preoperative work-up and planning for the surgery [37]. Surgical treatment of urinary tract endometriosis must be performed when the patient does not respond to TREATMENT medical treatment, if the patient suffers from infertility or if the lesion has an impact on the kidney Medical treatment (ureteral obstruction, hydronephrosis or uretero- Medical treatment using progestins, oral hydronephrosis) [47,48]. Due to the fact that the contraceptives and GnRH agonists can be used in the obstruction of the ureter is due to fibrosis, patients will treatment of patients with endometriosis [38-40]. The not respond well to medical treatment [49,50]. During contraindications of medical treatment in patients the initial work-up and planning for the surgical with urinary tract endometriosis are: evidence of the intervention, the symptoms exhibited by the patient
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and the imaging investigations can guide the whether a multidisciplinary approach is in order therapeutic conduct and anticipate the complexity of (gynaecologist, urologist and colorectal surgeon) the case [51,52]. This is a key aspect in deciding the [53,54]. The treatment for bladder endometriosis is optimal intervention for the patient and anticipate represented by the surgical excision of the lesion.
Figure 2: Robotic ureterolysis (Personal collection of Prof. Elvira Brătilă)
The surgical approach can be performed by lesion affecting the ureter is extrinsic. During the laparotomy, laparoscopy or robotic surgery (Figure 2) laparoscopic and robotic surgery, the transperitoneal [55-57]. The treatment for ureteral endometriosis approach way allows a thorough evaluation of the consists of the surgical excision of the lesions involving extension of the disease. the ureters in order to prevent ureteral compression When the ureters are affected intrinsically, the (Figure 3). ureteral segment can be infiltrated by the endometriotic lesions. In this case, a resection of the Figure 3: Endometriotic lesion of that affected the ureter extrinsically at the level of the vesicoureteral junction affected segment and reimplantation can be an (Personal collection of Prof. Elvira Brătilă) alternative if ureterolysis cannot be performed [58,59].
After the completion of the ureterolysis (dissection of the tissue up to the level of the cardinal ligament), a thorough assessment of the remaining segment is required [60]. This must take into account the possibility of another obstruction of the ureter. The level at which the ureter is affected represents a factor for the intraoperative decision to perform ureterolysis, ureteral resection and anastomosis or ureteroneocystotomy [61,62]. If the lesion is located in the distal part of the ureter, the affected segment can be resected and the ureter can be reimplanted in the bladder. If the lesion is located in the upper third of
the ureter, the affected segment can be resected and repaired with an uretero-ureteral anastomosis. The Ureterolysis is the first procedure performed when the choice between ureterolysis and resection cannot be
34 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine made preoperatively. the lesions in order to assess the complexity of the intervention and to choose the optimal approach CONCLUSIONS [65,66]. Ultrasound, sonovaginography with gel and MRI are useful imaging techniques for evaluating In patients with pelvic endometriosis in advanced patients with deep infiltrating endometriosis [67]. The stages, the urinary tract is frequently involved. surgical management of patients with deep infiltrating Laparoscopic and robotic management of these cases endometriosis that involve the urinary tract consists of is a good therapeutic alternative [63,64]. Preoperative ureterolysis, ureteral resection and anastomosis and work-up of patients with deep infiltrating ureteral reimplantation [68-70]. endometriosis is aimed at evaluating the extension of
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Constantinoiu S, Bârlă R, Iosif C, Cociu L, Gîndea C, Hoară Matasariu DR. The Influence of progesterone on P, Bratu O, Ruşitoru L. Difficulties in diagnosis and surgical immunohystochemical markers in endometriosis. Rev Chim treatment of a giant retroperitoneal lipoma. Chirurgia, 2009, (Bucharest), 2018, 69 (3): 581-584. 104(3): 363-367. 44. Socea LI, Visan DC, Barbuceanu SF, Apostol TV, Bratu 32. Marcu R. D., Spinu A. D., Socea B., Bodean M. O., OG, Socea B. The Antioxidant activity of some Diaconu C. C., Vasilescu F., Neagu T. P., Bratu O. Castleman's acylhydrazones with dibenzo[a,d][7]annulene moiety. Rev Disease - Clinical, Histological and Therapeutic Features. Rev Chim (Bucharest), 2018, 69(4): 795-797.
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Article received on August 19, 2018 and accepted for publishing on November 9, 2018. ORIGINAL ARTICLES
The strategic importance of vaccination for national defense and security
Viorel Ordeanu1
Abstract: Public health is the most important power factor of a nation, from which all other factors derive. Infectious diseases are the most important cause of morbidity and mortality in humans. Vaccination is the most important method of prophylaxis of infectious-contagious diseases. Mass implementation of vaccination prevents the occurrence of epidemics, epizootic diseases or homonymous pandemics, and at the individual level ensures the specific active immunity (total or partial). So the vaccination of the population and/or the risk groups is of strategic importance to the nation, both in peacetime and in time of war. The national antidote production along with anti-infectives (vaccines, therapeutic serums, immunomodulators, antimicrobial chemotherapies and pesticides) has a strategic importance for the health of the population and of the troops. Biological crisis situations are cases of force majeure, where the Medicines Law provides the exception for manufacturing and use, even without a "marketing authorization". The military scientific research could make micro-production of specific drugs (antidotes, antiinfectives) for the needs of the army and the risk groups of the population. An example would be the preparation of vaccines for the prophylaxis of diseases caused by BWA and bioterrorism as niche products. Nothing hinders the preparation of any medication, such as magistral and galenical preparations, or pilot batch, provided there is adequate space, equipment, staff and procedures according to the law or the exception. Keywords: vaccination, public health, national defense, national security, military production
INTRODUCTION security. This context also causes direct or indirect risks to the population, and economic, social and other We live in turbulent times, and the disruptions reduce the standard of living. current international context is volatile. Even in our east-westerly Not only does war and uprising implicitly cause a vecinity, hybrid wars, prolonged polytrauma epidemic, but it also profoundly affects for many years and without the the public health. Premises for epidemics (right at this clear prospect of their cessation, time, the measles outbreak is happening in the EU) take place. These exacerbate the and epizootic diseases (right at this time, the African risk for national defense. The swine fever epizootic is happening in the EU) are
1 Military Medical Research social unrest, stimulated both created, extending as far as biological attacks, Center, “Titu Maiorescu” domestically and internationally, bioterrorism and bio-crime. And if we attempt to University amplifies the risk for national interpret the military-medical health situation in the
38 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine country, we can think that the current epidemics are Western model imported from France. The sanitary favored by the propaganda of the antivaccinists, facilities monitored all people (not just citizens or whose hidden interests and their coordinator still policyholders) and all businesses in the assigned remain unknown. territory, so that no man and no square meter in Romania remained outside the sanitary system: As far as the current epizootic is concerned, it is a viral prophylaxis, diagnosis and treatment. In parallel, the disease for which there is no vaccine for prophylaxis or veterinary districts supervised domestic and wild specific antiviral treatment, and the economic effects animals. The County Health Directorates and can be catastrophic. The distribution of outbreaks on Departments, as well as the Sanitary-Veterinary the map shows that the virus has penetrated the Directorates centralized the activity and reported it to country at the Hungarian border and spreads to the the central authorities, to establish the necessary interior of Transylvania (a major producer and measures to be implemented, locally, nationally or exporter of pork). A second wave followed, shortly internationally. after, at the Ukrainian border, extending to northern Dobrogea and eastern Bărăgan, gradually reaching As an example, in the 1990s, the Medical Directorate Bucharest and the border with Bulgaria. Until now, of the Ministry of National Defence organized in Sinaia over 1,000 outbreaks of African swine fever have been the first working meeting between Romanian and identified by Romanian veterinarians in domestic NATO military doctors. We presented the (farm or house) pigs in different places in the country, arrangement of the anti-epidemic surveillance in but not in wild boars who were initially believed to Romania, integrating human, military, veterinary, have carried the virus. Therefore, how did the disease phytosanitary and environmental medicine, which come to exist and how does it spread? The breeders now represents the One health concept. When we assume that through forages (including by industrial made the statement that "In Romania the anti- premixes); however, these are not a supportive epidemic surveillance is not of sound quality..." we environment for the preservation or multiplication of were interrupted by the American representative who viruses. The only possible explanation would be the stated that "It is our case as well!". However, we intentional contamination with this virus, thus, a likely continued our idea as follows: "In Romania, the anti- new bioterrorist attack with an economic goal. But the epidemic surveillance is not of sound quality, but of hypothesis has to be confirmed with scientific very high-quality: we have 50 Health Directorates, 41 evidence, by laboratory analysis and molecular Sanitary Veterinary Directorates, 41 Agricultural epidemiology; otherwise, it shall only resemble the Directorates, 41 County Environmental Inspectorates, "conspiracy theories" partly projected by the press. 5 Medical University Centers, various Institutions and Until now, the secret services have found nothing Central Laboratories, we are members of the World (being probably occupied with other issues) and the Health Organization, and the Cantacuzino Institute is military medicine has not received samples for part of the Pasteur Institute network, etc." The analysis, although it has advanced microbiological approval that came from the present audience closed diagnostic capabilities and has the ability and expertise the topic. However, in the meantime, the Sanitary to test possible biological attacks. Reform has altered some of the problem's data.
The public health was also effectively supported by the THE PUBLIC HEALTH Romanian pharmaceutical industry by providing the The public health is the most important power factor national needs and exports of medicines, vaccines, of a nation (large or small), from which all other factors reagents, parapharmaceuticals, pesticides and derive. In Romania, it was effectively supported by the medical devices, to which the Cantacuzino Institute territorial healthcare system introduced after World has contributed significantly since 1921. Until recently, War I by Prof. Ioan Cantacuzino (at that time the persisted the moment of glory of the Romanian Minister of Health), according to the most advanced medicine where, with the existing forces and means
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and with reasonable funding, major progress was supposed infectious dementia etc.); thus, these are made in the public health sector, the eradication or equally infectious diseases. quasi-eradication of infectious-contagious diseases, Vaccination is the most important method of the decrease of infant mortality, the improvement of prophylaxis of infectious and contagious diseases. The the quality of life, the extension of the duration of life massive application of vaccination prevents the and labour. occurrence of the epidemic, epizootic or homonymous However, the public health in Romania has been pandemic, and at the individual level ensures specific partially undermined by the abolition of the active immunity (total or partial). Therefore, the territorialisation in primary healthcare and the drastic vaccination of the population and/or the risk groups is reduction of the pharmaceutical industry, in such a of strategic importance to the nation, both in time of way that from the status of exporters of medication peace as well as in time of armed conflict. we have become importers, and the medication crisis The history of vaccinology begins in the Middle Ages, is current. Although the new Constitution of the with the empirical immunization and continues in the country still provides for the country's obligation to Modern Age with scientific immunization. The first ensure the public health, this role has been mass vaccinations were made in the 1800s, when significantly reduced. A system where the health is Napoleon ordered the compulsory vaccination of the highly expensive and the foreign investors are Great Army (hundreds of thousands of soldiers) as exaggeratedly gaining through medical insurance and prophylaxis in military campaigns. From antiquity to trade in medicines and pharmaceuticals. However, the the contemporary era, many battles and even wars results of medical assistance do not seem to be have been lost due to epidemics that have weakened superior to those of previous years, and even in the the combatants' ability to fight. Prof. N. Iorga once said field of infectious and contagious diseases there is a "read history to know what shall come" [10]; and, the worsening of the situation, and the press publicly history of medicine is a component of history and presents this situation. At times, the doctors are being partially overlaps with military history. It is not the tried as natural persons as an explanation for the intention of this article to present a history of inefficiency of the current healthcare system and vaccinology in general, so we will limit ourselves to the sanitary reform. Overall, the increase in costs has not chronological presentation of the vaccine production been accompanied by an increase in efficiency, and in Romania and the national development of public health is declining, according to statistics from vaccination as a medical protection against infectious the National Institute of Statistics. diseases. VACCINATION In the last century, the appearance of sulphamides and antibiotics led to antibacterial chemotherapy which, Infectious diseases are the most important cause of along with vaccination and hygiene, has rapidly morbidity and mortality in humans. Diseases caused improved the public health to its current level and the by parasitic living beings (bacteria, viruses, prions, population of the planet is growing exponentially. It is fungi, protozoa and parasitic animals) have prevailed the most important demographic success of the since ancient times and are still the most common in human species, and it is mainly based on the advances underdeveloped countries. But also in developed of medicine in regards to vaccinology and anti- countries (including Romania), where these diseases infective therapy. Vaccinology saved more lives than are officially ranked third (after cardiovascular surgery. diseases and cancers), there are many diseases that actually have a known infectious origin (such as gastric After the discoveries in biology of the chemist Pasteur, and duodenal ulcers, which are caused by a bacterium, the founder of modern microbiology, Romanian or some cancers caused by certain viruses, etc.) or not scientists were also attracted by this field. Victor Babeş yet known (unidentified bacterial endocarditis, studied in the West and published in French the first
40 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine microbiology handbook in the world. Ioan Cantacuzino biological drugs. For comparison, “Formulaire ASTIER, worked at the Pasteur Institute in Paris, under the 9-e Edition, Vade-mecum de Medecine Pratique”, guidance of Prof. Mecinikov, and returned to Paris, 1942, 1306 p (representing the most advanced Bucharest as a professor at the Faculty of Medicine, medicine of the time) describes 21 vaccines, 19 where in the Experimental Medicine Laboratory therapeutic sera and some biological therapeutic (which he created in 1901) prepared sera and anti- methods. [1]. Romania was at a European level even infective vaccines. These were successfully used for before being a member of the European Union. the protection of the population and the Romanian In 1944, the Sera and Vaccines Institute "Dr. I. Army during the Balkan Wars (he was also the Head of Cantacuzino" publishes the "Guidelines for the Use of the Army’s Sanitary Service, ranked as Colonel) and Sera and Vaccines, 1944 Edition", Bucharest, George during World War I, including the "great Romanian Ionescu – Pharmacist, 143 p. [3]. The work could be experience", during which he ended the terrible considered as the first handbook of vaccinology in plague epidemic, and later (in 1921) the Institute that Romanian. There are 21 vaccines, 13 therapeutic sera, was named after him was founded, and was led by him 4 bacteriophages, 14 biological reagents, 2 biological until the moment of his death in 1936. dressings, a total of 54 biological drugs. During the Prof. Al. Slatineanu, along with ŞL C-tin. Ionescu same year, appears the second edition of the Mihăeşti and Dr. Mihai Ciucă ("laboratory assistant for Handbook of Infectious Diseases, 320 p. [9], based on serum preparation", the future professor and director the experience of the World War II. 23 vaccines, 17 of the Cantacuzino Institute), published in 1915 the therapeutic sera, 4 bacteriophages, 6 biological first Military Epidemiology Handbook: "Notions in reagents, the immunotransfusion and sulfamido- epidemiology and serovaccinations (with special therapy are presented. application in the campaign)", The laboratory of Prof. C. Ionescu-Mihaesti and Prof. M. Ciuca, as experimental medicine, Bucharest, State Printing students and followers of Prof. Ioan Cantacuzino, who House, 95 p. [12]. This article is based on the medical further developed the Institute, published in 1945, in experience during the Balkan Wars, which has been English, the first International Handbook on Infectious useful during the First World War, when the Romanian Diseases under the auspice of the League of Nations: Army faced major epidemics. The four vaccines “League of Nations. Handbook of infectious diseases produced at that time are also presented here: the with notes on prophylaxis, serum treatment and anti-vitiligo, anticholeric, anti-plague and vaccination” by the Staff of the Cantacuzene Institute, antivarioulous vaccine. under the direction of Professors C. Ionescu-Mihaesti In 1939, Prof. C. Ionescu-Mihaesti and Prof. M. Ciuca, and M. Ciuca” Series of League of Nations, Publications together with 27 specialists from the Cantacuzino III Health, Geneva, 1945. III. 1. 331p. [8]. The handbook Institute, published the first "Handbook of infectious also addresses the field of immunological medicinal disease with prevention concepts, serotherapy and products: 23 preventive and therapeutic vaccines, 19 vaccinations, drawn up by the Cantacuzino Institute", therapeutic sera, 10 diagnosis sera, phage therapy, the Foundation for literature and art "King Carol II", immunotransfusions, sulfamidotherapy and, for the the National Printing House, Bucharest, 1940, 313p. first time in a handbook, antibiotherapy – in chap. IX [9]. The work is based on the World War I medical Anti-biotic products of microbic origin (fungi, experience and the advances in inter-war medicine, bacteria). being useful in the Second World War, when the After the regime change, "R.P.R. Ministry of Health, Romanian Army experienced no more epidemics. The Institute of Sera and Vaccines Dr.I. Cantacuzino, main infectious and contagious diseases, 18 vaccines, Guidelines for the Use of Sera and Vaccines" State 16 therapeutic sera, 6 in vivo reagents, Printing House, Medical Literature, Bucharest, 1949, immunotransfusion therapies, with bacteriophages, 144 p. [2]. The work describes 11 vaccines, 4 anatoxins, with sulfamides, etc., are presented in a total of 43 7 therapeutic sera, 2 bacteriophages and 17 biological
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reagents, a total of 41 anti-infective biological but there are good prospects. products. In 1952, the Ministry of Health and Social During those periods of production, vaccinations were Welfare publishes the "The Prophylaxis of free of charge (material and labor) and compulsory, communicable diseases", re-published in 1961 [4] etc. according to the Annual vaccination schedule of the In 1962, MSPS publishes "Vaccines, Sera and Biological Ministry of Health for the civilian population, including Diagnosis Products", 227 p. which features 87 children, of the Ministry of National Defence for the assortments. [7] Military and of the Ministry of Agriculture for animals. After the military-political shock of 1968, the "Dr. I. The safety of vaccinations Cantacuzino" Institute is revitalized and publishes "Vaccines, serums, biological diagnosis products, The Romanian production of sera and vaccines for culture media and laboratory animals” Medical human use (with circulating strains in the country) has Printing House, 1969, 285 p., which describes 251 protected Romanians from infectious-contagious biological products, of which 18 vaccines. In total, from diseases and epidemics for 113 years (armed with 75 assortments in 1947, 340 were produced after between 100-500 thousand soldiers and populations 1969. [5]. between 11-22 million people), also achieving a very rich vaccination experience, with no major medical However, after the 1989 Revolution, the Cantacuzino incidents. Institute gradually lost its importance, and gave up a part of its staff (by restructuring, retirement, The testing base on millions of people of all ages and relocation, unemployment, etc.), its External over a century provides a large-scale epidemiology Departments of the province (Iaşi, Timişoara, Dârvari and pharmacovigilance study confirming the etc.), part of its portfolio of anti-infectives and effectiveness of vaccinations and the quality of microbiological diagnosis products. According to the vaccines prepared by the Romanian Pharmaceutical latest INCDMI “Cantacuzino” Product Catalog for Industry, primarily at Cantacuzino Institute. It would 2009, of the 802 products previously in the portfolio be interesting to have a retrospective scientific were produced 13 vaccines, 2 therapeutic sera, etc. research on vaccination in Romania that would and in 2013 only one vaccine (flu), no therapeutic sera quantify the data objectively and extract the and only one part of the other microbiological appropriate conclusions. When the theory, or the Law products. [6] Then followed: the financial crisis, the of Medicine, does not fit the practice, the theory cancellation by the MS/ANMDM of production should be corrected (if there are no hidden interests). authorizations and the crisis of authority and Vaccinology is an important concern of global medical competence, which led to the complete cessation of research, of the epidemiology and the pharmaceutical the production of vaccines and therapeutic sera. There industry; new vaccines, new regulations, new forms of was a need for drastic measures to relaunch the administration have been created worldwide, but we production of biological medicine, including the still do not have vaccines for all infectious-contagious takeover by the Ministry of National Defence, so that diseases. The antivaccinist current is also added to the the Cantacuzino National Military-Medical existing challenges, which, out of ignorance or bad Development Research Institute could be run by the faith, opposes vaccination for various reasons: the fear military and concrete results are expected. of supposed adverse effects, the desire to let nature The evolution of the production of vaccines and sera take its course, the belief that sickness and health for human use in Romania (incrementa et come from God, the antisocial attitude, financial decrementa), exemplified by specialized medical interests etc. Some adverse effects exist with varying publications, shows the following dynamics: 1901 = 0; degrees of severity, but are very rare and the risk/ 1915 = 4; (1921 establishment of IC); 1939 = 34; (1942 effectiveness ratio is considerably favorable, = 40 in France); 1944 = 40; 1945 = 42; 1949 = 22; 1969 particularly in social terms. No medication, including = 25; 2009 = 15; 2013 = 1; 2014 = 0; and currently = 0, the vaccine, is granted the "marketing authorization"
42 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine if it does not meet the Efficacy and Safety conditions unsatisfactory results, and additional intervention by a set by the drug legislation. The World Health U.S. Army Medical Brigade, which applied general Organization (WHO), as a specialized UN forum, medical countermeasures combined with military recommends the necessary vaccinations anywhere in discipline to enforce anti-epileptic precautions, was the world and at any time, and national authorities needed. comply, but sometimes only within the limits of The niche production for vaccines of military-medical financial possibilities, through self production and/or interest (WBA + Bioterrorism) imports. The military-medical scientific research also aims at WHO List 2017 Essential Medicines Vaccines Section: maintaining health and combat and labor capacity BCG, Diphtheria, Hemophilus Type B, Hepatitis B, HPV, (troops and population) as well as their recovery in the Measles, Pertussis, Pneumococcal, Polio, Rotavirus, case of common or specific illnesses (eg CBRN). The Rubella, Tetanus, Japanese Encephalitis, Yellow Fever, Center for Scientific Military-Medical Research Tick-borne encephalitis, Cholera, Hepatitis A, (CCSMM), established in 1967/1968/1969, Meningococcal, Rabies, Typhoid, Influenza (Seasonal), permanently collaborated with the Cantacuzino Mumps, Varicella. Institute (1921/2017), the national producer of serums NATO's List of Biological War Agents (BWA) in and vaccines, for the medical protection against conformity with STANAG 4632: biological weapons, including for vaccinology (the Dermojet automated injector, lyophilized intradermal . Bacteria Bacillus anthracis, Yersinia pestis, vaccines, specific tests, etc.). Francisella tularensis, Vibrio cholerae*, Brucella melitensis, Burkholderia mallei, Coxiella burnetti; Medical countermeasures are based on: diagnosis, . Viruses VEE virus, Ortopox virus, Yellow fever virus* prophylactic treatment, pre-, intra- and post-exposure . Toxins Ricin, Saxitoxin, Botulinum toxin, SEB, T2 prophylaxis, recovery treatment for combat, work or mycotoxin life. It is well known that the best military recovery results for the battle were obtained by the German Note: Only the two BWAs marked with * are found in army (on the principle of phased evacuation), and the the WHO List, meaning that the civilian medicine is not best recovery results for labour or life were obtained particularly interested in the biological warfare; by the US army (on the principle of evacuation by therefore, implicitly, this task rests with the military destinations). In fact, the two principles of evacuation medicine. of sanitary losses apply in different situations of The European Medicines Agency has published the List conducting military operations, namely classical front of Biological Agents Usable in Bioterrorism (equivalent or expeditionary actions. to CDC USA): EMA BA 2002, 2007 and 2014, presenting The effect of the disseminated biological agent may in summary: the disease, treatment and prophylaxis. It differ depending on many factors and their should be noted that for some diseases there is association: pathogenicity, virulence, toxigenesis, treatment, for others there is no "recommended resistance to the environment, resistance to treatment", for some diseases there is a vaccine treatment, unprotected population, specifically non- (which is or is not available), for others there is no vaccinated, without pre-exposure prophylaxis, vaccine, and is or is not undergoing research/ without intra-exposure prophylaxis, without post- authorization. An example could be the recent Ebola exposure prophylaxis, without anti-infective epidemic, a disease caused by a long-known virus, but treatment, cases of illness and outbreaks, as well as in the epidemic still did not exist: a diagnostic reagent, sanitary-pharmaceutical logistics: forces, means, a prophylactic vaccine, and no specific antiviral money, etc., the result being expressed in terms of treatment. Only the existence of the epidemic has financial and social costs. prompted scientific research to produce them. As a result, the international collaboration has had The national antidote production along with anti-
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infectives (vaccines, therapeutic serums, immune- preparation of any medication, such as magistral, modulators, antimicrobial chemotherapies and galenical preparations, or pilot batch, provided there pesticides) has a strategic importance for the health of is adequate space, equipment, staff and procedures, the population and of the troops. Biological crisis according to the rules: of good pharmaceutical situations are cases of force majeure, where the practice, good manufacturing practice (GMP), good Medicines Law provides the exception for laboratory practice (GLP), good practice for safety manufacturing and use, even without a "marketing check and the exception of force majeure. [11] authorization". Public health must be an obligation of the state towards its citizens and not a business of CONCLUSION producers or importers. Vaccination is very important for national defence and The military scientific research could make micro- security. Vaccine production started in 1901, production of specific drugs (antidotes, antiinfectives) developed since 1921, had a glory period before the for the needs of the army and the risk groups of the financial crisis of 2009 (regardless of the regime), went population. An example would be the preparation of into decline and is currently only declared intent. The vaccines for the prophylaxis of diseases caused by military-medical scientific research could resume the BWA and bioterrorism as niche products, in order to production of vaccines, complying with specific avoid the competition of the large multinational conditions, especially as niche production, possibly pharmaceutical producers, whose turnover exceeds through national and/or international partnerships. the state budget of Romania. Nothing hinders the The vaccines production must continue.
References:
1. *** “Formulaire ASTIER, 9-e Edition, Vade-mecum de serum treatment and vaccination” by the Staff of the Medecine Pratique”, Paris, 1942, 1306p. Cantacuzene Institute, under the direction of Professors C. 2. *** “R.P.R. Ministerul Sănătăţii, Institutul de seruri şi Ionescu-Mihaesti and M. Ciuca” Series of League of Nations, vaccinuri Dr. I. Cantacuzino, Instrucţiuni pentru Publications III Health, Geneva, 1945. III. 1. 331p. întrebuinţarea serurilor şi vaccinurilor” Editura de Stat, 9. Ionescu-Mihaesti C., M.Ciuca“Manual de boli infecţioase Literatura medicală, Bucureşti, 1949, 144 p. cu noţiuni de profilaxie, seroterapie şi vaccinatiuni, alcătuit 3. *** Institutul de seruri şi vaccinuri “Dr. I. Cantacuzino” de Institutul Cantacuzino”, Fundaţia pentru literatură şi artă publică “Instrucţiuni pentru întrebuinţarea serurilor şi “Regele Carol II” Imprimeria Naţională, Bucureşti, 1940, vaccinurilor, ediţia 1944”, Bucureşti, George Ionescu – 313p. farmacist, 143 p. 10. Iorga N. “Cuvântare la deschiderea cursului de istorie” 4. *** Ministerul Sănătăţii şi Prevederilor Sociale 1936 “Profilaxia bolilor transmisibile”, 1952 şi reeditata în 1961 11. Ordeanu V., Sandulovici R.C. “Importanta vaccinării etc. pentru apărarea şi securitatea naţională” Comunicare la 5. *** “Vaccinuri, seruri, produse biologice de diagnostic, Simpozionul “Actualităţi şi perspective în Medicină medii de cultură şi animale de laborator” Editura Medicală, Preventivă – 2018” INCDMM “Cantacuzino” Bucureşti, Bucureşti, 1969, 285 p., 07.09.2018 6. *** Cataloagele anuale de produse INCDMI 12. Ordeanu V. si colectiv. Proiecte de cercetare PSCD MApN “Cantacuzino” si Plan Intern CCSMM 7. *** MSPS “Vaccinuri, seruri şi produse biologice de 13. Slatineanu Al., C-tin. Ionescu Mihăeşti, Mihai Ciucă diagnostic” 1962, 227p. “Noţiuni de epidemiologie şi serovaccinatiuni (cu aplicaţiune specială în campanie)”, Laboratorul de medicină 8. Ionescu-Mihaesti C., M. Ciuca, “League of Nations. experimentală, Bucureşti, Imprimeria statului, 1915, 95 p.. Handbook of infectious diseases with notes on prophylaxis,
44 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine
Article received on October 1, 2018 and accepted for publishing on November 14, 2018. ORIGINAL ARTICLES
The role of metatarsophalangeal joint arthroscopy in hallux rigidus treatment: technique and early results
Ieronim O. Crișan1
Abstract: Introduction: The hallux rigidus is a term that signifies a mobility limitation of the metatarsophalangeal joint of the big toe due to osteoarthritic degeneration. Several factors are incriminated in the appearance of this pathology but without being able to establish the cause. The cartilaginous erosion of the metatarsal head and / or the base of the phalange, the dorsal osteophyte of the head of the first metatarsal were found during cadaveric studies. The main reason for consultation is pain and limitation of the dorsiflexion of the big toe during the step. Hypothesis: Arthroscopic debridement of the first metatarsophalangeal joint improves the early postoperative clinical score compared to isolated percutaneous treatment. Material and method: 11 patients divided into 2 groups were assessed clinically at 3 months postoperatively. All patients were hospitalized on an outpatient basis. Results: There was a gain in mobility at 3 months compared to the preoperative assessment in both groups, as well as an improvement in pain without being able to demonstrate the superiority of the additional arthroscopy to the percutaneous debridement. Hypothesis reversed.. Keywords: hallux rigidus, orthopedics, arthroscopy, osteophyte
INTRODUCTION The evolution towards the aggravation of the destruc- Pathogenesis tion is on the other hand Hallux rigidus is a term invented by Cotterill in 1888, well known. The cartilage- refers to a limitation in mobility of the meta- nous lesion is supposed to tarsophalangeal joint of the hallux. Although he did initiate synovitis, which not call it hallux rigidus, in 1887 Davies-Colley reported itself supports cartilage for the first time the resection of the base of the first destruction, accompanied phalanx for this pathology, which he called hallux by osteophyte formation flexus because of the flexion attitude of the and subchondral bone metatarsal-phalangeal joint and the limitation of involvement. [1] extension of this joint. Moreover, the understanding The degenerative process of this pathology has advanced thanks to radiological can begin in adolescence techniques, but the pathogenesis of the hallux rigidus when a traumatic event at is not yet defined. 1 Centre Hospitalier Colmar the metatarsophalangeal and Guebwiller, France
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joint damages the articular surface of the head of the extension, the arrival of the first phalanx against the first metatarsal. Repetitive strain injuries can also metatarsal cleavage site produces pain and reflex cause cartilage damage. Other causes are mentioned: flexion of the joint, limiting extension. Then the osteochondritis dissecans of the head of the first disease progresses, an osteophyte at the level of the metatarsal secondary of an osteochondral fracture at dorsal articular margin of the head of the first the level of the dorsal convexity of the articular metatarsal produces a stop during great toe extension. surface, the hyperextension of the first metatarsal, an This is the initial image of the patient: osteoarthritic excessive length of the first metatarsal and a severe changes in or around the metatarsophalangeal joint of pronation of the foot. The hallux rigidus of the adult is the hallux. Often the first metatarsal is in the dorsal most often caused by degenerative arthropathy or forcing position, decreasing its angle of plantar osteoarthritis of the metatarsophalangeal joint, while inclination on the profile X-rays (primus elevatus). This in adolescents the hallux rigidus results from a elevation of the first metatarsal is rather secondary to localized cartilaginous lesion of the head of the first metatarsophalangeal osteoarthritis than the cause of metatarsal most post traumatic time [1,2] this one. [1,2,3]
A system for classifying the severity of hallux rigidus Clinical takes into account passive mobility, pain, and The main reason for consultation is the progressive radiographic assessment to assign a stage from 0 to 4. onset of pain and the limitation of the articular This classification of Coughlin and Shurnas has been amplitudes of the hallux which is either fixed in plantar reported to be reliable in predicting the outcome of flexion or limited in dorsiflexion due to osteophytes surgical treatment. [1] present around the head of the first metatarsal, Despite the fact that the metatarsus primus elevatus especially on the dorsal surface. [1] (dorsal positioning of the first metatarsal on a lateral This is not the case on the plantar surface where there X-ray in load of the foot) has been incriminated as a is a normal mobility in flexion. The severity of the primary cause in the pathogenesis of hallux rigidus, degenerative changes is directly dependent on the this was not proved. No association was identified duration of the symptomatology. [2] between hallux rigidus and primus elevatus, hypermobility of the first ray, the first long metatarsal Muscular cramps in the extensor hallucis long tendon and stiffness of the Achilles tendons, abnormal without mechanical conflict can be found early in the posture of the foot, symptomatic hallux valgus, shoes course of the degenerative process. Gradually the or professional occupation. It is more frequently hallux becomes fixed in plantar flexion and the patient associated with hallux valgus interphalangeal, bilateral is forced to walk on the outer face of the foot. [2] involvement in patients with family history, unilateral Unilateral involvement is the most common despite involvement in patients with traumatic history, female Nilson who postpones bilateral involvement in 60% of gender. [2] his cases. The aesthetic factor (the intolerance of McMaster reported that the most common finding in wearing shoes in the heel) gives a preponderance to seven patients with hallux rigidus was cartilaginous the female sex. Although Smith reported small series cleavage at the head of the first metatarsal without of older patients suffering from hallux rigidus, in the subchondral bone detachment and that the earliest literature the age of the first symptoms were radiological change was a small depression in the adolescence. [2] dome of the first metatarsal head. The cleavage is Radiological characteristics always between the top of the dome and the dorsal edge of the articular surface. McMaster believes that The flattening of the head of the first metatarsal, the the exquisite pain and dorsal range of motion joint narrowing, the presence of osteophytes of the limitation can be explained by the osteophytic lesion dorsal, medial and lateral faces of the metatarsal head on the dorsal metatarsal head. When hallux is in and the base of the phalanx, subchondral sclerosis and
46 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine the formation of cysts at the level of the head of the of at least 70°. The success rate varies between 56% first metatarsal are common elements in the elderly and 92%, with better results for stage 1 and 2 and for population. Sometimes the proximal phalanx is held in patients over 60 years of age. The gait analysis showed plantar flexion due to posterior conflict, and stress that there is an overload in the lateral part of the head images can confirm that the osteophyte block of the first metatarsal after joint debridement and that prevents extension of the metatarsophalangeal joint. these changes can lead to future joint degeneration. An osteochondral lesion is occasionally observed in [1,2] the metatarsal head in adolescents according to The modified Keller procedure (arthroplasty- Goodfellow and McMaster. [1,2] resection), in which the short extensor hallux tendon Conservative treatment and the capsule were used as interposition materials, has been described for the treatment of severe hallux For most patients, surgical correction is necessary to rigidus, but the results vary.[2] relieve pain and improve function; however, Yee and Lau, in a review of the hallux rigidus literature, have Interposition arthroplasty was also modified by determined that non-operative measures such as foot oblique resection of the proximal phalanx. [2] orthotics, shoe modifications, and corticosteroid and Silicone-rubber interposition arthroplasty was a short hyaluronic acid infiltrations prior to surgery should be term solution because of silicone synovitis. The considered. [2] hemiarthroplasty of the proximal phalanx with a Surgical treatment metallic component was also described, with good results, but there are no long-term studies to evaluate Despite several recommended surgical procedures for this technique. A study of 23 hemiarthroplasties the treatment of hallux rigidus, (including the dorsal reported that 91% of patients were satisfied with the subtraction osteotomy of the base of the first phalanx results at 5.7 years and that the scores of the American or the distal portion of the first metatarsal, the Keller Society of Foot and Ankle were significantly improved. operation or metatarsophalangeal arthrodesis) no [1,2] procedure has proved its superiority. The indication for the metatarsophalangeal arthrodesis is the Arthroscopic treatment articular narrowing objectivized not only on the frontal The first author to describe the arthroscopy of the and lateral incidences but also on the oblique hallux was Watanabe in 1972. The procedure gained incidence which shows that the remaining articular clinical importance in the 1990s when several authors space is absent on the frontal and lateral incidences. described the technique. The advantage of Modern fixation techniques using compression screws arthroscopy at this level is to have a fast recovery and or dorsal plates result in high melting rates (between professional reintegration, reduction of postoperative 94% and 98%) and acceptable clinical outcomes for pain, less scar problems and a mobility and strength of patients. the metatarsophalangeal satisfactory. [3,4,5] Gait studies showed significant improvements in The working hypothesis: Arthroscopic treatment propulsive force, foot load, and walking stability after improves mobility and decreases pain compared to arthrodesis for hallux rigidus. [2] isolated percutaneous debridement under image The justification for metatarsophalangeal debride- intensifier. ment is the pain relief due to mechanical conflict suppression between the dorsal osteophyte of the first MATERIAL AND METHOD metatarsal and the base of the phalanx and the boot. The study is retrospective. The debridement is performed by resection of the osteophyte and other bone growths on each side of The inclusion criteria was the hallux rigidus stages 1 the joint with the aim of a dorsal flexion of the hallux and 2, without limitation of the walking perimeter.
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The exclusion criteria was the diabetic foot and the arthroscopy debridement (group 2) and 4 patients neurological foot. underwent isolated percutaneous debridement (group 1), among them 1 patient had to have a Results evaluation was simple based on subjective bilateral hallux rigidus surgery at 5 months interval. pain (0-10 where 0 signifies absence of pain and 10 Patients were evaluated at 3 months postoperatively. signifies insupportable pain) and local range of motion (hallux extension). The main symptom was the pain of the hallux when walking, and the additional assessment includes Between November 2015 and March 2016 at Centre standard loading X-ray of the front foot, anterior- Hospitalier Colmar and Guebwiller (France) 11 posterior, lateral-lateral and three quarters (figure 1). patients, 6 women and 5 men were undergo surgical treatment of hallux rigidus. Seven patients underwent
Figure 1: Hallux rigidus, stage 2, presence of the dorsal osteophyte on the lateral and three quarters X-Ray
Percutaneous articular debridement was accom- joint, laterally or medially to the long extensor tendon plished using a specific Shannon TM drill 2.0x8 of the great toe, image intensifier serves in checking millimeters under image intensifier within regional the correct intraarticular positioning. To avoid dorsal anesthesia, no tourniquet needed. sensory branches damage the incision is placed slightly plantar affecting the skin only, while a Kelly or Halsted Metatarsal-phalangeal hallux arthroscopy was forceps is used for deep dissection. To prevent performed under regional anesthesia (popliteal block) cartilage damage a small cannula is introduced. A 2.4 with a calf tourniquet in all patients. mm scope is used and placed preferably postero- The patient is placed supine, heel in the vacuum, with medial while the instruments are placed postero- a pad under the ipsilateral buttock to ensure a strictly lateral. In doubt X-Ray checking is desirable to confirm vertical position of the foot. The surgeon is positioned the correct intra-articular instruments positioning. at the end of the table, scrub nurse left of the surgeon Articular distraction gap is performed by a “Japanese (left-handed surgeon), arthroscopy column next to the fingerstall [3]” or by pulling out the hallux with a patient's head (figure 2). Velpeau band (figure 3). By pulling the toe with the Hallux flexion-extension movements helps identifying hand and placing the probe within the joint, the metatarsophalangeal space. A needle is placed in the anatomical structures can be explored during flexion-
48 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine extension movements (sesamoid and head of the first metatarsal) (figure 4).
Figure 2: Patient positioning, the hardware and the operating room display. Artisanal traction by Velpeau band.
Often the posterior synovium and the lateral and In first and second stages, a cartilage lesion is usually medial gutters must be cleaned along using a Shaver found centrally or dorsally on the first phalanx or on TM to obtain a good visualization of the joint, paying the dorsal metatarsal head, while the subchondral attention to the extensor tendon of the hallux (figure bone remains intact (Figure 6). 5). [3] [4] [5] Figure 4: The medial sesamoid Figure 3: Hallux arthroscopic approach
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Cartilaginous valves are regularized with a curette and Figure 6: Cartilaginous valve and head of the metatarsus the debridement and osteophytes resection continues with the shaver or radiofrequency probe. If the subchondral bone is exposed, micro fractures by a 15 millimeters diameter Kirschner wire are produced to stimulate neo cartilage induction.
Figure 5: Hallux extensor tendon
The pre- and postoperative dorsiflexion are measured by laterally X-Ray checks, allowing us to note in the operative report the mobility gain (figure 7).
Figure 7: Left image: 45° of dorsal flexion on preoperative X-Ray; right image: 80° dorsal flexion of the great toe on postoperative x-ray
At the end of the procedure, the release of the RESULTS AND DISCUSSION tourniquet enables bleeding control, the skin is The average age for group 1 was 53.2 years and 56.8 stitched with resorbable sutures, and a compressive years for group 2. dressing is realized. The preoperative mobility for group 1 was 26° of Postoperatively walking without crutches is allowed extension and 17.5° of flexion on average; for group 2 the next day and the wearing of a medical soft padded the hallux extension was at 47° for 15° flexion. At the shoe is recommended for the next two weeks. end of the procedure, the dorsiflexion obtained was at In all cases, patients needed one day hospital stay. least 80°. The average duration of the percutaneous
50 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine and arthroscopic procedure was 64 minutes, no Weaknesses of the study: retrospective study with a adverse events were reported. small series of patients, no long-term results.
Operative follow-up was simple with minimal residual The literature is poor in this field, no comparison was pain (VAS = 1) for both groups and one return to work made. at 3 months with one exception, 1 patient who had 4 months off work due to persistent pain (VAS = 4). CONCLUSION
At 3 months of the operation the group 1 had 77° The arthroscopy of the hallux makes it possible to extension of the hallux for 8° of flexion while for the achieve an accurate joint assessment and a suitable group 2 one notes 85° of extension for 15° of flexion. treatment. In our very short experience and to confirm In terms of increased mobility at 3 months, the arthroscopic debridement and the synovectomy arthroscopy has not yet shown superiority over complementary to the percutaneous pruning isolated percutaneous articular pruning, but in terms improves the subjective score of the treatment of the of subjective satisfaction, group 2 reported better early hallux rigidus, but it remains to define the result results in terms of pain. Only one patient underwent a and in particular the gain of mobility at a distance and bilateral pruning, and he declared himself more at to quantify the progression towards osteo- satisfied on the side operated by arthroscopy plus phalangeal osteoarthritic degeneration. percutaneous pruning than by the side operated by isolated percutaneous pruning. Abreviations VAS: Visual Analog Scale Our working hypothesis was therefore invalidated. Acknowledgements There are no conflict of interest.
References:
1. Campbell’s Operative Orthopaedics, twelfth edition, S. Metatarsophalangeal Joint Degeneration: Arthroscopic Terry Canale, James H. Beaty- First metatarsophalangeal Treatment.Schmid T1, Younger A2 joint arthroscopy, p 2389 4. Foot Ankle Clin. 2015 Hallux metatarsophalangeal 2. Clin Orthop Relat Res. 1979 Jul-Aug;(142):57-63.Hallux arthroscopy: indications and techniques.Siclari A1, Piras M2. rigidus: A review of the literature and a method of 5. Foot Ankle Int. 2015 Jan;36(1):113-9. doi: treatment.Mann RA, Coughlin MJ, DuVries HL. 10.1177/1071100714559728.Hallux metatarsophalangeal 3. Foot Ankle Clin. 2015 Sep;20(3):413-20. doi: (MTP) joint arthroscopy for hallux rigidus.Hunt KJ1. 10.1016/j.fcl.2015.04.004. Epub 2015 Jun 6.First
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Article received on March 28, 2018 and accepted for publishing on August 14, 2018. ORIGINAL ARTICLES
Women’s facial attractiveness nowadays – results from analysis of public figures
Cristina T. Preoteasa, Sabina Iordache, Marina Imre, Paula Perlea, Ana Maria C. Tancu, Elena Preoteasa
Abstract: Aim. To identify the main facial features associated to facial attractiveness in women nowadays. Method. A descriptive study was conducted on a sample of 20 female public figures, very famous and successful women, most frequently actresses, singers or models, considered very beautiful nowadays. Their selection followed the analysis of several recent tops that aimed identifying most beautiful women, in which raters were lay persons. Data was collected by analyzing photos from frontal and lateral view, during rest position and smiling. Results. The persons analyzed registered diverse facial traits. Most obvious trends, encountered in more than 75% of them, included: Caucasian race; straight and long hair; average nasal tip protrusion; maxillary dental midline concordant to facial midline; a thicker lower lip compared to the upper lip; exposure of only maxillary incisors during smile; decreased or absent buccal corridor; maxillary central incisors of oval/rectangular shape; absence of maxillary teeth crowding. Other frequently encountered features were: American nationality; brown hair; eyes with medium size, almond shape, wide set, of green color; nose with an average width; face with a decreased lower third and a slightly convex profile; a thick lower lip and an average upper lip; exposure during smiling till the first molar, with a normal smile line. Conclusions. The public beautiful women nowadays register features that are generally associated to an increased facial attractiveness. Knowledge of trends in facial beauty is useful in dental practice, in order to understand better patient’s need in terms of esthetic expectations. Keywords: esthetics; beautiful; dentistry
INTRODUCTION including dental treatments. Exposure to mass media (television, internet, movies) influenced perception of Nowadays, in the modern human attractiveness, which registered in time society physical appea- changes, some of the considerable. Consequently, rance and facial esthetics more and more in the dental field preoccupations that play an important part in target providing esthetic outcomes can be observed. communication in every- In this context, the dentist must know and understand day life, which associated what is considered attractive nowadays, in order to 1 Faculty of Dental changes of patients’ Medicine, “Carol Davila” perception on various University of Medicine and Corresponding author: Cristina T. Preoteasa Pharmacy, Bucharest aspects related to them, [email protected]
52 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine explain to the patient what are the possibilities and consensus was achieved together with a third limits of the interventions provided by him. The evaluator afterword. Study variables included diversity of clinical situation require dental treatment personal data (age, sex, nationality, race), general individualization, and a specific plan in order to features of the face, hair, eyes and nose, lips, teeth, enhance facial attractiveness. Considering beauty has some registered during rest or smile position. a biological inherent dimension, each treatment Data on medical interventions with impact on face should be adapted according to ones features. One attractiveness was also searched, main being triggered particular intervention that had a good outcome from two directions – dental treatment (e.g, prosthetic an esthetic point of view in one person, does not restorations, orthodontic treatment, tooth whitening) necessary have a similar good outcome in another. and plastic surgery or other interventions to the face, The aim of this study was to identify the main facial nose or lips. Data was collected through photo features associated to facial attractiveness in women inspection aided by metric and angular measurements nowadays. performed in Adobe Photoshop software.
Data analysis was mainly based on descriptive METHOD statistics, targeting describing facial attractiveness A descriptive study was conducted on a sample of patterns by describing most frequent encountered female public figures, very famous and successful characteristics in females considered very beautiful women, most frequently actresses, singers or models, and attractive. Microsoft Excel and SPSS (Statistical considered very beautiful nowadays. Their selection Package for the Social Sciences) were used. followed the analysis of several recent tops that aimed identifying most beautiful women nowadays, in which RESULTS raters were lay persons that voted online, of different The persons analyzed registered diverse facial traits. ages and nationality. In the study sample was targeted Of the 20 persons, for one was not found any picture to be included 20 women, most frequently while smiling. Most obvious trends, encountered in encountered in these tops, as being considered very more than 75% of them, included the following: beautiful and attractive. Caucasian race; straight and long hair; average nasal Data upon facial characteristics was collected by tip protrusion; maxillary dental midline concordant to analyzing photos from frontal and lateral view, during facial midline; a thicker lower lip compared to the rest position and smiling. Considering the inability to upper lip; exposure of only maxillary incisors during personally examine the subjects, an extensive search smile; decreased or absent buccal corridor; maxillary was conducted in order to identify as many photos as central incisors of oval/rectangular shape; absence of possible. Two persons evaluated each person maxillary teeth crowding; presence of teeth independently, and for discrepancies between them whitening.
Figure 1: Aspect of the lips of the women analyzed
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Other frequently encountered features, found in more a slightly convex profile; a thick lower lip and an than 50% of the analyzed persons, were: American average upper lip; exposure during smiling till the first nationality; brown hair; eyes with medium size, molar, with a normal smile line (Table 1, Figure 1 and almond shape, wide set, of green color; nose with an 2). average width; face with a decreased lower third and
Table 1: General and facial characteristics of the beautiful women analyzed Age (years) mean: 31; median: 29.5; range: 24-49 Nationality American (n=11); Indian (n=2); English (n=2); Ukrainian (n=2) Race Caucasian (n=18); African-American (n=2) Hair color: brown (n=11); blond (n=8); brunette (n=1) aspect: straight (n=16); curly (n=4) length: long (n=17); short (n=3) Eyes size: medium (n=13); big (n=4); small (n=3) shape: almond eyes (n=10) position: wide set eyes (n=11); average set eyes (n=7); close set eyes (n=2) color: green (n=10); brown (n=6); blue (n=4) Nose nose width: average (n=12); narrow (n=5); wide (n=3) nasal tip protrusion: average (n=15); protruded (n=4); retruded (n=1) nasolabial angle: increased (n=12); medium (n=6); decreased (n=2) Face shape pentagon (n=7); oval (n=6); square (n=3); round (n=2); rectangular (n=2) Dental midline to facial concordant (n=17); slightly deviated (n=2) midline Vertical facial proportion decreased lower third of the face (n=12); similarity of lower and middle third (n=5); increased lower third (n=3) Profile slightly convex (n=14); straight (n=6) Lips upper lip volume average (n=12); thick (n=7); thin (n=1) lower lip volume: thick (n=13); thin (n=7) comparative evaluation: thicker lower lip (n=18); thicker upper lip (n=2) Tooth exposure while only maxillary teeth (n=16); maxillary and mandibular teeth (n=3) smiling till the first molar (n=10), second premolars (n=8), canines (n=1) normal exposure of maxillary central incisors/smile line (n=13); lower exposure of maxillary central incisors (n=3); gummy smile (n=4) Buccal corridor decreased or absent (n=14) Central maxillary incisors form: oval/rectangular (n=15); triangular (n=4) size: average (n=15); bigger (n=4) Maxillary teeth crowding absent (n=16); mild (n=3) Interventions with impact dental prosthesis (n=2); teeth whitening (n=14); orthodontic treatment on facial esthetics (n=2); interventions to the nose (n=3); interventions to the chin (n=1)
DISCUSSION American nationality and Caucasians. This may be primarily linked to the way study sample was formed, This study’s results, by the high percentages observed more precisely of actresses, singers and models. The in many facial traits, suggest that in the public opinion American movie and music industries are very well there is a facial pattern of female attractiveness. Some developed and mediatized worldwide, through this of them (e.g. facial symmetry, normal smile line) are in probably influencing lay person perception of facial accordance to general norm that define a beautiful attractiveness. face. The age of the persons included in this study sample In this study the majority of the persons were of was variable, from 29 to 49 years old. In this regard,
54 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine should be noticed that it can be said that beautiful and attractive women in current society does not equal young women, but also middle-aged ones.
Figure 2: Aspect of the smile of the women analyzed
Oval and pentagonal face forms are generally role in smile appearance [7,8]. This aspect is confirmed considered as being most attractive form face [1], by this study results as most persons had normal smile these being the most frequently observed in this study line, and an important part tooth whitening. Also, sample. Also, symmetry is another aspect that is most of the persons presented an increased smile known to influence facial attractiveness [2], which is width and a decreased or absent buccal corridor, also supported by the results of this study. In our which is confirmed by some studies to be related to an sample of women considered very attractive there increased facial attractiveness [9,10]. were found most frequently persons with a reduced An attractive facial profile includes often, beside ones lower facial third, and very few with an increased natural traits, also artificial improvements through lower facial third, results that are supported by the interventions, some medical, as the dental ones. In this findings of numerous studies [3]. study was tried to identify medical interventions made Lips are considered to play an important role in facial in order to increase facial esthetics. This aspect is attractiveness, one important parameter being lips’ difficult to analyze but, even so, by comparing thickness [4,5]. In females analyzed in this study were nowadays to previous photos, there were identified generally found to have thick lips, most frequently the several dental interventions, namely presence of fixed lower lip being thicker than the upper lip. Generally an prosthetic restoration, tooth whitening and equal thickness of upper and lower lip is perceived as orthodontic treatment, for the previous one pictures unaesthetic, this situation not being encountered in of the persons or/and their own statements being this study. used. Considering that, it is important for the dentists of various specialty (e.g., orthodontists, Smile is considered as greatly influencing facial prosthodontist) to know and understand lay persons’ attractiveness, dental treatments being often solicited perception on facial attractiveness, in order to deliver for remediating some problems as perceived by most appropriate interventions, in accordance to patients, therefore an accurate evaluation of it being patient’s need and expectations [11-13]. recommended [6]. Aspects as color of teeth and gingival display are well known to play an important
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Among study limitation can be mentioned the method facial attractiveness. Knowledge of trends in facial of data collection, considering the difficulties in finding beauty is useful in dental practice, in order to adequate photos for a correct analysis and difficulties understand better patient’s need in terms of esthetic in assessing prior intervention made to enhance facial expectations, and for adapting to his practice by esthetics. Even so, there were mainly registered including newest treatment that aim improving variables that were relatively easy to be assessed. esthetics. The dentist can also use example of public Also, another limitation is the relative small sample beautiful women in order to explain and argument his size, considering the numerous beautiful women that recommendations regarding certain treatment are public figures nowadays. conduct, from an esthetic point of view.
CONCLUSIONS Acknowledgements The authors reported no conflicts of interests related to this The public beautiful women nowadays register paper’s information and also reported equal contribution to features that are generally associated to an increased this paper elaboration.
References:
1 Goodman GJ. The Oval Female Facial Shape--A Study in influence on personality. Angle Orthod. 2007;77(5):759-765. Beauty. Dermatol Surg. 2015;41(12):1375-1383. 8 Draghici R, Preoteasa CT, Ţâncu A, Preoteasa E. Dental 2 Little AC, Jones BC, DeBruine LM. Facial attractiveness: color assessment through TTB exercises. J Med Life. 2016; evolutionary based research. Philosophical Transactions of 9(1):61-65. the Royal Society B: Biological Sciences. 2011; 9 Dong JK, Jin TH, Cho HW, Oh SC. The esthetics of the smile: 366(1571):1638-1659. a review of some recent studies. Int J Prosthodont. 3 Johnston DJ, Hunt O, Johnston CD, Burden DJ, Stevenson 1999;12(1):9-19. M, Hepper P. The influence of lower face vertical proportion 10 Martin AJ, Buschang PH, Boley JC, Taylor RW, McKinney on facial attractiveness. Eur J Orthod. 2005;27(4):349-354. TW. The impact of buccal corridors on smile attractiveness. 4 Hall D, Taylor RW, Jacobson A, Sadowsky PL, Bartolucci A. Eur J Orthod. 2007;29(5):530-537. The perception of optimal profile in African Americans 11 Melescanu Imre M, Marin M, Preoteasa E, Tancu AM, versus white Americans as assessed by orthodontists and the Preoteasa CT. Two implant overdenture-the first alternative lay public. Am J Orthod Dentofacial Orthop. treatment for patients with complete edentulous mandible. 2000;118(5):514-525. J Med Life. 2011; 4: 207-209. 5 Ferrario VF, Sforza C, Poggio CE, Tartaglia G. Facial 12 Preoteasa E, Florica LI, Obadan F, Imre M, Preoteasa CT. morphometry of television actresses compared with normal Minimally Invasive Implant Treatment Alternatives for the women. J Oral Maxillofac Surg. 1995;53(9):1008-1014. Edentulous Patient-Fast & Fixed and Implant Overdentures. 6 Preoteasa CT, Axante A, Hagiu AM, Criastea AD, Preoteasa In: Turkyilmaz I editor. Current Concepts in Dental, in Dental E. Comparative analysis of phonetic tests used for assessing Implantology, InTech, 2015, 77-103. the smile display. Romanian Journal of Oral Rehabilitation. 13 Preoteasa E, Imre M, Preoteasa CT. A 3-year follow-up 2016; 8(1):43-50. study of overdentures retained by mini-dental implants. Int 7 Van der Geld P, Oosterveld P, Van Heck G, Kuijpers- J Oral Maxillofac Implants. 2014; 29: 1170-1176. Jagtman AM. Smile attractiveness. Self-perception and
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Article received on September 17, 2018 and accepted for publishing on November 15, 2018. CLINICAL PRACTICE
The semi-centenary of a prestigious medical unit: Military- Medical Research Center
Viorel Ordeanu1,2
Abstract: The Military Medical Research Center (CCSMM) is a health research unit, subordinated to the Medical Directorate of the Ministry of National Defence. The overall objective is represented by conducting researches on the medical protection against weapons of mass destruction (ADM) that use chemical, biological, radiological and nuclear (CBRN) agents, on the accidents involving CBRN agents and on the military-medical expertise in the field. The CCSMM specialists develop methods and techniques for diagnosis, prophylaxis, treatment and recovery to optimize medical countermeasures during peace, war, or crisis situations. The activity is complementary to the one carried by the “Cantacuzino” National Military-Medical Institute for Research and Development which deals with the diagnosis of infectious diseases (microbiology and epidemiology) and the production of reagents and biological medicinal products for infectious diseases. In conclusion, CCSMM is a unique healthcare unit nationwide, by its field of activity, having a tradition of over half a century, during which it has formed specialists and has had outstanding achievements in the medical protection against CBRN weapons and agents. There are prerequisites for the further development and visibility of the institution. Keywords: military medical research, CBRN medical protection, biological warfare agents, bioterrorism, microbiology
INTRODUCTION Development (INCDMM) which deals with the diagnosis of The Military Medical Research Center (CCSMM) is a infectious diseases (microbiology health research unit, subordinated to the Medical and epidemiology) and the Directorate of the Ministry of National Defence. The production of reagents and overall objective is represented by conducting biological medicinal products for researches on the medical protection against weapons infectious diseases. It also of mass destruction (WMD) that use chemical, cooperates with the CBRN Defence biological, radiological and nuclear (CBRN) agents, on and Ecology Scientific Research the accidents involving CBRN agents and on the Center (CCSACBRNE) which seeks military-medical expertise in the field. The CCSMM the CBRN non-medical protection. specialists develop methods and techniques for Each of the three research diagnosis, prophylaxis, treatment and recovery to institutions addresses the issue of 1 optimize medical countermeasures during peace, war, Military Medical the protection of troops and the Research Center, or crisis situations. The activity is complementary but Bucharest, Romania civilian population from another distinct to the one carried by the “Cantacuzino” 2 Titu Maiorescu perspective, without overlapping National Military-Medical Institute for Research and University, Bucharest
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but being complementary. As a result, they must wards and work stations. To the personnel recruited cooperate. from the Ministry of Health were added the military and civilian specialists, and from the Military Hospitals HISTORICAL BACKGROUND in the territory were selected the most valuable specialists, who became scientific scholars. The In the military-political context of the Cold War, there ranking was made for real personal merits and was also the danger of nuclear attack. The Romanian professional experience, not by “competition”. Ministry of Health set up a research healthcare unit in 1967, which functioned on the platform of Fundeni CLASSIFICATION AND ENDOWMENT Hospital in Bucharest, called the "Center of Radiobiology and Molecular Biology". This unique The first commander, since December 1st 1968, the institution in Romania did not happen by chance. We Center’s founder, was the late Colonel Alexandru remind that at that time on Romanian territory was Popescu M.D., an exceptional microbiologist with prohibited the stationing of nuclear weapons, so as experience in exotic and tropical diseases, and who not to be considered a pretext for a nuclear attack on also participated in the fight against the plague and the country. The international context was strained: cholera epidemics in India. He would later become the "missile crisis" had just ended in which the US Head of the Medical Directorate, Major General nuclear missiles from Incirlik (Turkey) had been Professor A.G. Popescu, PhD. directed to Moscow, and the Soviet ones from Cuba Other personalities of military medicine were also in had been directed towards Washington, and the "mid- charge: the Colonel Laurenţiu Dragomirescu M.D., range missiles" problem was debated in Europe from Colonel Aurel Andrieş M.D., Colonel Tudor Toma M.D., the east and west coast of the continent. Colonel Ion Urseanu M.D. A special stage in the As a result of the events of August 1968, when the evolution of CCSMM began during the mandate of the USSR invaded Czechoslovakia, and Romania was in commander Colonel Victor Voicu M.D., who was to danger of being invaded, the Romanian Army was become Head of the Medical Directorate, Major reorganized and this Center was taken over from the General Acad. Professor Victor A. Voicu, M.D., PhD Ministry of Health by the Ministry of Armed Forces former Secretary General and current Vice President (which later became the Ministry of National Defence) of the Romanian Academy and President of the by HCM no. 2423/31.10.1968. Starting with December Department of Medicine of the Romanian Academy, 1st, 1968 it functioned as a military unit called the member of the Medical Academies in Bucharest and "Radiobiology Center". Its aim was scientific research Paris etc. Colonel Mihail Silviu Tudosie M.D. (currently in the field of medical protection against the effects of the commander of the Military-Medical Institute) and the nuclear weapon. Colonel Radu Gabriel Hertzog M.D., the current CCSMM commander, followed. In 1969, through the Order of the Chief of Staff, the Center's attributions were extended to the medical During this period, the CCSMM gradually benefited protection against the other WMDs as well, and the from several workplaces, suitable for the scientific name which it still preserves was changed to the research activity: the Bratianu villa from 37 C.A. "Military Medical Research Center". The unit had an Rosetti Street (Pavilion A for Command and independent brigade rank subordinated to the Administration and Pavilion B for the Toxicology Medical Directorate, and the commanding ranks were Laboratory), a radiobiology pavilion at Fundeni at Division level of Lieutenant General, M.D. and Major Hospital, subsequently completed with vivarium and General, M.D. The three component laboratories the underground pavement of the Accelerator for corresponded to the NBC classification (nuclear, Cancer Therapy; the Microbiology Laboratory at the biological and chemical), being ranked regimental, and Cantacuzino Institute (1st Ward), 7th floor and were run by Colonels – medical doctors, who were also another at the Cernica Fort (2nd Ward), the scientific scholars. The laboratories were made up of Department of Clinical Toxicology at the Floreasca
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Emergency Hospital, the Psychophysiology and the SPECIFIC MILITARY ACTIVITIES Psycho-pharmacology Laboratory at the Central CCSMM has also been directly involved in military Military Hospital (in a pavilion originally designed and activities such as national and international exercises built to belong to CCSMM), etc. But as a result of and applications, participating in the Persian Gulf War successive restructurings, since 1986 and those (1991), in Somalia and Angola, providing military- following the December 1989 Revolution, the staff has medical expertise in CBRN incidents, expertise of been progressively reduced and the rank of the unit suspected objects brought by the Romanian has fallen to regimental level. After the annulment of Intelligence Service (e.g. “biological bomb” discovery the Warsaw Treaty, it was assumed that there would or “anthrax letter” of U.S. Embassy), MAI, the Military be no more wars (!!) and the Center was in danger of Police (e.g. control for aircontainers), DIR, BOS (e.g. being completely abolished. Several spaces were Afghanistan suspect probes), CBRN equipment testing successively lost, the remaining staff and research in laboratory and in field, postal biological control equipment were and will probably be deployed. (letters and box) etc. which constitute situational THE SCIENTIFIC RESEARCH ACTIVITY experiments for validating research and training in real terms. The unit was certified as a scientific research institution (IP) through GD no. 551/2007 and ANCS PUBLISHING ACTIVITY Decision no. 9806/2008. Currently, Romania, being a The CCSMM staff actively participate in the scientific member of the European Union and NATO, grants due life through communications to national and importance to national defense and security, including international scientific events, publishing of books, to the medical protection against the CBRN WMD. In chapters and articles (including hundreds of ISI articles this context, CCSMM is in the period of renewal of indexed in the Web of knowledge), inventions, staff, premises, endowment and work procedures, for didactics and publicity in the military and civilian press. modernization and openness to new trends in military In 1998, Major General Acad. Professor Victor A. medicine and military scientific research. Voicu, M.D., PhD organized a NATO scientific event, in The results of the scientific research activity have Bucharest, entitled “Proceeding of the NATO materialized through processes, methods of Advanced Research Workshop on Antidotes, treatment or diagnosis, and experimental Protectors and Decorporators”, the papers of which development of new protective compounds and were published by the Kluwer Publishing House in antidote products, protective equipment, etc. These 1999. Scientific papers have been published in the have been endorsed, received, approved, and some Journal of Military Medicine, the National Defense have been patented as inventions. CCSMM had at its University Bulletin, Strategic Impact, the Military former headquarters a permanent exhibition of Science Journal, Strategic Universe, NBC Defense, the experimental models and prototypes of reagents, Military Observatory, Medical Life, etc. Books were medicines, antidotes, complete kits and models published by the Military Publishing House, the developed within the research projects. Many of them Medical Publishing House, the "Carol Davila" were also presented at military exhibitions: The University Publishing House, as well as own publishing. permanent exhibition of military technology from Through these activities, the scientific knowledge of ACTTM Clinceni, EXPOMIL 2011 and 2013, BSDA 2014, interest disseminates and the visibility of CCSMM 2016 and 2018, the National Exhibition of Inventors increases, both in the country and abroad. 2012 and 2013 (where the Golden Medal and Diplomas of Excellence were obtained), etc. Some of EDUCATIONAL ACTIVITIES them have been practically used on missions in the CCSMM specialists are also involved in academic and country and abroad (Saudi Arabia, Iraq, Somalia, university activities, at the Military-Medical Institute, Angola etc.). the "Carol Davila" University of Medicine and
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Pharmacy in Bucharest, the "Titu Maiorescu" formation of a new generation of specialists to take University, Bioterra University, the Medical School of over for the future. Besides the main field of scientific Non-comissioned Officers in Focşani, etc. The CCSMM research and expertise for medical protection against researchers have benefited from recognition of their CBRN/WMD, new and related areas are also work: excellence diplomas, awards, decorations, successfully addressed, which are concerned with biographies mentioned in encyclopedias, etc. specific military pathology. Thus, in May 2018, an original work of regenerative medicine was awarded a PROSPECTS FOR DEVELOPMENT prize at the 23rd Congress of the Balkan Military Medical Committee (BMMC) in Antalya, Turkey. The The military-medical scientific research, which seemed operationalization of the Integrated Platform of to be forgotten by decision-makers in recent years, is Scientific Research and Expertise of CBRN agents for reviving. The military-political world situation, which is medical protection will support the work of CCSMM "volatile", brings to the forefront the importance of and will allow new research directions to be addressed military medicine and, implicitly, of military-medical within existing laboratories. The latest participation is scientific research, primarily in regards to the medical of 16th Medical Biodefense Conference in Munich, 23- protection against CBRN weapons/agents. The 31 October 2018. prospects for the quantitative and qualitative development of CCSMM materialize and, as CONCLUSIONS consequence, the context favorable for the cooperation with an old collaborator occurs, the CCSMM is a national military-medical unit, unique in “Cantacuzino” Military-Medical Research- its field of activity with a tradition of more than half a Development National Institute, which was also taken century, during which it has formed exceptional over from the Ministry of Health by the Ministry of specialists and has had outstanding achievements in National Defense. the scientific research on medical protection against the CBRN weapons and agents. There are The current situation also allows the area of scientific prerequisites for the further development and preoccupations to be extended in order to cover other visibility of the institution. areas of medical and military interest, as well as the
References:
1. Internet, ccsmm.ro 4. Ordeanu V. “Repere ale cercetarii stiintifice medicale: Orizont 2020” Revista Viata Medicala, nr. 1240, 42, 2013 2. Ordeanu V. “Semicentenarul Centrului de Cercetari Stiintifice Medico-Militare” Revista de Stiinte Militare, Nr. 4, 5. Popescu G. “Aniversarea Centrului de Cercetari 2018 Stiintifice Medico-Militare” Revista de Medicina Militara, nr. 4, 2013. 3. Ordeanu V. “45 de ani de cercetari stiintifice medico- militare” Revista Viata Medicala, nr. 1251, 1, 2014
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Article received on May 15, 2018 and accepted for publishing on August 21, 2018. CLINICAL PRACTICE
Black hairy tongue due to antibiotic intake
Catalina E. Lavric1, Silviu V. Dumitrescu2
A 65-year-old man presented to our clinic for a sudden main problem is its unsighty appearance [3]. onset of black hairy tongue. The patient who has no significant medical history was explored 9 days before for non-specific gastrointestinal symptoms which had progressively accentuated in the past two months. Physical examination showed epigastric tenderness and bloating. Blood tests were within normal ranges but stool antigen test revealed Helicobacter pylori infection. Triple therapy was initiated with 1 gram amoxicillin, 500 mg clarithromycin and 30 mg lansoprazole, all recomanded twice daily for 14 days. In the 9th day he presented with a black hairy tongue which appeared "overnight". Sometimes patients may complain of a burning sensation on the tongue and halitosis. Black hairy tongue doesn't typically require medical treatment [4].
In this case the patient stopped the antibiotic intake on his own initiative and was encouraged to have a good oral hygene. He continued taking 30 mg of lansoprazole for three more weeks.
One month later the tongue Black hairy tongue represents a defective recovers its normal characteristics. desquamation of the filiform papillae on the dorsal Reevaluation of the stool test surface of the tongue, usually due to a lack of showed the efficiency of the short mechanical stimulation and debridement [1]. A range course of treatment, Helicobacter of medications [2] have been linked to hairy tongue pylori being eradicated. including amoxicillin, penicillin, bismuth, linezolid. This 1 Nicolae Malaxa Clinical condition is reported more often in males and the Hospital, Bucharest 2 St Milcu Military Medical Center, Bucharest
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References:
1. https://www.accessdata.fda.gov/drugsatfda_docs/label 0Z7lTEkCQ0QrO0ZMt%2FrtxvhmTGEkBJd%2FsGPYa%2BToE /2015/50542s02950754s01950760s01950761s016lbl.pdf oLjuhFnUEHw%3D%3D 2. https://www.dermnetnz.org/topics/hairy-tongue/ 4. https://www.mayoclinic.org/diseases-conditions/black- 3. https://emedicine.medscape.com/article/1075886- hairy-tongue/diagnosis-treatment/drc-20356080. overview?pa=Fzg1qOkpsMoFvlesuYt1VZFQaBDsCQVd%2BD
62 Vol. CXXI • No. 3/2018 • December • Romanian Journal of Military Medicine
Article received on August 10, 2018 and accepted for publishing on October 20, 2018. CLINICAL PRACTICE
Atypical case of achalasia
Andreea Grigore1, Bianca Săndulescu1, Alexandra Lulache1, Andrada Popescu1,2, Săndica Bucurică1,2, Mihai Șotcan1, Florina Vasilescu1, Petruț Nuță1, Mariana Jinga1,2, Florentina Ioniță Radu1,3, Daniel O. Costache1, Raluca S. Costache1,2
INTRODUCTION the patient had a stroke in 2014 and in 2015 was diagnosed with hepatic cirrhosis of unspecified Esophageal cancer, represented by squamous etiology. The patient was a smoker with a 30 pack per carcinoma and adenocarcinoma, is ranked 8th in year history and didn’t work in a toxic environment. incidence among all the types of neoplasm in the world (456,000 new cases in 2012, 3.2% of total The patient was underweight (BMI = 18.0 kg/m2), but cancers), and is characterized by a significant lethal had a satisfactory overall condition. The abdomen was potential, being the 6th cause of cancer-induced dense and painful on palpation. mortality (400,000 in 2012, 4.9% of total cancers) [1]. The patient had hepatomegaly, was cardio-respiratory 5 years survival after diagnosis is less than 5%, as balanced and did not show any esophageal cancer causes symptoms when more than significant changes in the other 60% of the esophagus is infiltrated by tumor [2]. organs and systems.
CASE REPORT At the time of admission, stage diagnostics included dysphagic A 48-year-old patient presented for progressive syndrome, abdominal algic dysphagia to solids, weight loss of about 15 kg and syndrome, underweight, post- diffuse abdominal pain for the last 3 months. In gastrectomy status, sequelae of addition, the patient noticed moderate dyspnea and stroke, liver cirrhosis in intense pain localized at the right shoulder, without observation. relation to movements. Two months before presentation, the patient performed a superior It is to be mentioned the infla- digestive endoscopy, which diagnosed him with mmatory syndrome (fibrinogen = 484 mg/dL), cholestasis (total 1 Carol Davila University ulcerative esophagitis, but without improvement of Central Emergency the symptoms despite recommended treatment. The bilirubin = 1.47 mg/dL, direct Military Hospital, patient is known with two surgical procedures, a bilirubin = 0.45 mg/dL, alkaline Bucharest phosphatase = 145 U/L, GGT = 322 2 Carol Davila University Billroth I anastomosis for perforated gastric ulcer 12 of Medicine and years ago, and a cholecystectomy in 2018. Moreover, U/L), hyposideremia (Fe = 58 Pharmacy, Bucharest micrograms/dL) without anemia 3 Titu Maiorescu Corresponding author: Daniel O. Costache (Hb = 14.2 g/dL, Ht = 41.2%, RBC University, Faculty of Medicine, Bucharest [email protected] count 4.70 million/mm3). During
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hospitalization, hemoglobin, hematocrit, and RBC computerized thoracic and abdominal tomography count decreased but did not indicate iron deficiency with contrast substance was performed. Computed anemia (hemoglobin = 13.6 g/dL, hematocrit = 39.5, tomography revealed pulmonary diffuse multiple number of erythrocites = 4.5 million/mm3). The micronodular lesions of millimetric dimension. At the patient's hormonal profile indicated euthyroidism. The eso-gastric junction a tumor block was described, with patient was tested for HIV infection, hepatitis B and C exophytic growth, with polylobate form and virus infection, Kohn bacillus infection, but the results iodophyllic aspect, with a maximum diameter of about refuted those diagnostics. CEA and CA 19-9 had 5.5/3.8 cm, with small necrosis included, causing elevated values (CEA = 58.21 ng/mL, CA19-9 = 47.53 distension and stasis in the upstream esophagus. U/mL) and α-fetoprotein was slightly above the Additionally, adenopathy blocks in the small gastric normal range (AFP = 1.1 ng/mL). curvature and celiac trunk were present, measuring up to 6 cm in diameter, the largest being without Abdominal ultrasound and thoracic radiography did boundaries of demarcation with the celiac and not reveal pathological changes in the first phase. At pancreatic trunks. The liver was increased in size, with upper digestive endoscopy fluid debris were present in a maximum cranio-caudal diameter of 19.5 cm, with the esophagus and stomach that prevented irregular contour, and irregular inhomogeneous visualization of the digestive tract. At the repeated structure due to the presence of multiple nodular upper digestive endoscopy, white deposits were lesions, randomly developed in the entire parenchyma attached to the normal mucosa at the level of the that measured up to 1.8 cm, iodophyllic, some with a esophagus, characteristic of mycotic esophagitis. tendency to conflate, compatible with secondary Initially, we couldn’t overcome the cardia with the lesions. Intrahepatic peripheral bile ducts in the left normal endoscope, which is why we turned to lobe exhibited slight dilation, most likely by infiltration babyscope. There were no pathological changes in the generated by secondary lesions while extrahepatic bile stomach and duodenum I and II, and the mouth of ducts were unchanged. No pathological changes were anastomosis from the perforated ulcer surgery was detected in the abdominal vein circulation as well as in supple. Due to these endoscopic findings, the patient the spleen, pancreas, kidneys or adrenal glands. underwent esophageal manometry, and was diagnosed with type 2 achalasia (panesophageal Concluding the tomographic examination, it showed pressurization 100%, IRP = 80.2 mmHg). that the patient had a esogastric junction tumor with bilateral pulmonary and hepatic metastasis and abdominal adenopathy. Later on, the oncological consult confirmed the suspicion of eso-gastric tumor with metastases and recommended biopsy of the hepatic nodules in order to perform the pathological anatomy and immunohistochemical examinations. Hepatic tissue fragments were thus obtained by ultrasound-guided biopsy puncture and the result were: small fragments of liver tissue with neoplastic infiltrates of poorly differentiated carcinoma which is arranged in nests of different sizes. Tumoral cells were cytokeratin7 positive and CDX2 positive. The immune- histochemistry and histopathologic aspects sustain the diagnosis of hepatic metastasis of poorly Taking into account the persistent symptoms and the differentiated gastric adenocarcinoma. changes of the above mentioned laboratory analyzes,
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The patient was then referred to a thoracic surgical immediately after swallowing, the symptoms are often consult which stated that the tumor had no surgical located precisely in the neck and in some cases food indication and in the event of total dysphagia the and fluids follow the path of the trachea or the nose. therapeutic indication was to place an esophageal Another type of dysphagia is esophageal that can be stent or a gastrostomy. caused by primary disorders of motility (achalasia, esophageal spasm, esophageal hypercontractility or An esophageal stent was place and the patient other disorders of the peristalsis) or secondary remains under oncologic surveillence. disorders of motility (Chagas' disease, dysfunction of DISCUSSIONS gastroesophageal reflux disease, scleroderma), or may be due to intrinsic structural pathologies (benign or The differential diagnosis in this case started from malignant tumor, diverticulum, eosinophilic dysphagia, the symptom which was the most intense esophagitis, esophageal rings, foreign bodies, peptic and disturbing for patient. One type of dysphagia is the stricture) or extrinsic ones (mediastinal tumors, oropharyngeal dysphagia (diseases of the mouth, osteophytes spinal, vascular compression) [3]. hypopharynx, esophagus above) in which case the Considering the patient's features of the dysphagia, cause can either be neuromuscular (SLA, central progressive dysphagia for solids accompanied by nervous system tumors, multiple sclerosis, myasthenia weight loss, there was an initial suspicion of a gravis) or structural (carcinoma, throat infections, mechanical cause with a higher likelihood of malignant Zenker's diverticulum) [3]. However, in this type of tumor formation. In general, peptic strictures caused dysphagia, coughing and choking are described by gastroesophageal reflux disease are accompanied
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by chronic heartburn and do not cause weight loss. An interesting aspect to be mentioned is that the The normal endoscopic examination of the esophageal relationship between achalasia and cancer may be a mucosa initially directed the attention to a motility causal one, which is already known in medical practice. disorder, the most common being achalasia, a Patients with achalasia are at risk of developing pathology characterized by poor relaxation of the esophageal cancer, with the predominance of the lower esophageal sphincter in swallowing and lack of squamous cell cancer and the adenocarcinoma in peristalsis in the smooth esophageal muscles. some situations. On one hand, achalasia causes Dysphagia in this disease is progressive, occurs both esophageal stasis with bacterial overpopulation and for solid and liquid foods and is frequently associated production of various chemical compounds, while with regurgitation, chest pain, weight loss symptoms causing chronic inflammatory changes in the that usually progress insidiously within about 2 years esophageal mucosa and dysplasia. Although this [4]. Although manometry diagnosed the patient with complication of achalasia is reduced in frequency, the achalasia, the other symptoms, namely diffuse prevalence of cancer in achalasia being variable abdominal pain, dyspnea, and shoulder pain required according to several studies, there were several the continuation of the investigations, the problem reported cases in literature [7]. Rios-Galvez et al raised being if all the patient's symptoms were in the published a case of a patient, known with achalasia for context of the same disease or another disease more de 15 years, whose symptomatology had overlapping the esophageal pathology. From significantly aggravated within 6 months and who, paraclinical examinations, elevated tumor markers after following investigations, is diagnosed with have turned attention to a possible malignant tumoral squamous carcinoma of the esophagus [8]. What is pathology at the abdominal level that required CT different in our case is precisely the absence of the examination, which was the one that brought the most personal pathological history, achalasia requiring a important information to the case. prolonged period of illness for the esophageal malignancy to occur. On the other hand, esophageal The particularity of this case is that although the adenocarcinoma occurs more frequently in the patient was initially diagnosed with type II achalasia, context of gastroesophageal reflux disease as a the manometry examination showed pseudoachalasia complication of the interventional treatment of in the context of esophageal cancer. Data from achalasia by esophageal dilatation and myotomy [7]. literature suggest that such presumptive results in any manometry examination are not specific to achalasia CONCLUSION and under the conditions of sudden symptoms in less than 1 year, with a weight loss of more than 7 kg in a In conclusion, dysphagia may occur in many benign or patient over 50, the suspicion of pseudoachalasia is malignant conditions, but in a patient with alarming raised. Thus, 5% of the manometric results indicating signs such as age, marked weight loss, even under the achalasia are actually given by tumor pseudoachalasia condition of a diagnosis of neuromuscular motility [5]. Such a case has been published by Segal et al, a disorder, the suspicion of a malignant process must case of a 50-year-old UK patient with the same always be raised and we should act accordingly, symptomatology as the one of the patient in our following paraclinical investigations that can confirm center where the diagnostic process indicated or refute it. achalasia in the first phase, but metastatic adenocarcinoma was eventually detected [6].
References:
1. Ferlay J, Soerjomataram I, Ervik M, et al. Globocan 2012 CancerBase No. 11 [Internet]. v1.0. Cancer Incidence and Mortality Worldwide: IARC 2. Lyon, France: International Agency for Research on
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Cancer; 2013. Available from: http://globocan.iarc.fr. 701-732 Accessed on June 30th 2018 6. Ajani JA, Barthel JS, Bekaii-Saab T, et al. Esophageal cancer. 3. Mayer RJ. Gastrointestinal Tract Cancer. In: Harrison’s J Natl Compr Canc Netw. 2008; 6: 818-849 Principles of Internal Medicine, volume 1, 18th ed. Longo DL, 7. Segal J, Lagundoye A, Carter M. Achalasia leading to Fauci AS, Kasper DL. New York: Mc Graw Hill Medical; 2011: diagnosis of adenocarcinoma of the oesophagus. BMJ Case 764-776 Rep. 2017. doi:10.1136/ bcr-2017. 10.1136/bcr-2017- 4. Devault KR. Symptoms of Esophageal Disease. In: 219386. Accessed on June 30th 2018 Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 8. O’Neill OM, Johnston BT, Coleman HG. Achalasia: A review volume 1, 10th ed. Feldman M, Friedman L, Brandt L. Elsevier of clinical diagnosis, epidemiology, treatment and outcomes. Saunders; 2016: 185-193 World J Gastroenterol. 2013; 19(35): 5806-5812 5. Pandolfino JE, Kahrilas PJ. Esophageal Neuromuscular 9. Rios-Galvez S, Meixeueiro-Daza A, Remes Troche JM. Funtion and Motility Disorders. In: Sleisenger and Fordtran’s Achalasia: a risk factor that must not be forgotten for Gastrointestinal and Liver Disease, volume 1, 10th ed. esophageal squamous cell carcinoma. BMJ Case Rep. 2015. Feldman M, Friedman L, Brandt L. Elsevier Saunders; 2016: doi:10.1136/bcr-2014-204418. Accessed on June 30th 2018
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Romanian Journal of Military Medicine New Series, Vol. CXXI, No 2/2018, August ISSN-L 1222-5126; eISSN 2501-2312; pISSN 1222-5126