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Volume XIII, Number 3, 2009 - Therapeutics Pharmacology and Clinical Toxicology


The pandemic flu

Victoria Arama
Abstract: National Institute of Infectious Diseases `Prof. Dr. Matei Bals` Bucharest Associate Professor, University of Medicine and Pharmacy Carol Davila BucharestEditorial Department Chief of Th erapeutics, Pharmacology and Clinical Toxicology

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Treatment and Prophylaxis of Nerve Agent Organophosphates Intoxication

Jiri Bajgar
Abstract: Basic mechanism of action of organophosphates (OP)/nerve agents is based on acetylcholinesterase (AChE) inhibition and subsequent accumulation of neuromediator acetylcholine at the cholinergic synapses, either peripheral or central, causing cholinergic hyperstimulation and development of symptoms of poisoning, followed by metabolic dysbalance and, without eff ective prophylaxis/treatment leading to death. Th e treatment of nerve agents poisoning consists of administration of parasympatholytics (preferably atropine), cholinesterase reactivators (oximes) and anticonvulsants (usually diazepam). Th e choice of reactivators is not so simple. Th eir administration alone is not eff ective but simultaneous administration with atropine potentiates their antidotal eff ects based on AChE reactivation at the cholinergic nerve synapses. AChE reactivation at the peripheral nervous system is indisputable; however, their passing the blood-brain-barrier facilitating their central eff ect is discussed. On the basis of our own and literature data, central reactivation effi cacy of some oximes in vivo is demonstrated. Th ough the research is very intensive, unfortunately, up to now, there is not universal reactivator suffi ciently eff ective against all nerve agents/OP. A possible direction solving this problem is discussed - it is the use of combination of more reactivators. Th e good raectivating and therapeutic eff ect of combination of trimedoxime and HI-6 against tabun poisoning in rats is demonstrated. Prophylaxis against nerve agent intoxication is based on various approaches: Keeping AChE, key enzyme for toxic action of OP/nerve agents intact (protection of cholinesterases) is a basic requirement for eff ective prophylaxis. Detoxifi cation realised by administration of the enzymes splitting the OP or evaluating specifi c enzymes (cholinesterases) is another possibility (stoichiometric and catalytic scavengers). Th e antidotes currently used for the treatment of OP poisoning including reactivators are to be tested as prophylactics. Th is principle can be considered as a `treatment in advance`. Th e problem with use of reactivators is the timing, duration and achievement of suffi cient levels of these antidotes after the administration. Transdermal administration of reactivators solves these diffi culties. As a result of this research, prophylactic antidote TRANSANT (transdermal patch containing HI-6) was developed as the prophylactic mean and introduced into the Czech Armed Forces. Future development will be focused on scavengers (cholinesterases and other enzymes) acting before the binding of nerve agent to the target sites, and to other drugs either reversible cholinesterase inhibitors (e.g. huperzine A, physostigmine, acridine derivatives etc.)

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Genetic polymorphism and pathogenic factors influencing the risk of metabolic syndrome among HIV-infected patients

Victoria Arama, s¾. S. Arama, Daniela Adriana Ion, C. Tiliscan, Raluca Mihailescu, Ioana Olaru
Abstract: The metabolic syndrome is characterized by the clustering of classic and emerging risk factors for cardiovascular disease and diabetes. If the diagnosis can be accomplished by simple clinical and biochemical tests, its pathophysiologic chain of events is complex and not comprehensively understood. Since the introduction of HAART changes in fat distribution, dyslipidemia, dysglycemia, and other metabolic abnormalities are increasingly observed, and they present major challenges for clinicians involved in screening, evaluation and treatment of HIV/AIDS. Th ere is an increasing literature suggesting that all metabolic syndrome components are strongly inherited. Given the high prevalence of these metabolic complications among HIV-positive patients, an increasing number of authors suggest that it might be useful to test the genetic individual risk, prior to the introduction of HAART. In doing so, it will be possible to design individual HAART regimens for each patient and the clinician will be able to take early measures to prevent the cardiovascular and metabolic complications.

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Investigation of correlation stress hyperhomocysteinemia, in rats

Albu E., Filip C., Zamosteanu N., Dimitriu D.C., Jaba I.M., Gheorghita N., Jerca L., Mungiu O.C.
Abstract: Today it is generally accepted that the so called -stress- plays an important role in the process of aging. The main mechanism through which stress is involved in the aging process seems to be represented by reactive species generation. On the other hand, hyperhomocysteinemia, a risk factor in cardiovascular diseases, disturbs the normal endothelium functions and generates thrombosis through a mechanism in which reactive species seem to be also involved. In our work, we have studied the infl uence of stress and hyperhomocysteinemia on antioxidant intraand extracellular systems, in order to establish if there is a cumulative eff ect of these two parameters, in rats. Experimental stress was induced by reversing the normal cycle day/night (18oo - 6oo light) at the animals of experience for a 15 days period. Experimental hyperhomocisteinemia was induced by oral administration of methionine 2g/kg body weight, single dose daily, for a 15 days period. The activities of intracellular superoxide dismutase (SOD), glutathione peroxidase (GPx) and plasma total antioxidant status (TAS) were measured using Randox kit for manual use. The plasmatic concentrations of homocysteine were measured using a Roche standardized kit Diazyme. Our data show an increase in SOD activity, simultaneously with the decrease of GPx activity. The total antioxidant status and homocysteine levels have no signifi cant changed. In conclusion, subacute stress activates the antioxidant defense systems but doesnt infl uence the total antioxidant capacity and homocysteine levels, in rats.

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Biocompatibility and effects of a composite nanomaterial containing silver

B. A. Hagiu, V. Tura, Doina Mahaila, M. Fantanaru, O. C. Mungiu
Abstract: Our previous studies revealed the ability of composite materials based on Ag nanoparticles to induce hair follicle regeneration. As a step forward in this research, the present study investigates the biocompatibility of composite materials consisting of polyurethane-urea nanofi bers functionalized with silver nanoparticles by subcutaneous implantation in rabbits. In the same time, we recorded the infl uence of these materials on hair follicles. Macroscopically we noticed acceleration of surgical wound cicatrisation and of hair growth in the area located above the composite material implant. Microscopic analysis revealed that the infl ammatory response produced by implantation was minimal, the nanofi brilar matrix serving as support for the multiplying of young fi broblasts, and above it the hair follicles proliferate in the hypodermis and dermis. Th e biological eff ects suggest that these composite materials could be used as dressings for teguments covered with hair.

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Experimental study on the analgesic effect of dimethylsulfoxide in mice using the writhing test

H. Paunescu, Oana Andreia Coman, Eugenia Panaitescu, Andreea Anca, Isabel Ghita, I. Fulga
Abstract: DMSO (dimethylsulfoxide) is frequently used in fundamental pharmacology as solvent for diff erent organic compounds, due to its amphipathic molecule, which is soluble in both aqueous and nonpolar, organic media. Aim. In the present experiment we tried to explore if DMSO has an analgesic eff ect per se in the writhing test, pure or diluted 1:1 in saline. If so, the question remains if it can be used without any problem as vehicle for nonpolar substances with a possible visceral analgesic eff ect. Materials and methods. Five groups of albino mice were tested with DMSO, pure or diluted in saline 1:1 vol/vol, metamizole sodium+saline and metamizole sodium+DMSO diluted in saline 1:1 vol/vol. Th e writhing test was performed 120 min after substances administration and the observation of writhes lasted for 5 minutes. Statistic analysis of data was made with the programs Excel and SPSS 15. Results and discussions. A statistically signifi cant diff erence between the tested groups was obtained using a nonparametric statistic test (Kruskal Wallis). DMSO pure had a signifi cant analgesic eff ect, while DMSO diluted 1:1 in saline did not. DMSO associated to metamizole sodium had a nonsignifi cant tendency to increase the analgesic eff ect of metamizole sodium in the writhing test. Conclusions. Th ese results raise the question of a possible interference of DMSO, used as vehicle, on the analgesic eff ects of other substances assayed in the writhing test.

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The angiotensin II arrhythmogenic potential through central nervous mechanism in rats

Gabriela Cioca, Liviu Safta, Dana Gosa
Abstract: Angiotensin II (ATII) causes through the central nervous mechanism certain cardiovascular disorders. Th e participation of a central nervous component in the genesis of cardiac arrhythmia caused by Angiotensin is stated. Th e present paper describes the action exerted by ATII on the cardiac rhythm, after intracerebroventricular administration (icv) in rats anesthetized with ethylic urethane. Th e disorders of the cardiac rhythm induced by the ATII may be prevented or attenuated by blocking the AT1 receptors with and adequate antagonist, administered through icv.

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Experimental researches on the effects of a selective kappa opioid agonist in cutaneous and visceral pain models in mice

Liliana Tartau, Calin Andritoiu, Elena Teslariu, Corina Dima, Eusebiu Viorel s¾indrilar
Abstract: Experimental researches on the eff ects of a selective k opioid receptor agonist in cutaneous and visceral pain models in mice. Material and method Th e experiments were carried out on white Swiss mice (20-25g), divided into 4 groups of 7 animals each, treated intraperitoneally with the same volume of solution, as follows: Group I: distilled water (Control) 0,3ml; Group II (U-50488H 10): U-50488H 10mg/kbw; Group III (U-50488H 20): U-50488H 20mg/kbw; Group IV (MOR): morphine 2mg/kbw. Experimental protocols were implemented in accordance to the recommendations of the committee of research and ethics of the International Association for the Study of Pain. Th e nociceptive cutaneous testing was performed using the tail fl ick assay. Th e model of visceral pain consisted of infl ammatory cystitis after intraperitoneal injection of cyclophosphamide (200 mg/kbw). Th e data were presented as +/- SD and signifi cance was tested by SPSS for Windows version 13.0 and by the ANOVA method, followed by the Neumann Keuls test as post hoc. Results and conclusions. In our experimental conditions, U50,488H (10mg/kbw) determined antinociceptive signifi cant eff ects in tail fl ick test, 30 minutes after thermal noxious stimulation, but did not infl uence visceral nociceptive responses in cyclophosphamideinduced cystitis. Intraperitonal administration of selective k opioid agonist U50,488H, 20mg/kbw, resulted in a potent analgesia in both cutaneous and visceral pain models.

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Original Papers

Therapeutical Practice

Correlations between non-invasive explorations and liver biopsy in the determination of liver fibrosis in chronic viral hepatitis C

A. Streinu-Cercel, Liliana Preotescu, Anca Streinu-Cercel, Ruxandra Calin, Anca Budulac, Oana Streinu-Cercel
Abstract: An adequate diagnosis of fi brosis in viral hepatitis C is essential for treatment decisions and disease prognostic. Because of the limitations of liver biopsy, noninvasive explorations of fi brosis are frequently employed nowadays. Th is studys aim was that of evaluating the correlation between the currently available noninvasive standardized tests (FibroTest and FibroScan) and liver biopsy. Material and methods The study cluster consisted of n=26 naive patients with chronic viral hepatitis C, which underwent antiviral treatment in the National Institute for Infectious Diseases `Prof. Dr. Matei Bals`, Bucharest, Romania, during December 2007 - December 2008. Fibrosis was assessed before commencement of the combined treatment (Pegylated Interferon and Ribavirin) by means of liver biopsy, FibroScan and FibroTest and at 48 weeks through FibroScan and FibroTest, verifying the statistic correlation of the results acquired through the three methods. Results. The values obtained through FibroScan ranged between min 4.9 kPa and max 49.1kPa, respecting the validation criteria IQR<30%, SR>60%. The cut-off values were: 7.1kPa for F2, 9.5 kPa for F3 and 12.5 kPa for F4. FibroScan and FibroTest results have correlated in a 92% percentage. When the results of FibroScan and FibroTest coincided, biopsies were statistically correlated at AUROC 0.79 for F>= 2, 0.91 for F>=3 and 0.97 for F>=4. The frequency of grounds for discrepancy of the three evaluation methods was: LB 5%, Fibroscan 2%, Fibrotest 1%. Conclusions. FibroScan is a new, simple, noninvasive method which is available at the patients bedside for quick evaluation of liver fi brosis degree with accuracy similar to that of the FibroTest, especially for the assessment of signifi cant hepatic fi brosis (F2-F4). The combined use of FibroScan and FibroTest results for the evaluation of hepatic fi brosis degree can permit avoiding liver biopsy in a considerable number of patients with chronic viral hepatitis C.

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Chronic cough in childhood: a clinical and therapeutic approach part II

Doina Plesca,Victoria Hurduc, Iulia Ioan,Anca Badarau
Abstract: The article is divided of two parts. In the first part, the authors discuss about the chronic cough, a subject of a great interest in pediatric practice. Physiopathology, the most important etiologic categories, clinical and paraclinical data, principles of therapy of chronic cough are reviewed. The authors underline the importance of the history of the disease, in establishing the cause of chronic cough in children. A cough that worsens at night may be caused by sinusitis, asthma, or gastroesophageal refl ux. The cough that disappears during sleep, suggests a psychogenic cause. Clinical examination has to be thorough, complete and repeated, focused on ENT segment, chest, respiratory and cardio-vascular system. When clinical data and history cannot establish the cause of chronic cough, paraclinical evaluation is necessary. Any child with chronic cough, no matter the age, must have chest X-Ray examination to eliminate aspiration of foreign body or another severe disease (congenital anomaly, cystic fi brosis, bronchiectasis, cardiomegaly, mediastinal mass). In the second part, the authors present the main clinical entities (cough variant asthma and eosinophilic bronchitis, cough during and after respiratory infections, allergic rhinitis, chronic sinusitis and rhinoadenoiditis, passive smoking, gastroesophageal refl ux, bronchiectasis, aspiration syndrome / foreign body aspiration, deglutition diffi culties, vocal cords dysfunction, compression syndrome, psychogenic cough, otogenic causes - Arnold ear - cough refl ex, cough as a side eff ect of the medication) and the etiologic treatment. The indications of an etiologic treatment have to be infl uenced by a detailed history of the disease and by clinical examination. In the absence of an etiologic factor, the patient will receive symptomatic treatment only if the cough is responsible for awakeness, vomiting and fatigue. Tolerability of cough is the element that determines the indications for inhibitors of cough.

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The experience of palivizumab administration in Romania

Silvia Maria Stoicescu, Ramona Ciocoiu, D. Oraseanu
Abstract: Viral bronchiolitis is the most frequent pathology of the respiratory tract in infants and toddlers (under 2 years of age), the respiratory syncytial virus being one of the most commonly incriminated agents. Th e incidence of respiratory syncytial virus bronchiolitis reported by the Clinical Emergency Hospital for Children `Grigore Alexandrescu` during the past years is increasing. Materials and methods. retrospective study over 2 years (2007 - 2008). In 2007, 9 Romanian Maternities started out in the program for prevention of the respiratory infection with respiratory syncytial virus with Palivizumab provided through donations. Results. 140 newborns were passively immunized, none of them presented respiratory syncytial virus infection. Conclusions. Th ere is need for the elaboration of an administering guide for Palivizumab and there is need for a national program which would include clear selection criteria, specifi c to the newborn population from our country, which could benefi t from the prophylaxis of the respiratory syncytial virus.

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Echocardiographic aspects in HIV infected AIDS children and adolescents

Ana Maria Tudor, Ioana Anca
Abstract: Cardiac lesions are described in HIV infected patients, including children. Th e most characteristic anatomic aspect on echocardiography in HIV cardiomyopathy is dilated left ventricle. Cardiomyopathy correlates with low survival rate. We performed a retrospective study on 59 HIV infected children and adolescents to identify the echocardiographic changes associated with AIDS. Main cardiac lesions found were dilated cardiomyopathy and left ventricle hypertrophy. Cardiac involvement was more frequent in immunosuppressed patients.

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Combined use of embolic agents in the treatment of uterine fibroma

B. Popa, Monica Popiel, L. Gulie
Abstract: Uterine leiomyoma, commonly known as fi broids, are extremely common benign lesions of the uterus, usually surgically managed when symptomatic. The surgical options (myomectomy or hysterectomy) are associated with signifi cant morbidity in terms of increased blood loss, duration of surgery, postoperative complications and longer hospital stay. Another alternative treatment is hormonal therapy using gonadotropin releasing hormone (GnRH) agonists which are primarily used as temporary preoperative measure for reducing tumour size and vascularity. Though this approach dramatically improves symptomatology and reduces fi broid size, these tumours re-grow to their original size within a few months of discontinuing treatment and are associated with adverse eff ects (osteoporosis, amenorrhea). Uterine artery embolization is one of the new treatment options presently available in major institutions as an alternative to hysterectomy in women wishing to preserve reproductive function. Embolization is a minimally invasive means of blocking the arteries that supply blood to the fi broids. It is a procedure that uses angiographic techniques to place a catheter into the uterine arteries. Small particles are injected into the arteries, which results in the blockage of the arteries feeding the fi broids. Uterine artery embolization is also cost-eff ective and is associated with a short hospital stay and may be an option in women with major medical illness. The following treatise addresses the selection of patients, contraindications, details of the procedure and available evidence with regard to safety and benefi ts of the procedure.

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Prolonged febrile syndrome caused by retroperitoneal fibrosis

Al. Crisan, Emilia Nicoara, Ruxandra Laza
Abstract: Because of its multiple causes, prolonged febrile syndrome often represents a real challenge. Clinical experience divides the causes of this syndrome into: infections (30-40%), neoplasia (10-30%), autoimmune diseases (9-15%), various other causes (15-20%), while 7-10% are of unknown origin. The case we report belongs to other causes group and stands out because it is a new entity among the causes identifi ed in the past: hyperthyroidism, Addisons disease, Crohn disease, sarcoidosis, atrium myxoma, fever caused by drugs, pulmonary embolism etc. We present the case of a 52 year-old male patient with prolonged febrile syndrome and lumbar pain. The laboratory studies revealed nonspecifi c infl ammatory syndrome and high BUN and serum creatinine levels. The abdominal ultrasound found a retroperitoneal mass and right hydronephrosis, while the computed tomography scan showed retroperitoneal fi brosis and identifi ed the cause of the hydronephrosis: the right ureter was included in the fi brous process. A laparotomy was performed and revealed the retroperitoneal fi brosis localized in front of the lower part of the aorta and cava, under the kidneys, all the way to the emergence of the iliac vessels. The fi brous process involved both ureters. The histological exam confi rmed the presence of a chronic, noninfectious fi brosis. Early diagnosis followed by surgical intervention prevented the occurrence of obstructive renal failure. The long-term prognosis depends on whether the fi brosis is a primary or a secondary process and whether it is associated with another immune pathology.

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Risk Assessment and Management of Metabolic Syndrome Due To Antipsychotic Medication

Rucsandra Danciulescu Miulescu, Madalina Musat, Suzana Danoiu, Catalina Poiana, C. Dumitrache
Abstract: The metabolic syndrome is comprised of several cardiovascular risk factors such as central obesity, hyperglycemia, hypertension and hyperlipidemia, most probably pathogenically correlated. Patients with schizophrenia have an increased risk of developing metabolic syndrome due to inappropriate physical activity, disorders of food intake or secondary to antipsychotic medication. Due to the increased prevalence of metabolic syndrome and diabetes mellitus in patients with schizophrenia, the American Association of Psychiatry recommends screening and follow-up for metabolic risk factors. Thus the recommendation is to assess fasting glycemia and glycated hemoglobin at 4 months from commencement of a new drug therapy, then annually. BMI has to be monitored every 3 to 6 months. Except for the patients with a BMI below 18.5, every increment of their BMI of 1kg/m2 should be followed by either a change in antipsychotic medication or the admission of the patient in a weight control program.

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Effective sodium thiosulphate therapy in calciphylaxis

Ina Kacso, Simona Racasan, Daniela Anghel, Claudia Macarie, Raluca Moldovan, Mirela Gherman Caprioara
Abstract: Calciphylaxis is a life-threatening complication of hemodialysis involving calcium deposition in media of hypodermic arteries and skin necrosis. With current unsatisfactory treatment, the calcium chelator and antioxidant sodium thiosulphate emerges as a possible new therapy. We report the case of a dialysis patient with parathyroidectomy for secondary hyperparathyroidism complicated by severe hypoparathyroidism and hypocalcemia, requiring sustained Ca and vitamin D treatment. Within a year, typical calciphylaxis developed on the breasts, associated with extensive calcifi cation of medium-sized arteries on mammography. Cessation of calcium load and aggressive wound care led to no improvement. Sodium thiosulphate 25g thrice weekly for 2 months resulted in dramatic healing. Besides unusual location on the breasts, onset of lesions in the setting of an adynamic bone is noteworthy and probably favored by calcium load. Th is is, to our knowledge, the fi rst use of sodium thiosulphate in calciphylaxis associated to low bone turnover, a valuable therapeutic asset since unlike in hyperparathyroidism, other treatment options lack. Also this is the fi rst use of sodium thiosulphate for treatment of calciphylaxis in Romania, the drug being prepared in our University.

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Case Report

Hemolytic-uremic syndrome associated with acute diarrheic disease in children

Rozina Iagaru, Monica Luminos, Dorina Duma, Alina Cibea, Gh. Jugulete, Elena Gheorghe, Violeta Marinescu
Abstract: The Haemolytic-Uremic Syndrome (HUS) is the most frequent cause of renal failure in small children. Th is disease is often preceded by an episode of acute gastroenterocolitis caused by an enterohemorrhagic strain of Escherichia coli (0157:H7); the syndrome has been rarely associated with other bacterial or viral infections. HUS is more common in children younger than 4-5 years of age. The diagnosis is confi rmed by microangiopathic haemolytic anemia, thrombocytopenia, and acute renal failure. A more careful medical evaluation of the hematological and renal manifestations, together with early and repeated hemodialysis, give the best chance of recovery, even in the acute phase of the diseases.

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Trichinosis in a patient with familial thrombophilia

Rodica Rusu
Abstract: The author presents the case of an 11 year-old child who developed cerebral and peripheral vascular thromboses over a background genetic coagulation disease, revealed by a parasitic disease - trichinosis. The diagnosis was problematic and the clinical evolution was severe and prolonged due to the association of the two diseases and due to the patients precarious immune condition. The clinicians should be informed regarding the existence of a coagulation pathology, often ignored, whose prompt and correct diagnosis can save the patients life or ameliorate the diseases evolution and prognostic.

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The influence of the marginal adaptation of the prosthetic crown on the gingival tissue

M. Sandulescu
Abstract: Soft tissue management has a major infl uence on the esthetic result of a restorative dentistry treatment. The esthetic zone not only plays a signifi cant role in the physical appearance of a person, but it also has a subtle but defi nite infl uence on the psychology of that person. The clinical exam of a 22 year-old female revealed a chronic gingivitis around the central right incisor (tooth 1.1). Moreover, the probing depths around 1.1 were increased, and were accompanied by severe bleeding. As such, the patient was dealing with a displeasing appearance of her smile which determined her to deprive herself of the social communication instrument that laughter is. We proceeded to removal of the crown and contoured a shoulder preparation of the tooth. We gave the periodontium time to heal (10 days), as well as time for the swelling to go down. The fi nal impression was taken only after the gingival architecture was considered to be stable (another 14 days). During the whole treatment, the patient wore a provisional crown which played a signifi cant role in the healing process of the gingival tissue. The fi nal restoration consisted of a full ceramic crown (with ideal marginal adaptation), which provided a superior translucency and, as such, a more natural appearance of the tooth. Th is restorative dentistry case emphasizes the importance of marginal adaptation of a prosthetic crown for preserving the health of the marginal periodontium of the tooth, as well as the esthetic aspect.

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