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Papers accepted for publication

1. Natural and semisynthetic candidate molecules for COVID-19 prophylaxis and treatment

Andrei Bita, Ion Romulus Scorei, Laurentiu Mogoanta, Cornelia Bejenaru, George Dan Mogosanu, Ludovic Everard Bejenaru

Coronaviruses (CoVs) represent a family of viruses that have numerous animal hosts, and they cause severe respiratory, as well as systemic and enteric infections, in humans. Currently, there are limited antiviral strategies for treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The lack of specific antiviral medicines and SARS-CoV-2 vaccines continues to aggravate the situation. Natural product-based antiviral drugs have been used in the two previous CoV outbreaks: Middle East respiratory syndrome coronavirus (MERS-CoV) and the first SARS-CoV. This review emphasizes the role of natural and semisynthetic candidate molecules for coronavirus disease 2019 (COVID-19) prophylaxis and treatment. The experimental evidence suggests that nature could offer huge possibilities for treatment of the COVID-19 pandemic.

Corresponding author: Ion Romulus Scorei, Professor, Biochem, PhD; e-mail: romulus_ion@yahoo.com

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2. Latest advances in chronic rhinosinusitis with nasal polyps endotyping and biomarkers, and their significance for daily practice

Alma Aurelia Maniu, Maria Ida Perde-Schrepler, Corina-Bianca Tatomir, Mihai Ionut Tanase, Maximilian George Dindelegan, Vlad Andrei Budu, Gheorghe Doinel Radeanu, Marcel Cosgarea, Carmen Aurelia Mogoanta

The term chronic rhinosinusitis (CRS) comprises of an assortment of diseases that share a common feature: inflammation of the sinonasal mucosa. The phenotype classification of CRS, based on the presence of polyps, has failed to offer a curative treatment for the disease, particularly in refractory cases. Chronic rhinosinusitis with nasal polyps (CRSwNP) remains a challenging entity. Researchers have made efforts trying to characterize subtypes of the disease according to the endotypes, which are delineated by different immunological pathways, using biomarkers. Even if the inflammatory processes controlling CRSwNP are not fully understood, data suggested that the disease associated with a type 2 inflammatory mechanisms can be also linked to the type 1 or type 3 pathomechanism, being highly heterogeneous. Biomarkers for CRSwNP are proposed, such as: eosinophil count, cytokines, metalloproteinases, bitter and sweet taste receptors, and the nasal microbiome. For endotyping to be clinically applicable and simply determined, biomarkers referring to the intrinsic biomolecular mechanism still need to be found. Precision medicine is becoming the new standard of care, but innovative therapies such as biologics may be rather challenging for the clinicians in their daily practice. This new approach to CRSwNP implies patient selection and a simple algorithm for deciding the right treatment, easy to implement and adjust. Our review points out the ongoing new research on the pathophysiology of CRSwNP, biomarkers and treatment opportunities. It allows clinicians to keep abreast of current evidence-based knowledge and to individualize the management of CRSwNP, especially in refractory cases.

Corresponding author: Vlad Andrei Budu, Senior Lecturer, MD, PhD; e-mail: vladbudu@yahoo.com; Mihai Ionut Tanase, MD, PhD Student; e-mail: dr.mihaitanase@gmail.com

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3. Syphilis associated with abdominal trauma and splenic rupture in pregnancy

Liliana Steriu, Roxana-Cleopatra Penciu, Corina Madalina Nour, Silvia Izvoranu, Iulia-Diana Mocanu, Gabriela-Izabela Baltatescu, Oana Cojocaru, Vlad-Iustin Tica

We present a case of a pregnant woman in the third trimester who came to the Department of Emergency, Sf. Apostol Andrei Emergency County Hospital, Constanta, Romania, in September 2016, for abdominal pain and ascites. After admission, the patient was periodically tested (biochemically and by ultrasound). We also payed attention to the fetal well-being. During the hospitalization, the patient was also found positive for syphilis. Biochemical values have progressively altered, the fetus started to present acute fetal distress and the patient gave birth by Caesarean section after two days of hospitalization. The intraoperatory surprise was hemoperitoneum caused by posttraumatic splenic rupture. The relevance of this case consists in its rarity (we were not able to find in the literature a case with the association of pregnancy, syphilis, trauma, and splenic rupture), in the difficult histopathological clear assertion and in the clinical awareness of such a condition.

Corresponding author: Liliana Steriu, MD; e-mail: lilianasteriu@yahoo.com

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4. New 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones: analgesic activity and histopathological assessment

Florica Barbuceanu, Elena-Valentina Rosca, Theodora-Venera Apostol, Oana-Cristina Seremet, Constantin Draghici, Dragos Paul Mihai, Simona Negres, George Mihai Nitulescu, Stefania-Felicia Barbuceanu

This paper reports the synthesis, analgesic activity, acute toxicity and histopathological (HP) assessment of four new compounds from oxazol-5(4H)-ones class that contain in their molecule a diarylsulfone moiety. The new 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones were obtained by reaction of 2-(4-(4-bromophenyl-sulfonyl)benzamido)acetic acid intermediate with aromatic aldehydes (benzaldehyde, 4-methoxy, 4-nitro or 4-bromobenzaldehyde), in acetic anhydride and in the presence of anhydrous sodium acetate. The new compounds have been characterized by spectral techniques, such as: Fourier-transform infrared spectroscopy (FT-IR), mass spectrometry (MS), proton nuclear magnetic resonance (1H-NMR) and by elemental analysis. The acute toxicity of the new oxazol-5(4H)-ones in mice was assessed through acute toxic class method, according to Organization for Economic Co-operation and Development (OECD) Guidelines. The HP assessment of some preserved organs collected from mice has been performed. The analgesic activity of all new synthesized compounds was carried out with two pharmacological tests: the writhing test and the hot plate test. In order to predict the binding affinities of the synthesized oxazol-5(4H)-ones derivatives against molecular targets involved in pain and inflammation, molecular docking simulations were performed. The results of the writhing test indicated that the most active compound was the oxazolone that contains in the molecule a methoxy group. The acute oral toxicity study revealed no lethal effect of new compounds. The HP assessment of the preserved organs collected from mice did not indicate any cytohistopathological aspects that can be linked to any inflammatory, neoplastic or cytotoxic process, demonstrating the low toxicity of new compounds.

Corresponding author: Elena-Valentina Rosca, Pharm, PhD Student; e-mail: elena.rosca@drd.umfcd.ro

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5. Hereditary leiomyomatosis and renal cell cancer syndrome - case report and review of the literature

Liliana Gabriela Popa, Raluca Silvia Lutuc, Mara Madalina Mihai, Irina Ahmed Salem, Silvius Ioan Negoita, Calin Giurcaneanu, Simona Vasilica Fica

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is an exceptionally rare autosomal dominant condition caused by a germline heterozygous mutation of the fumarate hydratase gene. It manifests as multiple piloleiomyomas, associated with numerous, early-onset uterine leiomyomas in female patients, as well as a highly increased risk of renal cell carcinoma (RCC), most often type 2 papillary RCC. HLRCC has been described in association with adrenal cortical hyperplasia, pheochromocytoma, adrenal cortical carcinoma, and other solid tumors, but the exact relationship between these disorders has not yet been clarified. We present a case of HLRCC associated with bilateral adrenal cortical hyperplasia and discuss the pathogenesis, clinical and paraclinical features of HLRCC, as well as the adequate management of these patients.

Corresponding author: Mara Madalina Mihai, Assistant Professor, MD, PhD; e-mail: mara.mihai@umfcd.ro

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6. Evaluation of placental vascularization in thrombophilia and intrauterine growth restriction (IUGR)

Nicoleta-Loredana Voicu, Roxana Elena Bohiltea, Sabina Berceanu, Cristina Jana Busuioc, Gabriela-Camelia Rosu, Stefan Paitici, Anca-Maria Istrate-Ofiteru, Costin Berceanu, Damian Ditescu

The placenta is an essential organ in the proper development of pregnancy, and it can present a lot of structural and vascular lesions that can affect fetal development. One of the pathologies associated with pregnancy, which can change the placental structure is thrombophilia (TPh), and this can be correlated with an intrauterine growth restriction (IUGR) of the fetus. Maternal clinical aspects (age, weight) can be correlated with fetal ones (weight, gender), but also with the structural and vascular aspect of the placenta. The placental structure associated with TPh and IUGR shows macroscopic changes, such as fibrin deposition, calcifications and placental infarctions, but microscopic lesions are best highlighted by classical staining techniques: Hematoxylin-Eosin (HE), Masson s trichrome (MT) and Periodic Acid-Schiff (PAS)-Hematoxylin, but also by immunohistochemistry technique with the help of anti-cluster of differentiation 34 (CD34) antibody that could make it possible to quantify vascular density depending on the pathology. Microscopic changes were massive infarcts caused by vascular ischemia, intravenous and extravillous fibrin deposits, calcifications, and vascular thrombosis. All these clinical, morphological and morphopathological data are interconnected and may vary in the presence of TPh and IUGR.

Corresponding author: Anca-Maria Istrate-Ofiteru, Assistant, MD, PhD; e-mail: ancaofiteru92@yahoo.com; Costin Berceanu, Associate Professor, MD, PhD; e-mail: dr_berceanu@yahoo.com

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7. The role of non-invasive scores in determining the liver fibrosis in NAFLD and psoriatic patients

Carmen-Daniela Neagoe, Anca-Smaranda Farmazon, Anca-Maria Amzolini, Cristina-Elena Singer, Simona-Laura Ianosi, Cristina-Violeta Tutunaru, Amelia-Valentina Genunche-Dumitrescu, Nicolae-Gabriel Ianosi, Ion Paun, Polliana-Mihaela Leru, Oana-Sorina Tica, Mihaela Popescu

According to recent data, psoriatic patients have an increased prevalence of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome, compared with the general population. In some published studies, the severity and presence of psoriasis disease were correlated with the severity of NAFLD. In the current study, we aimed to compare the sensibility and specificity of the non-invasive scores and liver biopsy in determining fibrosis in patients with NAFLD and moderate to severe psoriasis. We performed the scientific research from June 2014-December 2017 and we included 71 patients: 40 patients with NAFLD and 31 patients with moderate to severe psoriasis according to Psoriasis Area and Severity Index (PASI) score and NAFLD, who received Etanercept treatment for at least one year. Based on the clinical and laboratory data, we calculated the following scores for fibrosis: body mass index (BMI), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, diabetes (BARD) score, Fibrosis-4 (FIB-4) score, and NAFLD fibrosis score (NFS). For liver biopsy, we used the Menghini technique. By calculating Kendall s test, we also observed a strong direct correlation between the degree of fibrosis and FIB-4 (tau=0.558) and NFS (tau=0.490) scores, with a critical statistical impact, and the lack of a correlation with the BARD score (tau=0.095; p=0.332). The hepatic biopsy allowed the more accurate establishment of the role of the non-invasive tests in the diagnosis of the lesions of steatosis, steatohepatitis, and hepatic fibrosis. The non-invasive tests are most useful for the exclusion of the evolution lesions and for the confirmation of the advanced stages of the disease. Among these, the NFS score proved a high statistically significant correlation (p<0.0001) with the fibrosis histological lesions.

Corresponding author: Simona-Laura Ianosi, Associate Professor, MD, PhD; e-mail: simonaianosi@hotmail.com; Ion Paun, Associate Professor, MD, PhD; e-mail: dripaun@gmail.com

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8. Mesangioproliferative glomerulonephritis with extracapillary crescents - unexpected fatal complication in a 17-year-old patient with implanted left ventricular assist device

Elena Carmen Opris, Horatiu Suciu, Ioan Jung, Catalin Bogdan Satala, Hussam Al Hussein, Marius Mihai Harpa, Cosmin Marian Banceu, Simona Gurzu

The continuous flow left ventricular assist device (cf-LVAD) is the life-saving solution for patients with end-stage global heart failure. We present the case of a young patient with biventricular dilated cardiomyopathy, who had a cf-LVAD implantation and died as result of progressive renal failure. In the first year after implantation, he suffered repeated strokes and episodes of pneumonia with Klebsiella pneumoniae and Escherichia coli. The patient had hypertension, which was kept under control with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. After multiple bleeding episodes, the patient died at 21 months after the LVAD implant. At autopsy, parenchymatous brain hemorrhage was found to be associated with pulmonary hemorrhages. The unexpected features related to mesangioproliferative and extracapillary glomerulonephritis, with focal glomerulosclerosis. The proliferated parietal cells of Bowman s capsule proved to express cluster of differentiation 44 (CD44), whereas remnant podocytes and mesangial cells showed Wilms tumor 1 (WT1) positivity. Since CD44 might be involved in fibrogenesis, but ACE inhibitors can exert a protective role against glomerular deterioration, we performed a synthesis of literature data which enabled us to propose a hypothesis with a potential clinical impact. We conclude that, in patients with LVAD implants, high blood pressure and high serum level of angiotensin II, the association between ACE inhibitors and anti-CD44 agents might exert glomerular protection and increase the survival time. Experimental studies are necessary to support our hypothesis and to explain the mechanism of possible glomerulopathy installed after LVAD implant.

Corresponding author: Simona Gurzu, Professor, MD, PhD; e-mail: simonagurzu@yahoo.com

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9. Corrigendum to the paper The impact of imagistic evaluation of premalignant and malignant lesions of the breast confirmed in histopathological terms

Alina Oana Rusu-Moldovan

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Corresponding author: Alina Oana Rusu-Moldovan, MD, PhD Student; e-mail: alinaomoldovan@yahoo.com

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10. Analysis of TP53 gene and particular infrastructural alterations in invasive ductal mammary carcinoma

Corina Elena Mihalcea, Ana-Maria Morosanu, Daniela Murarasu, Liliana Puiu, Sabin-Aurel Cinca, Silviu Cristian Voinea, Nicolae Mirancea

This study was conducted in order to determine the mutational status of TP53 gene and to determine some particular aspects from ultrastructural level in invasive mammary ductal carcinoma. The cellular signaling pathway involving the TP53 gene acts in biological deoxyribonucleic acid (DNA) repair processes and cell cycle arrest following a signal transmitted to the p53 protein when posttranslational changes occur in the cell due to stress induced in the cell by both intrinsic and extrinsic factors. Cellular stress activates the transcription factor function of the protein that initiates, as the case may be, either DNA repair or programmed cell death (apoptosis). The TP53 gene is commonly mutated in many human cancers and also has a highly polymorphic grade. To determine the mutational status of the exons 4-9 of the TP53 gene, we used extracted DNA from fresh breast tissue, and we analyzed it through direct sequencing. In mammary carcinoma, the mutation frequency of TP53 is running between 20-40% and, in regards the polymorphism, at least 14 different forms were identified, that are associated with cancer risk. The mutation type distribution showed a predominance of deletions and a reduced frequency of substitutions comparing with International Agency for Research on Cancer (IARC) database. Taken in consideration the importance of the tumor associated stroma in tumor development, we have also investigated some particular aspects at the infrastructural level of invasive mammary ductal carcinoma, notably concerning telocytes as tumor stroma interstitial cells by transmission electron microscopy analysis.

Corresponding author: Nicolae Mirancea, PhD, Senior Scientist grade I; e-mail: nick_mirancea@yahoo.com

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11. Multiple and giant coronary artery aneurysm - case report and a review of the literature

Elena Emilia Babes, Victor Vlad Babes, Mihaela Mirela Zdrinca, Ilarie Brihan, Razvan Marius Vicas, Monica Adriana Motorca, Larisa Renata Pantea-Rosan, Alina Cristiana Venter

We report an unusual case of a 70-year-old female patient admitted in the Department of Cardiology, Emergency County Hospital, Oradea, Romania, for unstable angina and heart failure. Coronary angiography and computed tomography revealed multiple coronary artery aneurysms, some of them giant, associated with significant coronary artery disease. Coronary artery aneurysm is a rare disease, but the frequency of diagnostic increased with the development of coronary angiography. However, very rarely coronary artery aneurysm is very large and can be termed giant aneurysm, and a small number of reports have been described in literature. The management and the prognosis of the disease is still controversial.

Corresponding author: Elena Emilia Babes, Lecturer, MD, PhD; e-mail: babes.emilia@gmail.com; Victor Vlad Babes, Assistant Professor, MD, PhD; e-mail: babesvlad@gmail.com

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12. 100 Years since the birth of Ladislau Steiner. Creativity of Neurosurgery

Mircea Vicentiu Saceleanu, Aurel George Mohan, Andrei Alexandru Marinescu, Alexandru Vlad Ciurea

Ladislau Steiner (1920-2013) was a Romanian neurosurgeon, born in the historic and picturesque region of Fagaras. He was educated by some of the best doctors and professors in Romania, during the communist regime. After his escape through the communist regime, in 1961, at 41 years old, he started his neurosurgical and radiosurgical career at Karolinska Institute, in Stockholm, under the renown Herbert Olivecrona and Lars Leksell. He worked here for 25 years, until he retired in 1987 as head of 1st and 2nd Departments of Neurosurgery in the institute s affiliated clinic Sophiahemmet Hospital. He is most known in Sweden as the first to introduce microsurgical techniques in neurosurgery, but internationally he is known as the unofficial emissary of Gamma Knife Surgery. After his retirement, he continued his practice at University of Virginia, USA, for another 23 years and another two years at International Neurosciences Institute, Hannover, Germany, being a Professor of Neurosurgery and Radiology of Gamma Knife Surgery. Thanks to his efforts, Romanian neurosurgery had an accelerated progress after the fall of communism, in 1989. Also, thanks to him, Romania was the first Southeast European country with a Gamma Knife unit. For his efforts, he was appointed Honorary President of the Romanian Society of Neurosurgery. We pay tribute to a great Romanian neurosurgeon who managed to touch the lives of thousands of patients and doctors from almost all countries in the world, in time when the world was divided between east and west, communism and freedom.

Corresponding author: Aurel George Mohan, Associate Professor, MD, PhD; e-mail: mohanaurel@yahoo.com

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13. Morpho-functional and radiological approach of poststroke seizures

Iulian Dan Cuciureanu, Delia Hinganu, Cristian Statescu, Anca Sava, Marius Valeriu Hinganu, Mihaela Dana Turliuc, Tudor Cuciureanu, Radu Andy Sascau

Epilepsy is characterized by recurrent seizures that cannot be associated with other specific causes. The presence of a single convulsive or tonic seizure after a stroke does not necessarily mean that a person develops a form of epilepsy unless the convulsions become chronic and recurrent poststroke epilepsy. The purpose of our study is to highlight the existence of a connection between the type and the topography of a vascular stroke on the one hand, and on the other hand, the type of seizures that have occurred and how long they have occurred after the stroke. The study was conducted in a total of 165 patients at the Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iasi, Romania, diagnosed with stroke and spastic seizures after stroke and who survived for at least one year. In this study, the ideal patient should be the patient diagnosed for the first time with temporal lobe epilepsy, followed longitudinally by high-resolution imaging techniques. Studying topography and morphopathology of poststroke sequelae can lead to an increase in accuracy prediction of epilepsy after it.

Corresponding author: Delia Hinganu, University Lecturer, MD, PhD; e-mail: delia_f24@yahoo.com; Cristian Statescu, University Lecturer, MD, PhD; e-mail: cstatescu@gmail.com

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14. The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature

Octavian Munteanu, Monica Mihaela Cirstoiu, Florin Mihail Filipoiu, Maria Narcisa Neamtu, Irina Stavarache, Tiberiu Augustin Georgescu, Ovidiu Gabriel Bratu, Gabriela Iorgulescu, Roxana Elena Bohiltea

Anencephaly is a severe malformation of the central nervous system (CNS), being one of the most common types of neural tube defects. It is defined as total or partial absence of the calvarium, with absence of the brain. Anencephaly has an incidence of 1 to 5 in every 1000 births, and the mortality rate is 100% during intrauterine life or within hours or days after birth. The etiology of anencephaly remains unclear, but various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins, genetic polymorphisms and mutations, as well as positive family history for neural tube defects. One of the most important nutritional factors in the development of anencephaly is folate deficiency. Methylenetetrahydrofolate reductase (MTHFR) gene codes the enzyme involved in the intracellular metabolism of folic acid; the 677C-T polymorphism of this gene causes the thermolability of the enzyme and decreased enzymatic activity, which is also dependent of folate plasmatic level. Etiopathogenesis of anencephaly includes several mutations in various other genes, such as: platelet-derived growth factor receptor alpha (PDGFRA), cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 (CELSR1), Vang-like 1 (VANGL1) and Vang-like 2 (VANGL2), the last two being involved in the process of neurulation. Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination. During the first trimester US screening, anencephaly is now detected in all cases, but in order to decrease the complication rate of pregnancy termination, the diagnosis should be established as soon as possible, during the pregnancy confirmation US. We conclude that given that anencephaly is a severe malformation of the CNS, morphological characterization could improve the screening by US that is mandatory in the first trimester in order to plan the best, safe and early management.

Corresponding author: Tiberiu Augustin Georgescu, Assistant Professor, MD, PhD; e-mail: tiberiuaugustin.georgescu@gmail.com; Gabriela Iorgulescu, Senior Lecturer, MDD, MA, BA, PhD; e-mail: gabriella_iorgulescu@yahoo.com

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