Papers accepted for publication
1. Alcohol-induced structural and cellular brain alterations: molecular and histopathological mechanisms
Iulia Balutoiu, Sorin Nicolae Dinescu, Andrei Gresita, Lucretiu Radu, Citto Iulian Taisescu, Alexandra-Daniela Rotaru-Zavaleanu, Madalina Aldea, Mihai Andrei Ruscu, Rossy Vladut Teica, Marian Valentin Zorila, Mircea-Sebastian Serbanescu
Chronic alcohol consumption is a leading cause of acquired neurodegeneration with well-documented structural and ultrastructural brain alterations. This review analyzes the cellular and molecular mechanisms underlying alcohol neurotoxicity, integrating findings from animal models, human post-mortem studies, and neuroimaging investigations. Ethanol crosses the blood-brain barrier and generates toxic metabolites including acetaldehyde and reactive oxygen species, triggering oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Chronic exposure induces glutamatergic and gamma-aminobutyric acid (GABA)ergic adaptations leading to excitotoxicity during withdrawal. Cell death occurs through apoptotic, necrotic, and necroptotic pathways, while microglial and astrocytic activation perpetuates neuroinflammation. Histopathological (HP) changes include selective neuronal loss in the prefrontal cortex, hippocampus, and cerebellum, dendritic simplification, and synaptic alterations. White matter pathology manifests as demyelination and axonal degeneration. Associated thiamine deficiency produces characteristic lesions in the mammillary bodies, thalamus, and cerebellar vermis. Neuroimaging techniques provide valuable HP correlates and biomarkers for disease monitoring. While some changes demonstrate partial reversibility with abstinence through remyelination and synaptic plasticity, extensive neuronal loss remains irreversible. Understanding these mechanisms is essential for developing neuroprotective therapeutic strategies.
Corresponding author: Radu Lucretiu, Associate Professor, MD, PhD; e-mail: radu.lucretiu@umfcv.ro; Citto Iulian Taisescu, Professor, MD, PhD; e-mail: citto.taisescu@umfcv.ro
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2. Formaldehyde in pathology services: from molecular toxicity to histopathological change and occupational risk
Mircea-Sebastian Serbanescu, Alexandra-Daniela Rotaru-Zavaleanu, Lucretiu Radu
Background and Objective: Formaldehyde (FA), classified as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC), constitutes a significant occupational hazard within hospital pathology service, where it remains the gold standard fixative for tissue preservation. Despite widespread recognition of its toxicological properties, the specific carcinogenic and non-carcinogenic health risks confronting pathology personnel subjected to chronic, low-level, and intermittent exposures remain incompletely characterized. This review synthesizes the current body of evidence regarding the cellular and molecular mechanisms of FA toxicity, histopathological (HP) alterations in target tissues, and associated occupational health risks among pathology staff. Study selection for review: A comprehensive literature search was conducted across PubMed/MEDLINE, Web of Science, and Scopus databases, encompassing publications through December 2025. Studies were selected based on relevance to FA toxicity mechanisms, HP effects, and occupational exposure in pathology settings. Given the heterogeneity of study designs and outcomes, a narrative synthesis approach was adopted. Evidence synthesis: The synthesized evidence demonstrates that pathology personnel are routinely exposed to FA concentrations exceeding recommended occupational exposure limits (OELs). At the cellular level, FA exerts toxicity through deoxyribonucleic acid (DNA)-protein crosslink formation, oxidative stress induction, and inflammatory pathway activation. HP examination of exposed individuals reveals a characteristic progression from ciliary loss and goblet cell hyperplasia through squamous metaplasia to epithelial dysplasia in the nasal mucosa. Non-carcinogenic health effects, including respiratory symptoms and genotoxicity biomarker elevation, are highly prevalent. However, direct epidemiological evidence substantiating elevated cancer risk within this specific occupational cohort remains limited, mainly due to improper (occupational medicine) reporting. Conclusions: This review confirms substantial non-carcinogenic health effects among pathology personnel, with documented HP alterations representing preneoplastic changes at the portal of entry. The mechanistic evidence supports biological plausibility for carcinogenic risk, though epidemiological confirmation specific to this workforce remains lacking, highlighting a critical research gap.
Corresponding author: Alexandra-Daniela Rotaru-Zavaleanu, MD; e-mail: alexandra.rotaru@umfcv.ro
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3. Eduard Pernkopf s Atlas: morphological innovation and ethical legacy in the history of anatomical illustration
Immacolata Belviso, Ferdinando Paternostro, Domenico Ribatti
Eduard Pernkopf (1888-1955), a prominent representative of the Viennese Anatomical School, produced one of the most detailed and visually refined anatomical atlases in the history of medicine: Topographische Anatomie des Menschen. Despite its exceptional scientific and artistic value, the Atlas remains deeply controversial because of its association with National Socialist ideology and the probable use of bodies of executed prisoners during its production. This study provides a historical, morphological, and ethical analysis of Pernkopf s life, scientific work, and enduring influence on anatomical education. Special attention is devoted to the morphological and methodological innovations of Pernkopf s topographical dissection technique, including his systematic layer-by-layer anatomical stratification and the unprecedented three-dimensional realism of his anatomical illustrations. Through analysis of the historiographical and bioethical literature, the study examines the epistemological significance of Pernkopf s anatomical method, the historical context of Nazi-era anatomical science, and the ongoing debate regarding the Atlas s contemporary use. Pernkopf s Atlas emerges as both a landmark in morphological representation and a lasting ethical warning for the anatomical sciences. Its legacy underscores both the enduring methodological influence of Pernkopf s topographical anatomical approach and the necessity of integrating scientific excellence with ethical accountability in modern anatomical science.
Corresponding author: Ferdinando Paternostro, Associate Professor, MD, PhD; e-mail: ferdinando.paternostro@unifi.it
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4. Primary gallbladder melanoma - a rare entity or a diagnostic pitfall?
Radu Gheorghe Dan, Gabriel Veniamin Cozma, Adrian Iosif Moldoveanu, Diana Maria Orzata, Ovidiu Alexandru Mederle, Emil Florin Hut
Primary gastrointestinal (GI) melanoma is an exceptionally rare and controversial diagnostic entity. Because the mucosa of the gallbladder, stomach, small bowel, and large bowel is not considered a common site of melanocytic proliferation, most GI melanomas are regarded as metastatic lesions originating from a primary cutaneous melanoma. Whether some of these tumors may truly arise primarily in GI sites remains a matter of debate. The diagnosis is further complicated by the possibility of occult, clinically subtle, or amelanotic cutaneous melanomas that may remain unrecognized until advanced metastatic disease becomes symptomatic. In addition, spontaneous regression of the primary cutaneous lesion may lead to complete or partial disappearance of the original tumor, creating further diagnostic uncertainty. We performed a literature review focused on GI and gallbladder melanoma, with emphasis on the distinction between primary and metastatic lesions and the role of spontaneous regression. In addition, we analyzed all cases of GI and gallbladder melanoma diagnosed in our department during the last five years. Three cases were identified: one gallbladder melanoma and two small bowel melanomas. These cases illustrated distinct clinical scenarios, including GI bleeding associated with gallbladder involvement, amelanotic ileal melanoma, and intussusception caused by metastatic melanoma from a known cutaneous primary lesion. Our findings support the need for cautious interpretation when diagnosing primary GI melanoma. Metastatic disease from occult, regressed, or previously undiagnosed cutaneous melanoma should always be carefully excluded through multidisciplinary clinicopathological evaluation.
Corresponding author: Adrian Iosif Moldoveanu, Assistant Professor, MD, PhD Student; e-mail: adrian.moldoveanu@umft.ro
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5. Cleft lip/palate. From embryology to developmental pathogenesis
Marcello Guarino
Cleft of the lip associated with or unassociated with cleft of the palate and cleft palate (CLP) represent frequent birth defects, and the mechanisms by which they occur are not completely clear. On the other hand, knowledge of the normal mechanisms underlying lip development and palatogenesis is still incomplete, and therefore a better understanding and consolidation of our knowledge in this field could help to study these deformities. Upper lip and secondary palate formation are complex processes, involving the subtle integration of several biological events, the disruption of which causes the clefting phenotype. Indeed, these developmental events imply a series of morphogenetic changes involving concerted cell survival, migration, growth, pattern generation, modulation of adhesiveness, death and differentiation. In recent years, genetically engineered animal models and in vitro palate cultures have greatly advanced our knowledge of the cellular and molecular pathways underlying normal orofacial morphogenesis, and abnormally developed CLP as well. Indeed, most of the morphogenetic events of craniofacial development are highly conserved amongst vertebrates, therefore animal models have revealed major insights into the mechanisms that take place in human orofacial development. Given their complexity, it is easy to imagine that the failure of the highly coordinated processes that guide the union of the lip and palate causes various forms of clefts. This article provides an overview of the embryological development of the lip and secondary palate, as well as the mechanisms underlying deviant development resulting in CLP, concentrating on the cellular and molecular characteristics.
Corresponding author: Marcello Guarino, MD; e-mail: marcello.guarino@gmail.com
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6. Neurological symptoms observed in patients with COVID-19
Roberta Andreea Cercel, Florin Ionut Buibas, Mircea-Sebastian Serbanescu, George Popescu, Ionica Pirici, Nina Ionovici, Laurentiu Mogoanta
Infection with the novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) has triggered the largest pandemic of the early 21st century. The disease primarily affects the respiratory system and may present as a common respiratory viral infection, but more severe cases can progress to acute pneumonia or acute respiratory distress syndrome, with heart and kidney failure, digestive symptoms, liver failure, and sometimes death. In SARS-CoV-2 infection, respiratory symptoms are frequently accompanied by neurological manifestations ranging from headaches, dizziness, anosmia, and asthenia to severe complications such as ataxia, seizures, and strokes. A study was conducted on a cohort of 5649 patients clinically and paraclinically diagnosed with coronavirus disease 2019 (COVID-19), admitted to the Victor Babes Clinical Hospital for Infectious Diseases and Pneumophthisiology, Craiova, Romania, between 2020 and 2022, to identify the most common signs of neurological involvement. The most common signs of neurological involvement in COVID-19 were asthenia, headache, and myalgia. The most severe complications in COVID-19 were strokes.
Corresponding author: Nina Ionovici, Associate Professor, MD, PhD; e-mail: nina.ionovici@umfcv.ro
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1. Alcohol-induced structural and cellular brain alterations: molecular and histopathological mechanisms
Iulia Balutoiu, Sorin Nicolae Dinescu, Andrei Gresita, Lucretiu Radu, Citto Iulian Taisescu, Alexandra-Daniela Rotaru-Zavaleanu, Madalina Aldea, Mihai Andrei Ruscu, Rossy Vladut Teica, Marian Valentin Zorila, Mircea-Sebastian Serbanescu
Chronic alcohol consumption is a leading cause of acquired neurodegeneration with well-documented structural and ultrastructural brain alterations. This review analyzes the cellular and molecular mechanisms underlying alcohol neurotoxicity, integrating findings from animal models, human post-mortem studies, and neuroimaging investigations. Ethanol crosses the blood-brain barrier and generates toxic metabolites including acetaldehyde and reactive oxygen species, triggering oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Chronic exposure induces glutamatergic and gamma-aminobutyric acid (GABA)ergic adaptations leading to excitotoxicity during withdrawal. Cell death occurs through apoptotic, necrotic, and necroptotic pathways, while microglial and astrocytic activation perpetuates neuroinflammation. Histopathological (HP) changes include selective neuronal loss in the prefrontal cortex, hippocampus, and cerebellum, dendritic simplification, and synaptic alterations. White matter pathology manifests as demyelination and axonal degeneration. Associated thiamine deficiency produces characteristic lesions in the mammillary bodies, thalamus, and cerebellar vermis. Neuroimaging techniques provide valuable HP correlates and biomarkers for disease monitoring. While some changes demonstrate partial reversibility with abstinence through remyelination and synaptic plasticity, extensive neuronal loss remains irreversible. Understanding these mechanisms is essential for developing neuroprotective therapeutic strategies.
Corresponding author: Radu Lucretiu, Associate Professor, MD, PhD; e-mail: radu.lucretiu@umfcv.ro; Citto Iulian Taisescu, Professor, MD, PhD; e-mail: citto.taisescu@umfcv.ro
Abstract - Download PDF PDF2. Formaldehyde in pathology services: from molecular toxicity to histopathological change and occupational risk
Mircea-Sebastian Serbanescu, Alexandra-Daniela Rotaru-Zavaleanu, Lucretiu Radu
Background and Objective: Formaldehyde (FA), classified as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC), constitutes a significant occupational hazard within hospital pathology service, where it remains the gold standard fixative for tissue preservation. Despite widespread recognition of its toxicological properties, the specific carcinogenic and non-carcinogenic health risks confronting pathology personnel subjected to chronic, low-level, and intermittent exposures remain incompletely characterized. This review synthesizes the current body of evidence regarding the cellular and molecular mechanisms of FA toxicity, histopathological (HP) alterations in target tissues, and associated occupational health risks among pathology staff. Study selection for review: A comprehensive literature search was conducted across PubMed/MEDLINE, Web of Science, and Scopus databases, encompassing publications through December 2025. Studies were selected based on relevance to FA toxicity mechanisms, HP effects, and occupational exposure in pathology settings. Given the heterogeneity of study designs and outcomes, a narrative synthesis approach was adopted. Evidence synthesis: The synthesized evidence demonstrates that pathology personnel are routinely exposed to FA concentrations exceeding recommended occupational exposure limits (OELs). At the cellular level, FA exerts toxicity through deoxyribonucleic acid (DNA)-protein crosslink formation, oxidative stress induction, and inflammatory pathway activation. HP examination of exposed individuals reveals a characteristic progression from ciliary loss and goblet cell hyperplasia through squamous metaplasia to epithelial dysplasia in the nasal mucosa. Non-carcinogenic health effects, including respiratory symptoms and genotoxicity biomarker elevation, are highly prevalent. However, direct epidemiological evidence substantiating elevated cancer risk within this specific occupational cohort remains limited, mainly due to improper (occupational medicine) reporting. Conclusions: This review confirms substantial non-carcinogenic health effects among pathology personnel, with documented HP alterations representing preneoplastic changes at the portal of entry. The mechanistic evidence supports biological plausibility for carcinogenic risk, though epidemiological confirmation specific to this workforce remains lacking, highlighting a critical research gap.
Corresponding author: Alexandra-Daniela Rotaru-Zavaleanu, MD; e-mail: alexandra.rotaru@umfcv.ro
Abstract - Download PDF PDF3. Eduard Pernkopf s Atlas: morphological innovation and ethical legacy in the history of anatomical illustration
Immacolata Belviso, Ferdinando Paternostro, Domenico Ribatti
Eduard Pernkopf (1888-1955), a prominent representative of the Viennese Anatomical School, produced one of the most detailed and visually refined anatomical atlases in the history of medicine: Topographische Anatomie des Menschen. Despite its exceptional scientific and artistic value, the Atlas remains deeply controversial because of its association with National Socialist ideology and the probable use of bodies of executed prisoners during its production. This study provides a historical, morphological, and ethical analysis of Pernkopf s life, scientific work, and enduring influence on anatomical education. Special attention is devoted to the morphological and methodological innovations of Pernkopf s topographical dissection technique, including his systematic layer-by-layer anatomical stratification and the unprecedented three-dimensional realism of his anatomical illustrations. Through analysis of the historiographical and bioethical literature, the study examines the epistemological significance of Pernkopf s anatomical method, the historical context of Nazi-era anatomical science, and the ongoing debate regarding the Atlas s contemporary use. Pernkopf s Atlas emerges as both a landmark in morphological representation and a lasting ethical warning for the anatomical sciences. Its legacy underscores both the enduring methodological influence of Pernkopf s topographical anatomical approach and the necessity of integrating scientific excellence with ethical accountability in modern anatomical science.
Corresponding author: Ferdinando Paternostro, Associate Professor, MD, PhD; e-mail: ferdinando.paternostro@unifi.it
Abstract - Download PDF PDF4. Primary gallbladder melanoma - a rare entity or a diagnostic pitfall?
Radu Gheorghe Dan, Gabriel Veniamin Cozma, Adrian Iosif Moldoveanu, Diana Maria Orzata, Ovidiu Alexandru Mederle, Emil Florin Hut
Primary gastrointestinal (GI) melanoma is an exceptionally rare and controversial diagnostic entity. Because the mucosa of the gallbladder, stomach, small bowel, and large bowel is not considered a common site of melanocytic proliferation, most GI melanomas are regarded as metastatic lesions originating from a primary cutaneous melanoma. Whether some of these tumors may truly arise primarily in GI sites remains a matter of debate. The diagnosis is further complicated by the possibility of occult, clinically subtle, or amelanotic cutaneous melanomas that may remain unrecognized until advanced metastatic disease becomes symptomatic. In addition, spontaneous regression of the primary cutaneous lesion may lead to complete or partial disappearance of the original tumor, creating further diagnostic uncertainty. We performed a literature review focused on GI and gallbladder melanoma, with emphasis on the distinction between primary and metastatic lesions and the role of spontaneous regression. In addition, we analyzed all cases of GI and gallbladder melanoma diagnosed in our department during the last five years. Three cases were identified: one gallbladder melanoma and two small bowel melanomas. These cases illustrated distinct clinical scenarios, including GI bleeding associated with gallbladder involvement, amelanotic ileal melanoma, and intussusception caused by metastatic melanoma from a known cutaneous primary lesion. Our findings support the need for cautious interpretation when diagnosing primary GI melanoma. Metastatic disease from occult, regressed, or previously undiagnosed cutaneous melanoma should always be carefully excluded through multidisciplinary clinicopathological evaluation.
Corresponding author: Adrian Iosif Moldoveanu, Assistant Professor, MD, PhD Student; e-mail: adrian.moldoveanu@umft.ro
Abstract - Download PDF PDF5. Cleft lip/palate. From embryology to developmental pathogenesis
Marcello Guarino
Cleft of the lip associated with or unassociated with cleft of the palate and cleft palate (CLP) represent frequent birth defects, and the mechanisms by which they occur are not completely clear. On the other hand, knowledge of the normal mechanisms underlying lip development and palatogenesis is still incomplete, and therefore a better understanding and consolidation of our knowledge in this field could help to study these deformities. Upper lip and secondary palate formation are complex processes, involving the subtle integration of several biological events, the disruption of which causes the clefting phenotype. Indeed, these developmental events imply a series of morphogenetic changes involving concerted cell survival, migration, growth, pattern generation, modulation of adhesiveness, death and differentiation. In recent years, genetically engineered animal models and in vitro palate cultures have greatly advanced our knowledge of the cellular and molecular pathways underlying normal orofacial morphogenesis, and abnormally developed CLP as well. Indeed, most of the morphogenetic events of craniofacial development are highly conserved amongst vertebrates, therefore animal models have revealed major insights into the mechanisms that take place in human orofacial development. Given their complexity, it is easy to imagine that the failure of the highly coordinated processes that guide the union of the lip and palate causes various forms of clefts. This article provides an overview of the embryological development of the lip and secondary palate, as well as the mechanisms underlying deviant development resulting in CLP, concentrating on the cellular and molecular characteristics.
Corresponding author: Marcello Guarino, MD; e-mail: marcello.guarino@gmail.com
Abstract - Download PDF PDF6. Neurological symptoms observed in patients with COVID-19
Roberta Andreea Cercel, Florin Ionut Buibas, Mircea-Sebastian Serbanescu, George Popescu, Ionica Pirici, Nina Ionovici, Laurentiu Mogoanta
Infection with the novel coronavirus (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) has triggered the largest pandemic of the early 21st century. The disease primarily affects the respiratory system and may present as a common respiratory viral infection, but more severe cases can progress to acute pneumonia or acute respiratory distress syndrome, with heart and kidney failure, digestive symptoms, liver failure, and sometimes death. In SARS-CoV-2 infection, respiratory symptoms are frequently accompanied by neurological manifestations ranging from headaches, dizziness, anosmia, and asthenia to severe complications such as ataxia, seizures, and strokes. A study was conducted on a cohort of 5649 patients clinically and paraclinically diagnosed with coronavirus disease 2019 (COVID-19), admitted to the Victor Babes Clinical Hospital for Infectious Diseases and Pneumophthisiology, Craiova, Romania, between 2020 and 2022, to identify the most common signs of neurological involvement. The most common signs of neurological involvement in COVID-19 were asthenia, headache, and myalgia. The most severe complications in COVID-19 were strokes.
Corresponding author: Nina Ionovici, Associate Professor, MD, PhD; e-mail: nina.ionovici@umfcv.ro
Abstract - Download PDF PDF