OBJECTIVE:Pseudoglandular hyperplasia of the conjunctiva (PHC) is a rare benign epithelial pseudotumor. We report herein a new case of this rare entity, review its histopathological features and discuss its differential diagnoses. METHODS:The morphologic findings of PHC of the right eye occurring in a 65-year-old man are reported with a review of the related literature. RESULTS:The patient consulted for a swollen conjunctiva mass. MRI revealed a well-limited hypervascular nodule in the right superior palpebral conjunctiva. Surgical excision was performed. On microscopic examination, the specimen was covered with a regular stratified squamous epithelium containing numerous goblet cells. The epithelium showed invagination into the stroma with formation of pseudoglandular structures of various sizes. There was neither nuclear atypia nor mitosis. The diagnosis of PHC was made. CONCLUSION:PHC is defined as a proliferation of the conjunctival epithelium with prominent glandular structures. Awareness of this entity is crucial to distinguish it from well-differentiated adenosquamous carcinoma to ensure the appropriate treatment.

PFIC4 is a chronic liver disease which cannot be diagnosed based on clinical and biochemical findings with an unpredictable evolution. Here, we reported three consanguineous families with 9 children suffering from intrahepatic cholestasis with low GGT-activity. Three probands were chosen to undergo genetic testing. In silico analyses were conducted to assess the functional impact of the identified variant, along with variants occurring at highly conserved positions within the protein. Additionally, close clinical monitoring was carried. Targeted-NGS sequencing ruled out the diagnosis of PFIC1 and PFIC2. Subsequently, WES allowed the establishment of PFIC4 diagnosis for the three families through the identification of a homozygous TJP2 variant p. Gly532Arg classified as likely pathogenic with a structural damage predicted based on biomolecular modeling and simulation analysis. In-depth in silico analysis of 90 nsSNPs occurring in highly conserved residues in PDZ domains showed 14 ones seems to be relevant in the clinical practice. Clinically, a pronounced phenotypic variability is noted. In conclusion, our study described a homozygous missense PFIC4-related variant with a highlight on the pathogenic power of such types of variants. The clinical evaluation provided information about the importance of close monitoring to prevent liver failure and clarified the unexpected course of PFIC4.

Histone post-translational modifications (PTMs) have been linked to various pathological processes, especially in cancer onset, where they are envisaged as obvious diagnostic biomarkers and pivotal predictors for pathological prognosis. Consequently, their mapping and characterization constitute a critical field of study facilitated by recent advances in the high-throughput mass spectrometry technique. The current study aimed to clarify the neurotoxicity mechanisms at the epigenetic level induced by environmental stressors by examining their potential to induce aberrant histone methylation as it is the most involved modification in carcinogenesis. Our protocol first consisted of a 3D in vitro neurospheroid model derived from human high-grade gliomas, followed by treatment with a pesticide mixture. Furthermore, we analyzed histone isoform-digested peptides by shotgun proteomics with high-resolution tandem mass spectrometry, complemented by Western blotting to validate epigenetic changes. Our results revealed two major findings: First, histone demethylation in nontreated samples emphasizes the aggressiveness and poor prognosis of high-grade gliomas. Second, histone hypermethylation phenotype in treated samples underlies the adaptive strategy employed by cancer cells to overcome stress and promote progression, which is a hallmark characteristic of isocitrate dehydrogenase (IDH)-mutated gliomas. Hence, our findings not only help bridge the gap in knowledge about chromatin regulation but also pave the way for the development of targeted therapeutic approaches modulating histone hypermethylation in gliomas.

Human brain tumors were commonly monitored in hospital/clinical laboratories by immunohistochemistry (IHC) technique, which provides major insights into their classification. However, this technique remains laborious and still shows pitfalls. Therefore, the current study was endeavored to reveal the assets of the application of high-throughput mass spectrometry (MS) for medical diagnosis. In this study, we focused on the Grade IV astrocytoma and meningioma brain tumors. The collected specimens were first monitored for histopathological diagnosis, followed by IHC staining for the characterization of stemness gene marker, then analyzed by a shotgun proteomic-based approach with high-resolution tandem MS. The IHC analysis only confirmed the histopathological diagnosis, whereas the proteomic analysis unraveled several differently expressed proteins. By bioinformatics, the major enriched pathways and the significance of each protein with its meaningful relationships were identified. The key hub genes were allied for prognostic biomarkers of malignant, metastatic, and invasive forms of cancer with poor prognosis. Overall, the high-throughput MS technique is the most powerful tool to achieve medical analysis at high sensitivity and accuracy and in a very straightforward and timely manner. Hence, its medical implementation in the hospital management system is imperative to counteract the caveats of traditional diagnostic methods and improve the quality of healthcare performance and therapeutic targets.

INTRODUCTION AND IMPORTANCE:Epstein-Barr virus (EBV) is a common virus infecting more than 90 % of the adult population, typically without symptoms. While most infections remain asymptomatic, EBV is associated with over 200,000 new cancer cases annually. It is linked to several malignancies, including leiomyosarcoma (LS) in immunocompromised patients, a rare occurrence with fewer than 100 new cases per year globally. This report highlights the case of an EBV-associated intracranial leiomyosarcoma in a 4-year-old immunodeficient child. CASE PRESENTATION:A 4-year-old girl with a history of primary immune deficiency and multiple infections presented with febrile dyspnea. Imaging revealed a right temporo-parietal brain mass, which increased in size over 50 days. Surgical excision was performed, and histological examination showed a tumor with smooth muscle cell characteristics. Immunohistochemical analysis was positive for vimentin and CD99, while EBV genome presence was confirmed by in situ hybridization. The final diagnosis was EBV-associated malignant smooth muscle tumor. The postoperative course was favorable, and chemotherapy was not indicated. CLINICAL DISCUSSION:Leiomyosarcoma is extremely rare in immunocompetent children but more common in immunocompromised individuals, where EBV infection plays a significant role in tumor development. Although EBV-related leiomyosarcomas occur more frequently in immunodeficient children, intracranial cases are exceptionally rare. These tumors are often challenging to diagnose due to their undifferentiated appearance. The detection of EBV DNA using in situ hybridization is crucial for confirming the diagnosis. While EBV-associated leiomyosarcomas generally respond well to therapy, the optimal treatment remains unclear, with surgery and radiotherapy being the primary approaches. CONCLUSION:EBV-associated smooth muscle tumors are rare but increasing in incidence among immunocompromised patients. Early recognition of EBV infection in smooth muscle tumors, especially in children with immune deficiencies, is vital for diagnosis. Histological and molecular examination, including in situ hybridization, is essential to confirm the presence of EBV. Treatment typically involves complete surgical excision, with chemotherapy's role still uncertain.

This study aimed to investigate the effects of copper (CuSO4) and zinc (ZnSO4) overload on male reproductive toxicity and the potential of a polysaccharide extracted from green alga Chaetomorpha linum (PS) in mitigating their toxicities. Adult male mice strain of 25 +/- 2 g of weight was subdivided into eight groups. Group 1 served as control; group 2 received PS (200 mg/kg), and groups 3 and 4 received intraperitoneally zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), respectively. Group 5 received both zinc (60 mg/kg b.w) and copper (33 mg/kg b.w), group 6 received zinc (60 mg/kg b.w) associated with PS (200 mg/kg), group 7 received copper (33 mg/kg b.w) associated with PS (200 mg/kg), and group 8 received zinc (60 mg/kg b.w) and copper (33 mg/kg b.w) associated with PS (200 mg/kg). Results suggested that ZnSO4 and CuSO4 significantly decreased the functional sperm parameters. Furthermore, extended exposure to these elements increased oxidative stress biomarkers, including malondialdehyde (MDA) as a measure of lipid peroxidation and advanced oxidation protein products (AOPP) indicating protein oxidative damage. This process also reduces the activity of antioxidant enzymes such as glutathione (GSH) and glutathione peroxidase (GPx), which neutralize and catalyze free radicals. Histopathological changes in mice testis were also studied. However, the co-treatments with PS significantly reduced these effects and promoted the reproductive parameters in male mice. In conclusion, PS exhibited protective effects against zinc and copper-induced reproductive toxicity, making it a potential adjuvant treatment for testicular toxicity.

Lung pleomorphic carcinoma is a rare and aggressive cancer that uncommonly metastasizes to the colon and only a few case reports have been published thus far. We present an exceptional case of colon metastasis from lung pleomorphic carcinoma in a 68-year-old man which was revealed by large bowel perforation, and we review the previous three published cases. Metastasis to the bowel from primary lung malignancy often lacks specific symptoms which result in delayed diagnosis. Bowel metastasis is a poor prognostic factor in patients with lung pleomorphic carcinoma, regardless of management strategy.

Abstract Introduction: Castleman’s disease (CD), known as angiofollicular lymph node hyperplasia, is an uncommon condition. The two most common histological subtypes are hyaline vascular and plasma cell. We performed a retrospective analysis to define the clinic-pathological features and survival of CD, which is quite rare focusing on the particularities of our series with a review of the recent literature. Methods: This is a retrospective study conducted in the department of internal medicine of Hedi Chaker hospital in Sfax, Tunisia over 25 years. The disease was histologically confirmed in all patients. For each file, we collected a set of data by filling in a pre-designed form. Results: 18 patients were included. There were 8 men and 10 women with a mean age of 42.8 years. CD was monocentric in 5 cases (28%) and multicentric in 13 cases (72%). Clinically, peripheral adenopathy was present in 77.7% of patients and deep adenopathy in 72.2%. Systemic signs were found in 13 patients, including general condition (4.4%), fever (16.6%), serositis (27.7%), and skin involvement (33.3%). A biological inflammatory syndrome accompanied the clinical picture in 66% of patients. Abnormalities in the blood count were found in 12 cases (66%), with anemia in 11 cases, thrombocytosis in 3 cases, and hypereosinophilia in 3 cases. Cutaneous Kaposi’s sarcoma was associated with Castleman’s disease in 2 cases, Hodgkin’s lymphoma, angioimmunoblastic T-cell lymphoma, and lymph node T-cell lymphoma were found in 1 case respectively. 3 of the patients had associated connective tissue diseases such as Sjögren’s syndrome in 2 cases and rheumatoid arthritis in 1 case. HHV8 serology was positive in 1 case with a multicentric plasma cell form. Histologically, the plasma cell form represented 50% of cases, hyaline-vascular (39% of cases), and mixed (11% of cases). Therapeutically, high-dose corticosteroid therapy was initiated in 13 cases. As a second-line treatment, MOPP chemotherapy was used in 1 case due to transformation into Hodgkin’s lymphoma, and biotherapy (rituximab) was used in 2 cases in the multicentric form. Surgical removal of superficial adenopathy was performed in 2 patients with monocentric CD. Conclusion : Castleman’s disease (CD) is a non-malignant lymphoproliferation of localized or multicentric form with a wide and heterogeneous clinical spectrum. Diagnosis can be difficult due to the lack of clinical and radiological specificity. Management depends on the clinical form involving surgical and/or medical management.

Introduction Le lupus érythémateux chronique (LEC) peut se présenter sous multiples variantes cliniques. La forme la plus répandue est le lupus discoïde. Le lupus mélanotique (LM) en est une forme rare de LEC récemment décrite. Patients et méthodes Depuis 2019, le diagnostic de LM a été retenu dans notre service de dermatologie sur des critères cliniques et histologiques. Résultats Nos 3 patientes étaient âgées respectivement de 25, 49 et 53 ans. Elles avaient un phototype IV. La médiane de la durée d’évolution était de 7 mois (45 jours–9 ans). Cette dernière patiente n’a consulté qu’après le développement d’un carcinome épidermoïde de la lèvre inférieure. Les patientes présentaient une hyperpigmentation gris ardoisée mal limitée, ovalaire dans 2 cas et diffuse dans un cas. Elle touchait le visage (3 cas), le cou (1 cas) et les avant-bras (1 cas). L’atteinte était prurigineuse dans un cas. Une patiente décrit un érythème précédant l’hyperpigmentation. Deux patientes rapportaient une photosensibilité et des polyarthralgies. Deux patientes avaient une alopécie frontale avec raréfaction des sourcils dans un cas. Une patiente avait une chéilite compliquée de carcinome de la lèvre inférieure. La dermoscopie faite pour 2 patientes montrait des globules bruns et un peppering périfolliculaire, un fond d’érythème était observé dans un cas. Le taux des anticorps antinucléaires (AAN) était positif et moucheté dans tous les cas s’associant à des anticorps anti-DNA natifs et anti SSA positifs dans un cas. L’histologie montrait dans tous les cas une dermite d’interface avec présence de tunnels cornés, une couche basale vacuolisée et un infiltrat inflammatoire lympho-plasmocytaire péri vasculaire et péri annexiel avec des mélanophages. Le traitement par photoprotection, dermocorticoïdes et hydroxychloroquine (HCQ) n’a entraîné qu’une amélioration modérée. Discussion Le LM est une nouvelle variété de LEC récemment décrite avec seulement une trentaine de cas publiés. Il survient chez les sujets de phototype moyen a foncé avec un âge relativement avancé. Il peut se présenter sous forme de plaques hyperpigmentées mal limitées ou une hyperpigmentation diffuse touchant généralement la face en l’absence de squames, d’atrophie cutanée ou de télangiectasies. Le LM peut s’associer à une photosensibilité dans 50 % des cas. Il s’associe rarement à une atteinte systémique. Les lésions alopéciques et la chéilite compliquée d’un carcinome épidermoïde constatées chez nos patientes sont particulières. Les caractéristiques dermoscopiques sont dominées par les signes folliculaires et les structures pigmentaires. L’examen histopathologique, indispensable au diagnostic, montre une orthokératose, une atrophie épidermique, une dégénérescence vacuolaire de la couche basale, des kératinocytes nécrotiques, un épaississement de la membrane basale, une incontinence pigmentaire, un bouchon folliculaire et un infiltrat lymphocytaire péri vasculaire et péri folliculaire dans le derme. Par rapport au lichen plan pigmentaire, les infiltrats inflammatoires dans le LM ont tendance à entourer et à impliquer les parties profondes des structures folliculaires. La pathogenèse du LM pourrait s’expliquer par l’incontinence pigmentaire entraînée par la dermite d’interface, en particulier chez les individus à phototype foncé. La prise en charge du LM n’est pas bien codifiée. Des résultats encourageants ont été obtenus avec des DC et l’HCQ. Les patients atteints d’une forme localisée de LM semblent obtenir de meilleurs résultats par rapport à ceux présentant une pigmentation diffuse. Conclusion Le LM est une entité rare de LE. Il faut y penser devant toute hyperpigmentation diffuse ou localisée du visage.

The widespread use of pesticides, particularly in combinations, has resulted in enhanced hazardous health effects. However, little is known about their molecular mechanism of interactions. The aim of this study was to assess the neurotoxicity effect of pesticides in mixtures by adopting a 3D in vitro developed neurospheroid model, followed by treatment by increased concentrations of pesticides for 24 h and analysis by a shotgun proteomic-based approach with high-resolution tandem mass spectrometry. Three proteins, namely, glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), α-enolase, and phosphoglycerate-kinase-1, were selected as key targets in the metabolic process. Only high doses of pesticides mitigated cell-density proliferation with the occurrence of apoptotic cells, which unlikely makes any neurological alterations in environmental regulatory exposures. The proteomic analysis showed that majority of altered proteins were implicated in cell metabolism. De novo peptide sequencing revealed ion losses and adduct formation, namely, a trityl-post-translational modification in the active site of 201-GAPDH protein. The study also highlights the plausible role of pyrethroids to be implicated in the deleterious effects of pesticides in a mixture. To the best of our knowledge, our finding is the first in toxicoproteomics to deeply elucidate pesticides’ molecular interactions and their ability to adduct proteins as a pivotal role in the neurotoxicity mechanism.

Although bone tumors (BT) are relatively uncommon among the human neoplasm, they constitute the most frequent tumors in children and adolescents (CAA). Little information is available about the epidemiologic features of BT in CAA. We aimed to present and discuss epidemiological characteristics of BT in CAA in southern Tunisia, regarding the different histological types. This is a retrospective study including cases of BT in CAA collected in the pathology department at the Habib Bourguiba university hospital over a period of 15 years (2006- 2020). A total of 266 BT was diagnosed in our institution (42,7% among all BT in Southern Tunisia) divided into 200 benign bone tumors (BBT) (75,2%) and 66 malignant bone tumors (MBT) (24,8%). The mean age for all BT was 14,2 years (3-20 years) with male predominance (sex ratio: 1,48). The most common tumor was osteochondroma (42.2%) followed by osteosarcoma (14.6%) and Ewing sarcoma (6.4%). For BBT, the most affected age group was the 16 to 20 year - old - group (50,7%) with a male predominance (59.8%) and a predilection for lower limb (66.8%) then the upper limb (16,8%). Osteochondroma was the most common histological type (56.5%) followed by aneuvrysmal cyst (8,5%) and osteoid osteoma (6,5%). For MBT, the mean age was 12,5 years (5-20 years) and the most affected age group was the 11 to 15 year -old -group (59%). Boys were more affected (60.6%), with a preference for the lower limb (57%) followed by the pelvis (15,6%). Osteosarcoma was the most common MBT (60%) followed by Ewing sarcoma (24%). Given their rarity and heterogeneity, the diagnosis of BT is particular in CAA and requires a multidisciplinary approach. The reporting of epidemiological studies remains essential in order to expand our knowledge regarding these uncommon tumors.

Pesticides are widely used, resulting in continuing human exposure with potential health impacts. Some exposures related to agricultural works have been associated with neurological disorders. Since the 2000s, the hypothesis of the role of pesticides in the occurrence of central nervous system (CNS) tumors has been better documented in the literature. However, the etiology of childhood brain cancers still remains largely unknown. The major objective of this work was to assess the potential role of pesticide exposure as a risk factor for CNS tumors based on questionnaires and statistical analysis of information collected from patients hospitalized in the Neurosurgery Department of the Habib Bourguiba Hospital Medium in Sfax, Tunisia, during the period from January 1, 2022, to May 31, 2023. It also aimed to develop a simple and rapid analytical method by the gas chromatography-mass spectrometry technique for the research traces of pesticide metabolites in some collected human brain tumor tissues in order to more emphasize our hypothesis for such a correlation between pesticide exposure and brain tumor development. Patients with a history of high-risk exposure were selected to conduct further analysis. Chemometric methods were adapted to discern intrinsic variation between pathological and control groups and ascertain effective separation with the identification of differentially expressed metabolites accountable for such variations. Three samples revealed traces of pesticide metabolites that were mostly detected at an early age. The histopathological diagnosis was medulloblastoma for a 10-year-old child and high-grade gliomas for 27- and 35-year-old adults. The bivariate analyses (odds ratio >1 and P value <5%) confirmed the great probability of developing cancer by an exposure case. The Cox proportional hazards model revealed the risk of carcinogenicity beyond the age of 50 as a long-term effect of pesticide toxicity. Our study supports the correlation between pesticide exposure and the risk of development of human brain tumors, suggesting that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased childhood brain tumor risk. This hypothesis was enhanced in identifying traces of metabolites from the carbamate insecticide class known for their neurotoxicity and others from pyridazinone, organochlorines (OCs), triazole fungicide, and N-nitroso compounds known for their carcinogenicity. The 2D-OXYBLOT analysis confirmed the neurotoxicity effect of insecticides to induce oxidative damage in CNS cells. Aldicarb was implicated in brain carcinogenicity confirmed by the identification of oxime metabolites in a stress degradation study. Revealing "aziridine" metabolites from the OC class may better emphasize the theory of detecting traces of pesticide metabolites at an early age. Overall, our findings lead to the recommendation of limiting the residential use of pesticides and the support of public health policies serving this objective that we need to be vigilant in the postmarketing surveillance of human health impacts.

This study aimed to evaluate the potentiality of a mineral and antioxidant-rich methanolic extract of the red marine alga Falkenbergia rufolanosa (FRE) against methyl-thiophanate (MT)-induced toxicity in adult rats. The animals were allocated into four groups: controls, MT (300 mg/kg), MT + FRE, and FRE-treated group for 7 days. Our results demonstrated severe mineral perturbations due to MT treatment, especially in calcium and phosphorus levels in plasma, urine, and bone. Similarly, the hematological analysis revealed increased red blood cells, platelets, and white blood cells associated with striking genotoxicity. Interestingly, a significant rise in lipid peroxidation and advanced oxidation protein products level in erythrocytes and bone were noted. Meanwhile, a depletion of the antioxidant status in both tissues occurred. These biochemical alterations were in harmony with DNA degradation and histological variation in bone and blood. In the other trend, data showed that treatment with alga improved MT-induced hematotoxicity, genotoxicity, and oxidative stress in the blood and bone. Osteo-mineral metabolism and bone histo-architecture were also noted. In conclusion, these findings demonstrated that the red alga Falkenbergia rufolanosa is a potent source of antioxidant and antibacterial agents, as revealed by the in vitro analysis.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Mixed hepatocellular-neuroendocrine carcinoma (HCC-NEC) is a rare entity with a poor prognosis. We report a case of a 44-yearold Tunisian man who was admitted for diffuse abdominal pain. Body computed tomography showed multinodular hepatomegaly. Pathologic findings concluded to HCC-NEC. Clinicians should be aware about this entity. Further collection of case reports is needed to standardize the optimal treatment.

A sulfated polysaccharide from tetrasporophyte tufts of Asparagopsis armata (Falkenbergia rufolanosa) (FRP) was extracted, then its structural, morphological and thermal properties were characterized. Antioxidant potential, enzymatic inhibitory effect and anticoagulant activities through activated partial thrombosis time, thrombin time and prothrombin time were also established. Additionally, this polymer was tested in vivo for its hepato-protective effect against toxicity induced by the fungicide — methyl thiophanate (MT). After MT injection, our data revealed a significant disruption in all biochemical and oxidative stress parameters associated with the hepatotoxicity features. Further, hepatic homogenates showed increased levels in inflammatory proteins consorted with detection of Bcl-2, IL-1beta, and P53 examined via immunohistochemistry revelation. These data were consolidate by liver histo-architecture and molecular investigation. However, the pre-treatment with FRP led to an effective healing process against MT's injuries. In summary, our data suggest that FRP could be assigned as a novel candidate for use as antioxidant, anticoagulant and hepato-protective agent.

Pesticides are increasingly used in combinations in crop protection, resulting in enhanced toxicities for various organisms. Although protein adductomics is challenging, it remains a powerful bioanalytical tool to check environmental exposure and characterize xenobiotic adducts as putative toxicity biomarkers with high accuracy, facilitated by recent advances in proteomic methodologies and a mass spectrometry high-throughput technique. The present study aims to predict the potential neurotoxicity effect of imidacloprid and λ-cyhalothrin insecticides on human neural cells. Our protocol consisted first of 3D in vitro developing neurospheroids derived from human brain tumors and then treatment by pesticide mixture. Furthermore, we adopted a bottom-up proteomic-based approach using nanoflow ultraperformance liquid chromatography coupled with a high-resolution mass spectrometer for protein-adduct analysis with prediction of altered sites. Two proteins were selected, namely, calcium-calmodulin-dependent protein kinase-II (CaMK2) and annexin-A1 (ANXA1), as key targets endowed with primordial roles. De novo sequencing revealed several adduct formations in the active site of 82-ANXA1 and 228-CaMK2 as a result of neurotoxicity, predicted by the added mass shifts for the structure of electrophilic precursors. To the best of our knowledge, our study is the first to adopt a proteomic-based approach to investigate in depth pesticide molecular interactions and their potential to adduct proteins which play a crucial role in the neurotoxicity mechanism.

Background: Intra-amniotic umbilical vein varices are characterized by a focal dilatation of the extra abdominal umbilical vein. Case report: We report a full-term baby female with extra-abdominal umbilical vein varices misdiagnosed clinically as an omphalocele. The umbilical vein was ligated and excised near the level of the liver. The infant died one day after surgery due to extrinsic compression of the renal pedicle by a massive thrombus, resulting in severe renal failure and life-threatening hyperkalemia despite intensive resuscitation. Conclusion: Large intra-amniotic umbilical vein varices can be clinically misdiagnosed as an omphalocele. Their resection near the level of the fascia, as with normal umbilical veins, could be a better management with a better prognosis.