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Daniel Oltean-Dan,1 Gabriela-Bombonica Dogaru,2 Maria Tomoaia-Cotisel,3,4 Dragos Apostu,1 Alexandru Mester,5 Horea-Rares-Ciprian Benea,1 Mihai-Gheorghe Paiusan,1 Elena-Mihaela Jianu,6 Aurora Mocanu,3 Reka Balint,3 Catalin-Ovidiu Popa,7 Cristian Berce,8 Gyorgy-Istvan Bodizs,9 Alina-Mihaela Toader,10 Gheorghe Tomoaia1,41Iuliu Hatieganu University of Medicine and Pharmacy, Department of Orthopedics and Traumatology, 400132 Cluj-Napoca, Romania; 2Iuliu Hatieganu University of Medicine and Pharmacy, Department of Medical Rehabilitation, 400347 Cluj-Napoca, Romania; 3Babes Bolyai University, Faculty of Chemistry and Chemical Engineering, Department of Chemical Engineering, Research Center of Physical Chemistry, 400028 Cluj-Napoca, Romania; 4Academy of Romanian Scientists, 050085 Bucharest, Romania; 5Iuliu Hatieganu University of Medicine and Pharmacy, Department of Oral Rehabilitation, Oral Health and Management, 400012 Cluj-Napoca, Romania; 6Iuliu Hatieganu University of Medicine and Pharmacy, Department of Histology, 400349 Cluj-Napoca, Romania; 7Technical University of Cluj-Napoca, Department of Materials Science and Engineering, 400641 Cluj-Napoca, Romania; 8Iuliu Hatieganu University of Medicine and Pharmacy, Center for Experimental Medicine, 400349 Cluj-Napoca, Romania; 9Rehabilitation Clinic, 400347 Cluj-Napoca, Romania; 10Iuliu Hatieganu University of Medicine and Pharmacy, Department of Physiology, 400006 Cluj-Napoca, RomaniaPurpose: Bone consolidation after severe trauma is the most challenging task in orthopedic surgery. This study aimed to develop biomimetic composite for coating Ti implants. Afterwards, these implants were tested in vivo to assess bone consolidation in the absence or the presence of high-frequency pulsed electromagnetic short-waves (HF-PESW).Materials: Biomimetic coating was successfully developed using multi-substituted hydroxyapatite (ms-HAP) functionalized with collagen (ms-HAP/COL), embedded into poly-lactic acid (PLA) matrix (ms-HAP/COL@PLA), and subsequently covered with self-assembled COL layer (ms-HAP/COL@PLA/COL, named HAPc).Methods: For in vivo evaluation, 32 Wistar albino rats were used in four groups: control group (CG) with Ti implant; PESW group with Ti implant+HF-PESW; HAPc group with Ti implant coated with HAPc; HAPc+PESW group with Ti implant coated with HAPc+HF-PESW. Left femoral diaphysis was fractured and fixed intramedullary. From the first post-operative day, PESW and HAPc+PESW groups underwent HF-PESW stimulation for 14 consecutive days. Biomimetic coating was characterized by XRD, HR-TEM, SEM, EDX and AFM.Results: Osteogenic markers (ALP and osteocalcin) and micro-computed tomography (CT) analysis (especially bone volume/tissue volume ratio results) indicated at 2 weeks the following group order: HAPc+PESW>HAPc≈PESW (P>0.05) and HAPc+PESW>control (P

Introduction: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents diverse clinical manifestations and multi-organ involvement. This study aimed to evaluate the extra-pulmonary histopathological patterns underpinning COVID-19-induced lesions in cardiac, hepatic, renal, brainstem, and splenic tissues., Materials and Methods: The research involved conventional forensic autopsies conducted between April 2020 and April 2021 on individuals with confirmed SARS-CoV-2 infection in Cluj-Napoca, Romania. Tissues were processed and stained for histological examination. Differences in patients with and without diffuse alveolar damage (DAD) were evaluated., Results: In our study of 79 COVID-19 autopsies conducted on unvaccinated patients besides lung involvement, the patients had histological changes in at least two out of five (brain, heart, liver, kidney, and spleen) organs. Notable findings include hepatitis observed in 46.8 % of cases, 21.5 % with lobular hepatitis, and 41.8 % with liver steatosis. Additionally, 69.6 % exhibited acute tubular necrosis, and 55.7 % had varying degrees of splenic lymphocyte depletion. Almost 41 % of cases had pericardial effusion, 36.7 % myocarditis, 24.1 % myocardial infarction, and 12.7 % of cases had encephalitis. Acute tubular necrosis (78.6 %) was the most frequent histopathological finding observed in patients with DAD. Myocarditis was described in 45.9 % of the patients without DAD., Discussion: The autopsy findings in our cohort of COVID-19 victims align with international scientific literature. Distinguishing viral-induced myocarditis, encephalitis, hepatitis, or systemic inflammatory syndrome remains challenging., Conclusion: Post-mortem analysis identified lesions associated with SARS-CoV-2 in multiple organs, highlighting the systemic nature of the virus and emphasizing the need for continued research into organ-specific damage and long-term sequelae of COVID-19., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The paper provides an overview of the current understanding of different cells and structures' biology [e.g., blood-retinal barrier, Bruch membrane, Clara (club) cells, brush cells and tuft cells, Merkel cells, Hofbauer cells, cytokeratins], including their origin, structure, function, and role in disease pathogenesis, and of the latest findings in the medical literature concerning the paracortex of the lymph nodes., Competing Interests: The authors declare that they have no conflict of interests.

The primary targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the lungs are type I pneumocytes, macrophages, and endothelial cells. We aimed to identify lung cells targeted by SARS-CoV-2 using viral nucleocapsid protein staining and morphometric features on patients with fatal COVID-19. We conducted a retrospective analysis of fifty-one autopsy cases of individuals who tested positive for SARS-CoV-2. Demographic and clinical information were collected from forensic reports, and lung tissue was examined for microscopic lesions and the presence of specific cell types. Half of the evaluated cohort were older than 71 years, and the majority were male (74.5%). In total, 24 patients presented diffuse alveolar damage (DAD), and 50.9% had comorbidities (56.9% obesity, 33.3% hypertension, 15.7% diabetes mellitus). Immunohistochemical analysis showed a similar pattern of infected macrophages, infected type I pneumocytes, and endothelial cells, regardless of the presence of DAD ( p > 0.5). The immunohistochemical reactivity score (IRS) was predominantly moderate but without significant differences between patients with and without DAD ( p = 0.633 IRS for type I pneumocytes, p = 0.773 IRS for macrophage, and p = 0.737 for IRS endothelium). The nucleus/cytoplasm ratio shows lower values in patients with DAD (median: 0.29 vs. 0.35), but the difference only reaches a tendency for statistical significance ( p = 0.083). Our study confirms the presence of infected macrophages, type I pneumocytes, and endothelial cells with a similar pattern in patients with and without diffuse alveolar damage.

Endometriosis is a common gynecological condition with a complex physio-pathological background. This study aimed to assess the role of Rubus idaeus leaf extract (RiDE) as a potential therapeutic agent in reducing the size of the endometriotic lesions and modulate the plasma expression of MMP-2, MMP-9, and TGF-β1. The endometriotic lesions were induced in a rat model by the autologous transplant of endometrium. Thirty-six female rats, Wistar breed, with induced endometriosis, were divided into four groups and underwent treatment for 28 days. The CTRL group received 0.5 mL/day of the vehicle; the DG group received 1 mg/kg b.w./day dienogest; the RiDG group received 0.25 mL/kg b.w./day RiDE and the D+RiDG group received 1 mg/kg b.w./day dienogest and 0.25 mL/kg b.w./day RiDE, respectively. Rats' weight, endometriotic lesion diameter and grade, and plasma levels of MMP-2, MMP-9, and TGF-β1 were assessed before and after treatment. The administration of RiDE in association with dienogest vs. dienogest determined a lower weight gain and a reduction in diameter of the endometriotic lesions. RiDE administration restored MMP2 and MMP9 plasma levels to initial conditions. Rubus idaeus extract may help in reducing dienogest-associated weight gain, lower the size of endometriotic lesions, and have anti-inflammatory effects through MMP2 and MMP9 reduction.

We aimed to evaluate the primary lung postmortem macro- and microscopic biomarkers and factors associated with diffuse alveolar damage in patients with fatal coronavirus (COVID-19). We retrospectively analyzed lung tissue collected from autopsies performed in Cluj-Napoca, Romania, between April 2020 and April 2021 on patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examined 79 patients with confirmed SARS-CoV-2 infection, ages 34 to 96 years, split into two groups using the cut-off value of 70 years. Arterial hypertension (38%) and type 2 diabetes mellitus (19%) were the most common comorbidities with similar distribution between groups ( p -values > 0.14). Macroscopically, bloody exudate was more frequently observed among patients < 70 years (33/36 vs. 29/43, p -value = 0.0091). Diffuse alveolar damage (53.1%) was similarly observed among the evaluated groups ( p -value = 0.1354). Histopathological biomarkers of alveolar edema in 83.5% of patients, interstitial pneumonia in 74.7%, and microthrombi in 39.2% of cases were most frequently observed. Half of the evaluated lungs had an Ashcroft score of up to 2 and an alveolar air capacity of up to 12.5%. Bronchopneumonia (11/43 vs. 3/36, p -value = 0.0456) and interstitial edema (9/43 vs. 2/36, p -value = 0.0493) were significantly more frequent in older patients. Age (median: 67.5 vs. 77 years, p -value = 0.023) and infection with the beta variant of the virus ( p -value = 0.0071) proved to be significant factors associated with diffuse alveolar damage.

The paper provides an overview of the current understanding of different cells' biology (e.g., keratinocytes, Paneth cells, myoepithelial cells, myofibroblasts, chondroclasts, monocytes, atrial cardiomyocytes), including their origin, structure, function, and role in disease pathogenesis, and of the latest findings in the medical literature concerning the brown adipose tissue and the juxtaoral organ of Chievitz.

This article focuses on the latest histological knowledge in the field regarding the peripheral lymphoid system [mucosa-associated lymphoid tissue (MALT), bronchus-associated lymphoid tissue (BALT), gut-associated lymphoid tissue (GALT)], the thymus stroma, some of the various corpuscles of the human body (Hassall's corpuscles in thymus, arenaceous corpuscles in pineal gland, corpora amylacea in prostate and other locations) and Fañanas glial cells in the cerebellum.

Innovative nanomaterials are required for the coatings of titanium (Ti) implants to ensure the activation of Ti surfaces for improved osseointegration, enhanced bone fracture healing and bone regeneration. This paper presents a systematic investigation of biomimetic composite (BC) coatings on Ti implant surfaces in a rat model of a diaphyseal femoral fracture. Methodological approaches of surface modification of the Ti implants via the usual joining methods (e.g., grit blasting and acid etching) and advanced physicochemical coating via a self-assembled dip-coating method were used. The biomimetic procedure used multi-substituted hydroxyapatite (ms-HAP) HAP-1.5 wt% Mg-0.2 wt% Zn-0.2 wt% Si nanoparticles (NPs), which were functionalized using collagen type 1 molecules (COL), resulting in ms-HAP/COL (core/shell) NPs that were embedded into a polylactic acid (PLA) matrix and finally covered with COL layers, obtaining the ms-HAP/COL@PLA/COL composite. To assess the osseointegration issue, first, the thickness, surface morphology and roughness of the BC coating on the Ti implants were determined using AFM and SEM. The BC-coated Ti implants and uncoated Ti implants were then used in Wistar albino rats with a diaphyseal femoral fracture, both in the absence and the presence of high-frequency pulsed electromagnetic shortwave (HF-PESW) stimulation. This study was performed using a bone marker serum concentration and histological and computer tomography (micro-CT) analysis at 2 and 8 weeks after surgical implantation. The implant osseointegration was evaluated through the bone-implant contact (BIC). The bone-implant interface was investigated using FE-SEM images and EDX spectra of the retrieved surgical implants at 8 weeks in the four animal groups. The obtained results showed significantly higher bone-implants contact and bone volume per tissue volume, as well as a greater amount of newly formed bone, in the BC-coated Ti implants than in the uncoated Ti implants. Direct bone-implant contact was also confirmed via histological examination. The results of this study confirmed that these biomimetic composite coatings on Ti implants were essential for a significant enhancement of osseointegration of BC-coated Ti implants and bone regeneration. This research provides a novel strategy for the treatment of bone fractures with possible orthopedic applications.

Microsatellite instability (MSI) or the deficiency of mismatch repair (MMR) proteins is one of the molecular pathways of colorectal tumorigenesis and may have important clinical implications in predicting the treatment response. We evaluated the relationship between clinicopathological features and MMR proteins [mutL homologue 1 (MLH1), mutS homologue 2 (MSH2), mutS homologue 6 (MSH6), postmeiotic segregation increased 2 (PMS2)], adhesion molecules (E-cadherin, beta-catenin) and caudal-type homeobox 2 (CDX2) in 31 patients with colon adenocarcinoma, using immunohistochemistry. We also aimed to assess the prognostic value of the studied proteins. MLH1 loss was correlated to PMS2 loss (p=0.006) and MSH2 loss (p=0.023); MSH2 loss was significantly associated to MSH6 loss (p=0.011). Tumors with MSH6 loss, together with tumors with PMS2 loss, covered all the patients with MSI status. We found a significant correlation between MSI tumors and mucinous histological type (p=0.03), but no significant associations with other clinicopathological features or with survival rate. There was a significant correlation between E-cadherin expression and differentiation degree (p=0.018) and between beta-catenin expression and lymph node invasion (p=0.046). No significant association between CDX2 loss and any clinical or pathological features was found (p>0.05). No significant differences were identified in overall survival according to E-cadherin, beta-catenin or CDX2 expression (p>0.05). In our study, PMS2 loss was significantly correlated with CDX2 loss (p=0.03). In conclusion, the molecular analysis of biological markers for colon cancer may be important for patient stratification, in order to select the optimal treatment algorithm. Our results suggest that probably the double panel (MSH6 and PMS2) is enough to detect the MSI status, instead of using the quadruple panel.

Psoriasis vulgaris, a chronic inflammatory skin disorder, is the result of immune mediated processes, genetic background and environmental factors. Prolactin and the vascular endothelial growth factor seem to play a key role in psoriasis pathogenesis regarding hyperproliferation of epidermal keratinocytes and dermal vascular ectasia. The aim of the study was to investigate the expression of tumor necrosis factor-α (TNF-α), vascular endothelial growth factor receptor 2 (VEGFR2) and prolactin receptor (PRLR) in psoriatic skin by immunohistochemical analysis and to evaluate the correlation with disease severity. Two skin biopsies, psoriatic lesion and perilesional skin, obtained by punch biopsy from 19 nontreated psoriasis patients were examined in hematoxylin and eosin staining and immunohistochemistry (IHC) for TNF-α, VEGFR2 and PRLR. The indirect IHC reaction was carried out automatically and visualized by 3,3-diaminobenzidine (DAB) technique. The average number of DAB-positive cells and the intensity of cell staining were quantified on a predefined scale. The results show a significant difference in the quantity and distribution of TNF-α positive cells in the two sample groups. In psoriatic plaque skin, an increased expression of TNF-α was found in the perivascular dermis and epidermic keratinocytes. In perilesional skin the immunostaining was predominant in the basal layer keratinocytes, while in psoriatic plaque, all the layers were positively marked, with stronger expression at the base. A statistically significant difference was found between the intensity of the immunostaining in the two types of tissue. Positive cells for VEGFR2 and PRL were identified in the basal layer keratinocyte cells (VEGFR2), sweat glands and hair outer shaft sheath (PRLR), without significant differences between the two types of samples. Our findings confirm the importance of TNF-α in psoriasis pathogenesis and a positive correlation with lesions severity. No significant differences were found for VEGFR2 and PRLR, but additional studies are necessary to establish their role.

In vitro studies showed that high-frequency pulsed electromagnetic fields (HF-PEMFs) increase the activity/expression of early and late osteogenic markers and enhance bone mineralization. The main aim of this study was to investigate the in vivo effects of HF-PEMFs on fracture healing using a rat model. A femur fracture was established by surgery in 20 male Wistar rats. Titanium nails were implanted to reduce and stabilize the fracture. After surgery, 20 rats were equally divided into untreated control and treated group (from the first postoperative day HF-PEMFs at 400 pulses/sec [pps] were applied for 10 minutes/day, for two weeks). Quantitative and qualitative assessment of bone formation was made at two and eight weeks following surgery and included morphological and histological analysis, serological analysis by ELISA, micro-computed tomography (micro-CT), and three-point bending test. At two weeks in HF-PEMF group, soft callus was at a more advanced fibrocartilaginous stage and the bone volume/total tissue volume (BV/TV) ratio in the callus area was significantly higher compared to control group (p = 0.047). Serum concentration of alkaline phosphatase (ALP) and osteocalcin (OC) was significantly higher in HF-PEMF group (ALP p = 0.026, OC p = 0.006) as well as the mechanical strength of femurs (p = 0.03). At eight weeks, femurs from HF-PEMF group had a completely formed woven bone with dense trabeculae, active bone marrow, and had a significantly higher BV/TV ratio compared to control (p = 0.01). HF-PEMFs applied from the first postoperative day, 10 minutes/day for two weeks, enhance bone consolidation in rats, especially in the early phase of fracture healing.

Background and Aim: Psoriasis vulgaris, a chronic inflammatory skin disease, requires a long term medication, in order to avoid relapsing episodes. TNF-alpha, one of the targeted molecule in psoriasis therapy, seems to be also involved in thyroid disorders etiopathogenesis. The aim of this study was to evaluate the relationship between anti TNF-alpha therapy and thyroid parameters: serum level of triiodothyronine (T3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and antithyroidperoxidase antibody (AbTPO) in psoriasis treated population., Methods: The study was performed on 44 patients with psoriasis vulgaris (20 patients under antiTNF-alpha treatment (etanercept), 24 patients with no previous systemic therapy). Serum concentrations of hormones, AbAntiTPO and TNF-alpha were measured and a thyroid ultrasonographic evaluation was performed for each patient., Results: The mean serum level of FT4 was significantly higher in patients with no systemic treatment (p<0.05). The patients treated with etanercept had a significantly higher level of TNF-alpha (p<0.05). No significant difference was observed for the other evaluated parameters. Also, we found a significant negative correlation between TNF-alpha and TSH levels (r=-0.366, p=0.015)., Conclusions: We only found that the mean level of FT4 was significantly higher in patients with no systemic treatment. Also, a negative strong correlation was seen between serum level of TSH and TNF-alpha. Based on our data, comparison with other anti TNF-alpha therapies might be of interest in future studies.

Pituitary adenomas are benign tumors of the brain, with a relatively high prevalence in the general population, being responsible for 14.4-16.7% from all brain tumors. These tumors, although benign, have a local invasive behavior in approximately 35% of the cases. The aim of this study was to identify the differences in expression of molecular markers between primary and relapsed pituitary adenomas (as an aggressiveness indicator), as well between secreting and non-secreting pituitary adenomas. Tumor fragments were collected from 51 patients with invasive pituitary adenomas. Of these, 10 cases were operated a second time due to tumor recurrence. The tumor fragments were retrieved from the archives of the Department of Pathology, Emergency County Hospital, Cluj-Napoca, Romania. Immunohistochemical staining was performed for nine markers on 51 invasive pituitary adenomas: Ki-67, β-catenin, E-cadherin, Bcl-2, galectin-3, p53, p27, CD117, and CD44. We compared the expression differences between two groups: the first one including primary and relapsed invasive pituitary adenomas, and another one including prolactin (PRL)-secreting and non-secreting invasive pituitary adenomas. Ki-67, p53 and Bcl-2 expressions were found significant in the PRL-secreting group. CD44 immunostaining was significant only in relapsed invasive pituitary adenomas. For the β-catenin, E-cadherin, galectin-3, p27 and CD117 expression levels were not registered statistically significant differences between our groups. Our study is the first one to report a statistically significant difference between the expression of CD44 in primary and relapsed invasive pituitary adenomas and it could be used as a negative impact prognostic marker.