Histological Signs Research Articles

LEPROMATOUS LEPROSY REVEALED BY PALMOPLANTAR NODULAR LESIONS

Leprosy is a chronic debilitating disorder caused by the acid-fast bacilli Mycobacterium leprae (M. leprae).This bacilli exhibit a distinctive predilection for the skin and peripheral nerves, although they can potentially impact any system in the body.Palmoplantar involvement has been infrequently reported in leprosy and is an easily misdiagnosed entity.We report a case of a young female presented with a palmo plantar nodular lesions for wich a skin biopsy showed histological signs consistent with lepromatous leprosy.

Macrophagic activation syndrome complicating miliary tuberculosis: A case report

Macrophage activation syndrome (MAS), also known as hemophagocytic syndrome or lymphohistiocytic activation syndrome, is a rare but potentially fatal disease. It results from inappropriate stimulation of macrophages in the bone marrow and lymphoid organs. The diagnosis of MAS is based on a combination of clinical, biological, and histological or cytological signs. MAS is categorized into primary forms, which mainly affect newborns and infants with a family history, and secondary forms, which occur in the context of neoplastic, autoimmune, or infectious diseases. Treatment involves addressing the specific causative agent of MAS and, in certain cases, early administration of corticosteroids and immunoglobulins. MAS is rarely associated with tuberculosis. We report the case of an immunocompetent patient presenting with miliary tuberculosis complicated by macrophage activation syndrome.

Impact of Single Blast Exposure on Neuronal Damage and Protein Levels in the Rat Brain at Varying Pressures

Abstract Introduction Brain injuries from blasts are increasingly common in both civilian and war settings. The impact of blast injuries at different pressure levels remains unclear, and their long-term effects are not well understood. This study investigates how varying blast pressures affect the rat brain over time. Materials and Methods Forty adult Sprague-Dawley rats were randomized into four groups of 10. Three groups were exposed to blasts, while one served as a control and was only subjected to blast sounds. Each group received a single blast at different pressures, followed by neuropsychological tests. After 28 and 84 days, the rats were sacrificed to measure tau protein and acetylcholine esterase levels and to conduct histological examinations of brain tissues. Results A single blast exposure did not significantly impact visuospatial memory or recall. Despite the lack of noticeable cognitive deficits, histopathological and biochemical analyses revealed reduced tau protein levels, indicating ongoing neuronal damage. Conclusion While a single blast did not significantly impair visuospatial memory or recall in this rat model, there were decreases in tau protein and acetylcholine esterase levels, along with histological signs of neuronal damage.

Oxidized ATP Suppresses B Lymphocyte Activity to Attenuate Antibody-mediated Rejection of Kidney Allografts in Mice

Background. Antibody-mediated rejection (AMR) is a major cause of renal allograft dysfunction and loss. Targeting B cells and/or donor-specific antibody removal using plasma exchange and anti-CD20 antibodies are increasingly used in clinical practice, but the efficacy remains limited. Recent studies suggest that targeting purinergic P2X7 receptor/ATP axis can have profound immune regulatory effects in transplant models, but the mechanisms involved remain incompletely defined. Methods. Purified B cells were isolated from the spleen of Balb/C mice and cultured with oxidized ATP at different concentrations. Proliferation and differentiation of B cells were examined. Effects of oxidized ATP were examined in a presensitized animal model where kidney allograft rejection mimics aspects of clinical AMR. Histopathology was assessed at the time of rejection or on day 5 after kidney transplantation. Infiltrating immune cells in renal allografts were detected by flow cytometry. Results. Oxidized ATP inhibited B-cell activation and proliferation in vitro, significantly attenuated histological signs of graft injury and prolonged kidney allograft survival. Mechanistically, oxidized ATP inhibited antibody secretion by activated B cells in response to lipopolysaccharide stimulation and markedly suppressed the production of donor-specific antibody in kidney allograft recipients. Oxidized ATP also reduced graft infiltration by other inflammatory cells. Conclusions. These findings provide evidence for the involvement of the purinergic P2X7 receptor pathway in AMR and suggest that targeting this pathways may have important clinical implications.

Intrathyroidal Parathyroid Adenoma.

Intrathyroidal parathyroid adenoma is a rare anomaly with an incidence of 1.4-6%. A cause of failure in the therapeutic management of hyperparathyroidism is the ectopic localization of the adenoma, particularly intrathyroidal. This is the case of a 51-year-old patient with no particular pathological history who presented with neck pain and whose clinical examination revealed a goiter. Parathyroid myocardial perfusion imaging (MIBI) scintigraphy revealed an elective MIBI-fixing focus with an upper left polar projection compatible with a parathyroid origin. A left loboishmectomy was performed. Anatomopathological study showed a parathyroid adenoma associated with dystrophic thyroid parenchyma, with no obvious histological signs of malignancy. Post-therapeutic laboratory work-up was normalized. Parathyroid adenoma, intrathyroidal, is an uncommon lesion but may be responsible for therapeutic failure in hyperparathyroidism. MIBI parathyroid gland scintigraphy is the gold standard for the diagnosis of parathyroid ectopy.

Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis.

Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF). In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients. Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival. Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases.

Removal of the infrapatellar fat pad and associated synovium benefits female guinea pigs in the Dunkin Hartley model of idiopathic osteoarthritis.

Several tissues contribute to the onset and advancement of knee osteoarthritis (OA). One tissue type that is worthy of closer evaluation, particularly in the context of sex, is the infrapatellar fat pad (IFP). We previously demonstrated that removal of the IFP had short-term beneficial effects for a cohort of male Dunkin-Hartley guinea pigs. The present project was designed to elucidate the influence of IFP removal in females of this OA-prone strain. It was hypothesized that resection of the IFP would reduce the development of OA in knees of a rodent model predisposed to the disease. Female guinea pigs (n=16) were acquired at an age of 2.5 months. Surgical removal of the IFP and associated synovium complex (IFP/SC) was executed at 3 months of age. One knee had the IFP/SC resected; a comparable sham surgery was performed on the contralateral knee. All animals were subjected to voluntary enclosure monitoring and dynamic weight-bearing, as well as compulsory treadmill-based gait analysis monthly; baseline data was collected prior to surgery. Guinea pigs were euthanized at 7 months. Knees from eight animals were evaluated via histology, mRNA expression, and immunohistochemistry (IHC); knees from the remaining eight animals were allocated to microcomputed tomography (microCT), biomechanical analyses (whole joint testing and indentation relaxation testing), and atomic absorption spectroscopy (AAS). Fibrous connective tissue (FCT) replaced the IFP/SC. Mobility/gait data indicated that unilateral IFP/SC removal did not affect bilateral hindlimb movement. MicroCT demonstrated that osteophytes were not a significant feature of OA in this sex; however, trabecular thickness (TbTh) in medial femorae decreased in knees containing the FCT. Histopathology scores were predominantly influenced by changes in the lateral tibia, which demonstrated that histologic signs of OA were increased in knees containing the native IFP/SC versus those with the FCT. Similarly, indentation testing demonstrated higher instantaneous and equilibrium moduli in the lateral tibial articular cartilage of control knees with native IFPs. AAS of multiple tissue types associated with the knee revealed that zinc was the major trace element influenced by removal of the IFP/SC. Our data suggest that the IFP/SC is a significant component driving knee OA in female guinea pigs and that resection of this tissue prior to disease has short-term benefits. Specifically, the formation of the FCT in place of the native tissue resulted in decreased cartilage-related OA changes, as demonstrated by reduced Osteoarthritis Research Society International (OARSI) histology scores, as well as changes in transcript, protein, and cartilage indentation analyses. Importantly, this model provides evidence that sex needs to be considered when investigating responses and associated mechanisms seen with this intervention.

The multiple roles of nerve biopsy in the diagnosis and prognosis of suspected immune neuropathies

IntroductionThe value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value.Methods190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed.Results51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity.DiscussionThe main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.

MULTIDISCIPLINARY APPROACH TO A DIFFICULT CASE OF ACUTE HEART FAILURE DUE TO POSSIBILE ISOLATED CARDIAC SARCOIDOSIS

Abstract Background Cardiac sarcoidosis (CS) is a rare, infiltrative cardiomyopathy that results from granulomatous inflammation affecting the heart with high morbidity and mortality. It is usually associated with a systemic (i.e. pulmonary) involvement, but lone heart involvement has been described. Even with extensive multidisciplinary evaluation making a firm diagnosis is difficult, especially in case of isolated CS where the endomyocardial biopsy (EBM) diagnostic yield is low (20–30%). Case Description A 71–year–old patient, heavy smoker with no previously known diseases, was admitted with a 3–month history of dyspnea. On admission he showed typical features of heart failure with reduced ejection fraction (HFrEF). A coronary angiography excluded coronary artery disease, while echocardiography (TTE), cardiac magnetic resonance (CMR), and positron emission tomography (FDG–PET) showed a pattern consistent with a non–ischemic dilated cardiomyopathy with reduction in systolic function, and signs of active inflammation (highly suspected CS). Two electroanatomic mapping driven EBM were made but no clear histological signs of CS (i.e., granulomatous inflammation) were detected. The patient was treated with corticosteroids and HFrEF optimal medical therapy (sacubitril/valsartan, mineralocorticoid receptor antagonists, beta–blockers, dapagliflozin) and a temporary wearable defibrillator (LifeVest) was applied. At 2–month follow–up, despite a moderate improvement in the systolic function and HF symptoms, after a multidisciplinary discussion, considering the extensive left ventricle scar, inflammatory involvement, and the presence of multiple non–sustained ventricular tachycardia, a permanent cardioverter–defibrillator (ICD) was implanted. Conclusion This case highlights how, even with (repeated) extensive multidisciplinary evaluation (TTE, CRM, FGD–PET, EBM), a definitive diagnosis of isolated CS often remains presumptive. The presence of an experienced cardiomyopathy team (HF specialists, cardiac imager, electrophysiologists, internal medicine doctor) can help in the diagnostic–therapeutic management of these patients with inflammatory heart disease.

Characterisation of a Japanese Encephalitis virus genotype 4 isolate from the 2022 Australian outbreak

Human infections with the Japanese encephalitis virus (JEV) are a leading cause of viral encephalitis. An unprecedented outbreak of JEV genotype 4 was recently reported in Australia, with an isolate (JEVNSW/22) obtained from a stillborn piglet brain. Herein we conduct a thorough characterization of JEVNSW/22 in three different mouse strains and in human cortical brain organoids (hBOs), and determined the ability of JEVNSW/22 to be neutralized by sera from humans vaccinated with IMOJEV. JEVNSW/22 was less virulent than JEVFU (genotype 2) and JEVNakayama (genotype 3) in C57BL/6J mice and in interferon regulatory factor 7 deficient (Irf7−/−) mice, with infection of wild-type and knockout murine embryonic fibroblasts indicating JEVNSW/22 is more sensitive to type I interferon responses. Irf7−/− mice provide a new model for JEVNSW/22, showing higher viremia levels compared to C57BL/6J mice, and allowing for lethal neuroinvasive infection. All JEV strains were universally lethal in Ifnar−/− mice by day 3, with histological signs of brain hemorrhage, but no other lesions. There were no indications of brain infection in Ifnar−/− mice, with viral protein detected in blood vessels, but not neurons. All JEV isolates showed robust cytopathic infection of human cortical brain organoids, albeit lower for JEVNSW/22. IMOJEV vaccination in humans induced antibodies capable of neutralizing JEVNSW/22, although, for all JEV strains, cross-neutralization titers declined with increasing divergence from IMOJEV in the envelope amino acid sequences. Overall, our study establishes JEVNSW/22 mouse and hBO models of infection, allowing for possible lethal neuroinvasive infection in mice that was rarer than for other JEV genotypes. JEV vaccination regimens may afford protection against this newly emerged JEV genotype 4 strain, although neutralizing antibody responses are sub-optimal.

Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma

The application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.

The histamine H4 receptor antagonist 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-4-methyl-piperazine(LINS01007) prevents the development of DSS-induced colitis in mice

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with growing incidence worldwide. Our group reported the compound 5-choro-1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (LINS01007) as H4R antagonist (pKi 6.2) and therefore the effects and pharmacological efficacy on a DSS-induced mice model of UC were assessed in this work. Experimental acute colitis was induced in male BALB/c mice (n = 5–10) by administering 3 % DSS in the drinking water for six days. The test compound LINS01007 was administered daily i.p. (5 mg/kg) and compared to control group without treatment. Body weight, water and food consumption, and the presence of fecal blood were monitored during 7-day treatment period. The levels of inflammatory markers (PGE2, COX-2, IL-6, NF-κB and STAT3) were also analyzed. Animals subjected to the acute colitis protocol showed a reduction in water and food intake from the fourth day (p < 0.05) and these events were prevented by LINS01007. Histological signs of edema, hyperplasia and disorganized intestinal crypts, as well as neutrophilic infiltrations, were found in control mice while these findings were significantly reduced in animals treated with LINS01007. Significant reductions in the levels of PGE2, COX-2, IL-6, NF-κB and STAT3 were observed in the serum and tissue of treated animals. The results demonstrated the significant effects of LINS01007 against DSS-induced colitis, highlighting the potential of H4R antagonism as promising treatment for this condition.

Shift from Pro- to Anti-Inflammatory Phase in Pelvic Floor Muscles at Postpartum Matches Histological Signs of Regeneration in Multiparous Rabbits.

Background and Objectives: Pelvic floor muscles (PFM) play a core role in defecation and micturition. Weakening of PFM underlies urogynecological disorders such as pelvic organ prolapse and stress urinary incontinence. Vaginal delivery damages PFM. Muscle trauma implies an inflammatory response mediated by myeloid cells, essential for subsequent recovery. Molecular signaling characterizing the pro-inflammatory phase shifts M1 macrophages to M2 macrophages, which modulate muscle repair. The present study aimed to evaluate histological characteristics and the presence of M1 and M2 macrophages in bulbospongiosus (Bsm) and pubococcygeus muscles (Pcm). Materials and Methods: Muscles from young nulliparous (N) and multiparous rabbits on postpartum days three (M3) and twenty (M20) were excised and histologically processed to measure the myofiber cross-sectional area (CSA) and count the centralized myonuclei in hematoxylin-eosinstained sections. Using immunohistochemistry, M1 and M2 macrophages were estimated in muscle sections. Kruskal-Wallis or one-way ANOVA testing, followed by post hoc tests, were conducted to identify significant differences (p < 0.05). Results: The myofiber CSA of both the Bsm and Pcm of the M3 group were more extensive than those of the N and M20 groups. Centralized myonuclei estimated in sections from both muscles of M20 rabbits were higher than those of N rabbits. Such histological outcomes matched significant increases in HLA-DR immunostaining in M3 rabbits with the CD206 immunostaining in muscle sections from M20 rabbits. Conclusions: A shift from the pro- to anti-inflammatory phase in the bulbospongiosus and pubococcygeus muscles of multiparous rabbits matches with centralized myonuclei, suggesting the ongoing regeneration of muscles.

QUINQUAUD’S DISEASE IN THE SPECTRUM OF CONCOMITANT DERMATOLOGIC PATHOLOGY

Cicatrical alopecia is one of the acute issues of modern dermatology due to a permanent cosmetic defect in the form of bald areas with non-recoverable loss of hair follicles. Interrelation of cicatrical alopecia with other dermatoses and somatic diseases is also topical. The article presents a clinical case of development of Quinquaud’s disease of the scalp combined with parapsoriasis lichenoides and multiple seborrheic keratosis on the top of already administered targeted therapy in connection with previously removed skin melanoma. Among the features of this pathology, we noted: appearance of rashes after a past oncological disease, erythema diffusely spreading throughout the entire scalp, multiple follicular pustules and rapid formation of cicatricial atrophy, severe itching and soreness, resistance to the ongoing therapy, as well as multiple rashes on the skin of body and extremities in the form of lichenoid papules and plaques. For differential diagnostics, multifocal biopsic examination of the skin was carried out, which showed presence of histologic signs of three dermatoses, which make up a spectrum of the concomitant pathology in the patient. Taking into account the important role of staphylococcal infection in the pathogenesis of Quinquaud’s disease and parapsoriasis lichenoides, we can assume similar pathogenetic mechanisms for the development of these diseases in the patient, associated with disorders of cutaneous microbiome. It is possible that a history of the oncological pathology and targeted therapy could lead to a decrease in resistance and suppression of the immune system, which was also a factor contributing to the development of concomitant dermatoses. Appearance of multiple eruptive seborrheic keratomas on skin of the body and extremities may be an indicator of a paraneoplastic process and require oncological screening. Understanding the causes and common factors of formation of dermatoses comorbid with cicatricial alopecia is extremely important for a dermatologist, because it allows performing early diagnostics in a timely manner, assigning treatment and preventing development of the permanent cosmetic defect leading to a decrease in the quality of life.

QUINQUAUD’S DISEASE IN THE SPECTRUM OF CONCOMITANT DERMATOLOGIC PATHOLOGY

Cicatrical alopecia is one of the acute issues of modern dermatology due to a permanent cosmetic defect in the form of bald areas with non-recoverable loss of hair follicles. Interrelation of cicatrical alopecia with other dermatoses and somatic diseases is also topical. The article presents a clinical case of development of Quinquaud’s disease of the scalp combined with parapsoriasis lichenoides and multiple seborrheic keratosis on the top of already administered targeted therapy in connection with previously removed skin melanoma. Among the features of this pathology, we noted: appearance of rashes after a past oncological disease, erythema diffusely spreading throughout the entire scalp, multiple follicular pustules and rapid formation of cicatricial atrophy, severe itching and soreness, resistance to the ongoing therapy, as well as multiple rashes on the skin of body and extremities in the form of lichenoid papules and plaques. For differential diagnostics, multifocal biopsic examination of the skin was carried out, which showed presence of histologic signs of three dermatoses, which make up a spectrum of the concomitant pathology in the patient. Taking into account the important role of staphylococcal infection in the pathogenesis of Quinquaud’s disease and parapsoriasis lichenoides, we can assume similar pathogenetic mechanisms for the development of these diseases in the patient, associated with disorders of cutaneous microbiome. It is possible that a history of the oncological pathology and targeted therapy could lead to a decrease in resistance and suppression of the immune system, which was also a factor contributing to the development of concomitant dermatoses. Appearance of multiple eruptive seborrheic keratomas on skin of the body and extremities may be an indicator of a paraneoplastic process and require oncological screening. Understanding the causes and common factors of formation of dermatoses comorbid with cicatricial alopecia is extremely important for a dermatologist, because it allows performing early diagnostics in a timely manner, assigning treatment and preventing development of the permanent cosmetic defect leading to a decrease in the quality of life.

Modulation efficiency of clove oil nano-emulsion against genotoxic, oxidative stress, and histological injuries induced via titanium dioxide nanoparticles in mice

Titanium dioxide nanoparticles (TiO2-NPs) have found wide applications in medical and industrial fields. However, the toxic effect of various tissues is still under study. In this study, we evaluated the toxic effect of TiO2-NP on stomach, liver, and kidney tissues and the amelioration effect of clove oil nanoemulsion (CLV-NE) against DNA damage, oxidative stress, pathological changes, and the apoptotic effect of TiO2-NPs. Four groups of male mice were subjected to oral treatment for five consecutive days including, the control group, the group treated with TiO2-NPs (50 mg/kg), the group treated with (CLV-NE) (5% of the MTD), and the group treated with TiO2-NPs plus CLV-NE. The results revealed that the treatment with TiO2-NPs significantly caused DNA damage in the liver, stomach, and kidney tissues due to increased ROS as indicated by the reduction of the antioxidant activity of SOD and Gpx and increased MDA level. Further, abnormal histological signs and apoptotic effect confirmed by the significant elevation of p53 expression were reported after TiO2-NPs administration. The present data reported a significant improvement in the previous parameters after treatment with CLV-NE. These results showed the collaborative effect of the oils and the extra role of nanoemulsion in enhancing antioxidant effectiveness that enhances its disperse-ability and further promotes its controlled release. One could conclude that CLV-NE is safe and can be used as a powerful antioxidative agent to assess the toxic effects of the acute use of TiO2-NPs.

Modern approaches to the treatment of primary multiple unilateral synchronous lung tumors (literature review)

The review article focuses on recent approaches to the treatment of primary multiple unilateral synchronous and metachronous lung tumors. Unilateral primary multiple lung cancer is diagnosed relatively rare. The introduction of modern computed tomography into clinical practice made it possible to diagnose a peripheral tumor at the initial stages. The second synchronous, usually central lung cancer is more often detected during surgery or during bronchoscopy. Despite the established criteria, differential diagnosis of primary tumor and intrapulmonary metastasis in synchronous PMRL remains a difficult task. Often histological signs do not allow differentiating the primary tumor from metastasis. The use of next generation genomic sequencing (NGS) makes it possible to distinguish a primary tumor from a metastasis. To date, there are no unambiguous recommendations for staging primary multiple unilateral lung cancer. There is no clear understanding of what criteria and classification to use to determine the stage of primary multiple cancer, and the type of surgical intervention depends on it. Based on the 8th classification of staging according to the TNM system, patients with primary multiple lung cancer often need to undergo extensive surgical interventions, up to pneumonectomy. Staging each tumor separately allows us to expand the indications for anatomical segmentectomies and reconstructive plastic surgery. For the treatment of PMLC, the main type of surgery is an operative manual with lobectomy. Reconstructive plastic surgeries and anatomical segmentectomies have little effect on increase in frequency of local relapses, on worsening of survival rates. However, the methods are a reasonable alternative for some types of tumors and poor functional indicators. Stereotactic radiation therapy is the standard of treatment for patients who refuse surgery or in patients with functional limitations with early stage primary multiple lung cancer. Moreover, systemic therapies such as targeted therapy in patients with driver mutations and immunotherapy have shown outstanding results.

Difficulties in Diagnosing Pulmonary Nodular Lymphoid Hyperplasia

The article presents a rare case of verified pulmonary nodular lymphoid hyperplasia (PNLH) in a 49-year-old man with history of chemotherapy and radiation therapy for stage 3B Hodgkin lymphoma with metastases in peripheral lymph nodes and the spleen. It describes computed tomographic semiotics of PNLH and the histological signs of the specimens collected during surgical treatment.

Flanagan's condensed protocol for neurodegenerative diseases. Implementation in a clinical autopsy setting with partial supervision of a neuropathologist.

The Condensed Protocol (CP) was originally developed for the evaluation of Alzheimer's Disease (AD) and other neurodegenerative diseases as a workable alternative to the complex and costly established autopsy guidelines. The study objective is to examine the degree of implementation of the CP in the pathology department of a third level university hospital in a period of 5years. Clinical autopsies performed between 2016 and 2021 on patients aged 65years or over and did not require a specific neuropathological examination were reviewed. Histological screening and staging of neurodegenerative diseases was performed using the original immunohistochemical stains. Out of 255 autopsies, 204 met the inclusion criteria and 190 could be reviewed. The CP was applied to 99 cases; histological signs of neurodegenerative disease were observed in 92. Sampling errors were detected in 59 cases. Immunohistochemical studies were performed in 68 cases. The diseases identified were: 31 cases of AD (12 low grade; 19 intermediate), 18 amyloid angiopathy, 15 primary age-related tauopathy, 6 argyrophilic grain disease, 3 progressive supranuclear palsy, 1 Lewy body disease (of 22 cases), and 2 limbic-predominant age TDP43 encephalopathy (of 5 cases). In 30 out of 83 cases, there was more severe vascular pathology in complete sections of frontal cortex and lentiform nucleus. The CP allows reliable detection and staging of AD and related neurodegenerative diseases in clinical autopsies. However, supervision by a neuropathologist seems necessary for a fully successful implementation of the CP in a clinical hospital setting.

Diagnosing Polyomavirus Nephropathy Without a Biopsy: Validation of the Urinary Polyomavirus-Haufen Test in a Proof-of-Concept Study Including Uromodulin Knockout Mice.

Polyomavirus (PyV) nephropathy (PyVN) leads to kidney transplant dysfunction and loss. Since a definitive diagnosis requires an invasive kidney biopsy, a timely diagnosis is often hampered. In this clinical dilemma the PyV haufen-test, centering around the detection of 3-dimensional PyV aggregates in the urine, might provide crucial diagnostic information. A multistep experimental design was used. The hypothesis was that PyV-haufen form within the kidneys under high concentrations of uromodulin, a kidney-specific protein and that PyV-haufen are, therefore, kidney-specific disease biomarkers. The first investigative step showed colocalization of uromodulin with aggregated PyV (1) in 10 kidneys with PyVN by immunohistochemistry, (2) in urine samples containing PyV-haufen by electron microscopy/immunogold labeling (n = 3), and (3) in urine samples containing PyV-haufen by immunoprecipitation assays (n = 4). In the in vitro experiments of the next step, only high uromodulin concentrations (≥1.25 mg/mL) aggregated PyV, as is expected to occur within injured nephrons. In contrast, in voided urine samples (n = 59) uromodulin concentrations were below aggregation concentrations (1.2-19.6 µg/mL). In the third investigative step, none of 11 uromodulin-/- knockout mice (0%) with histologic signs of PyVN showed urinary PyV-haufen shedding, compared with 10 of 14 uromodulin+/+ wild-type mice (71%). PyV-haufen form within kidneys under high uromodulin concentrations. Thus, PyV-haufen detected in the urine are specific biomarkers for intrarenal disease (ie, definitive PyVN).