Mononuclear Infiltration Research Articles

Acute tubulointerstitial nephritis following coronavirus disease 2019 mRNA vaccination: a pediatric case report.

Coronavirus disease 2019 (COVID-19) mRNA vaccines have been linked to various kidney adverse events including acute tubulointerstitial nephritis (ATIN). This report describes a 15-year-old female who developed persistent fever and fatigue 54days after receiving her second dose of the BNT162b2 2 SARS-CoV-2 vaccine. She presented with elevated serum creatinine and urinary β2-microglobulin (β2MG) levels. Kidney biopsy revealed mononuclear infiltrate with some eosinophils, confirming the diagnosis of ATIN. Repeatedly positive lymphocyte transformation test results for the vaccine suggested a relationship between the vaccine and interstitial nephritis. Initially, treatment with prednisolone was effective. However, an increase in urinary β2MG level was observed 7months later, and the introduction of mycophenolate mofetil (MMF) allowed for the gradual reduction and eventual cessation of prednisolone. This case represents one of the rare pediatric instances of ATIN following COVID-19 vaccination. MMF can be an effective alternative in corticosteroid-dependent cases.

Subcortical plaques and inflammation reflect cortical and meningeal pathologies in progressive multiple sclerosis.

It remains elusive whether lesions and inflammation in the sub/juxtacortical white matter reflect cortical and/or meningeal pathologies. Elucidating this could have implications for MRI monitoring as sub/juxtacortical lesions are detectable by routine MRI, while cortical lesions and meningeal inflammation are not. By large-area microscopy, we quantified total and mixed active plaque loads along with densities and sizes of perivascular mononuclear infiltrates (infiltrates) in the sub/juxtacortical white matter ≤2 mm from the cortex, intra-cortically and in the meninges. Data were related to ante-mortem clinical parameters in a false discovery rate-corrected analysis. We compared 12 patients with primary progressive multiple sclerosis (PPMS) and 15 with secondary progressive MS to 22 controls. Fifteen patients and 11 controls contributed with hemispheric sections. Sections were stained with haematoxylin-eosin, for myelin and for microglia/macrophages. B cells and T cells were confirmed in a subset. Immunoglobulin G depositions in selected cortical plaques resembled depositions described before in "slowly expanding" plaques in the white matter. We quantified plaque activity by measuring microglia-dominated and macrophage-dominated areas. Sub/juxtacortical plaques (load and activity) reflected plaque activity in the cerebral cortex. Plaque activity and infiltrates were more pronounced in the sub/juxtacortical white matter than in the cerebral cortex while conversely, the total plaque load was highest in the cortex. Infiltrates correlated trans-cortically and sub/juxtacortical plaque activity reflected cortical and meningeal infiltrates. Sub/juxtacortical infiltrate sizes correlated with shorter survival after progression onset. Two patients with PPMS and putatively fatal brain stem lesions argue against incidental findings. Trans-cortical inflammatory flares and plaque activity may be pathogenic in progressive MS. We suggest emphasis on sub/juxtacortical MRI lesions as plausible surrogates for cortical and meningeal pathologies and, when present, as indicators for cognitive testing.

Structural and functional features of the endometrium in chronic endometritis and implantation failure in IVF cycles

BACKGROUND: Implantation failure of the endometrium in women with chronic endometritis remains a subject of discussion, despite certain progress in the diagnosis and treatment of this pathology. It has been proven that chronic endometritis is a predictor of endometrial dysfunction, which contributes to the disruption of the morphogenesis of the endometrium necessary for its implantation capacity. Implantation disorders associated with chronic endometritis are related to pathology of the receptor profile and vascular bed, as well as dysregulation of proliferative and apoptotic mechanisms. AIM: The aim of this study was to evaluate the expression of estrogen and progesterone receptors, endothelial marker and apoptosis-inducing factor in the endometrium of patients with chronic endometritis and ineffective embryo transfer in IVF protocols. MATERIALS AND METHODS: This study enrolled 50 patients with ineffective embryo transfers in IVF protocols and 25 women in the control group with positive reproductive outcomes. All patients underwent a comprehensive morphological study of the endometrium including histological examination, immunohistochemical study with assessment of the receptor profile [estrogen (ERα) and progesterone (PR) receptor expression], chronic endometritis (CD8+, CD4+, CD20+, CD138+), apoptosis [antibodies to apoptosis-inducing factor (anti-AIF [E20])], and angiogenesis (CD34+), with microscopic, morphometric and statistical methods used as well. RESULTS: Endometrial implantation failure is associated with a history of urogenital infection, benign cervical diseases, high incidence of endometrial pathology and reproductive loss. It is characterized by the presence of follicle-like mononuclear infiltrates in the endometrium, fibroplastic changes in the stromal component, vascular sclerosis, abnormal increase in the pro-inflammatory cell count, multifocal decrease in estrogen (ERα) and progesterone (PR) receptor expression, as well as activation of pathological neoangiogenesis and apoptosis in the stroma. CONCLUSIONS: Chronic endometritis leads to disruption of the structural and functional characteristics of the endometrium, stimulates pathological neoangiogenesis and dysregulates proliferative and apoptotic mechanisms, which forms a vicious circle of endometrial implantation failure and inefficiency of embryo transfer in IVF protocols.

Insight into didecyl dimethyl ammonium bromide toxicity following acute exposure in pullets (Gallus gallusdomesticus).

Didecyl dimethyl ammonium bromide (DDAB) is a quaternary ammonium compound used for the sanitation of drinking water of poultry and water pipelines in farms. There is scarcity of information on the toxicology of DDAB in poultry. This study set out to profile the acute toxicity of DDAB in poultry. Issa brown pullets (n = 34) as experimental birds were orally administered varying doses of DDAB, using a syringe, after 12h fasting, and observed for toxicity over 14 days. Control birds (n = 10) were similarly given normal saline orally. Toxic signs in the experimental birds were depression, anorexia, adipsia, vocalization with foamy salivation, later emaciation and death. The LD50 was calculated as 458.00mg/kg. Birds given 2151mg/kg DDAB died within 24h, while those treated with 516mg/kg succumbed on Day 14. At necropsy, grossly, there were necrosis and sloughing of the oesophagus and intestines, pale and friable liver, congested and necrotic lungs, friable popped out kidneys and emaciated carcasses. Microscopically, desquamation and necrosis of the oesophagus, crop, proventriculus and intestines and disruption of the koilin membrane of the gizzard were observed. The lungs, liver and kidneys were congested with mononuclear cellular infiltration plus loss of architecture in the lungs and liver. In conclusion, at high doses, DDAB caused significant toxicity in chickens and these findings provide new information which could serve as a guide in the diagnosis of quaternary ammonium toxicity in chicken. The results could be extrapolated to other quaternary ammonium toxicities in related avian species.

Acetylsalicylic acid and dihydroartemisinin combined therapy on experimental malaria-associated acute lung injury: analysis of lung function and the inflammatory process

BackgroundSevere malaria can cause respiratory symptoms, which may lead to malaria-acute lung injury (MA-ALI) due to inflammation and damage to the blood-gas barrier. Patients with severe malaria also often present thrombocytopenia, and the use of acetylsalicylic acid (ASA), a commonly used non-steroidal anti-inflammatory drug with immunomodulatory and antiplatelet effects, may pose a risk in regions where malaria is endemic. Thus, this study aimed to investigate the systemic impact of ASA and dihydroartemisinin (DHA) on ALI induced in mice by Plasmodium berghei NK65 (PbNK65).MethodsC57BL/6 mice were randomly divided into control (C) and PbNK65 infected groups and were inoculated with uninfected or 104 infected erythrocytes, respectively. Then, the animals were treated with DHA (3 mg/kg) or vehicle (DMSO) at the 8-day post-infection (dpi) for 7 days and with ASA (100 mg/kg, single dose), and analyses were performed at 9 or 15 dpi. Lung mechanics were performed, and lungs were collected for oedema evaluation and histological analyses.ResultsPbNK65 infection led to lung oedema, as well as increased lung static elastance (Est, L), resistive (ΔP1, L) and viscoelastic (ΔP2, L) pressures, percentage of mononuclear cells, inflammatory infiltrate, hemorrhage, alveolar oedema, and alveolar thickening septum at 9 dpi. Mice that received DHA or DHA + ASA had an increase in Est, L, and CD36 expression on inflammatory monocytes and higher protein content on bronchoalveolar fluid (BALF). However, only the DHA-treated group presented a percentage of inflammatory monocytes similar to the control group and a decrease in ΔP1, L and ΔP2, L compared to Pb + DMSO. Also, combined treatment with DHA + ASA led to an impairment in diffuse alveolar damage score and lung function at 9 dpi.ConclusionsTherapy with ASA maintained lung morpho-functional impairment triggered by PbNK65 infection, leading to a large influx of inflammatory monocytes to the lung tissue. Based on its deleterious effects in experimental MA-ALI, ASA administration or its treatment maintenance might be carefully reconsidered and further investigated in human malaria cases.

Immuno-pathogenesis study of local infectious bronchitis virus G1-1 lineage variant showed altered tissue tropism in experimental broiler chickens.

Infectious bronchitis (IB) is an acute contagious disease of poultry caused by infectious bronchitis virus (IBV). This study investigated the immunopathogenesis and tissue tropism of an Indian IBV field isolate (IBV/Chicken/India/IVRI/Rajasthan/01/2023) in experimental broiler chickens. This isolate belongs to the G1-1 lineage and is closely associated with the Mass genotype. 106.23 EID50/0.2 mL of the virus was administered intranasally and intraocularly to the IBV-challenge group, whereas uninoculated allantoic fluid was administered to the control group. Clinical signs, gross and histopathological lesions, immunohistochemistry (IHC), viral load, humoral responses, and the relative expression of immune response genes were evaluated at seven observation points. The infected group showed a significant reduction in weight gain from 3 dpi onwards, with clinical signs of varying severity from 3 to - 11 dpi. Gross lesions and microscopic changes were observed in the nasal turbinates, trachea, lungs, and kidneys, mainly representing epithelial degeneration and necrosis with mononuclear infiltrates. The caecal tonsils also showed microscopic lesions at 7-9 dpi. Absolute viral load estimation in the organs corroborated the lesion severity scores and IHC results. The expression of innate immune responses broadly demonstrated higher expression in the trachea and lungs of the IBV-infected group during the early phase of infection, whereas similar responses were observed in the kidneys and caecal tonsils during the later phases of infection. This study suggests that the given IBV isolate may cause significant production losses in broilers and exhibit tissue tropism for both respiratory and non-respiratory tissues, triggering varying innate and adaptive immune responses.

Interdigitating Dendritic Cell Tumour: A Rare Case Report with Review of Literature

Background and Aims: Interdigitating dendritic cell tumour/sarcoma (IDCS) is an exceedingly uncommon and aggressive tumour with a dismal prognosis. IDCS arises from antigen-presenting cells, which involve nodal and extranodal sites. The aim of the study is to evaluate a case of IDCS and its diagnostic challenges. Methods: A 21-year-old female with no comorbidities, a bone marrow aspirate and biopsy and an excision biopsy of the lymph node shows atypical mononuclear infiltrates that were immunohistochemically positive for S100-diffuse, CD68, LCA and Ki67. Results: Here, we report a single case of IDCS with a tumour arising from the lymph node and bone marrow infiltration. Discussion: IDCS is an aggressive disease with uncertain behaviour; strong suspicion is required to establish a diagnosis.

Abstract Mo077: Cardiac Troponin I3 Kinase in Viral Myocarditis

Myocarditis is a leading cause of heart failure and sudden cardiac death. Often caused by viral infection, myocarditis is defined histopathologically as mononuclear immune infiltration in the heart muscle. While most patients recover with no long-term effects, some deteriorate rapidly. It is unknown what controls this variable susceptibility to severe disease. Without this knowledge, the ability to develop targeted therapies for acute myocarditis is limited. Previous studies utilizing mouse genetics identified a locus that controls susceptibility to viral myocarditis. Cardiomyocyte-specific kinase TNNI3K is one candidate gene within this locus, but its role in myocarditis has not been established. Importantly, millions of people throughout the world carry natural variants of TNNI3K. My overall hypothesis is that TNNI3K confers resistance to viral myocarditis in a kinase-dependent manner. In an initial study, we infected strain background-matched wild-type, Tnni3k knockout, and Tnni3k kinase-dead mice with heart-passaged coxsackievirus B3. After 10 days, during the peak of acute myocarditis, mice missing functional Tnni3k protein were found to have higher viral genomes and greater presence of immune cell markers (CD45+), clearly demonstrating the role of Tnni3k in the response to viral myocarditis. H&E-stained heart sections show large clusters of hematoxylin-stained nuclei, indicating infiltration of ventricular tissue by immune cells, with more of these clusters in Tnni3k knockout hearts. Because kinase-dead mutants are similarly compromised as fully null mice, this indicates that the kinase activity of TNNI3K is critical in the antiviral response. These results are the first demonstration of the in vivo activity of a specific gene that modifies viral myocarditis sensitivity. Future work will expand on this study by examining the effects of coxsackievirus B3 infection of Tnni3k mutant mice at early and late time points. Additionally, efforts are currently underway to identify the specific mechanisms by which TNNI3K regulates the immune response to viral infection.

Protective role of melatonin against diclofenac-induced acute kidney injury

Diclofenac (DF), a non-steroidal anti-inflammatory drug, is commonly used to relieve pain and inflammation. High doses of DF might induce acute kidney injury (AKI), particularly in elderly, a known vulnerable population. AimWe aimed to assess the protective role of melatonin (Mel) on DF-induced AKI in aged rats and to highlight the underpinning mechanisms include, oxidative stress and inflammation focusing on microRNA-34a (miR-34a), nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 (Nrf2/HO-1) and NLR family-pyrin domain containing-3 (NLRP3) inflammasome pathways, and to elucidate the possibility of epithelial sodium channel (ENaC) involvement. Materials and methodsThirty old male Wistar rats were allocated randomly into 3 groups: Control, DF and Mel-DF groups. Key findingsMelatonin provided nephroprotective effects against DF-induced AKI via attenuating the expression of renal miR-34a and subsequently promoting the signaling of Nrf2/HO-1 with elevation of the antioxidant defense capacity and suppressing NLRP3 inflammasomes. Melatonin alleviated DF-induced hypernatremia via decreasing the ENaC expression. Renal histopathological examination revealed significant reduction in vascular congestion, mononuclear infiltration, glomerulo-tubular damage, fibrosis and TNF-α optical density. SignificanceIt can be assumed that melatonin is a promising safe therapeutic agent in controlling DF-induced AKI in elderly.

Regression of an ALK-Negative Cerebral Inflammatory Myofibroblastic Tumour by Steroid Therapy: A Case Report and Literature Review

Introduction: Inflammatory myofibroblastic tumours (IMTs) are non-neoplastic lesions characterized by collagenous stroma and polyclonal mononuclear infiltrates. IMTs typically arise in the lung, retroperitoneum or abdominal region but rarely in the central nervous system (CNS). The primary therapeutic option is surgical resection, and other therapies are currently controversial. Case report: We report a case of 23-year-old male ALK-negative cerebral IMT patient from Han population via steroid therapy. No relapse is observed at the follow-up visit. Conclusion: These results support the role of internal medication and promote the use of personalized therapy in genome-profiled IMTs.

The Possible Effect of Platelet Rich Plasma on Liver and Small intestine in Adult and Aged Male Rats. A Histological and Immunohistochemical Study

Abstract Introduction There is a general modest decline in the function of different organs in the body with aging. In the small intestine, there may be alterations in the intestinal morphology, as well as a decline in the absorption of fatty acids and sugars. The aging process decreases regenerative ability which significantly delays the restoration of liver function. Platelet-rich plasma (PRP) has recently attracted interest in many medical fields. PRP might has benefit effect on aged male rats. Aim of the Work This study aims to investigate the structural changes that might occur during normal aging and the possible effect of PRP intraperitoneal injection on adult and aged male albino rats. Materias and Methods Forty-two male albino rats were classified according to age into adult group and old aged groups. Adult male rats (300 -350 g), their age range between 6-8 months. Aged male rats (570-660 g), their age range between 12-24 months. They were divided randomly into four groups: Group I (Control adult): Included 14 rats that further subdivided into 2 equal subgroups: subgroup IA: untreated rats and subgroup Ib: rats were injected by sterile saline intraperitoneally (0.5 mL/kg by intraperitoneal injection 3 times/week). Group II (Control Aged): Included 14 rat that further subdivided into 2 similar subgroups as group I, Group III (Adult treated): Included 7 rats that received intraperitoneal injection of PRP (0.5 mL/kg by intraperitoneal injection 3 times/week), Group IV (Aged treated): Included 7 rats that received intraperitoneal injection of PRP as group III. Animals were kept under observation and the treated groups received intraperitoneal injections for 21 days. At the end of the experiment, Liver and small intestine specimens were processed for histological and immunohistochemical examination. Morphometric and statistical analysis was also done. Results Group II showed decrease in height of intestinal villi with disruption of their epithelium surface, increase spacing between enterocytes and abundant mononuclear cellular infiltration. Changes in the liver comprised nuclear and cytoplasmic changes that included an increase in nuclei number in hepatocytes with droplets fat infiltration. Treated Groups showed decreasing mononuclear cellular infiltration with decreasing collagen fibres and congested blood vessels. Conclusion Aging process enhanced the vulnerability to injury and inflammation in both the liver and small intestine. PRP had ameliorating effects on these changes.

Effect of Consumption of Caffeinated Energy Drinks on the Myocardium of the Adult Male Albino Rat (A Histological and Morphometric Study)

Abstract Background Energy drinks are non-alcoholic beverages containing mainly caffeine. Chronic consumption of energy drinks may be associated with increased blood pressure, and cardiac work load, as well as, increased heart rate. Energy drinks consumption has been related to myocardial infarction in healthy young adult. Aim of the Work The aim of the present work was to study the harmful effect of energy drinks histologically and morphometrically, on the myocardium of the adult male albino rats. Material and Methods 20 Adult male albino rats aging 4-6 moths were divided randomly into two groups; Group I (Control group) which consisted of 10 male albino rats with free access to food (rat chew) and water and Group II (Experimental group): 10 male albino rats which received 3.75 ml/kg body weight red bull through oral gavage daily for 4 weeks with free access to food (rat chew) and water. At the end of experiment, rats werescarificed, and cardiac muscle was extracted and processed into paraffin blocks for light microscopic examination. Morphometric study and statistical analysis were done. Results The present work demonstrated that Red Bull induced several histopathological changes of the cardiac muscle. The results showed the cardiac muscle of rats with irregularities in the arrangement of fibers and wide spaces in between. Some cardiomyocytes showed areas of pale stained sarcoplasm, partial loss of the cross striations and ill-defined intercalated discs. Localized areas of hyaline degeneration and areas of tissue disruption were also noticed with less frequently localized coalesced cytoplasmic vacuoles. The nuclei of the cardiomyocytes appeared small, darkly stained, and pyknotic. Others were flattened and deeply stained. Congested, and thick walled blood vessels were also observed, with mononuclear cellular infiltrations. In Masson’s Trichrome sections, relative increase in collagen deposition between the cardiac muscle fibers was observed which was associated with focal fibrous degeneration. Examination of the semithin sections showed partial disruption of the cardiomyocytes. The nuclei of the cardiomyocytes were small, darkly stained with perinuclear degeneration. Some nuclei were eccentric, or with an irregular outline, and peripheral chromatin condensation. The characteristic finding was the presence of longitudinal wavy cardiac muscle fibers with relatively wide spaces in between and localized areas of partially lost cross striations and intercalated discs. Dilated, thick walled blood vessels was noticed between the bundles of cardiac muscle. Mononuclear inflammatory cellular infiltrations were also detected. Conclusion The present study demonstrated the degenerative and cardiotoxic effects of Red Bull as an example of energy drinks on the histological structure of the cardiac muscle.

The Potential Role of Bone Marrow Mesenchymal Stem Cells Derived Exosomes on Experimentally Induced Osteoarthritis of Knee Joint in Male Albino Rats. Histological and Immunohistochemical Study

Abstract Introduction Osteoarthritis (OA) is the most common joint disorder worldwide characterized by progressive loss of articular cartilage. This study was conducted to evaluate the role of bone marrow mesenchymal stem cells (BMSCs) derived Exosomes as a promising therapy for treating osteoarthritis. Aim of the Work to study the healing potential of BMSCs derived exosomes on experimentally induced knee osteoarthritis. Materials and Methods Forty adult male albino rats, weighing 200-250 gm, were used in this study, five rats used as a source of BM-MSCs derived exosomes. The other thirty-five rats were randomly divided into three main groups Group I: The control group (20 rats) in which rats were subdivided into four subgroups. Subgroups IA and IB were sacrificed 2 and 6 weeks after the beginning of the experiment. Subgroup IC left for 2 weeks then were received intra-articular injection of 0.1ml Phosphate buffer saline (PBS) in right knee joint once weekly for 4 weeks Subgroup ID: left for 2 weeks then given intra-articular injection of purified exosome concentrate in the right knee joint once weekly for 4 weeks then the animals were sacrificed Group II:(15 rats) in which OA was induced by intra-articular injection of 2% formaldehyde solution in the right knee joints. The rats of group II were subdivided into two subgroups. Subgroups IIA and IIB were sacrificed 2 and 6 weeks after induction of OA respectively. Group III (5 rats), Osteoarthritis induced, as in group II and animals left for 2 weeks then treated by intra-articular injection of purified exosome concentrate in right knee joint once weekly for 4 weeks. The right joints from all groups were collected, decalcified and processed for histological studies. Morphometric and statistical measurements were done. Results Histological examination of the right knee joints of OA group (subgroups IIA and IIB) showed surface erosions, decrease cartilage thickness, chondrocytes with pyknotic nuclei and areas of chondrocytes loss with longitudinal clefts reaching the deep zone. Synovial membrane of group II showed increased thickness of the intima, mononuclear cellular infiltration with abundant collagen fibres deposition and dilated congested blood vessels in subintima, apparent increase in the number of iNOS positive intimal synovial cells. Meanwhile, group III showed smooth articular surface, with multiple colonies of chondrocytes and multiple cell nests, significant increase in the mean area percentage of PCNA positive chondrocytes in animals of group Ш when compared to all the other groups. Conclusion BMSCs derived exosomes improved OA induced damage of articular cartilage and synovial membrane. Therefore, it offers a cell-free treatment of OA and joint damage.

Biopreparation of titanium dioxide nanoparticles mediated by Calendula officinalis flower extract for catalytic reduction of 4-nitrophenol and treatment of allergic conjunctivitis

This study investigates the an eco-friendly synthesis for the production of titanium dioxide nanoparticles (TiO2 NPs) by employing the water-soluble flower extract of Calendula officinalis as a natural reducing and stabilizing agent. The green produced TiO2 NPs/C. officinalis were characterized using different advanced analytical techniques, including FT-IR, FE-SEM, EDS-elemental mapping, XRD, ICP-OES and TEM. It represents the TiO2 NPs were found to be spherical in shape and well distributed without agglomeration. It also revealed the particle sizes were in the range of 30–50 nm. EDX represented the Ti atomic species along with C and O are seen to be well-dispersed in a homogeneous manner. The broad absorption band appeared at 3200–3450 cm−1 assigned to OH bond stretching belong to the adsorbed water over the titanium dioxide nanoparticles. Further, newly synthesized TiO2 NPs/C. officinalis are used as a nanocatalyst for the reduction of 4-nitrophenol (4-NP). A UV–Vis spectrophotometer is employed to track the effectiveness of the reduction process. Recyclability in 8 further degradation cycles is used to assess the sustainability of this catalyst, and the results show a steady and notable degradation activity. After a week of daily treatment, the allergic conjunctivitis clinical scores in Dunkin-Hartley guinea pigs were evaluated. The guinea pigs were sensitized with intraperitoneal ovalbumin and then subjected to topical conjunctival challenge. Different doses of TiO2 NPs/C. officinalis (20 and 100 µg/kg), prednisolone (30 mg/kg), chlorpheniramine (10 mg/kg), or PBS (10 mL/kg) were administered. The levels of serum Immunoglobulins were measured by ELISA. It was observed that the levels of ovalbumin-specific IgE notably decreased. Notably, the treatment with TiO2 NPs/C. officinalis at both doses led to a notably lower clinical score for allergic conjunctivitis. Furthermore, the TiO2 NPs/C. officinalis-treated guinea pigs conjunctival tissue showed mild mononuclear infiltration compared with the intense conjunctival tissue inflammatory infiltration observed in the PBS-treated group. These data suggest that TiO2 NPs/C. officinalis may have clinical efficacy in alleviating allergic conjunctivitis.

Oral lichen planus-like lesions in skin of color: a review.

In dermatology, lichenoid describes lesions with a violaceous hue that is a clinical reflection of basal cell damage in the epithelium and dense mononuclear infiltrate in the sub-epithelium. The violaceous color results from pigment incontinence due to basal cell damage and the Tyndall effect. Although classically described in lichen planus, a lichenoid hue is noted in the oral mucosa in several other disorders that often lead to diagnostic dilemmas. Early and accurate diagnosis is important for the appropriate management of the underlying condition and prognostication. Dermatologists play a central role in managing such patients since, apart from the oral mucosa findings, the cutaneous features also help to significantly differentiate various conditions. Mimickers of oral lichen planus include nicotine stomatitis, oral submucous fibrosis, oral lichenoid lesions, mucosal discoid lupus erythematosus, pemphigus vulgaris, paraneoplastic pemphigus, mucous membrane pemphigoid, fixed drug eruption, plasma cell cheilitis/gingivitis, and erythema multiforme. While a detailed history and clinical examination can help reach a diagnosis in most cases, histopathology, immunofluorescence, and other relevant investigations help establish the diagnosis.

Histological Evaluation of the Protective Role of β-glucan Against Cisplatin-Induced Hepatotoxicity

Cisplatin is a commonly used chemotherapeutic agent in the treatment of many cancers. The most important dose-limiting side effect is hepatotoxicity. Some studies have shown that antioxidant treatment with cisplatin reduces the toxic effect. In the present study, we were aimed to investigate the protective effects of antioxidant β-glucan on histological injury caused by cisplatin treatment in the liver. Wistar rats were randomly divided into three groups according to time of sacrifice, 7th day and 14th day (n=20 rats each). Both groups were then divided into four sub-groups Control, Cisplatin (10 mg/kg bw), β-glucan (100 mg/kg bw) and cisplatin+β-glucan (n=5 in each group). The rats were sacrificed at the 7th day and 14th day after the last injection. The liver sections were evaluated under a light microscope after the histological procedure. Histological injury caused by cisplatin in different days were evaluated as as sinusoidal congestion, hydropic degeneration, disorganization of hepatic cords, and mononuclear cellular infiltration in liver. When β-glucan was administered with cisplatin, it was determined that cellular damage caused by cisplatin decreased considerably in the liver in the different days groups. The light microscopic examination showed that the antioxidant beta-glucan protects against hepatotoxicity caused by cisplatin with its free radical scavenging effect. In conclusion, β-glucan may improve patients' quality of life by reducing cisplatin's toxicity on the liver.

Pharmacokinetics, pharmacodynamics, and toxicity of a PD-1-targeted IL-15 in cynomolgus monkeys.

e14568 Background: Interleukin (IL)-15 is a potent cytokine that enhances the proliferation and effector functions of IL-2Rβ/γ-expressing lymphocytes, such as NK cells and T cell subtypes (CD8+, CD4+, gd, and NKT). PF-07209960 is a novel bispecific fusion protein composed of an anti-PD-1 antibody and engineered IL-15 cytokine mutein with reduced binding affinity to its receptors. PD-1 is expressed on tumor-infiltrating T cells at relatively high levels. PF-07209960 has reduced activity on PD-1-negative NK cells and enhanced activity on PD-1-expressing intratumoral CD8+ T cells, therefore is expected to have improved therapeutic window. Methods: The pharmacokinetics (PK), pharmacodynamics (PD), and toxicity of PF-07209960 were evaluated following once every other week subcutaneous (SC) or intravenous (IV) administration to cynomolgus monkeys in a two-dose PKPD (0.01 – 0.3 mg/kg/dose) study and in a three-dose (SC route) GLP toxicity study (0.1 – 3 mg/kg/dose). Results: PF-07209960 showed dose-dependent pharmacokinetics with a terminal T1/2 of 8 and 13 hours following IV administration at 0.03 and 0.1 mg/kg, respectively. The clearance is faster than a typical IgG1 antibody. Slightly faster clearance was also observed following the second dose, likely due to increased target pool and formation of anti-drug antibodies (ADA). Despite a high incidence rate of ADA (92%) observed in GLP toxicity study, PD-1 receptor occupancy, IL-15 signaling (STAT5 phosphorylation) and T cell expansion were comparable following the first and second doses. Activation and proliferation of T cells were observed with largest increase in cell numbers found in gamma delta T cells, followed by CD4+ and CD8+ T cells, and then NK cells. The expansion of T cells and NK cells in peripheral blood peaked around Day 8 and waned to near baseline levels by Day 15. Release of cytokines IL-6, IFNɣ, and IL-10 were detected, which peaked at 72 hours postdose. All animals at 3 mg/kg/dose were euthanized in a moribund condition on Day 4 of the dosing phase, coincident with the peak of cytokine release. Four out of six monkeys administered 1 mg/kg were euthanized between Day 6 and Day 16 due to thrombocytopenia, bleeding, and poor physical condition. Microscopic evaluations revealed generalized mononuclear infiltration in various tissues. Both the no observed adverse effect level (NOAEL) and the highest non severely toxic dose (HNSTD) were determined to be 0.3 mg/kg/dose, which corresponded to mean Cmax and AUC48 values of 1.15 µg/mL and 37.9 µg*h/mL, respectively. Conclusions: PF-07209960 demonstrated dose-dependent exposure and robust PD (T cell and NK cell subsets expansion and cytokine release) in cynomolgus monkeys, with well-characterized safety profile. In summary, the results of the present study support Phase I clinical evaluation of PF-07209960 in cancer patients.

A potential defensive role of TIM-3 on T lymphocytes in the inflammatory involvement of diabetic kidney disease.

The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression. A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed. Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened. Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.

Characterization, histopathology and immunogenicity of the lumpy skin disease virus isolated during 2019-20 in Bangladesh.

Lumpy skin disease (LSD) is a highly contagious vector-borne viral disease of cattle. LSD has emerged in Bangladesh in 2019, causing significant economic losses due to its high morbidity and mortality. This research was designed to isolate, identify, and assess the immunogenicity of LSD virus (LSDV) using nodular tissue samples obtained from affected cattle during the 2019-20 outbreak across nine districts of Bangladesh. To determine the presence of LSDV in nodular tissues, we initially used iiPCR and PCR, followed by histopathological examination. 151 were positive via iiPCR and PCR among the 180 collected samples. The PCR positive 151 samples were then inoculated into 10-day-old embryonated chicken eggs via the CAM route to isolate LSDV, confirmed through PCR. Subsequently, partial sequencing and phylogenetic analysis of the P32 gene were performed to determine the origin of the circulating LSDV strain. The immunogenicity of selected LSDV strains was assessed through an ELISA test. The PCR results revealed a distinct positive band at 192 bp in both the nodular tissue samples and the LSDV isolated from chicken embryo inoculations. Microscopic analysis of the nodular lesions revealed thickening of the epidermis, ballooning degeneration of keratinocytes, and proliferation of follicular epithelia. Additionally, mononuclear infiltration was observed at the demarcation line between infected and healthy tissue, with necrosis of muscular tissues beneath the epidermis. The LSDV isolate from Bangladesh exhibited a close genetic relationship with LSDV strains isolated from neighboring and other regional countries including India, Myanmar, and Mongolia. This observation strongly suggests the possibility of a transboundary spread of the LSD outbreak in Bangladesh during 2019-2020. The results of the immunogenicity test showed that the serum antibody titer remained at a protective level for up to 18 months following secondary immunization with inactivated LSDV antigen. This finding suggests that the inactivated LSDV antigen could be a potential vaccine candidate to protect cattle in Bangladesh against LSDV. In conclusion, our research successfully isolated, identified, and characterized LSDV in cattle nodular tissues from the 2019-20 outbreak in Bangladesh. Furthermore, it provided insights into the probable origin of the circulating strain and investigated a potential vaccine candidate to protect cattle in the region from LSDV.

Sub Chronic Toxicity Study of Aqueous Leaves Extract of Maytenus Gracilipes on Some Biochemical Parameters and Histopathology of Liver and Kidneys in Mice

Introduction: Traditional medicine is an ancient medical practice that is still widely used in prevention and treatment of various health problems worldwide, including Ethiopia. M.gracilipes is one of medicinal plant in Ethiopia used for treatment of various ailments still is very common. This study evaluated the sub-chronic toxic effects of M. gracilipes aqueous leaves extract on biochemical parameters and histopathology of liver and kidneys. Methods: For sub-chronic toxicity study a total of 30 mice were used, three groups (I–III) of mice (10 animals each) were used. Group I served as control and received a vehicle while groups II and III daily administered with 700 and 2100 mg/kg extract respectively orally by using oral gavage for 90 days. At the end of the experiment, the mice were sacrificed by using diethyl ether; blood was collected for assessing biochemical parameters and histopathological evaluations on liver and kidneys were performed. Results: Sub chronic treatment of extract for 90 days, at 700 and 2100 mg/kg body weight did not induce any sign of illness and /or death and had no adverse effect on biochemical parameters and blood parameters. Liver and kidney sections also revealed normal architecture, except some pyknotic nuclei and focal mononuclear leukocytic infiltrations observed in some of the liver and kidney tissues at higher dose (2100mg/kg). Conclusion: The results of this sub chronic toxicity study showed that M. gracilipes aqueous leaves extract is safe at daily doses of 700 mg/kg body weight, even when taken for longer period. At higher doses, however, the extract may induce mild hepatorenal toxicity.