Marked Fibrosis Research Articles

Multiple pleural nodules diagnosed as IgG4-related disease: a case report

BackgroundImmunoglobulin G4 (IgG4)-related diseases are characterized by abnormal IgG4 levels, swelling, and marked infiltration and fibrosis of the lymphocytes and IgG4-positive plasma cells, causing hypertrophic lesions or nodules. The cause is currently not well understood. IgG4-related diseases involving lesions limited to the pleura are extremely rare. Herein, we report an IgG4-related disease presenting with multiple pleural nodules confirmed by thoracoscopic surgical biopsy.Case presentationA 74 year-old man was referred to our department for definitive diagnosis of multiple pleural nodules after 1 year of follow-up. Computed tomography of the chest revealed multiple pleural nodules, while 2-deoxy-2-( 18F)-fluorodeoxyglucose positron emission tomography imaging exhibited tracer accumulation in the nodules. A thoracoscopic surgical biopsy was performed. Histopathological examination revealed hyalinized fibrous tissue with a high degree of plasma cell-based inflammatory cell infiltration. Immunohistochemically, IgG4-positive cells were conspicuous, accounting for 70.5% of the plasma cells. The postoperative serum IgG4 concentration was 289 mg/dL. We diagnosed the patient with an IgG4-related disease with multiple pleural nodules. The postoperative course was good, and the patient is currently being followed up.ConclusionIgG4-related disease should be considered in cases presenting with multiple pleural nodules.

Clinico-pathological diagnosis of Facioscapulohumeral Dystrophy in a 22-year-old Male

Background: Facioscapulohumeral dystrophy (FSHD) is a rare hereditary disease with a prevalence of 2.03–6.8 per 100,000 individuals. FSHD is the third most common type of muscular dystrophy after the Duchene muscular dystrophy and myotonic dystrophy. To the best of our knowledge, the current case report is the first to report probable FSHD case mainly diagnosed using clinico-pathological evidence from sub-Saharan Africa (SSA).
 Case Report: A 22-year-old right-handed male college student presented with progressive proximal muscular weakness associated with wasting. The weakness started from the bilateral facial muscles and progressively involved proximal upper and lower limbs muscles associated with scapular winging, waddling gait, and bilateral foot drops. His bulbar, sensory, autonomic, and cognitive systems were spared. Muscles EMG showed myopathic patterns and normal serum CK. Muscle biopsy from affected muscles showed variation in fiber size with groups of angular fibers, preserved fibers, and hypertrophic fibers with marked fibrosis and adipose tissue replacement with no apparent inflammation and necrosis which is consistent with pathological features of muscular dystrophy. Considering the clinical semiology, physical findings, EMG findings, and pathological findings diagnosis of FSHD of scapuloperoneal variant was made. The patient was managed with analgesics, nutritional advice, and ankle prosthesis for foot drops. Currently, the patient is in a similar condition with modest improvement in his musculoskeletal pain complaints.
 Conclusion: This case highlights the fact that a careful clinical evaluation with thorough utilization of diagnostic investigations available at our disposal may support the diagnosis of FSHD in resource-limited areas where the necessary genetic tests were not available.
 Keywords: facioscapulohumeral muscular dystrophy, dystrophy, clinico-pathology, sub-Saharan Africa

Myocarditis as a Manifestation of a T Cell Lymphoproliferative Disorder in a Patient Undergoing Left Ventricular Assistance Device Implantation

<h3>Introduction</h3> Left ventricular assist device (LVAD) core pathology may provide definitive cardiomyopathy etiology and guide management. We present a case of progressive cardiomyopathy concerning for myocarditis in a patient with cutaneous T cell lymphoma (CTCL) undergoing LVAD implantation. <h3>Case Report</h3> A 63-year-old man presented with mildly reduced left ventricular ejection fraction (LVEF) and ventricular tachycardia (VT). He had an extensive history of Gulf War Syndrome, heavy metal exposure, chronic kidney disease, hypercalcemia and cutaneous T cell lymphoma, managed with ultraviolet light therapy and methotrexate. Cardiac magnetic resonance (CMR) imaging demonstrated anteroseptal and inferolateral wall delayed gadolinium enhancement (DGE). Coronary angiography showed no coronary artery disease. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed reduced lateral and inferior wall perfusion but no myocardial FDG uptake or evidence of systemic CTCL. Endomyocardial biopsy demonstrated mild hypertrophy and marked interstitial fibrosis, however no evidence of sarcoidosis or myocarditis. Over the next 2 years, his cardiomyopathy progressed (LVEF 15-20%, LVDd 7.2cm). Upon readmission for VT and heart failure (HF), repeat FDG-PET showed myocardial FDG uptake - perfusion mismatch pattern prompting oral prednisone initiation. Durable LVAD was implanted 5 days later given clinical progression. LVAD core pathology showed myocardial T cell infiltration with a clonal T cell gene rearrangement (Figure 1). Peripheral blood and PET markers remained otherwise negative for CTCL. After LVAD, his HF and VT stabilized, and he is undergoing treatment plan for systemic T cell lymphoproliferative disorder. <h3>Summary</h3> We present a case of myocardial T cell lymphoproliferative disorder presenting as progressive cardiomyopathy and highlight the role of LVAD core pathology in diagnosis.

Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast.

Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well‐established to have antitumour and anti‐fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF‐LA@DSPE‐PEG and MMF‐LA@PEG‐PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG5k‐PLA8k and DSPE‐ PEG2k, respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti‐HCC efficacy of nanoparticles (NPs), whereas NIH‐3T3 fibroblasts and highly‐fibrotic HCC models were used to explore the anti‐fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF‐LA@DSPE‐PEG achieved significantly higher anti‐HCC efficacy than free MMF and MMF‐LA@PEG‐PLA both in C57BL/6 HCC model and highly‐fibrotic HCC models. Immunohistochemistry further confirmed that MMF‐LA@DSPE‐PEG dramatically reduced cancer‐associated fibroblast (CAF) density in tumours, as the expression levels of alpha‐smooth muscle actin (α‐SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF‐LA@DSPE‐PEG might act as a rational therapeutic strategy in treating HCC and preventing post‐transplant HCC recurrence.

Histopathological Characterization of Mitral Valvular Lesions from Patients with Rheumatic Heart Disease.

ResumoFundamentos:Os mecanismos subjacentes pelos quais a doença cardíaca reumática (DCR) levam à disfunção valvar grave não são totalmente compreendidos.Objetivo:O presente estudo avaliou as alterações histopatológicas nas valvas mitrais (VM) buscando uma associação entre o padrão de disfunção valvar predominante e os achados histopatológicos.Métodos:Em 40 pacientes submetidos à troca da VM devido a DCR e em 20 controles submetidos a transplante cardíaco, foram analisados os aspectos histológicos da VM excisada. Dados clínicos e ecocardiográficos também foram coletados. As análises histológicas foram realizadas usando coloração com hematoxilina-eosina. Determinou-se inflamação, fibrose, neoangiogênese, calcificação e metaplasia adiposa. Valores de p<0,05 foram considerados estatisticamente significativos.Resultados:A idade média dos pacientes com DCR foi de 53±13 anos, sendo 36 (90%) do sexo feminino, enquanto a idade média dos controles foi de 50±12 anos, semelhante aos casos, sendo a maioria do sexo masculino (70%). O endocárdio valvar reumático apresentou espessura maior que os controles (1,3±0,5 mm versus 0,90±0,4 mm, p=0,003, respectivamente), e infiltrado inflamatório mais intenso no endocárdio (78% versus 36%; p=0,004), com predominância de células mononucleares. Ocorreu fibrose moderada a acentuada mais frequentemente em válvulas reumáticas do que em válvulas controle (100% vs. 29%; p<0,001). Ocorreu calcificação em 35% das valvas reumáticas, principalmente entre as valvas estenóticas, associada à área valvar mitral (p=0,003).Conclusões:Apesar do intenso grau de fibrose, o processo inflamatório permanece ativo na valva mitral reumática, mesmo em doença tardia com disfunção valvar. A calcificação predominou em valvas estenóticas e em pacientes com disfunção ventricular direita.

Quantitative analysis of proteome dynamics in a mouse model of asthma

Asthma is an inflammatory disease of the respiratory system, and a major factor of increasing health care costs worldwide. The molecular actors leading to the development of chronic asthma are not fully understood and require further investigation. The aim of this study was to monitor the proteome dynamics during asthma development from early inflammatory to late fibrotic stages. A mouse asthma model was used to analyse the lung proteome at four time points during asthma development (0weeks=control, 5, 8 and 12weeks of treatment, n=6 each). The model was analysed using lung function tests, immune cell counting and histology. Furthermore, a multi-fraction mass spectrometry-based proteome analysis was performed to achieve a comprehensive coverage and quantification of the lung proteome. At early stages, the mice showed predominant eosinophilic inflammation of the airways, which disappeared at later stages and was replaced by marked airway hyper-reactivity and fibrosis of the airways. 3325 proteins were quantified with 435 proteins found to be significantly differentially abundant between the experimental groups (ANOVA p-value ≤.05, maximum fold change ≥1.5). We applied hierarchical clustering to identify common protein abundance profiles along the asthma development and analysed these clusters using gene ontology annotation and enrichment analysis. We demonstrate the correlation of protein clusters with the course of asthma development, that is eosinophilic inflammation and fibrotic remodelling of the airways. Proteome analysis revealed proteins that were previously described to be important during asthma chronification. Moreover, we identified additional proteins previously not described in the context of asthma. We provide a comprehensive data set of a long-term mouse model of asthma that may contribute to a better understanding and allow new insights into the progression and development of chronic asthma. Data are available via ProteomeXchange with identifier PXD011159.

1,25-(OH)2D3 ameliorates renal interstitial fibrosis in UUO rats through the AMPKα/mTOR pathway.

ObjectiveTo investigate the effects of 1,25(OH)2D3 on renal fibrosis associated with the AMP-activated protein kinase (AMPK)α/mechanistic target of rapamycin (mTOR) signalling pathway in a rat model of unilateral ureteral obstruction (UUO).MethodsA total of 54 male Sprague Dawley rats were randomly divided into three groups: sham-operation group, UUO group, and UUO plus calcitriol (3 ng/100 g) group. Renal tissue was excised for histological examination by immunohistochemistry and Western blot, and for gene expression analysis using real-time polymerase chain reaction.Results1,25(OH)2D3 enhanced AMPKα levels, inhibited mTOR levels and slowed the development of interstitial fibrosis in kidney tissue. Compared with the UUO plus calcitriol group, UUO rats demonstrated more severe renal damage characterized by marked tubular atrophy, interstitial fibrosis and significant induction of fibrogenic transforming growth factor-β1 and increased extra-cellular matrix proteins (α-smooth muscle actin and collagen type III), and decreased E-cadherin.ConclusionTreatment with 1,25(OH)2D3 altered the AMPKα/mTOR signalling pathway to suppress excessive fibroblast activation observed in UUO rats. This may serve as a novel mechanism to ameliorate renal dysfunction and fibrotic lesions.

. Effect of Nigella Sativa and Angiotensin converting Enzyme Inhibitor on Myocardial Fibrosis Induced by lipopolysaccharide

Background: Nigella sativa (NS) has anti-inflammatory and anti-oxidant activity; it exhibits a role in tissue fibrosis and wound healing. Angiotensin-converting enzyme (ACE) inhibitors improve the cardiac fibrosis. This study aimed to evaluate the effect of Nigella Sativa and ACE inhibitors and combination of both on myocardial fibrosis induced by lipopolysaccharide.Material and methods: Thirty-five male albino rats were divided into five groups. 1. Control group 2. LPS group in which rats were injected intraperitoneally (IP) with lipopolysaccharide (LPS) at a dose of (1 mg/kg/day) daily for three weeks. 3. NS treated group in which rats were IP injected with LPS then given NS oil orally at a dose of (1ml/ day) daily for three weeks 4. Captopril (CAP) treated group in which rats were IP injected with LPS then given CAP orally at a dose of (100 mg/kg/ day) daily for three weeks. 5. NS&CAP treated group in which rats were IP injected with LPS then given NS and CAP. Then the left ventricular tissues were examined for histopathological and immunohistochemical changes. Results: LPS induced loss of architecture of the cardiomyocytes with marked fibrosis indicated by significant increase in area % of collagen fibrosis and α-SMA immunostaining expression. NS and CAP improved these changes but the combination of both revealed marked improvement of the histopathological changes with significant decreasing in area % of collagen fibrosis and α-SMA immunostaining expression.Conclusion: we concluded that the combination of Nigella sativa and Angiotensin-converting enzyme inhibitor markedly improved the myocardial fibrosis induced by lipopolysaccharide.

Inhibitory and ameliorative effect of heliomycin derived from actinomycete on induced hepatocellular carcinoma in rats.

The hepatoprotective activity of heliomycin obtained from the culture broth of actinomycete AB5 against diethylnitrosamine (DEN)-induced hepatic cancer in Wistar rats was estimated. Heliomycin exhibited a significant decrease in the levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) compared to the positive control. For instance, the heliomycin group after 20 weeks showed a significant decline in ALT, AST, and ALP values (70.75 ± 5.12, 140.25 ± 11.75, and 163.25 ± 18.66, respectively) compared to the positive control group (170.00 ± 9.55, 252.75 ± 12.33, and 278.00 ± 21.32, respectively). Additionally, the isolated compound showed a highly significant decrease in serum alpha-fetoprotein (AFP) levels. After 8, 16, and 20 weeks, the mean values of AFP in the heliomycin group revealed a highly significant decrease (33.62 ± 2.46, 30.00 ± 4.05, and 28.50 ± 2.64, respectively) compared to the positive control group (49.45 ± 3.03, 81.90 ± 6.70, and 90.75 ± 5.12, respectively). The histopathological investigation of liver sections supported the results of biochemical analysis. It was demonstrated that heliomycin showed histological improvement of hepatocytes and marked increase of nuclear pyknotic with clear cytoplasm, which is a sign of improving the apoptotic pathway of malignant cells. It also displayed marked fibrosis at most of the malignant cells and the development of some regenerative nodules. Heliomycin showed moderate immunoreactivity with alpha-fetoprotein (AFP), and proliferation cell nuclear antigen (PCNA) compared to the positive control group. To the best of our knowledge, this is the first study to report the anticancer activity of heliomycin against hepatocellular carcinoma in vivo.

Возможность прогнозирования развития фиброза и цирроза при аутоиммунных заболеваниях печени у детей с помощью прямых биомаркеров

Materials and Methods. The study included 80 patients aged 5 to 17 years with chronic autoimmune hepatic disorders. Patients underwent marginal liver excision with laparoscopic control, then the morphology of biopsy samples was examined, HF was determined using METAVIR scale, and ELISA was used to assess blood C-I and HA concentrations. Study Results. Regressive coefficients demonstrated that reduction in C-I concentration by 1 ng/mL increases the odds of HC by 0.983 times, while HA increase by 1 ng/mL results in 1.032-fold increase in the odds of HC. Moreover, increase in HA concentration by 1 ng/mL raises the odds of marked HF or HC by 1.036 times. The resulting regression models are statistically significant (p &lt; 0.001 in both cases). Conclusion. We found statistically significant differences in serum concentration of C-I and HA at various hepatic fibrosis stages in children and developed four predicative models; three of them have satisfactory sensitivity and specificity to predict marked fibrosis and cirrhosis depending on biomarker concentration. Keywords: hyaluronic acid, type I collagen, hepatic cirrhosis, hepatic fibrosis, children.

Atypical cytological presentation of granular cell tumour: Tumour-associated fibrosis may affect fine-needle aspiration cytology accuracy.

The cytological features of granular cell tumour (GCT) are generally quite typical but, in some cases, the fine needle aspiration cytology (FNAC) diagnosis of GCT may be difficult or impossible because of unusual sites of onset or equivocal cytological features. In this report, two GCTs with atypical FNAC features are described in order to investigate the causes and provide possible diagnostic tips. From a series of nine histologically proven GCTs, two inconclusive FNAC cases were retrieved. Smears were poorly cellular showing isolated naked nuclei, anisonucleosis, granular chromatin and occasional small nucleoli. The background was finely granular in one case. Histological controls of these cases revealed marked fibrosis. Tumour-associated fibrosis in GCT is variable and does not seem to influence clinical behaviour but it influences the harvest and the integrity of granular cells collected by FNAC. When GCT smears are poorly cellular, attention should be paid to the granular background and to the few granular cells, if any, as they might be the only features to suggest a GCT.

Δ9-Tetrahydrocannabinolic Acid markedly alleviates liver fibrosis and inflammation in mice

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Medicinal cannabis and some neutral cannabinoids have been suggested as a potential therapy for liver diseases. HypothesisΔ9-tetrahydrocannabinolic acid (Δ9-THCA), the non-psychotropic precursor of Δ9-THC, is one of the most abundant cannabinoids presents in Cannabis Sativa. However, its biological activities have been poorly investigated. Herein, we studied the antifibrotic and antiinflammatory activities of Δ9-THCA in two different animal models of liver injury, providing a rationale for additional studies on the medicinal use of this cannabinoid in the treatment of liver fibrosis and the management of NAFLD. Study designThe antifibrotic activity of Δ9-THCA in vitro was investigated in the cell lines LX-2 and NIH-3T3-Col1A2-luc. Non-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Δ9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. MethodsTGFβ-induced profibrotic gene expression was analyzed by luciferase and qPCR assays. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose, insulin, leptin and triglyceride levels were measured in HFD mice. ResultsΔ9-THCA inhibited the expression of Tenascin C (TNC) and Col3A1 induced by TGFβ in LX-2 cells and the transcriptional activity of the Col1A2 promoter in fibroblasts. Δ9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. Δ9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. ConclusionsΔ9-THCA prevents TGFβ-induced fibrotic markers in vitro and liver inflammation and fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, for the treatment of liver fibrosis and the management of NAFLD.

Causes of recurrences after stereotactic radio-ablation for refractory ventricular tachycardia

Abstract Introduction Stereotactic radio-ablation (STAR) has been recently introduced for the management of ventricular tachycardia (VT) refractory to antiarrhythmic drugs (AADs) and catheter ablation (CA). The incidence and mechanisms of VT recurrences after STAR remain unknown. We report causes of recurrence in patients (pts) after STAR. Methods From 09.2017 to 01.2020, 12pts suffering from refractory VT were enrolled. The underlying cardiopathy was ischemic in 3, inflammatory in 3 and idiopathic in 6 pts. Before STAR, an invasive electro-anatomical mapping (Carto3) of the VT substrate (VT-sub) was performed. A mean dose of 22±2Gy was delivered to the VT-sub using the Cyberknife® system. Results The ablation volume was 24±7cc and involved the interventricular septum (IVS) in 10. After a median follow-up of 9±7 months, VT burden decreased by 78% (mean value, from 89 to 20 VT/semester). Out of the 12 pts, 9 (75%) presented some form of VT recurrence (table): 1) that spontaneously resolved in 2 pts; 2) remote from the VT-sub in 2 cases; 3) managed with AADs that had failed before STAR in 2 cases; 4) within the treated VT-sub in 3 cases. In the latter 3 cases, one recurrence came from a site adjacent to the circumflex artery (mean dosis 14.4 Gy), and two were located within the treated IVS (one displaying marked fibrosis, and one with sarcoidosis). Only 4/12 (33%) pts required additional CA. Conclusion STAR led in our patients to a strong VT burden reduction. Recurrences occurred at sites remote from the irradiated volume, within the IVS or in under-dosed sites adjacent to critical structures. Funding Acknowledgement Type of funding source: None

Rare Surgical Lung Biopsy Findings of Metastatic Pulmonary Calcification Associated with Chronic Renal Failure

Abstract Introduction/Objective Metastatic pulmonary calcification is a metabolic lung disease characterized by depositions of calcium in lung parenchyma. Depositions of calcium salts are usually caused by hypercalcemia and are associated with end-stage renal disease, primary and secondary hyperparathyroidism, and hemodialysis. It is mostly asymptomatic and clinically silent but can lead to life-threatening respiratory failure. Methods We present a case of a 53-year-old woman, with a failed renal transplant and on hemodialysis, admitted with cough and shortness of breath. Computed tomography showed extensive diffuse bilateral groundglass and nodular opacities. Bronchoscopy was unremarkable. BAL results were negative for infection. The initial differential diagnosis included pneumonitis, interstitial lung disease, and chronic obstructive pulmonary disease. VATS lung wedge resection was performed. Results Microscopically there were numerous interstitial, peribronchial and perivascular calcifications highlighted by Van Kossa stain. Calcifications were associated with a marked interstitial fibrosis confirmed by trichrome stain. There was no evidence of significant acute and chronic inflammation, granulomas, fibroblastic foci and vasculitis. Conclusion Metastatic pulmonary calcification is found in 60–80% of autopsies of patients undergoing dialysis treatment. It is rarely diagnosed during their lifetime, because patients are usually asymptomatic, or the imaging findings are negative. The diagnosis of metastatic pulmonary calcification in our patient prompt further evaluation for repeat kidney transplant and the patient is being considered for parathyroidectomy for her tertiary hyperparathyroidism.

Exogenous Lipoid Pneumonia Presenting as an Enlarging Lung Nodule in a Patient with a Long-standing Usage of Petroleum Jelly

Abstract Introduction/Objective Lipoid pneumonia is an uncommon inflammatory lung lesion resulting from the aspiration of endogenous or exogenous oily substances. It has no age or sex preponderance, and its mode of presentation is non- specific. Radiologic imaging findings may mimic that of a malignant lung lesion. Methods We report a case of a 69-year-old female with a history of chronic obstructive pulmonary disease, rheumatoid arthritis and a 30-pack year smoking. She was being followed for an enlarging PET positive spiculated left upper lung nodule. She underwent a CT-guided core biopsy of the lung nodule. Results Biopsy showed histiocytes and multinucleated giant cells with lipid vacuoles and associated marked fibrosis. Review of a percutaneous lung biopsy performed two years prior showed a chronic inflammatory process with associated fibrosis in the presence of nonpolarizable vacuoles, many of which were intracytoplasmic within multinucleate foreign body type giant cells. A re-assessment of the patient with further history taking revealed a longstanding practice of nighttime application of petroleum jelly to nostrils and lips. Together, these findings are consistent with an exogenous lipoid pneumonia. Conclusion Lipoid pneumonia although an entity with limited literature description, should be considered in patients presenting with enlarging lung nodules. Early diagnosis of this lesion ensures appropriate treatment and prevents unnecessary invasive procedures.

Molecular Magnetic Resonance Imaging of Liver Fibrosis and Fibrogenesis Is Not Altered by Inflammation.

Three groups of mice that develop either mild type 2 inflammation and fibrosis (wild type), severe fibrosis with exacerbated type 2 inflammation (Il10-/-Il12b-/-Il13ra2-/-), or minimal fibrosis with marked type 1 inflammation (Il4ra∂/∂) after infection with S. mansoni were imaged using both probes for determination of signal enhancement. Schistosoma mansoni-infected wild-type mice developed chronic liver fibrosis. The liver MR signal enhancement after either probe administration was significantly higher in S. mansoni-infected wild-type mice compared with naive animals. The S. mansoni-infected Il4ra∂/∂ mice presented with little liver signal enhancement after probe injection despite the presence of substantial inflammation. Schistosoma mansoni-infected Il10-/-Il12b-/-Il13ra2-/- mice presented with marked fibrosis, which correlated to increased signal enhancement after injection of either probe. Both MR probes, EP-3533 and Gd-Hyd, were specific for fibrosis in this model of chronic liver disease regardless of the presence or severity of the underlying inflammation. These results, in addition to previous findings, show the potential application of both molecular MR probes for detection and quantification of fibrosis from various etiologies.

Comparative Analysis of the Occurrence and Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Hemophilic Arthropathy and Osteoarthritis.

Objective Hemophilic arthropathy is characterized by recurrent bleeding episodes in patients with hemophilia leading to irreversible joint degeneration. The involvement of CX3CL1 (fractalkine) and its receptor CX3CR1 was observed in the pathogenesis of numerous arthritis-associated diseases. Taking this into account, we have presented a study investigating the role of the CX3CL1/CX3XR1 axis in the course of hemophilic arthropathy, including the CX3CL1-dependent expression of CD56+, CD68+, and CD31+ cells along with evaluation of articular cartilage and synovial membrane morphology. Methods The study was carried out using cases (n = 20) of end-stage hemophilic arthropathy with a severe type of hemophilia A and control cases (n = 20) diagnosed with osteoarthritis. The biofluids including blood serum and synovial fluid were obtained intraoperatively for the evaluation of CX3CL1 using the ELISA test. Tissue specimens including articular cartilage and synovial membrane were similarly collected during surgery and stained immunohistologically using selected antibodies including anti-CX3CR1, anti-CD56, anti-CD68, and anti-CD31. Additionally, the analysis included the assessment of articular cartilage, synovial membrane, and blood vessel morphology. Results In our study, we have documented increased average concentration of CX3CL1 in the blood serum of the study group (7.16 ± 0.53 ng/ml) compared to the control group (5.85 ± 0.70 ng/ml) without statistically significant difference in synovial fluid concentration at the same time. We have observed an increased macrophage presence with more marked proliferation and fibrosis of the synovial membrane in the study group. Remaining results such as expression of CX3CR1 presence of NK cells and larger surface area of blood vessels within the synovial membrane were noted also without statistical significance. Conclusions This study has demonstrated collective CX3CL1/CX3CR1 axis involvement in hemophilic arthropathy pathogenesis introducing new interesting diagnostics and a therapeutic target.

Discovery of os cordis in the cardiac skeleton of chimpanzees (Pan troglodytes)

Cardiovascular diseases, especially idiopathic myocardial fibrosis, is one of the most significant causes of morbidity and mortality in captive great apes. This study compared the structure and morphology of 16 hearts from chimpanzees (Pan troglodytes) which were either healthy or affected by myocardial fibrosis using X-ray microtomography. In four hearts, a single, hyperdense structure was detected within the right fibrous trigone of the cardiac skeleton. High resolution scans and histopathology revealed trabecular bones in two cases, hyaline cartilage in another case and a focus of mineralised fibro-cartilaginous metaplasia with endochondral ossification in the last case. Four other animals presented with multiple foci of ectopic calcification within the walls of the great vessels. All hearts affected by marked myocardial fibrosis presented with bone or cartilage formation, and increased collagen levels in tissues adjacent to the bone/cartilage, while unaffected hearts did not present with os cordis or cartilago cordis. The presence of an os cordis has been described in some ruminants, camelids, and otters, but never in great apes. This novel research indicates that an os cordis and cartilago cordis is present in some chimpanzees, particularly those affected by myocardial fibrosis, and could influence the risk of cardiac arrhythmias and sudden death.

Perivascular Fibro-Adipogenic Progenitor Tracing during Post-Traumatic Osteoarthritis

Perivascular mural cells surround capillaries and microvessels and have diverse regenerative or fibrotic functions after tissue injury. Subsynovial fibrosis is a well-known pathologic feature of osteoarthritis, yet transgenic animals for use in visualizing perivascular cell contribution to fibrosis during arthritic changes have not been developed. Here, inducible Pdgfra-CreERT2 reporter mice were subjected to joint-destabilization surgery to induce arthritic changes, and cell lineage was traced over an 8-week period with a focus on the joint-associated fat pad. Results showed that, at baseline, inducible Pdgfra reporter activity highlighted adventitial and, to a lesser extent, pericytic cells within the infrapatellar fat pad. Joint-destabilization surgery was associated with marked fibrosis of the infrapatellar fat pad, accompanied by an expansion of perivascular Pdgfra-expressing cellular descendants, many of which adopted α-smooth muscle actin expression. Gene expression analysis of microdissected infrapatellar fat pad confirmed enrichment in membrane-bound green fluorescent protein/Pdgfra-expressing cells, along with a gene signature that corresponded with injury-associated fibro-adipogenic progenitors. Our results highlight dynamic changes in joint-associated perivascular fibro-adipogenic progenitors during osteoarthritis.

Application of Autodermoplasty for Gunshot Injury of Penis and Scrotum at the Specialized Level of Medical Care (Clinical case)

In peacetime, closed and especially open injuries of the penis are rare in military personnel. In wartime, penile injuries, mainly gunshot and combined, occur quite often. During the WWII, gunshot wounds of the penis accounted for 14% of the total number of injuries of the genitourinary organs. Damage to the penis, especially with the subsequent loss of an organ or part of it, causes not just physical struggle, but also psychological trauma. Damage to the penis accounts for up to half of all injuries of the external genital organs. The frequency of damage to the penis during military conflicts is known and ranges from 10.3 to 16.2 %, according to various authors. Specialized urological care involves the closure of large defects by skin grafts, reconstructive surgery, treatment of complications, closure of the fistula of the bladder and urethra. Mortality among patients with isolated injuries of the penis is minimal, but such patients need emergent medical care, often prompt. Clinical observation of surgical treatment with autodermoplasty of a gunshot wound of the penis at the IV level of medical care is presented. Complete healing of the soft tissue defect of the penis was observed. In order to study the effectiveness of autodermoplasty of a skin defect after a gunshot wound of the penis with a flap of skin from the hip, a dermal fragment was histologically studied after 30 days. At the border of the two fragments, marked fibrosis of the dermis, angiomatosis was noted, foci of chronic inflammation are located in the deeper layers of the dermis, along with fragments of suture material are giant multinucleated cells of the type of foreign bodies. Genital function restored, erection saved. Gunshot combat damage to the external genitalia is an urgent problem for field surgeons and urologists. Despite the improvement of personal protective equipment and the introduction of a new doctrine of medical and evacuation support, methods of prevention, primary care and longterm treatment require attention.