Parenchymal Infiltration Research Articles

An Analysis Of Mechanisms Of Central Nervous System Infiltration In Acute Lymphoblastic Leukaemia Using Primary Cells Xenografted Into Immunodeficient Mice

Despite great advances in the treatment of paediatric acute lymphoblastic leukaemia (ALL), disease in the central nervous system (CNS) continues to pose challenges. Current diagnostic tests are insensitive and risk factors for CNS relapse are poorly understood. This results in all children receiving intensive CNS-directed therapy which may be associated with acute and/or chronic neurotoxicity. A better understanding of the mechanisms of CNS engraftment is a necessary pre-requisite for diagnostic and therapeutic advances. To investigate if primary cells infiltrate the CNS, and whether this property resides in any particular sub-clonal compartment we undertook a comprehensive analysis of the CNS engrafting potential of primary ALL cells in immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. In addition, we used this model to investigate whether chemokine receptor expression drives CNS infiltration in pre-B ALL, as previously shown for T-ALL.CNS engraftment was seen in 18/23 pre-B ALL samples (78%). A consistent pattern of engraftment was observed with plaques of disease in the leptomeninges, relative sparing of the ventricles and complete absence of parenchymal infiltration. This implies ALL transit across the blood-CSF barrier rather than the blood-brain barrier – an important distinction, as leucocytes utilise distinct physiological trafficking mechanisms to cross these two barriers. To examine the frequency of cells with CNS-engrafting potential, intra-femoral transfer of 10 to 10,000 cells was performed. CNS engraftment was seen with as few as 10 initial cells. In addition, the ability to engraft the CNS was not restricted to any particular immunophenotypic compartment and was seen in CD19+CD10high, CD19+CD10low, CD19+CD20low, CD19+CD20high, CD19+CD34high, CD19+CD34low fractions. These data suggest that CNS engraftment potential is present at high-frequency in the bulk leukaemic population at diagnosis. To examine candidate trafficking molecules governing CNS entry, we investigated chemokine receptor expression on pre-B ALL blasts using quantitative PCR and flow cytometry. The chemokine receptors CXCR3, CXCR4 and CXCR7 were expressed by pre-B ALL but were not up-regulated in cells retrieved from the CNS compared to the bone marrow (BM).In conclusion, in xenograft models of pre-B ALL, CNS engrafting potential is present at high frequency in patient diagnostic BM specimens and does not appear to be restricted to sub-clonal compartments. These findings have important implications for the design of risk-adapted CNS therapy. Firstly, our studies indicate that CNS entry is a common property of leukaemic blasts and therefore the current dogma of CNS-directed therapy for all patients appears to have a rational scientific basis. Secondly, it is unlikely that chemokine receptor expression profiling will be a useful biomarker for CNS disease in pre-B ALL. Finally, identifying factors that facilitate long-term survival of cells in the CNS (which may also enhance long-term survival in the bone marrow) may be a better therapeutic strategy than attempts to block cell entry. Disclosures:No relevant conflicts of interest to declare.

Lung perfusion findings on perfusion SPECT/CT imaging in non-hospitalized de-isolated patients diagnosed with mild COVID-19 infection

BackgroundThe aim of this retrospective study is to assess the incidence and type of lung perfusion abnormalities in non-hospitalized patients diagnosed with mild COVID-19 infection after de-isolation. Data from 56 non-hospitalized patients diagnosed with COVID-19 infection referred to our nuclear medicine department from July–December 2020 for a perfusion only SPECT/CT study or a ventilation perfusion SPECT/CT study were collected. Images were assessed for the presence and type of perfusion defects. The CT component of the study was also assessed for the presence of mosaic attenuation and COVID pneumonia changes.ResultsThirty-two (57.1%) cases had perfusion defects. There were 20 (35.7%) cases with defects in keeping with pulmonary embolism, 17 (30.4%) cases with defects associated with mosaic attenuation but not due to pulmonary embolism, and 6 (10.7%) of cases with defects due to pulmonary infiltrates from COVID pneumonia. A total of 24 (42.9%) cases had mosaic attenuation on CT, with 10 (17.9%) of them showing a pattern likely consistent with shunting on the perfusion images.ConclusionLung perfusion abnormalities are a common finding in non-hospitalized COVID-19 patients with mild disease. They are usually either due to pulmonary embolism, parenchymal infiltrates, or other causes of mosaic attenuation related to, but not specific to the pathophysiology of COVID-19 infection. The value of VQ SPECT/CT imaging is also shown in this study, in detecting and differentiating the various types of perfusion abnormalities.

Vasculotoxic snake bite induced multi-organ dysfunction- A case report

Background: A WHO report included snake envenomation in the list of most important Neglected Tropical Diseases (NTD) and 95% of these cases were reported within developing countries. The reason behind this given importance is the high morbidity and mortality rates of snake envenomation as well as the challenges in availability and affordability of anti-snake venom [1]. Vasculotoxic snake bites has a myriad of manifestations ranging from local complications like necrosis and cellulitis to systemic complications such as coagulopathy, acute renal failure, acute respiratory failure, and hemolysis. Case Presentation: We report a case of a young male patient who was bitten by a Russell viper snake and developed cellulitis and blackish discolorations of the local site. The patient developed altered sensorium and subsequent loss of consciousness with a CT scan of the brain showing intra-parenchymal and subarachnoid hemorrhage. The coagulation profile demonstrated disseminated intravascular coagulation. He was treated for the above complications with polyvalent anti-snake venom, fresh frozen plasma, and cryoprecipitate units. Three days later, the patient developed breathlessness and hemoptysis with a drop in haemoglobin level with bilateral parenchymal infiltrates and left lower lobe consolidation indicative of diffuse alveolar hemorrhage with acute respiratory distress syndrome. On the fifth day, the patient reduced urine output with raised serum and creatinine levels. The patient’s clinical status rapidly worsened despite mechanical ventilatory and inotropic support and unfortunately succumbed to death on the 7th day of admission. Conclusion: Although there are case reports of snake bite induced isolated organ involvement, little is known about multi-organ dysfunction due to snake envenomation. The widespread multi-systemic involvement of snake envenomation resulting in fatal intracranial hemorrhage, acute lung, and kidney injury in our patient has been illustrated in this case report.

MO166AUTOPTIC KIDNEY FINDINGS IN HOSPITALIZED PATIENTS WITH COVID-19

Background and AimsSARS-CoV-2, isolated for the first time at the end of 2019, is the third human infecting Coronavirus found so far. Acute kidney injury (AKI) is the most common presentation when kidney is involved. There is evidence that kidney damage is determined through different pathological mechanisms. Has been observed that pathological kidney lesions can be due to the direct cytopathic effect of the virus on tubular cells or by pro-inflammatory cytokine storm. Aim of this observation is to evaluate the clinical and pathological patterns of kidney damage mediated by Coronavirus.MethodWe analysed kidney autopsies of 4 patients with COVID-19 infection, hospitalized between March and April 2020, admitted to the Intensive Care Unit. The tissue samples have been observed by light microscopy and immunofluorescence. RT-PCR SARS-CoV-2 was performed in all cases.ResultsCase 1female, 69 y; affected by obesity, previous ictus; smoking habit. Admitted for COVID-related pneumonia. At onset creatinine 0.45 mg/dl. Progression of lung failure and exitus after 3 days. Autopsy: diffuse alveolar damage. Renal autopsy: acute tubular necrosis; mild glomerular ischemia, lymphocyte T CD4+ parenchyma infiltration.Case2male, 66 y; affected by hypertension with cardiac involvement. Admitted for persistent fever. At onset creatinine 0.98 mg/dl. Nasopharingeal swab COVID-19 positive. Progression of lung failure and oligoanuric AKIn 3 (creatinine 4.5 mg/dl, urea 239 mg/dl), dialysis dependent. Exitus after one week for diffuse alveolar damage and sepsis.Renal autopsy: proximal and distal acute tubular moderate injury, mild diffuse glomerular ischemia, glomerular capillaritis, overlap chronic nephropathy.Case 3male 45 y; affected by obesity and diabetes. Admitted for COVID-related pneumonia with acute lung failure requiring ECMO. After one week developed AKIn 3 dialysis dependent. Exitus for cardio-respiratory arrest. Renal autopsy: diffuse acute tubular necrosis, glomerular capillaritis, overlap chronic diabetic nephropathy.Case 4male, 51 y; affected by CKD grade IV, hypertension, previous ictus; drug abuser. Admitted for AKIn 2 and COVID-related pneumonia. After 3 days progression of lung and renal failure requiring intubation and dialysis treatment. Exitus the day after for diffusive alveolar damage and lymphocytic myocarditis. Renal autopsy: diffused acute tubular necrosis, glomerular ischemia with mild tuft collapsing, diffuse infiltration of lymphocytes CD4+.In all cases light microscopy examination showed diffuse proximal tubular injury, with isomeric and non-isomeric vacuolar degeneration; collapsing tuft, and interstitial inflammation. Virus RNA performed by RT-PCR on kidney tissue was positive in all patients. Moreover in some cases our patients showed multi-systemic organ involvement: lung in 4 cases, heart in 1, liver in 1.ConclusionOur observations show that the main pathological effect caused by Coronavirus is a direct cytopathic effect on the proximal tubules with variable degree of damage until acute tubular necrosis (ATN). In addition to this pathway, other factors contributing to kidney damage include systemic hypoxia, microvascular capillaritis. Associated sepsis can worse overall and renal survival. Previous comorbidities, especially obesity, diabetes, systemic hypertension and preexisting chronic renal failure, are significant negative prognostic factors.

Role of P2X7 Receptors in Immune Responses During Neurodegeneration.

P2X7 receptors are ion-gated channels activated by ATP. Under pathological conditions, the extensive release of ATP induces sustained P2X7 receptor activation, culminating in induction of proinflammatory pathways with inflammasome assembly and cytokine release. These inflammatory conditions, whether occurring peripherally or in the central nervous system (CNS), increase blood-brain-barrier (BBB) permeability. Besides its well-known involvement in neurodegeneration and neuroinflammation, the P2X7 receptor may induce BBB disruption and chemotaxis of peripheral immune cells to the CNS, resulting in brain parenchyma infiltration. For instance, despite common effects on cytokine release, P2X7 receptor signaling is also associated with metalloproteinase secretion and activation, as well as migration and differentiation of T lymphocytes, monocytes and dendritic cells. Here we highlight that peripheral immune cells mediate the pathogenesis of Multiple Sclerosis and Parkinson’s and Alzheimer’s disease, mainly through T lymphocyte, neutrophil and monocyte infiltration. We propose that P2X7 receptor activation contributes to neurodegenerative disease progression beyond its known effects on the CNS. This review discusses how P2X7 receptor activation mediates responses of peripheral immune cells within the inflamed CNS, as occurring in the aforementioned diseases.

Clinicopathological features of Chinese patients with B-cell lymphoproliferative disorders and kidney infiltration.

Direct kidney involvement in B-cell lymphoproliferative disease is a rare disorder with only a few studies reported in Caucasian patients. The clinicopathological characteristics and outcome of this entity remain poorly described. We retrospectively studied all adult Chinese patients who had histology-proven renal parenchymal infiltration by malignant B-cells between 1 January 2000 and 31 December 2018 at two tertiary hospitals in Hong Kong. Clinical, pathological and radiological data were collected from 20 patients. Follow-up data were analysed until 31 December 2019. Median follow-up duration was 22 (1-171) months. Only seven patients (35%) had established diagnosis of haematological cancer before kidney biopsy. Diffuse large B-cell lymphoma (DLBCL) was the most common subtype in our cohort (n=5, 25%). Others included low-grade B-cell lymphoma (n=11), intravascular large B-cell lymphoma (n=1), mantle cell lymphoma (n=1) and multiple myeloma (n=2). Fourteen patients (70%) presented with AKI while 12 patients (60%) had proteinuria. Seven patients (35%) had unilateral renal mass, one had bilateral renal masses and one had bilateral diffuse nephromegaly in computed tomography. Lymphomatous tubulointerstitial infiltration was the prevalent histological finding. Nine patients (45%) had coexisting renal lesions other than direct tumour infiltration. All but one patient received chemotherapy. Ten patients died and renal responders had a significantly better survival than non-renal responders (p=.03). Direct tumour infiltration can occur in a wide variety of B-cell lymphoproliferative disorders. Coexisting immunoglobulin-related nephropathy is frequently found. Renal biopsy is required for early diagnosis which allows timely and appropriate treatment.

Rising PGD Incidence Parallels Increased Recipient Disease Severity

<h3>Purpose</h3> Priority on waitlist urgency over post-transplant survival has decreased waitlist mortality with no appreciable change in short to mid-term survival. We sought to define the effects of increased pressure to transplant sicker candidates on PGD incidence and mortality as a leading indicator for long-term effects. <h3>Methods</h3> We used the multi-center prospective Lung Transplant Outcomes Group cohort study, designed to identify risk factors for PGD and mortality. Patients were enrolled from August 2011 to June 2018 at 10 centers. PGD was graded based on the 2016 PGD consensus ISHLT guidelines. Specifically, PGD was defined as grade 3 PGD (PaO2 /FiO2 ratio <200) at 48 or 72 hours after allograft reperfusion. Patients on ECMO post-transplant were graded as PGD only if there was evidence of parenchymal infiltrates on chest radiograph. <h3>Results</h3> 1,528 subjects were enrolled with a 25.6% incidence of PGD overall. PGD incidence increased from 14.3% to 38.2% over the course of the study. From 2012 to 2018, the median LAS increased from 38.7 to 42.9 and the use of ECMO salvage increased from 5.7% to 20.9% (Fig.1a). PGD was associated with mortality overall (p=0.0001, Fig.1b). Bridging strategies were not associated with mortality (p=0.66); however, salvage ECMO for PGD was significantly associated with mortality (HR 2.1 [1.6; 2.8]; p<0.0001). Restricted mean survival time comparison at 1-year demonstrated 101 days lost in VA salvaged recipients when compared to those without PGD and 29 days for VV. Effects on mortality increased over time (Fig1c). <h3>Conclusion</h3> Severity of illness continues to rise in modern surgical practice paralleled by significant increases in PGD incidence. Bridging strategies have increased but appear safe. PGD is highly associated with mortality and is increasingly treated with salvage ECMO. Though early mortality associated with salvage strategies is low, 1-year survival is significantly reduced. Given the increase in use of salvage ECMO, further work is needed on evaluating 2016 PGD definition.

Restrictive allograft syndrome after lung transplantation.

Despite recent advances over the past decade in lung transplantation including improved surgical technique and immunotherapy, the diagnosis and treatment of chronic lung allograft dysfunction remains a significant barrier to recipient survival. Aside from bronchiolitis obliterans syndrome, a restrictive phenotype called restrictive allograft syndrome has recently been recognized and affects up to 35% of all patients with CLAD. The main characteristics of RAS include a persistent and unexplained decline in lung function compared to baseline and persistent parenchymal infiltrates on imaging. The median survival after diagnosis of RAS is 6 to 18months, significantly shorter than other forms of CLAD. Treatment options are limited, as therapies used for BOS are typically ineffective at halting disease progression. Specific medications such as fibrinolytics are lacking large, multicenter prospective studies. In this manuscript, we discuss the definition, mechanism, and characteristics of RAS while highlighting the similarities and differences between other forms of CLAD. We also review the diagnoses along with current and potential treatment options that are available for patients. Finally, we discuss the existing knowledge gaps and areas for future research to improve patient outcomes and understanding of RAS.

Lung Functioning and Inflammation in a Mouse Model of Systemic Juvenile Idiopathic Arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an immune disorder characterized by fever, skin rash, arthritis and splenomegaly. Recently, increasing number of sJIA patients were reported having lung disease. Here, we explored lung abnormalities in a mouse model for sJIA relying on injection of IFN-γ deficient (IFN-γ KO) mice with complete Freund's adjuvant (CFA). Monitoring of lung changes during development of sJIA using microcomputer tomography revealed a moderate enlargement of lungs, a decrease in aerated and increase in non-aerated lung density. When lung function and airway reactivity to methacholine was assessed, gender differences were seen. While male mice showed an increased tissue hysteresivity, female animals were characterized by an increased airway hyperactivity, mirroring ongoing inflammation. Histologically, lungs of sJIA-like mice showed subpleural and parenchymal cellular infiltrates and formation of small granulomas. Flow cytometric analysis identified immature and mature neutrophils, and activated macrophages as major cell infiltrates. Lung inflammation in sJIA-like mice was accompanied by augmented expression of IL-1β and IL-6, two target cytokines in the treatment of sJIA. The increased expression of granulocyte colony stimulating factor, a potent inducer of granulopoiesis, in lungs of mice was striking considering the observed neutrophilia in patients. We conclude that development of sJIA in a mouse model is associated with lung inflammation which is distinct to the lung manifestations seen in sJIA patients. Our observations however underscore the importance of monitoring lung disease during systemic inflammation and the model provides a tool to explore the underlying mechanism of lung pathology in an autoinflammatory disease context.

Dwellers and Trespassers: Mononuclear Phagocytes at the Borders of the Central Nervous System.

The central nervous system (CNS) parenchyma is enclosed and protected by a multilayered system of cellular and acellular barriers, functionally separating glia and neurons from peripheral circulation and blood-borne immune cells. Populating these borders as dynamic observers, CNS-resident macrophages contribute to organ homeostasis. Upon autoimmune, traumatic or neurodegenerative inflammation, these phagocytes start playing additional roles as immune regulators contributing to disease evolution. At the same time, pathological CNS conditions drive the migration and recruitment of blood-borne monocyte-derived cells across distinct local gateways. This invasion process drastically increases border complexity and can lead to parenchymal infiltration of blood-borne phagocytes playing a direct role both in damage and in tissue repair. While recent studies and technical advancements have highlighted the extreme heterogeneity of these resident and CNS-invading cells, both the compartment-specific mechanism of invasion and the functional specification of intruding and resident cells remain unclear. This review illustrates the complexity of mononuclear phagocytes at CNS interfaces, indicating how further studies of CNS border dynamics are crucially needed to shed light on local and systemic regulation of CNS functions and dysfunctions.

A new imaging sign in COVID-19 pneumonia: vascular changes and their correlation with clinical severity of the disease.

It has come to our attention that specific vascular changes (VCs) appear more frequently in chest computed tomography (CT) of patients with coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate if these specific VCs in chest CT correlate with clinical severity of the disease. CT images of 102 patients who underwent low-dose noncontrast chest CT due to COVID-19 between 11 March 2020 and 11 April 2020 were evaluated retrospectively. The patients were divided into two groups based on the presence of VCs in CT images. VCs in chest CT of patients with COVID-19 were defined using the following descriptors: decreased lumen caliber, vascular wall irregularity, angulation in the course of the vessel, vascular disruption, and/or interruption. The relationship of these VCs with disease symptoms (fever, cough, shortness of breath), comorbid conditions (diabetes, hypertension, asthma), smoking habit, disease-specific laboratory changes (white blood cell-lymphocyte count, neutrophil/lymphocyte ratio, C-reactive protein [CRP], D-dimer, lactate dehydrogenase [LDH], ferritin, procalcitonin), lung parenchymal infiltration pattern (ground-glass opacity, crazy-paving pattern, consolidation) and its distribution (peripheral, central, mixed, upper lobes, lower lobes, right middle lobe) on CT were investigated by comparison of these variables between patients with and without VCs in chest CT. VCs were observed in 18 out of 102 patients (18%) with typical parenchymal involvement for COVID-19. There was no significant difference in terms of age and sex. We found an irregularity in the wall of the vascular structures in the distal branches and decreased lumen caliber of the vessels related to ground-glass opacities in 15 patients, concentric luminal narrowing in annular form in 4 patients, angulation/traction or springiness in the vascular structures towards the active lesions in 3 patients, and interruptions along the vascular course in 1 patient. VCs were significantly correlated with fever (12/18, 66.7%) and shortness of breath (7/18, 39%). These changes were significantly more remarkable in common disease involving both upper and lower lobes (10/18, 56%). In these cases, there was a substantial increase in CRP (15/18, 83%; mean, 5.7±6.3 mg/dL) and LDH (8/18, 44%) values compared to those who did not have any VCs. The results of this study suggest that specific VCs observed in chest CT may predict the disease severity in cases of COVID-19 pneumonia. These changes may be related to respiratory distress in the disease.

A severity-of-illness score in patients with tuberculosis requiring intensive care

Background. We previously retrospectively validated a 6-point severity-of-illness score aimed at identifying patients at risk of dying of tuberculosis (TB) in the intensive care unit (ICU). Parameters included septic shock, HIV infection with a CD4 count &lt;200 cells/µL, renal dysfunction, a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (P/F) &lt;200 mmHg, a chest radiograph demonstrating diffuse parenchymal infiltrates, and no TB treatment on admission. Objectives. To prospectively validate the severity-of-illness scoring system in patients with TB requiring intensive care, and to refine and simplify the score in order to expand its clinical utility. Methods. We performed a prospective observational study with a planned post hoc retrospective analysis , enrolling all adult patients with confirmed TB admitted to the medical ICU of a tertiary hospital in Cape Town, South Africa, from 1 February 2015 to 31 July 2018. The admission data of all adult patients with TB requiring admission to the ICU were used to calculate the 6-point severity-of-illness score and a refined 4-point score (based on the planned post hoc analysis). Descriptive statistics and χ 2 or Fisher’s exact tests (where indicated) were performed on dichotomous categorical variables, and t -tests on continuous data. Patients were categorised as hospital survivors or non-survivors. Results. Forty-one of 78 patients (52.6%) died. The 6-point scores of non-survivors were higher than those of survivors (mean (standard deviation (SD)) 3.5 (1.3) v. 2.7 (1.2); p =0.01). A score ≥3 v. &lt;3 was associated with increased mortality (64.0% v. 32.1%; odds ratio (OR) 3.75; 95% confidence interval (CI) 1.25 - 10.01; p =0.01). Post hoc , a P/F ratio &lt;200 mmHg and no TB treatment on admission failed to predict mortality, whereas any immunosuppression did. A revised 4-point score (septic shock, any immunosuppression, acute kidney injury and lack of lobar consolidation) demonstrated higher scores in non-survivors than survivors (mean (SD) 2.8 (1.1) v. 1.6 (1.1); p &lt;0.001). A score ≥3 v. ≤2 was associated with increased mortality (78.4% v. 29.3%; OR 8.76; 95% CI 3.12 - 24.59; p &lt;0.001). Conclusions. The 6-point severity-of-illness score identified patients at increased risk of death. We were able to derive and retrospectively validate a simplified 4-point score with superior predictive power.

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [64Cu]Cu-NOTA-anti-CD8 PET.

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET. We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells. Nontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors. Human CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.

Pathophysiology and Spectrum of Neuro-COVID

Some neurological manifestations may not be specific for COVID-19 and due to other causes but that COVID-19 must be considered as a differential of all acute neurological conditions. The following neuropathological abnormalities were found: acute microscopic thrombotic ischemic infarcts; microscopic haemorrhagic infarcts; petechial haemorrhage; focal perivascular parenchymal Tcell infiltrates; diffuse perivascular parenchymal T-cell infiltrates; leptomeningeal inflammation; interstitial brainstem inflammation with neuronal loss; capillary endothelium expression of ACE2 receptors; microglial nodules; and hypoxicischemia changes and neuronal loss.

Residue depletion and histopathological alterations in gilthead sea bream (Sparus aurata) after oral administration of oxytetracycline

ABSTRACT Aquaculture is a key component of the animal food industry, but intensive farming conditions increase the incidence of infectious diseases. Oxytetracycline (OTC) plays a major role for infectious diseases in fishes. Its MRLs include their 4-epimers, so in this trial, the depletion of residues of OTC and 4-epioxytetracycline in muscle and liver have been evaluated in gilthead sea bream (Sparus aurata) after oral administration. Hepatotoxicity has been investigated with histopathological effects on target tissues. A validated DAD-HPLC with SPE extraction has been applied. Residual levels in muscle and liver depleted with a similar k el, but mean retention time and t ½ß resulted longer in muscle than in liver because of different vascularization. The OTC concentrations were below the LMR at 48 h after dosing. No analytical peaks ascribable to 4-epi-OTC or other derivatives were detected, while histopathology of liver showed degenerated parenchymal hepatocytes, nuclear pyknosis, focal necrosis and inflammatory leucocytes infiltration. It can be concluded that the assessment of pharmacokinetic and residual depletion of antibiotics result fundamental to determine the most suitable therapeutic regime and to minimize the toxic effects in fish species.

МРТ-КАРТИНА ПОРАЖЕНИЯ ЛЕГКИХ ПРИ ПНЕВМОНИИ, АССОЦИИРОВАННОЙ С COVID-19

Purpose. To demonstrate MRI signs of COVID-19-associated lung damage in a patient with atypical clinical symptoms. Materials and methods. The analysis of literature data, the results of clinical examination, magnetic resonance imaging, using various pulse sequences, and computed tomography data are presented. The analysis of the features of the clinical picture and comparison of changes in the lungs detected using two different methods of tomographic imaging were performed. Results. MRI showed signs of parenchymal infiltration with pleural effusion in both lungs. Computed tomography confirmed a high likelihood of lung damage associated with COVID-19, coinciding in extent and location with MRI data. A feature of the presented observation is the dominance in the clinical picture of symptoms from the upper floor of the abdominal cavity, the absence of an increase in temperature and respiratory complaints. Infection of the patient with COVID-19 was confirmed by a reference test. MR imaging made it possible to promptly start treatment for pneumonia caused by COVID-19 and achieve the patient's recovery. Conclusion. MRI can detect changes characteristic of COVID-19-associated pneumonia. The vigilance of the radiologist regarding possible infiltrative changes in the lungs, which often covers the scan area with an MRI of the abdominal cavity, allows a timely targeted examination for COVID-19 and the initiation of patient treatment. It is advisable to study in more detail the possibilities of MRI as an alternative test in case of contraindications for ionizing imaging of the lungs in a pandemic of a new coronavirus infection.

Comparative Study of CT Severity Index and Outcome in Hospitalised Vaccinated and Non Vaccinated Patients of Covid 19 Pneumonia

SARS-CoV-2 virus typically causes lung infiltration causing acute respiratory distress syndrome (ARDS) and in later stages pulmonary fibrosis. Vaccines provide immunity against desired pathogen. Vaccines available in India against this virus are Covishield and Covaxin (majority of the patients are vaccinated with Covishield). COVID-19 causes lung parenchymal infiltration which leads to pneumonitis. The best modality available to study this is the HRCT. Analysis of the extent of lung parenchyma invasion of patients despite taking one or both the doses was done by us. For which , we did a single centered retrospective observational study in laboratory confirmed COVID-19 positive patients with sample size (n=274) being duration dependent (2 months). We found a statistically significant correlation between vaccination status and lung involvement based on HRCT Thorax. In conclusion the presence of vaccination reduces the severity of the CT severity score and improves the outcome in terms of survival of the patient.

Changes of vitamin D receptors (VDR) and MAPK activation in cytoplasmic and nuclear fractions following exposure to cigarette smoke with or without filter in rats

Cigarette smoke (CS) is a major cause of obstructive lung disease which is associated with significant disability and mortality. Vitamin D receptor (VDR) together with, mitogen activated protein kinases (MAPKs; ERK, JNK and p38) are the cellular transmission signals that mechanistically respond to CS and are recently found to have a role in lung pathogenesis. There are a few in vitro studies on subcellular VDR distribution involved MAPK but in vivo effects of cigarette smoke exposure with and without filter on this complex remain unclear. This study investigated subcellular VDR distribution and MAPK expression at early stages of both types of cigarette smoke exposure (CSE) in a rat model. Male Wistar rats were randomly divided into no-filter, filter and control groups. After 7 and 14 days of CSE, lung tissues were obtained to determine histopathology and protein expression. Cytoplasmic and nuclear VDR distribution significantly decreased on both CSE groups and corresponded with immunohistochemistry detection. The ratio of phosphorylated ERK to total ERK significantly increased in cytoplasm of both CSE on day 7. In particular, nuclear ERK MAPK significantly escalated in the filter group on day 14. In consistent with changes in intracellular markers, histopathological examination in both CSE groups showed significant increases in tracheal and peribronchiolar epithelial proliferation, alveolar macrophages and an increased trend of parenchymal infiltration. In summary, the evidence of lung injuries along with VDR depletion and MAPK activation observed in both CSE types indicated that there was no benefit of using cigarette filter to prevent protein damage or protect cells against cigarette smoke exposure in this model.

COVID-19: general overview, pharmacological options and ventilatory support strategies.

The novel coronavirus called “Severe Acute Respiratory Syndrome Coronavirus 2” (SARS-CoV-2) caused an outbreak in December 2019, starting from the Chinese city of Wuhan, in the Hubei province, and rapidly spreading to the rest of the world. Consequently, the World Health Organization (WHO) declared that the coronavirus disease of 2019 (COVID-19) can be characterized as a pandemic. During COVID-19 several immunological alterations have been observed: in plasma of severe patients, inflammatory cytokines are at a much higher concentration (“cytokine storm”). These aspects are associated with pulmonary inflammation and parenchymal infiltrates with an extensive lung tissue damage in COVID-19 patients. To date, clinical evidence and guidelines based on reliable data and randomized clinical trials (RCTs) for the treatment of COVID-19 are lacking. In the absence of definitive management protocols, many treatments are currently being evaluated worldwide. Some of these options were soon abandoned due to ineffectiveness, while others showed promising results. As for ventilatory strategies, at the moment there are still no consistent data published about the different approaches and how they may influence disease progression. What will probably represent the real solution to this pandemic is the identification of a safe and effective vaccine, for which enormous efforts and investments are being put in place. This review will summarize the state-of-the-art of COVID-19 current treatment options and those potentially available in the future, as well as high flow oxygen therapy and non-invasive mechanical ventilation approaches.

NIMG-62. AMPHETAMINE-ASSOCIATED CNS VASCULITIS MASQUERADING AS TUMOUR

Abstract Amphetamine-associated CNS vasculitis is controversial. There are few reports but none as a tumor mimic to our knowledge. We describe a pathology-proven, amphetamine-associated CNS vasculitis resembling a tumor. A 41-year-old man presented with six weeks of progressive confusion and left-sided weakness. CT head reported a right thalamic mass with vasogenic edema. Laboratory tests were unremarkable except for cannabinoids and amphetamine in urine. MRI brain showed enhancement in right frontotemporal lobe, basal ganglia, and thalamus concerning for glioblastoma multiforme. After high-dose IV dexamethasone, an initial biopsy showed reactive gliosis, perivascular lymphocytic cuffing by CD3+, rare CD20+ cells and no infection. He continued to decline. MRI 22 days after admission showed increased T2/FLAIR hyperintensity, multifocal areas of enhancement, microhemorrhages, and ischemia. High-grade glioma, lymphoma and infectious encephalitis remained on differentials. Treatment included broad-spectrum antibiotics and acyclovir. Biopsy on 23rd day showed reactive gliosis with parenchymal macrophage infiltration and perivascular cuffing with mixed inflammatory infiltrates. CSF: slightly elevated WBCs (8/µL), elevated protein (139mg/dL), normal glucose, and no infection. MRI whole spine and CT body were unremarkable. The patient was transferred to MDACC 5.5 weeks after initial presentation. He was alert with expressive aphasia, right gaze preference, left hemiplegia, and right hemiparesis. He underwent a right anterior temporal lobectomy. Pathology showed extensive cortical laminar and white matter necrosis with macrophage infiltration and microglial activation. In areas of the preserved cortex, vasculocentric lymphocytic aggregates were present and reticulin staining showed lymphocytic infiltration of the vascular walls. Immunophenotyping (CD3, CD20) showed an almost pure T-cell population. The predominance of intramural T-lymphocytes reflected a vasculitic process. The final diagnosis was cerebral vasculitis with subacute infarction. The patient died six days later. The autopsy findings were identical to the previous resection without evidence of systemic inflammation.