Splenic Atrophy Research Articles

Sorafenib safety evaluation: Real-world analysis of adverse events from the FAERS database

BackgroundSorafenib is approved for the targeted therapy of cancers such as liver cancer and renal cancer. Given its widespread use, drug-related adverse events have received attention, and the post-marketing regulatory link is crucial. ObjectiveBy using the FAERS database to mine the adverse events (AEs) related to sorafenib, comparing the association intensity of key AEs, and exploring potential drug-related AEs, it provides a reference for clinical medication. MethodsCollect ADE data related to sorafenib in the FAERS database from 2006 to 2023. Standardize the data, and map adverse events to system organ classes and preferred terms. Analyze using various signal quantification techniques such as ROR, PRR, BCPNN, and MGPS. ResultsAmong 18,520 adverse event reports (AERs) where sorafenib was the primary suspected drug, a total of 390 preferred terms (PTs) of adverse reactions were identified, covering 24 different system organ classes (SOCs). Specifically, the adverse events of sorafenib mainly involve the digestive system, skin and subcutaneous tissue, as well as non-specific physical discomfort including infection and injury. Among them, digestive system symptoms and skin toxicity are typical adverse reactions of sorafenib. We also observed uncommon but clearly strong AE signals, such as chloracne (n = 3, ROR 1756.39, PRR 1756.32, IC 8.78, EBGM 439.83), low-differentiated thyroid cancer (n = 4, ROR 585.47, PRR 585.44, IC 8.2, EBGM 293.22). It is worth noting that palmar-plantar erythrodysaesthesia syndrome (n = 2109, ROR 73.98, PRR 72.03, IC 6.01, EBGM 64.25) and hepatic encephalopathy (n = 457, ROR 37.44, PRR 37.23, IC 5.13, EBGM 35.07) have a higher incidence and signal intensity. In addition, we also observed some adverse events not mentioned in the official drug instructions, such as vitamin K deficiency or increased protein induced by antagonist II (PIVKA-II), abnormal alpha-fetoprotein, tumor metastasis, and splenic atrophy. ConclusionSorafenib carries the risk of various adverse reactions while providing therapeutic effects. In clinical applications, physicians should closely monitor the occurrence of digestive system reactions, skin lesions, endocrine system lesions, as well as injuries, infections, and other events.

Autoimmune manifestation in splenic atrophy presented with toxic shock syndrome: a case report

Splenic atrophy is an uncommon diagnosis, associated with autoimmune gastrointestinal disorders and other well-characterized connective tissue diseases. We would like to contribute a case report to support the association evidence of the real-world data. To our best knowledge, there is no similar case of splenic atrophy with the presentation of streptococcal toxic shock syndrome reported. Our patient was initially detected with atrophic spleen via CT scan and subsequently diagnosed with systemic sclerosis. Hyposplenism should be suspected in patients with adult-onset infections caused by encapsulated bacteria, especially if autoantibodies are present. Our patient received her pneumococcal vaccination before discharge and was followed in the clinic for further vaccination education and health check-up. Learning points: 1) Acquired splenic atrophy is a rare condition that may be suspected from persistent isolated thrombocytosis after the resolution of sepsis and Howell-Jolly bodies from peripheral blood film; 2) The pathophysiological mechanism of splenic atrophy in the context of autoimmune disorders remains unknown; 3) A high index of suspicion towards the evaluation of splenic function is required if a patient presented with community-acquired encapsulated organism bacteraemia; 4) Vaccination against encapsulated bacterial agents should be performed in patients with hyposplenism.

N-acetyl Cysteine Overdose Induced Acute Toxicity and Hepatic Microvesicular Steatosis by Disrupting GSH and Interfering Lipid Metabolisms in Normal Mice.

N-acetyl cysteine (NAC) is a versatile drug used in various conditions, but the limitations and toxicities are not clear. The acute toxicity and toxicological mechanisms of an intraperitoneal injection of NAC in normal mice were deciphered. The LD50 for male and female BALB/cByJNarl mice were 800 mg/kg and 933 mg/kg. The toxicological mechanisms of 800 mg/kg NAC (N800) were investigated. The serum biomarkers of hepatic and renal indices dramatically increased, followed by hepatic microvesicular steatosis, renal tubular injury and necrosis, and splenic red pulp atrophy and loss. Thus, N800 resulted in mouse mortality mainly due to acute liver, kidney, and spleen damages. The safe dose (275 mg/kg) of NAC (N275) increased hepatic antioxidant capacity by increasing glutathione levels and catalase activity. N275 elevated the hepatic gene expressions of lipid transporter, lipid synthesis, β-oxidation, and ketogenesis, suggesting a balance between lipid production and consumption, and finally, increased ATP production. In contrast, N800 increased hepatic oxidative stress by decreasing glutathione levels through suppressing Gclc, and reducing catalase activity. N800 decreased the hepatic gene expressions of lipid transporter, lipid synthesis, and interferred β-oxidation, leading to lipid accumulation and increasing Cyp2E1 expression, and finally, decreased ATP production. Therefore, NAC doses are limited for normal individuals, especially via intraperitoneal injection or similar means.

Possible pathogenic mechanisms for doxorubicin-induced splenic atrophy in a human breast cancer xenograft mouse model.

Doxorubicin-based chemotherapy is a widely used first-line treatment for breast cancer, yet it is associated with various side effects, including splenic atrophy. However, the pathogenic mechanisms underlying doxorubicin-induced atrophy of the spleen remain unclear. This study investigates that doxorubicin treatment leads to splenic atrophy through several interconnected pathways involving histological changes, an inflammatory response, and apoptosis. Immunohistochemical and western blot analyses revealed reduced size of white and red pulp, decreased cellularity, amyloidosis, and fibrotic remodeling in the spleen following doxorubicin treatment. Additionally, increased secretion of pro-inflammatory cytokines was detected using an antibody array and enzyme-linked immunosorbent assay (ELISA), which triggers inflammation through the regulation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-κB) signaling pathways. Further analysis revealed that the loss of regulators and effectors of the oxidative defense system, including sirtuin (Sirt)3, Sirt5, superoxide dismutase (SOD)1, and SOD2, was implicated in the upstream regulation of caspase-dependent cellular apoptosis. These findings provide insights on the pathogenic mechanisms underlying doxorubicin-induced splenic atrophy and suggest that further investigation may be warranted to explore strategies for managing potential side effects in breast cancer patients treated with doxorubicin.

Sex-dependent responses to high concentration of binge ethanol in spleen of adolescent F344 rats.

We previously reported that binge ethanol induces atrophy of the spleen, a key immune organ, in adolescent male F344 rats. Because there are significant sex effects in immune function, we investigated whether binge ethanol exerts sex-dependent effects on the spleen, including producing splenic atrophy. We gave F344 rats ethanol (4.8 g/kg/day; 52% w/v; i.g.) on postnatal days [PND] 36 ~ 38 and sacrificed them on PND 39 for spleen collection. We performed immunophenotyping analysis of splenic cells and examined the expression of 158 genes related to alcohol metabolism, epigenetic modification, and immune regulation in the spleens of adolescent (PND 39) male and female rats. Following a 3-day ethanol exposure, a loss of body weight, and absolute and relative spleen weight, was seen only in male adolescent rats. Ethanol altered the relative proportions of lymphocyte subtypes in both sexes with different patterns. We also found that 3-day ethanol exposure induced sex-dependent gene expression changes in spleen. Among the 158 genes studied, the expression of only three genes was significantly increased in female rats. However, the expression of 30 genes was significantly increased/decreased in male rats. Female rats had greater expression of alcohol metabolizing enzyme genes in the spleen under physiological conditions and when stimulated by binge ethanol. The genes are involved in epigenetic modification were differentially expressed in a sex-dependent manner. We found that male adolescent rats were more sensitive to binge ethanol than female rats. Differential expression of the genes related to alcohol metabolism and epigenetic modification (of DNA methyltransferase and histone deacetylases) between the sexes could account for the observed sex-dependent responses to binge ethanol in adolescent rats.

Abstract WP301: STAT3 Inhibition Reduces Infarct and Neuroinflammation in Experimental Stroke

Signal Transducer and Activator of Transcription 3 (STAT3) activation is increased in the brain following cerebral ischemia. STAT3, a transcription factor, is a positive regulator of cell survival and is implicated in cytoprotection following ischemia in multiple cell types, including neurons and endothelial cells. We hypothesized that pharmacological inhibition of STAT3 activation in mice during the reperfusion phase after middle cerebral artery occlusion (MCAO) will lead to increased infarct size. We subjected mice to 1-hour MCAO, following which they received STAT3 inhibitor Stattic (20 mg/kg), or vehicle, for 24 hours delivered subcutaneously via osmotic pump. Twenty-four hours later, infarct was measured by TTC and inflammatory cells were measured by flow cytometry. For experiments involving splenectomy, spleens were surgically removed 14 days prior to MCAO surgery. Surprisingly, we found that STAT3 inhibition reduces infarct after MCAO, with infarct in the hemisphere reducing from 49.90 ± 2.44 % in vehicle to 32.86 ± 1.55 % in Stattic-treated mice. Since STAT3 is involved in inflammatory processes, as well as cytoprotection, this led us to hypothesize that the reduction in infarct we observe may be due to decreased inflammation. We carried out FACS analysis and observed that Stattic inhibits MCAO-induced infiltration of B-, T- and dendritic cells into the brain. Neutrophil and monocyte infiltration into the brain were unaffected by Stattic. Since MCAO is known to induce splenic atrophy, with spleen size being inversely proportional to infarct volume, we measured spleen weights. Interestingly Stattic-treated mice had larger spleens (66.31 ± 5.40 g) compared to vehicle-treated mice (46.43 ± 4.60 g), indicating a dampened peripheral immune response upon inhibition of STAT3. Furthermore, Stattic was no longer effective in reducing infarct size in splenectomized mice. We conclude that pharmacological inhibition of STAT3 reduces infarct following MCAO, with the mechanism of protection involving differential regulation of the peripheral immune response.

The mechanisms underlying alcohol-induced decreased splenic size: A network meta-analysis study.

Organ weight change is widely accepted as a measure of toxicologic pathology. We and other groups have shown that excessive alcohol exposure leads to decreased spleen weight in rodents. This study explores the mechanisms underlying alcohol-induced splenic injury through a network meta-analysis. QIAGEN Ingenuity Pathway Analysis (IPA) and Mammalian Phenotype (MP) Ontology were used to identify alcohol-related molecules associated with the small spleen phenotype. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and IPA bioinformatics tools were then used to analyze the biologic processes and enriched signaling pathways engaging these molecules. In addition, the "downstream effects analysis" algorithm was used to quantify alcohol's effects. IPA identified 623 molecules affected by alcohol and a Venn diagram revealed that 26 of these molecules overlapped with those associated with the MP Ontology of small spleen. The 26 molecules are TGFB1, CASP8, MTOR, ESR1, CXCR4, CAMK4, NFKBIA, DRD2, BCL2, FAS, PEBP1, TRAF2, ATM, IGHM, EDNRB, MDM2, GLRA1, PRF1, TLR7, IFNG, ALOX5, FOXO1, IL15, APOE, IKBKG, and RORA. Some of the 26 molecules were also associated with the MP Ontology of abnormal white pulp and red pulp morphology of the spleen, abnormal splenic cell ratio, decreased splenocyte number, abnormal spleen physiology, increased splenocyte apoptosis, and reduced splenocyte proliferation. STRING and IPA "Core Analysis" showed that these molecules were mainly involved in pathways related to cell apoptosis, proliferation, migration, and immune responses. IPA's "Molecular Activity Predictor" tool showed that concurrent effects of activation and inhibition of these molecules led to decreased spleen size by modulating apoptosis, proliferation, and migration of splenocytes. Our network meta-analysis revealed that excessive alcohol exposure can damage the spleen through a variety of molecular mechanisms, thereby affecting immune function and human health. We found that alcohol-mediated splenic atrophy is largely mediated by increased apoptosis signaling, migration of cells, and inhibition of splenocyte proliferation.

Antiapoptotic and chemotaxis-stimulating effects of poly (d, l-lactide-co-glycolide)-chitosan and whey proteins against aflatoxicosis-induced splenic and thymic atrophy

BackgroundAflatoxin B (AFB) induces toxicological effects on the liver and immune organs. The whey proteins can modulate the immune response during aflatoxicosis. Our work evaluates the novel polylactic acid-glycolic acid-chitosan-encapsulated bovine and camel whey proteins against AFB-induced thymic and splenic atrophy in rats.Methods and resultsSeventy adult male Wister albino rats were divided into a control healthy group (G1) and six AFB1-intoxicated groups (G2–G7). One of the following supplements: distilled water, camel whey proteins (CWP), bovine whey proteins, poly (d, l-lactide-co-glycolide) (PLGA)- chitosan-loaded with camel whey protein microparticles (CMP), PLGA-chitosan loaded with bovine whey protein microparticles (BMP), and PLGA-chitosan nanoparticles were administered as prophylactic supplements to AFB1-intoxicated groups. The AFB-treated group showed significantly higher hepatic levels of oxidative stress and lower levels of antioxidants. In the aflatoxicated group, atrophy of the splenic lymphatic nodules and disfigurement in the organisation with an apparent decrease in the thickness of the cortex in the thymus were observed, as well as a decrease in splenic and thymic CD4+T and CD8+T lymphocytes. Moreover, CXCL12 levels were downregulated, whereas tumour necrosis factor-alpha, nuclear factor kappa B, and cleaved caspase-3 levels were upregulated. CWP, BMP, and CMP supplements markedly decreased oxidative stress, inflammation, and apoptosis, as well as significantly raised CXCL12, CD4+T, and CD8+T cells.ConclusionsThe CWP, BMP, and CMP supplements rescue the liver and immune tissues from the toxic effects of AFB through their antioxidant, antiapoptotic, anti-inflammatory, and chemotaxis-enhancing roles.

Spleen-preserving pancreatectomy with removal of splenic vessels: impact on splenic parenchyma ?

BackgroundWhile outcomes after spleen-preserving distal pancreatectomy (SP-DP) have been widely reported, impacts on splenic parenchyma have not been well studied. This study aimed to compare postoperative outcomes, particularly spleen-related outcomes, by assessing splenic imaging after SP-DP with or without splenic vessels removal.MethodsData for all patients who underwent SP-DP with splenic vessels removal (Warshaw technique, WDP) or preservation (Kimura technique, KDP) between 2010 and 2022 in two tertiary centres were retrospectively analysed. Splenic ischemia and volume at early/late imaging and postoperative outcomes were reviewed.ResultsEighty-seven patients were included, 51 in the WDP and 36 in the KDP groups. Median Charlson’s Comorbidity Index was significantly higher in the WDP group compared with the KDP group. Postoperative morbidity was similar between groups. There was more splenic ischemia at early imaging in the WDP group compared to the KDP group (55% vs. 14%, p = 0.018), especially severe ischemia (23% vs. 0%). Partial splenic atrophy was observed in 29% and 0% in the WDP and KDP groups, respectively (p = 0.002); no complete splenic atrophy was observed. Platelet levels at POD 1, 2 and 6 were significantly higher in the WDP group compared to KDP group. At univariate analysis, age, Charlson Comorbidity Index, platelet levels at POD 6, and early splenic infarction were prognostic factors for development of splenic atrophy. No episodes of overwhelming post-splenectomy infection or secondary splenectomy were recorded after a median follow-up of 9 and 11 months in the WDP and KDP groups, respectively.ConclusionsSplenic ischemia appeared in one-half of patients undergoing SP-DP with splenic vessels removal at early imaging, and partial splenic atrophy in almost 30% at late imaging, without clinical impact or complete splenic atrophy. Age, Charlson Comorbidity Index, platelet levels at POD 6, and early splenic infarction could help to predict the occurrence of splenic atrophy.

Cases of pediatric intra-abdominal solid organ injury induced by blunt trauma experienced over a 15-year period at two centers in Japan

ObjectiveThe present study attempts to clarify the clinical features of pediatric intra-abdominal solid organ injury at two institutions.MethodsThe injured organ, patient age, sex, injury grade, imaging findings, intervention, length of...

PATHOLOGICAL FINDINGS IN AN OLD FEMALE GIANT PANDA – A CASE REPORT

The giant panda (Ailuropoda melanoleuca) is one of the most endangered species in the world. Climate change and susceptibility to disease are two of the greatest threats to this species. We performed a necropsy and histopathological examination of the organs of an old panda and investigated the pathogenesis associated with death. Necropsy and histopathological observation revealed some typical age-related lesions, such as cataract, atherosclerosis, renal insufficiency and splenic atrophy. We also confirmed hepatic lesions associated with parasitic infection. Overall, our observations revealed that the predominant cause of mortality in this panda was multiple organ dysfunction (MOD). Key words: aged; giant panda; multiple organ dysfunction; pathology

Splenomegaly versus pathological lung volume during COVID-19 infection with or without cytokine storm; a linear regression analysis using CT volumetry

BackgroundDue to the paucity of scientific evidence, it is unclear among pulmonologists and physicians in critical care units if and when splenomegaly in novel coronavirus disease (2019) (COVID-19) patients is worrisome. This study aims to evaluate the significance of splenic volume during COVID-19 infection with or without cytokine storm and correlates splenic volume to the volume of pathological lung changes through linear regression analysis.ResultsA retrospective study collected 509 polymerase chain reaction proved COVID-19 patients (399 males, 110 females; mean age 48 years, age range 24–78 years) between June and November 2021, without a history of splenic pathology. A control group of age and sex-matched 509 healthy subjects was used and analyzed according to the splenic volume. Five consulting radiologists evaluated initial and follow-up computed tomography (CT) examinations using lung CT volumetry and splenic volume calculation in consensus. Three consulting pulmonologists correlated the severity of clinical and laboratory findings, including oxygen requirements and interleukin-6 (IL-6) levels. The T test results for comparison between the COVID-19 patients and the healthy subjects control group regarding the splenic volume were significant (T value was − 4.731452 and p value was 0.00002). There was no significant correlation between the severity of the disease and normal-sized spleen (26% of patients, p = 0.916) or splenomegaly (24% of patients, p = 0.579). On the other hand, all patients with a small spleen or progressive splenomegaly during serial follow-up imaging had clinically severe disease with a statistically significant correlation (p = 0.017 and 0.003, respectively). Ninety-seven percent of patients with clinically mild disease and splenomegaly had 0–20% lung involvement (CT-severity score 1) while all patients with clinically severe disease and splenomegaly had 27–73% lung involvement (CT-severity score 2 and 3) (r = 0.305, p = 0.030).ConclusionsSplenomegaly is a non-specific sign that may be found during mild and severe COVID-19 infection, it was not statistically correlated with the clinical severity and a weak positive relationship was found between the splenic size and the CT-severity score of the pathological lung volume. On the other hand, the presence of splenic atrophy or progressive splenomegaly was correlated with severe COVID-19 presentation and “cytokine storm”. Therefore, the splenic volume changes should not be overlooked in COVID-19 serial CT examinations, particularly in severe or critically ill patients with cytokine storms.

Astragaloside IV ameliorates peripheral immunosuppression induced by cerebral ischemia through inhibiting HPA axis

Post-ischemic peripheral immunosuppression increases vulnerability to infection which is a common complication and worsens outcome in ischemic stroke patients. Hypothalamic-pituitary-adrenal (HPA) axis plays a key role in post-ischemic immunosuppression. Astragaloside IV (ASIV), isolated from Astragalus membranaceus, possesses immunomodulatory and neuroprotective effects against cerebral ischemic injury. This study investigated the effect of ASIV on cerebral ischemia-induced peripheral immunosuppression and the underlying mechanism in a mouse model of middle cerebral artery occlusion (MCAO). Our results showed that ASIV significantly prevented the atrophy of spleen and the reduction of splenic cell count. Meanwhile, ASIV preserved cell numbers of splenic NK, T, and B cells in the spleen. ASIV also suppressed apoptosis of splenic cells and preserved their proliferation ability. In addition, ASIV robustly reduced the mRNA expression of TNF-α, IL-1β, IL-6 and CRH in the hypothalamus, as well as the enlargement of adrenal gland and the increase of corticosterone in blood, indicating the inhibition of HPA axis by ASIV. Furthermore, ASIV did not enhance the effect of HPA inhibition on reducing splenic atrophy and preserving splenic NK, T, and B cell numbers in MCAO mice. Of note, ASIV did not attenuate splenic cell apoptosis induced by prednisolone, suggesting that ASIV may ameliorate splenic apoptosis through reducing peripheral glucocorticoid level. Our findings demonstrate that ASIV ameliorates post-ischemic peripheral immunosuppression through inhibiting the activation of HPA axis and targeting HPA activation to ameliorate peripheral immunosuppression may be a promising strategy to improve clinical outcomes of ischemic stroke.

Autosplenectomy

A 30-year-old woman manifested fatigue and high fever. She was diagnosed with antiphospholipid antibodies positive-systemic lupus erythematosus (SLE), but she had never demonstrated any serious organ involvements including nephritis and thrombosis, and had never received immunosuppressants. Physical examination demonstrated costovertebral tenderness and pyuria, and she was treated with cefaclor for uncomplicated pyelonephritis. After ten days, she visited our emergency room with the same manifestations and was improved equally by cefaclor. However, just after ten days, she was raced to our hospital again with a shock state. She demonstrated costovertebral tenderness and pyuria with an elevated level of procalcitonin. She was diagnosed with urosepsis despite undetectable culture-proved bacteria, and was treated with meropenem and vancomycin, achieving a clinical improvement. Computed tomography revealed calcified splenic atrophy which was not observed a decade ago (Fig. 1). We diagnosed the patient with functional asplenia by autosplenectomy. She was finally recovered with antibiotics and received vaccination for pneumococcus and Haemophilus influenzae type b to prevent further life-threating infection. Although we do not supply emergency antibiotics, she is still infection-free.

Peripheral Immune Dysfunction: A Problem of Central Importance after Spinal Cord Injury.

Simple SummarySpinal cord injury can result in an increased vulnerability to infections, but until recently the biological mechanisms behind this observation were not well defined. Immunosuppression and concurrent sustained peripheral inflammation after spinal cord injury have been observed in preclinical and clinical studies, now termed spinal cord injury-induced immune depression syndrome. Recent research indicates a key instigator of this immune dysfunction is altered sympathetic input to lymphoid organs, such as the spleen, resulting in a wide array of secondary effects that can, in turn, exacerbate immune pathology. In this review, we discuss what we know about immune dysfunction after spinal cord injury, why it occurs, and how we might treat it.Individuals with spinal cord injuries (SCI) exhibit increased susceptibility to infection, with pneumonia consistently ranking as a leading cause of death. Despite this statistic, chronic inflammation and concurrent immune suppression have only recently begun to be explored mechanistically. Investigators have now identified numerous changes that occur in the peripheral immune system post-SCI, including splenic atrophy, reduced circulating lymphocytes, and impaired lymphocyte function. These effects stem from maladaptive changes in the spinal cord after injury, including plasticity within the spinal sympathetic reflex circuit that results in exaggerated sympathetic output in response to peripheral stimulation below injury level. Such pathological activity is particularly evident after a severe high-level injury above thoracic spinal cord segment 6, greatly increasing the risk of the development of sympathetic hyperreflexia and subsequent disrupted regulation of lymphoid organs. Encouragingly, studies have presented evidence for promising therapies, such as modulation of neuroimmune activity, to improve regulation of peripheral immune function. In this review, we summarize recent publications examining (1) how various immune functions and populations are affected, (2) mechanisms behind SCI-induced immune dysfunction, and (3) potential interventions to improve SCI individuals’ immunological function to strengthen resistance to potentially deadly infections.

COVID-19: a Disease with a Potpourri of Histopathologic Findings-a Literature Review and Comparison to the Closely Related SARS and MERS.

Since the coronavirus disease 2019 (COVID-19) pandemic has hit the entire world, there is ample knowledge regarding its clinical course and prognostic biomarkers. Still, the pathophysiology of COVID-19 is poorly understood. Since the first guidelines published in February 2020 for autopsy of both confirmed and suspected COVID-19 cases, there has been an increasing number of autopsies and literature reporting histopathological findings. However, our knowledge about the immunological response of various organ systems to the virus, as well as response patterns, is inadequate but is essential to understand and initiate timely and targeted antiviral, anti-inflammatory, or anticoagulative therapy. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is primarily considered a respiratory virus, current evidence shows that it causes life-threatening complications in almost all organ systems including the heart, brain, kidney, spleen, liver, and eyes. Hence, in this article, we reviewed the published case reports and case series in order to increase our understanding of COVID-19 pathophysiology. The main histopathological findings of the lungs include diffuse alveolar damage with activated type II pneumocytes, fibroblasts, protein-rich exudate, and hyaline membranes. Other significant histopathological findings include cardiomegaly, right ventricular dilation, splenic pulp atrophy, kidneys with severe podocytopathy, and collapsing glomerulopathy, and the brain showed hypoxic changes in the cerebellum and cerebrum. Furthermore, in this review, we also explained different pathological findings of SARS-CoV and MERS and compared them to SARS-CoV-2. This comprehensive review will improve our understanding of COVID-19 pathophysiology and various disease stages, hence promoting the application of targeted therapy.

Evaluation of chickens infected with a recombinant virulent NDV clone expressing chicken IL4

BackgroundThere is evidence that chicken IL4 (chIL4) functions similarly to its mammalian analogue by enhancing type 2 T helper (Th2) humoral immunity and promoting protection against parasitic infections; however, no studies have been performed to assess the effect of chIL4 on the pathogenesis of Newcastle disease (ND). To assess the role of chIL4 in velogenic NDV pathogenesis we created a vNDV infectious clone expressing chIL4. We hypothesized that co-expression of chIL4 during virus replication would result in decreased inflammation caused by the Th1 response and thereby increasing survival to challenge with vNDV. MethodsTo evaluate the effect of chIL4 during early infection with velogenic Newcastle disease virus (NDV) in chickens, recombinant NDV clones expressing either chIL4 (rZJ1-IL4) or a control expressing green fluorescent protein (rZJ1-GFP) were created by inserting an expression cassette in an intergenic region of the NDV genome. The pathogenesis of rZJ1-IL4 was assessed in 4-week-old specific pathogen free chickens. The extent of virus replication was evaluated by titration in mucosal secretions and immunohistochemistry in multiple tissues. Expression of chIL4 was confirmed in tissues using immunohistochemistry. ResultsInfection of birds with the rZJ1-IL4 resulted in successful viral replication in vivo and in vitro and generation of the chIL4 in tissues. All birds were clinically normal 2 DPI, with one bird in each group showing conjunctival swelling and enlarged spleens grossly. At 5 DPI, moderate or severe depression was observed in birds infected with rZJ1-GFP or rZJ1-IL4, respectively. Neurological signs and thymic atrophy were observed in one bird infected with rZJ1-IL4. Grossly, conjunctival swelling, mottled spleen and proventricular hemorrhages were observed at 5 DPI in one bird from each group. At 5 DPI, severe necrosis in the spleen, bursa and cecal tonsils were observed in birds infected with rZJ1-GFP, along with minimal evidence of chIL4 expression. In contrast, splenic atrophy, and moderate necrosis in the bursa and cecal tonsils were observed in birds infected with rZJ1-IL4. In addition, chIL4 signal was found in all tissues of rZJ1-IL4 birds at 5DPI. ConclusionsThe production of chIL4 by a recombinant NDV strain resulted in the activation of the positive feedback loop associated with IL4 production. Insertion of chIL4 into NDV may decrease necrosis to lymphoid organs while increasing the severity of lymphoid atrophy and prolonged disease. However, with a low number of birds it is difficult to determine whether these results are significant to disease outcome.

Thrombopoietin-Receptor Agonist Romiplostim Attenuates Hematopoietic System Injury By Promoting the Recovery of Early Hematopoiesis and the Hematopoietic Environment in the Bone Marrow and Spleen of Mice Exposed to Lethal Total Body γ-Irradiation

High-dose radiation exposure, usually caused by radiological accidents or nuclear disasters, can cause lead to acute radiation syndrome (ARS), which is a life-threatening condition. The International Atomic Energy Agency recommends the use of a combination of various cytokines or bone marrow (BM) transplant for treating high-dose exposure, depending on the degree of radiation exposure and ARS. Therefore, drugs that respond quickly, which can be used to treat a large number of radiation-associated casualties represent a good treatment option. However, certain hematopoietic cytokines, such as the granulocyte macrophage-colony stimulating factor and interleukin-3, which are effective against hematopoietic dysfunction and have been used in previous accidents, are not approved as pharmaceutical drugs in Japan. Although granulocyte-colony stimulating factor is only approved domestically for the treatment of ARS, it has been found that a single dose is insufficient to improve the survival rate of individuals exposed to lethal ionizing radiation. We have previously demonstrated that an effective protocol of drug therapy, based on approved pharmaceutical drugs in Japan, is the administration of romiplostim (RP), a thrombopoietin-receptor myeloproliferative leukemia virus proto-oncogene (c-mpl) agonist, at a dose of 50 μg/kg body weight/day for 3 consecutive days. This regimen achieved 100% survival at 30-days in 8-weekold female C57BL/6JJcl mice when administered immediately following exposure to a lethal dose (7 Gy) of 137Cs γ-rays. In the present study, we assessed the mechanisms by which RP ameliorated radiation-induced hematopoietic damage in mice after lethal total body γ-irradiation (TBI) by focusing on the recovery and regeneration of BM and spleen. Mice were divided into 4 groups: control group, RP group, TBI group, and TBI + RP group. On days 4, 10, 18, and 30 after TBI, morphological and histological changes of BM and spleen and antigen expression changes of cells isolated from both tissues were assessed. While the body weight of animals in the TBI group decreased significantly by day 18 compared to controls, that of mice receiving RP remained comparable. Similarly, on day 18, leukocyte, platelet, erythrocyte, and hemoglobin levels were the lowest in TBI mice. Conversely, these values markedly recovered in the TBI + RP group. Splenic atrophy was assessed by weighing the spleen after TBI, and it was observed that while the spleen contracted significantly following TBI, mice in the RP + TBI group showed a 3 to 4-fold increase in spleen weight and in cell numbers on day 18. Endogenous colonies, which are indicators of hematopoiesis, were also observed in the spleen after day 10. In addition, TBI induced severe myelosuppression that resulted in the loss of hematopoietic function. On day 18 after irradiation, while the BM exhibited obvious myeloablation, that of the RP + TBI treated mice was comparable to controls. Further, the number of BM cells in mice RP + TBI treated mice continued to increase till 30 days after TBI but did not attain pre-TBI levels. Additionally, analysis of cell-surface antigen expression in BM and spleen cells showed that, compared to the TBI group, RP administration promoted the recovery of hematopoietic stem cells, multipotent progenitor cells, and common lymphocyte precursor cells. In particular, a dramatic increase in the number of common myelo-erythroid progenitors were observed in the spleen on day 18 in the TBI + RP treated mice, accompanied with the disappearance of splenic cyst structures and acceleration of megakaryocyte hematopoiesis. These results suggest that thrombopoietin-receptor agonist RP promotes the recovery of early hematopoiesis and hematopoietic environment in both BM and spleen of lethal TBI mice, especially the promoting megakaryocytopoiesis in the spleen. As a result, treating lethally-irradiated mice with RP results in 100% survival. DisclosuresNo relevant conflicts of interest to declare.

Cystic Lesions of Celiac Disease

Cystic Lesions of Celiac Disease

Scalp Swelling and Headache in a 12-year-old Boy

1. Kathryn Westphal, MD* 2. Respicius Bakalemwa, MD† 3. Elizabeth Groothuis, MD, MPH* 1. *Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 2. †Department of Pediatrics, Bugando Medical Centre, Mwanza, Tanzania A 12-year-old boy with sickle cell disease (SCD) is admitted to a hospital in Mwanza, Tanzania, with acute onset of periorbital and scalp swelling. Associated symptoms include fever, headache, difficulty breathing, and back pain. Because resources in sub-Saharan Africa are limited, access to comprehensive care for patients with SCD is variable. The general principles of management focus on early diagnosis, parental education, prevention of infection with vaccinations and prophylactic medications, prompt treatment of infection and pain, the use of hydroxyurea for stroke prevention, and blood transfusions for life-threatening anemia. This patient has a known diagnosis of SCD but has infrequent pain episodes and no previous transfusions. He is not receiving hydroxyurea or prophylaxis against bacterial infections or malaria. He has no history of stroke and no known head trauma. On presentation he is afebrile and his heart rate is 120 beats/min, respiratory rate is 40 breaths/min, and blood pressure is 105/75 mm Hg. His oxygen saturation is 92% in room air. Physical examination is significant for pallor, periorbital edema, scalp edema, dyspnea without adventitious lung sounds, and splenomegaly with diffuse abdominal tenderness. His scalp edema is fluctuant and extends posteriorly from the periorbital region, encompassing the entire scalp. Swelling is most prominent in the frontal and parietal areas. The overlying skin is nonerythematous and nontender but is warm to the touch. His neurologic examination has no focal findings, although generally he appears tired. Initial laboratory results demonstrate a white blood cell count of 84,000/μL (84×109/L) with a lymphocytic predominance (57%), a hemoglobin level of …