Severe Infiltration Research Articles

Persistent spontaneous pneumomediastinum in a dog with pulmonary fibrosis

AbstractA 5‐year‐old, 5.8‐kg, neutered, male, mix‐breed dog was presented to the emergency service of a university hospital for assessment of respiratory distress. Thoracic radiographs identified a moderate pneumomediastinum, mild cervical subcutaneous emphysema and moderate bilateral diffuse bronchial and unstructured interstitial pulmonary patterns. The dog had a 6‐week long history of progressive respiratory signs before presentation, culminating in acute respiratory embarrassment in the absence of a precipitating event. Three sets of radiographs were performed before presentation, which demonstrated a persistent pneumomediastinum and progressively severe pulmonary infiltrates. The dog was humanely euthanased after 24 hours of hospitalised care, with a diagnosis of interstitial pulmonary fibrosis made at postmortem examination. Spontaneous pneumomediastinum is usually an acute condition, which resolves within a few weeks of diagnosis and does not recur. Persistent spontaneous pneumomediastinum has been described in people previously, and is a rare potential sequela to severe chronic pulmonary disease in dogs.

SARS-CoV-2 Spike Proteins and Cell-Cell Communication Induce P-Selectin and Markers of Endothelial Injury, NETosis, and Inflammation in Human Lung Microvascular Endothelial Cells and Neutrophils: Implications for the Pathogenesis of COVID-19 Coagulopathy.

COVID-19 progression often involves severe lung injury, inflammation, coagulopathy, and leukocyte infiltration into pulmonary tissues. The pathogenesis of these complications is unknown. Because vascular endothelium and neutrophils express angiotensin-converting enzyme-2 and spike (S)-proteins, which are present in bodily fluids and tissues of SARS-CoV-2-infected patients, we investigated the effect of S-proteins and cell-cell communication on human lung microvascular endothelial cells and neutrophils expression of P-selectin, markers of coagulopathy, NETosis, and inflammation. Exposure of endothelial cells or neutrophils to S-proteins and endothelial-neutrophils co-culture induced P-selectin transcription and expression, significantly increased expression/secretion of IL-6, von Willebrand factor (vWF, pro-coagulant), and citrullinated histone H3 (cit-H3, NETosis marker). Compared to the SARS-CoV-2 Wuhan variant, Delta variant S-proteins induced 1.4-15-fold higher P-selectin and higher IL-6 and vWF. Recombinant tissue factor pathway inhibitor (rTFPI), 5,5'-dithio-bis-(2-nitrobenzoic acid) (thiol blocker), and thrombomodulin (anticoagulant) blocked S-protein-induced vWF, IL-6, and cit-H3. This suggests that following SARS-CoV-2 contact with the pulmonary endothelium or neutrophils and endothelial-neutrophil interactions, S-proteins increase adhesion molecules, induce endothelial injury, inflammation, NETosis and coagulopathy via the tissue factor pathway, mechanisms involving functional thiol groups, and/or the fibrinolysis system. Using rTFPI, effectors of the fibrinolysis system and/or thiol-based drugs could be viable therapeutic strategies against SARS-CoV-2-induced endothelial injury, inflammation, NETosis, and coagulopathy.

The effect of fatty infiltration, revision surgery, and sex on lumbar multifidus passive mechanical properties.

Previous research has demonstrated increased stiffness in the multifidus muscle compared to other paraspinal muscles at the fiber bundle level. We aimed to compare single fiber and fiber bundle passive mechanical properties of multifidus muscle: (1) in 40 patients undergoing primary versus revision surgery and (2) in muscle with mild versus severe fatty infiltration. The degree of muscle fatty infiltration was graded using the patients' spine magnetic resonance images. Average single fiber and fiber bundle passive mechanical properties across three tests were compared between primary (N = 30) and revision (N = 10) surgery status, between mild and severe fatty infiltration levels, between sexes, and with age from passive stress-strain tests of excised multifidus muscle intraoperative biopsies. At the single fiber level, elastic modulus was unaffected by degree of fatty infiltration or surgery status. Female sex (p = 0.001) and younger age (p = 0.04) were associated with lower multifidus fiber elastic modulus. At the fiber bundle level, which includes connective tissue around fibers, severe fatty infiltration (p = 0.01) and younger age (p = 0.06) were associated with lower elastic modulus. Primary surgery also demonstrated a moderate, but non-significant effect for lower elastic modulus (p = 0.10). Our results demonstrate that female sex is the primary driver for reduced single fiber elastic modulus of the multifidus, while severity of fatty infiltration is the primary driver for reduced elastic modulus at the level of the fiber bundle in individuals with lumbar spine pathology.

Microglia play an important role in PRV infection-induced immune responses of the central nervous system

Pseudorabies virus (PRV) can infect multiple hosts and lead to fatal encephalitis. There is a significant increase in the number of microglia in the brain of animals infected with PRV. However, whether and how microglia contribute to central nervous system damage in PRV infection remain unknown. In the present study, we elucidated that PRV infection can cause more severe inflammatory cell infiltration, thicker and more numerous vessel sleeve walls, and more severe inflammatory responses in the brains of natural hosts (pigs) than in those of nonnatural hosts (mice). In a mice infection model, activated microglia restricted viral replication in the early stage of infection. Acute neuroinflammation caused by microglia hyperactivation at late-stage of infection. Furthermore, in vitro experiments revealed that microglia restricted viral replication and decreased viral infectivity. This may be associated with the phagocytic ability of microglia because we observed a significant increase in the expression of the membrane receptor TREM2 in microglia, which is closely related to phagocytosis, we observed that depletion of microglia exacerbated neurological symptoms, blood–brain barrier breakdown, and peripheral lymphocyte infiltration. Taken together, we revealed the dual role of microglia in protecting the host and neurons from PRV infection.

Delineation of the phenotypes and genotypes of facial infiltrating lipomatosis associated with PIK3CA mutations

BackgroundFacial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by unilateral facial swelling, for which surgery is the prevailing therapeutic option. Several studies have shown that the development of FIL is closely associated with PIK3CA mutations. This study aimed to further identify rare clinical features and underlying molecular variants in patients with FIL.ResultsEighteen patients were included in this study, and all patients presented with infiltrating adipose tissues confirmed by magnetic resonance imaging. Macrodactyly, polydactyly, hemimegalencephaly and hemihyperplasia were also observed in patients with FIL. In total, eight different PIK3CA mutations were detected in tissues obtained from sixteen patients, including the missense mutations p.His1047Arg (n = 4), p.Cys420Arg (n = 2), p.Glu453Lys (n = 2), p.Glu542Lys (n = 2), p.Glu418Lys (n = 1), p.Glu545Lys (n = 1), and p.His1047Tyr (n = 1) and the deletion mutation p.Glu110del (n = 3). Furthermore, the GNAQ mutation p.Arg183Gln was detected in the epidermal nevus tissue of one patient. Imaging revealed that several patients carrying hotspot mutations had more severe adipose infiltration and skeletal deformities.ConclusionsThe abundant clinical presentations and genetic profiles of FIL make it difficult to treat. PIK3CA mutations drive the pathogenesis of FIL, and PIK3CA hotspot mutations may lead to more extensive infiltration of lipomatosis. Understanding the molecular variant profile of FIL will facilitate the application of novel PI3K-targeted inhibitors.

Comprehensive pathological and genetic investigation of three young adult myotonic dystrophy type 1 patients with sudden unexpected death.

The mechanism and pathological substrate of arrhythmogenic events in dystrophic myopathy type 1 (DM1) have not been fully established, especially for patients without progression of motor and/or cardiac disability. Therefore, we aimed to clarify the pathological appearance and genetic factors, other than CTG repeats in DMPK, associated with sudden cardiac death in patients with DM1. A pathological investigation including the cardiac conduction system in the heart and whole-exome sequencing was conducted for three young adults (Patient 1; 25-year-old female, Patient 2; 35-year-old female, Patient 3; 18-year-old male) with DM1 who suffered sudden death. Only Patient 1 showed abnormal electrocardiogram findings before death. The pathological investigation showed severe fibrosis of the atrioventricular conduction system in Patient 1 and severe fatty infiltration in the right ventricle in Patient 2. Several minimal necrotic/inflammatory foci were found in both patients. Patient 3 showed no significant pathological findings. A genetic investigation showed CORIN_p.W813* and MYH2_p. R793* in Patient 1, KCNH2_p. V794D and PLEC_p. A4147T in Patient 2, and SCN5A_p.E428K and SCN3B_ p.V145L in Patient 3 as highly possible pathogenic variants. The present study showed varied heart morphology in young adults with DM1 and sudden death. Synergistic effects of various genetic factors other than CTG repeats may increase the risk of sudden cardiac death in DM1 patients, even if signs of cardiac and skeletal muscle involvement are mild. Comprehensive genetic investigations, other than CTG repeat assessment, may be useful to estimate the risk of sudden cardiac death in DM1 patients.

Gitar balıklarında (Rhinobatos rhinobatos) Vibrio hepatarius kaynaklı subakut enteritik septisemi

Common guitarfish (Rhinobatos rhinobatos) are an endangered species and are placed on the red list of “Critically Endangered, CR” by the International Union for Conservation of Nature. Guitarfish are kept in captivity and are protected in public aquaria globally, but there is limited information about the diseases for this species. In this research, mortalities (14%) observed in common guitarfish in a public aquarium are reported. Severe hemorrhagic lesions on the ventral body side and reduced feed intake were observed in the affected animals. Two guitarfish were referred for necropsy, microbiological and histopathological examination. Macroscopic findings included severe ecchymotic hemorrhages in the ventral body, bloating of the gastrointestinal tract due to invasive mass, and hyperemia of the colon vessels and obstruction of the colon lumen. Histopathological examination revealed degenerations and necrosis in the liver, desquamation of intestinal villi, severe mononuclear cell infiltration and fibrosis in distal intestine, severe bacterial aggregates in different organs, pancreatitis, vasculitis, and filamentous bacteria-like structures. Vibrio hepatarius was isolated and identified with multilocus sequence analysis (MLSA); multilocus sequence typing (MLST) revealed that the agent belonged to a novel sequence type, 247. After the first description of V. hepatarius in wild healthy adults of Whiteleg shrimp (Litopenaeus vannamei) from Ecuador, this is the first report of deaths due to V. hepatarius observed in common guitarfish kept in captivity in a public aquarium.

Blockade of P2X7 receptor-mediated purinergic signaling with A438079 protects against LPS-induced liver injury in rats.

The study aimed to investigate the hepatoprotective effects of purinergic receptor (P2X7R) antagonism by A438079 in liver damage. An experimental model of inflammation was performed by intraperitoneal (i.p.) lipopolysaccharide (LPS) administration in the rat. The groups were Control, A438079, dimethyl sulfoxide (DMSO), LPS, LPS + DMSO, and LPS + A438079. Following LPS (8 mg/kg) injection, A438079 (15 mg/kg) and DMSO (0.1 mL) were administrated (i.p) in the study groups. The blood and the liver tissues were removed for histological, biochemical, and western blot analyses. In the biochemical analysis, serum aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, the tissue glutathione (GSH) level, and superoxide dismutase (SOD) activity dramatically decreased and malondialdehyde (MDA) level increased in the LPS and LPS + DMSO groups compared to the LPS + A438079 group. In the histological analysis, severe sinusoidal dilatation, necrotic hepatocytes, and inflammatory cell infiltration were observed in the LPS and LPS + DMSO groups while these effects were lessened in the LPS + A438079 group. The relative protein expression levels of P2X7R, Nf-kB-p65, IL-6, and Caspase-3 were significantly higher in the LPS and the LPS + DMSO groups than in the LPS + A438079 group. On the other hand, these protein expressions were considerably lower in the Control, A438079, and DMSO groups compared to the LPS + A438079 group. In addition, Bcl-2 protein expression was significantly lower in the LPS and the LPS + DMSO groups and higher in the LPS + A438079 group compared to the other groups. The protective effect of A438079 against LPS-induced hepatic inflammation may be related to P2X7R antagonism, inflammatory mediators, and apoptotic cell death.

Huoxue Jiedu Recipe represses mitochondrial fission to alleviate submandibular gland inflammation in Sjögren's syndrome.

Sjögren's syndrome (SS) is the second most common autoimmune rheumatism. Huoxue Jiedu Recipe (HXJDR) is a kind of traditional Chinese medicine with a variety of pharmacological functions; however, its biological function in SS has not been studied yet. Peripheral blood mononuclear cells (PBMCs) and serum samples were isolated from healthy controls and patients with SS. NOD/Ltj mice were used for developing the SS mouse model. The levels of inflammatory cytokines and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related markers as well as dynamin-related protein 1 (Drp1) were determined by ELISA, quantitative real-time PCR, and western blot analysis, respectively. Hematoxylin and eosin and TUNEL staining detected the pathological damage. A transmission electron microscope was used to observe the mitochondrial microstructure. Inflammatory cytokines IL-18, IL-1β, B-cell activating factor (BAFF), BAFF-receptor (BAFF-R), IL-6, and TNF-α in serum samples and NLRP3 inflammasome-related makers (NLRP3, cysteinyl aspartate-specific proteinase 1 [caspase-1], apoptosis-associated speck-like protein containing a caspase-1 recruitment domain [ASC], IL-1β) in PBMCs were greatly upregulated in patients with SS. Furthermore, cytoplasmic phosphorylation of Drp1 and mitochondrial Drp1 level were significantly increased in PBMCs, while mitochondrial swelling and fuzzy inner ridge were observed in PBMCs of patients with SS, suggesting increased mitochondrial fission. Compared with control mice, SS mice showed decreased salivary flow rate, increased submandibular gland index, and more severe inflammatory infiltration and damage as well as mitochondrial fission in submandibular gland tissues. After HXJDR administration, these effects were significantly reversed. HXJDR treatment could alleviate the inflammatory infiltration and pathological damage in submandibular glands of SS mice by inhibiting Drp-1-dependent mitochondrial fission.

Histopathology and antibody responses describe the seasonal pattern of dicrocoeliosis in small ruminants in the Himalayan ranges of Pakistan

In some parts of the world, Dicrocoelium spp. lancet flukes cause significant production loss in pastoral livestock, and accurate diagnosis of infection is important. The aims of the present study were to describe the histopathology and to investigate the transmission patterns of Dicrocoelium amongst ten sheep and goat farms in Khyber Pakhtunkhwa and Gilgit Baltistan, Pakistan. The liver histology and indirect enzyme-linked immunosorbent assay (ELISA) analyses followed standard procedures. The liver histopathology showed intensive tissue destruction and biliary hyperplasia associated with presence of adult flukes, severe inflammatory cell infiltration, congestion of blood vessels, damaged hepatocytes, and sinusoids in the infected areas. The time of onset of infection was investigated by ELISA detection of antibodies in sheep (n = 164) and goats (n = 152). Colostral transfer of Dicrocoelium antibodies from seropositive mothers was detected in sheep and goats up to 16 weeks of age. In both sheep and goats, the estimated time of infection differed between farms and years. Infection was seen in both sheep flocks and goat herds, with high variation between flocks and herds, and the highest infection rate in lambs. Dicrocoelium infection was most prevalent in sheep and goats in September (n = 84) and August (n = 63) respectively. This study concluded Dicrocoelium causes severe inflammation and necrosis of liver tissues in sheep and goats. Colostral transfer of antibodies can be detected up to about ten weeks of age. Higher infection rates are observed during August and September in sheep than in goats, putatively due to effects of different grazing and browsing behaviors on the ingestion of ants. The results will aid in the development of effective disease control strategies to ensure optimal growth and productivity of sheep and goats.

#4359 LOSS OF GASDERMIN D LEADS TO AN EXACERBATION OF KIDNEY DAMAGE IN NEPHROCALCINOSIS-RELATED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Gasdermin D (GSDMD) is a membrane-targeting and pore-forming protein that is primarily expressed in immune cells. In the proinflammatory cell death process known as pyroptosis, cleaved GSDMD plays a crucial role through cell membrane pore formation, leading to the release of proinflammatory cytokines and membrane rapture. Despite this, the majority of GSDMD's other physiological functions remain to be elucidated. Previous reports have implicated GSDMD in the pathogenesis of kidney disease, utilizing some acute kidney injury (AKI) animal models and a few chronic kidney disease (CKD) animal models. However, it remains uncertain if GSDMD contributes to the pathogenesis of nephrocalcinosis-related CKD. Therefore, this study aimed to investigate the role of GSDMD in in this context. Method In our study, 8-week-old GSDMD-knockout (KO) mice and wildtype (WT) mice received an oxalate-rich diet (50 μmol/g sodium oxalate) for three weeks. All mice were sacrificed on day 21 and kidneys were harvested after the sacrifice. Plasma and urine samples were collected at different time points before the sacrifice. The glomerular filtration rate (GFR) was measured on day 0 and day 20 to assess kidney excretion function. Histological analysis was performed using Periodic Acid-Schiff (PAS) staining to assess renal injury, Sirius Red staining to check renal fibrosis, Pizzolato staining to evaluate calcium crystal deposition, F4/80 staining to evaluate the infiltration of macrophages, TUNEL staining to check for cell death, RIPK3 and phosphorylated MLKL (pMLKL) staining to detecting necroptosis. And GSDMD staining was also performed to examine the expression of GSDMD in the kidney. Results Pizzolato staining showed no differences in calcium crystal deposition between WT mice and KO mice. GFR was decreased in both WT mice and KO mice after the oxalate-rich diet (day 0 WT: 199.5±40.1 μl/min vs KO 175.0±44.8 μl/min, day 20 WT: 156.5±37.9 μl/min vs KO: 73.0±48.1 μl/min), and ΔGFR was much greater in KO mice (WT: −22.4±26.5% vs KO: −59.4±19.3%). The level of blood urea nitrogen was significantly higher in KO mice (WT: 41.9±3.90 mg/dl vs KO: 58.7±22.5 mg/dl) in accordance with the result of the GFR. PAS staining revealed more severe kidney injury in KO mice, and Sirius Red staining indicated a higher degree of renal fibrosis in KO mice. Furthermore, F4/80 staining showed greater infiltration of macrophages in KO mice. Although TUNEL staining showed no significant differences in positive cells between WT and KO, KO mice showed greater positive areas implicating more necroptosis in RIPK3 and pMLKL staining. GSDMD staining revealed that injured tubular cells during the chronic phase express GSDMD (Fig. 1). In in vitro experiments, we evaluated the functionality of macrophages such as phagocytic ability and migratory ability using bone marrow-derived macrophages (BMDMs), but we didn't find any significant disparities between BMDMs from WT mice and those from KO mice. Conclusion Genetic deletion of GSDMD resulted in more severe kidney injury, macrophage infiltration and fibrosis in mice with nephrocalcinosis-related CKD. Our results suggest a potential role for pyroptosis, especially GSDMD, in contributing to renal tubular cell necroptosis, a process downstream of calcium-oxalate crystal formation and deposition, in the progression of nephrocalcinosis-related CKD, similar to previous reports in mouse models of AKI.

Antimicrobial and Anti-inflammatory Activity of Thespesia populnea Mediated Nanoparticles in Murine Mastitis Model

Background: Bovine mastitis is a common inflammatory disease where bacterial resistance to antibiotics is a major concern in its treatment. Nanoparticles have been known in overcoming difficulties of treatment therapies including multi drug resistant bacterial infections but research on their role in mastitis treatment is limited. Nowadays Green synthesis of nanoparticles is gaining importance to overcome problems associated with chemical synthesis. Therefore, the present study was conducted to evaluate the ameliorative action of Thespesia populnea (T. populnea) mediated synthesized silver and zinc oxide nanoparticles in mastitis induced mice. Methods: A total of 48 mice were divided into six groups: where Group I served as control, groups II to VI were inoculated with Staphylococcus aureus (S. aureus) culture for mastitis induction. After mastitis induction, groups III, IV, V and VI received T. populnea methanolic extract (TPE), T. populnea methanolic extract mediated silver nano particles (TPSN) (»95 nm size), T. populnea methanolic extract mediated ZnO nanoparticles (TPZN) (» 85 nm size) and Ceftriaxone respectively. Whole blood was collected to analyze inflammatory indicators haptoglobin (Hp) and C reactive protein (CRP). The mammary gland weights, bacterial load and changes in tissue samples were studied. Result: The formation of brown colour solution and white crystalline precipitate indicated the formation of TPE mediated silver and zinc oxide nanoparticles respectively. The sizes of these TPSN and TPZN when characterized by SEM, were found to be 95 and 85 nm respectively. The values of mammary gland weight, bacterial load, Hp and CRP were elevated significantly in group II mice when compared to other treatment groups. Histopathological examination of mammary gland revealed bacterial clumps, severe leucocytic infiltration along with congestion and necrotic changes in group II. The ameliorating changes in damaged tissues of the experimental groups remained in the decreasing order of TPSN, ceftriaxone, TPZN and TPE respectively. Therefore, phytogenic nanoparticles can be effectively used to control the mastitis.

Photo gallery. Rare dermatoses. Part I

Orphan dermatoses are caused by both genetic causes and a number of autoimmune, inflammatory and infectious processes in the body. Congenital giant nevus is associated with serious complications: malignant melanoma, CNS lesions (neurocutaneous melanosis). Multiple epidermoid cysts are often a component of Gardner's syndrome. Angiolymphoid hyperplasia with eosinophilia, a vascular tumor formation with proliferation of histiocytoid endothelial cells, with severe lymphocytic and eosinophilic infiltration, recurs in 1/3 of cases. Morbigan's disease is persistent erythema and swelling of the middle third and upper part of the face. Skin mastocytosis in children is prone to spontaneous resolution during puberty. Squamous cell skin cancer accounts for 20% of all skin cancers and has a high risk of recurrence, metastasis, and death. Buschke's scleroderma is a scleroderma-like disease that causes progressive fibrous-mucinous thickening of the skin affecting the neck, shoulders, proximal upper extremities, and face. Fulminant (lightning) acne is a sharply exacerbated form of acne vulgaris, characterized by an acute onset and the appearance of confluent abscesses. Cases of acne fulminans have been observed during treatment with isotretinoin. Norwegian (crustose) scabies is associated with a compromised immune response, which allows the mites to multiply and can number in the millions. Pretibial myxedema (thyroid dermopathy) is a rare extrathyroid manifestation of Graves' disease along with thyrotoxicosis, thyroid hypertrophy, ophthalmopathy, and acropachy. Porokeratosis Mibelli predisposing factors of development are immunosuppressive conditions, malignancy is possible. Osteomas are formations from bone tissue in the dermis or subcutaneous fat as a result of metaplasia of fibroblasts into osteoblasts, or differentiation of primitive mesenchymal cells into osteoblasts and their migration to an ectopic site. Sarcoidosis of the skin is characterized by a variety of clinical forms, rarely observed before 40 years. Xanthomas with histiocytosis X ― a violation of lipid metabolism. The rural type of leishmaniasis (acute necrotizing) has a short incubation period, a significant spread of rashes and healing with the formation of scar tissue. The giant condyloma of BuschkeLevenshtein is characterized by progressive growth, large size and recurrent course, it can transform into squamous cell carcinoma. Degos disease ― malignant atrophic papulosis ― a rare disease caused by blockage of the arteries and veins.

Cobalt-induced neuro-behavioural alterations are accompanied by profound Purkinje cell and gut-associated responses in rats

Metal ions including cobalt (Co) ions reportedly exhibit neurotoxic and antimicrobial properties. We hypothesized that oral exposure to Co may have implications for gut-dysbiosis with possible alterations of microbiota-gut-brain signaling in the host. In this preliminary study, we sought to examine whether exposure of male Wistar rats to cobalt chloride (CoCl2) at 0, 25, 50 and 100 mg/kg for two weeks affects select neurobehavioural indices, vagus nerve and brain morphology along with evaluation of associated changes in faecal bacterial flora, faecal fatty acids and the morphology of the intestines. CoCl<sub>2</sub>-exposed rats showed a dose-dependent reduction in hanging latency in the hanging wire (HW) test, reduced tendency to recognize novel objects in a Novel Object recognition (NOR) test, but increased interaction with open arms in the elevated plus maze (EPM) test, compared to controls. There were dose-dependent reductions in total heterotrophic count, coliforms, <italic>E. coli, Enterococcal</italic> and <italic>Lactobacilli</italic> counts in the faeces. Administration of CoCl<sub>2</sub> at 100 mg/kg evoked the appearance of unsaturated fatty acids including palmitoleic, oleic and linoleic acids in the faeces as detected by gas chromatography-flame ion detection (GD-FID) analysis using fatty acid methyl esters (FAME) standards. Histopathological examination revealed chromatolysis of Purkinje cells in the cerebellum, although no significant lesions were present in the vagus nerve isolated from all the groups. In the intestines, there was moderate to severe infiltration of inflammatory cells into the duodenum, ileum, jejunum and colon while villi erosions were seen prominently in the ileum. These initial findings suggest that short-term exposure to Co can lead to gut-associated changes that may underlie neurotoxicity and alterations in behavior induced by Co.

Sinapic Acid Attenuate Liver Injury by Modulating Antioxidant Activity and Inflammatory Cytokines in Thioacetamide-Induced Liver Cirrhosis in Rats.

Sinapic acid (SA) is a natural pharmacological active compound found in berries, nuts, and cereals. The current study aimed to investigate the protective effects of SA against thioacetamide (TAA) fibrosis in rats by histopathological and immunohistochemical assays. The albino rats (30) were randomly divided into five groups (G). G1 was injected with distilled water 3 times/week and fed orally daily with 10% Tween 20 for two months. G2-5 were injected with 200 mg/kg TAA three times weekly for two months and fed with 10% Tween 20, 50 mg/kg silymarin, 20, and 40 mg/kg of SA daily for 2 months, respectively. The results showed that rats treated with SA had fewer hepatocyte injuries with lower liver index (serum bilirubin, total protein, albumin, and liver enzymes (ALP, ALT, and AST) and were similar to that of control and silymarin-treated rats. Acute toxicity for 2 and 4 g/kg SA showed to be safe without any toxic signs in treated rats. Macroscopic examination showed that hepatotoxic liver had an irregular, rough surface with micro and macro nodules and histopathology expressed by Hematoxylin and Eosin, and Masson Trichrome revealed severe inflammation and infiltration of focal necrosis, fibrosis, lymphocytes, and proliferation bile duct. In contrast, rats fed with SA had significantly lower TAA toxicity in gross and histology and liver tissues as presented by less liver tissue disruption, lesser fibrosis, and minimum in filtered hepatocytes. Immunohistochemistry of rats receiving SA showed significant up-regulation of HSP 70% and down-regulation of alpha-smooth muscle actin (α-SMA) protein expression compared to positive control rats. The homogenized liver tissues showed a notable rise in the antioxidant enzymes (SOD and CAT) actions with significantly lower malondialdehyde (MDA) levels compared to that of the positive control group. Furthermore, the SA-treated rats had significantly lower TNF-a, IL-6, and higher IL-10 levels than the positive control rats. Thus, the findings suggest SA as a hepatoprotective compound due to its inhibitory effects on fibrosis, hepatotoxicity, liver cell proliferation, up-regulation of HSP 70, and downregulation of α-SMA expression, inhibiting lipid peroxidation (MDA), while retaining the liver index and antioxidant enzymes to normal.

Prognostic value of increased intraepithelial lymphocytes and lymphocytic clonality in dogs with chronic enteropathy or small-cell lymphoma

The clinical significance of severe infiltration of small intraepithelial lymphocytes (IEL) and the results of polymerase chain reaction for antigen receptor rearrangement (PARR) in dogs with chronic enteropathy (CE) and small-cell lymphoma (SCL) are controversial. This cohort study aimed to evaluate the prognostic significance of the IEL and PARR results in dogs with CE or SCL. Although definitive diagnostic histopathological criteria for SCL in dogs have yet to be established, dogs with the histopathological findings of severe IEL infiltration were diagnosed with SCL in this study. One hundred and nineteen dogs were recruited, with 23 dogs classified as having SCL and 96 dogs as having CE. The positive rate of PARR was 59.6 % (71/119) in the duodenum and 57.7 % (64/111) in the ileum. Subsequently, three dogs with SCL and four dogs with CE developed large-cell lymphoma (LCL). The median overall survival (OS) of dogs with SCL was 700 days (range, 6–1410 days), and that of dogs with CE was not reached. In the log-rank test, shorter OS was observed in cases with histopathological SCL (P = 0.035), clonal TCRγ rearrangement in the duodenum (P = 0.012), and clonal IgH rearrangement in the ileum (P < 0.0001). The Cox proportional hazards model adjusted for sex and age showed that histopathological SCL (hazard ratio [HR] 1.74; 95 % confidence interval [CI], 0.83–3.65), duodenal clonal TCRγ rearrangement (HR, 1.80; 95 % CI, 0.86–3.75), and ileal clonal IgH rearrangement (HR, 2.28; 95 % CI, 0.92–5.70) could shorten overall survival, although their 95 % CIs included 1.0. These results indicate that severe IEL infiltration could be a useful histopathological feature for diagnosing SCL, and clonality-positive results could be a negative prognostic factor in dogs with CE. Furthermore, the development of LCL should be carefully monitored in dogs with CE and SCL..

Aggressive Behavior in a Critically Ill COVID-19 Patient: Possible Role of Medication Discrepancies

Coronavirus disease 2019 (COVID-19) has different clinical manifestations that besides its iatrogenic intervention could affect brain cognitive function. Medication omission has serious effects on a patient’s clinical course changing the disease’s mortality and morbidity; herein possible role of the iatrogenic intervention that increased the risk of psychological disturbance including medication omission was reported.&#x0D; A 40-years-old man with a history of gout treated with allopurinol was admitted due to productive cough and hemoptysis. His physical exam and lung spiral chest CT scan revealed moderate to severe lung infiltrations in favor of COVID-19 which was confirmed with COVID-19 RT-PCR. Due to his clinical course tocilizumab, methylprednisolone pulse, and other conservative therapies were started while allopurinol was omitted. During his hospitalization anxiety and irritability appeared and progressed gradually making him refuse to get oxygen supplementation. Through immediate intervention and controlling his behavioral symptoms with psychotherapy, selective serotonin reuptake inhibitors, benzodiazepines, and initiation of allopurinol, the patient’s psychological disturbance were relieved. In the end, he died due to acute respiratory distress syndrome.&#x0D; COVID-19 and its iatrogenic interventions could trigger a psychiatric disturbance in patients with a variety of pathways. Corticosteroid therapy, non-hypnotic antihistamines, quarantine stress conditions, hypoxia, and medication omission are underlying factors for it. Reporting this medication omission would help physicians become familiar with this pharmacological phenomenon, its prevention, and the way to respond to it. On the other hand, researchers can study the etiology of this phenomenon to understand the mood-stabilizing role of allopurinol in additional studies.

A new H9 influenza virus mRNA vaccine elicits robust protective immunity against infection.

Avian influenza virus (AIV) poses a great threat to the poultry industry and public health. However commercial vaccines only provide limited immunity due to rapid virus mutation and rearrangement. Here, we developed an mRNA-lipid nanoparticle (mRNA-LNP) vaccine expressing AIV immunogenic protein hemagglutinin (HA) and also assessed its safety and immune-protection efficacy in vivo. Specifically, its safety was tested by inoculation of SPF chicken embryos and chicks, and there showed no clinical manifestations and pathological changes in both. As for the immune efficacy, the antibody titers, IFN-γ production levels, and viral loads in various organs were analyzed. The results showed that chickens in the mRNA-LNP-inoculated groups produced higher specific antibody titers compared with that in the control group by hemagglutination inhibition (HI) test. Meanwhile, the ELISpot assay demonstrated that the expression of IFN-γ was markedly induced in the mRNA-LNP group, and the viral loads in multiple organs were decreased. In addition, HE shows no obvious pathomorphological changes in the lungs of the mRNA-LNP-inoculated group. While, there was severe inflammatory cell infiltration in the DMEM-treated group instead. Taken together, the vaccine prepared in this study was safe and could trigger potent cellular and humoral immune response to defend against virus infection.

Polystyrene nanoplastics exacerbated Pb-induced liver toxicity in mice.

Nanoplastics are widely distributed in the environment and can adsorb heavy metals, which poses a potential threat to human health through food chain. It is necessary to assess the combined toxicity of nanoplastics and heavy metals. The adverse effect of Pb and nanoplastics on liver, single or in combination, was evaluated in this study. The results showed that the Pb content in co-exposure group of nanoplastics and Pb (PN group) was higher than the group exposed to Pb alone (Pb group). And more severe inflammatory infiltration was observed in liver sections of PN group. The level of inflammatory cytokines and malondialdehyde were increased, while the superoxide dismutase activity was decreased in liver tissues of PN group. Moreover, the gene expression level of nuclear factor-erythroid 2-related factor 2, nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 and catalase, which is related to antioxidation, was downregulated. And the expression level of cleaved-Caspase9 and cleaved-Caspase3 were increased. However, with the supplementation of oxidative stress inhibitor N-Acetyl-L-cysteine, liver damage shown in PN group was evidently alleviated. In summary, nanoplastics evidently exacerbated the deposition of Pb in liver and potentially aggravated the Pb-induced liver toxicity by activating oxidative stress.

SAMHD1 Attenuates Acute Inflammation by Maintaining Mitochondrial Function in Macrophages via Interaction with VDAC1.

Over-activation of Toll-like receptor 4 (TLR4) is the key mechanism in Gram-negative bacterial infection-induced sepsis. SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) inhibits multiple viruses, but whether it plays a role during bacterial invasion remains unelucidated. Monocyte-macrophage specific Samhd1 knockout (Samhd1-/-) mice and Samhd1-/- macrophage cell line RAW264.7 were constructed and used as research models to evaluate the role of SAMHD1 in TLR4-activated inflammation. In vivo, LPS-challenged Samhd1-/- mice showed higher serum inflammatory factors, accompanied with more severe inflammation infiltration and lower survival rate. In vitro, Samhd1-/- peritoneal macrophages had more activated TLR4 pathway upon LPS-stimulation, accompanied with mitochondrial depolarization and dysfunction and a higher tendency to be M1-polarized. These results could be rescued by overexpressing full-length wild-type SAMHD1 or its phospho-mimetic T634D mutant into Samhd1-/- RAW264.7 cells, whereas the mutants, dNTP hydrolase-function-deprived H238A and phospho-ablative T634A, did not exert the same effect. Lastly, co-IP and immunofluorescence assays confirmed that SAMHD1 interacted with an outer mitochondrial membrane-localized protein, voltage-dependent anion channel-1 (VDAC1). SAMHD1 inhibits TLR4-induced acute inflammation and M1 polarization of macrophages by interacting with VDAC1 and maintaining mitochondria function, which outlines a novel regulatory mechanism of TLR signaling upon LPS stimulation.