Histological Signs Research Articles

Neurosensory abnormalities and stability of a mouse model of dry eye disease

This study aimed to use a mouse model of dry eye disease (DED) induced by topical administration of benzalkonium chloride (BAK) and assess its stability and the presence of neurosensory abnormalities, including ocular pain. Eight-week-old C57BL6/6 N male mice were used in this study. Mice were treated with 10 μL of 0.2% BAK dissolved in artificial tears (AT), administered twice daily for 7 days. After one week, animals were randomized into two groups: one was administered with 0.2% BAK in AT once per day for 7 days, while the other was not further treated. Corneal epitheliopathy was quantified at days 0, 3, 7, 12, and 14. Moreover, tear secretions, corneal nociception, and corneal nerve integrity were measured after BAK treatment. After sacrifice, corneas were dissected to assess nerve density and leukocyte infiltration by immunofluorescence. Topical BAK instillation for 14 days significantly increased corneal fluorescein staining (p < 0.0001) compared to day 0. On the other hand, interruption of BAK instillation was associated with improvement of corneal epitheliopathy (day 12, p < 0.0001; day 14, p < 0.001). BAK treatment increased ocular pain (p < 0.0001) and resulted in a significant increase in leukocyte infiltration in the cornea (p < 0.01). Moreover, corneal sensitivity was reduced (p < 0.0001), together with corneal nerve density (p < 0.0001) and tear secretion (p < 0.0001). One week twice a day, followed by one additional week once a day, of 0.2% BAK topical administration induces stable clinical and histological signs of DED, which is associated with neurosensory abnormalities, including pain.

What's New in Musculoskeletal Infection.

What's New in Musculoskeletal Infection.

Early life stress in mice leads to impaired colonic corticosterone production and prolonged inflammation following induction of colitis

Early life stress (ELS) is an environmental trigger linked to increased risk of inflammatory bowel disease (IBD). Our goal was to identify mechanisms whereby ELS in mice affects susceptibility to, and/or severity of, intestinal inflammation. We hypothesized that ELS alters the delicate balance of typical homeostatic mediators in the intestinal microenvironment, predisposing ELS-exposed individuals to IBD onset or worsened disease upon a pro-inflammatory triggering event within the gut. We utilized 2 published animal models of ELS. In the first model, newborn mice were separated from the dam daily for 4-8 hours beginning on postnatal day 2, then weaned early on postnatal day 17. Normally reared (NR) control mice were left undisturbed with the dams until standard weaning on postnatal day 21. In the second model, dams were fed the synthetic glucocorticoid – dexamethasone, or vehicle ad libitum in drinking water (3 μg/mL) on post-partum days 1-14. Colitis was induced in 4-week-old mice via intraperitoneal injection of IL-10 receptor blocking antibody (100 μg) every 5 days for 15 days. Five or 15 days later, histological colitis scores and colonic transcripts for Tnf, glucocorticoid receptors, and steroidogenic enzymes were measured. ELS-exposed mice displayed altered mucosa-associated immune cell balances, with an initial deficit in anti-inflammatory IL-10-producing CD4 T cells at 4-wks of age (n≥11, p&lt;0.05), followed by an increase in IFNγ-producing CD4 T cells at 8-wks of age (n≥7, p&lt;0.05). ELS-exposed mice also displayed reduced levels of the glucocorticoid, corticosterone in the plasma (n≥10, p&lt;0.01) as well as locally within the colon (n≥7, p&lt;0.05). Upon colitis induction, NR control animals showed improvements in indices of inflammation following cessation of IL-10 receptor blockade, whereas ELS-exposed animals maintained high levels of intestinal Tnf (n≥7, p&lt;0.01) and histological signs of colitis (n≥7, p&lt;0.05). In colitic animals, prior exposure to ELS was associated with significantly lower expression of genes associated with corticosterone synthesis ( Cyp11a1; n≥5, p&lt;0.05) and responsiveness ( Nr3c1, Nr5a2; n≥5, p&lt;0.01). Finally, ex-vivo TNF stimulation of colonic crypt cells from ELS mice led to increased inhibition of corticosterone synthesis, relative to NR control mice (n≥4, p&lt;0.05). Our study identifies impaired local colonic glucocorticoid production and responsiveness as a potential mechanism whereby ELS predisposes to chronic colitis in susceptible hosts. Crohn's and Colitis Foundation Research Initiatives Award This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors

Scleroderma renal crisis is a rare complication of systemic sclerosis characterized by a rapid decline in kidney function due to acute renal vascular injury. Recently, activating autoantibodies targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor have been implicated in the pathophysiology of scleroderma renal crisis by sensitizing the angiotensin II type 1 receptor and endothelin-1 type A receptor in renal resistance arteries to their natural ligands. Here, we describe a cohort of 10 patients with scleroderma renal crisis refractory to standard treatment, including blockade of the renin-angiotensin system. Multimodal therapy was initiated, targeting at the removal of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies by plasma exchange and the reduction of vasoconstrictive activity. Further treatment options included angiotensin II type 1 receptor and endothelin-1 type A receptor blockade, iloprost, intravenous immunoglobulins, and immunosuppression. Six patients were hypertensive. On kidney biopsy, concentric intimal sclerosis was present in all patients, whereas acute vascular injury was evident in eight. Levels of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies were significantly reduced by multimodal treatment. Kidney function improved in three patients with histological signs of severe acute renal vascular damage. This report demonstrates that intensive multimodal therapy taking account of potentially pathogenic anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies in concert with other vasodilatory interventions provides a salvage option for patients with refractory scleroderma renal crisis.

Management of patients with chronic gastritis after H. pylori eradication

Objective — to study the prevalence of H. pylori infection in patients with organic and functional dyspepsia in the central region of Ukraine and to perform clinical and morphological evaluation of the efficacy of “Gialera” preparation in the complex treatment of patients with chronic gastritis after H. pylori eradication.&#x0D; Materials and methods. To assess H. pylori prevalence, an analysis of endoscopic data and the frequency of contamination of the gastric mucosa with H. pylori was carried out in 5903 gastroenterological patients aged 18 to 94 years. The study was multicenter, multiplicative cross‑sectional and lasted from the year 2016 to 2022. The average age of patients was 50.5±15.6 years, there were 3188 (54.0%) women and 2715 (46.0%) men. The presence of H. pylori infection was assessed using a 13C‑urease breath test, performed according to the standard method before the start of the treatment. Sixty patients with chronic gastritis, who, after successful eradication of H. pylori, confirmed by a repeated 13C‑urease breath test, had dyspeptic symptoms after 1 month, were transferred to the second stage of the study. A multicenter, randomized, blinded, comparative study was conducted to evaluate the efficacy and safety of Giallera in the complex treatment of dyspepsia in patients with chronic gastritis after H. pylori eradication. The patients were divided into 2 groups: the first group — 30 patients received a proton pump inhibitor (PPI) in a dose of 40 mg/day and Gialera, the second group — 30 patients received only PPI in the same dose. In addition, in the presence of heaviness in the epigastrium, patients in both groups could take a prokinetic. All patients before and after treatment, in addition to clinical examination and assessment of the intensity of abdominal pain, underwent endoscopic examination of the esophagus, stomach and duodenum with a biopsy of the gastric mucosa. The biopsy was stained with hematoxylin and eosin, and PAS reaction and immunohistochemical study with tight junction sealing proteins claudins 1 and 7 were carried out.&#x0D; Results. Patients with functional dyspepsia predominate (51.1%) in the population of Ukrainian patients with lesions of the upper gastrointestinal tract, while patients with organic dyspepsia account for 46.1%, of which 52.8% have chronic gastritis with high H. pylori infection, which is the majority cases, eradication anti‑Helicobacter therapy is required. After eradication, some patients still have dyspeptic complaints in the presence of a morphological picture of chronic gastritis without signs of pronounced activity, with elements of gland atrophy with preserved mucus secretion, weak inflammatory cell infiltration and increased epithelial permeability with a decrease in the expression of sealing claudins.&#x0D; Conclusions. The use of combined therapy with Gialera resulted in a more rapid decrease in the intensity of abdominal pain and its stable absence after the end of treatment. Positive clinical symptoms in such patients are combined with improvement in morphological changes in the gastric mucosa (GM): minimization of histological signs of inflammation, improvement in mucosal formation and a tendency to stabilize the epithelial permeability of the GM, normalization of the expression of claudins 1 and 7.

Serum keratin 18-M65 levels detect progressive forms of alcohol-associated liver disease in early noncirrhotic stages.

The progression of alcohol-associated liver disease (ALD) in its early precirrhotic stages can be a silent process. Serum keratin 18 levels (K18-M65) predict severe events and mortality in advanced stages of ALD, but data on this biomarker in early stages are scarce. We evaluated the diagnostic accuracy of K18-M65 levels in identifying early forms of ALD. We prospectively evaluated two cohorts of actively drinking patients with alcohol use disorder (AUD) following a rehabilitation program (training (n = 162) and validation (n = 78)) and matched healthy controls (n = 21). Clinical, laboratory, and imaging data were used to distinguish AUD patients with simple steatosis (minimal ALD) and steatohepatitis/fibrosis (early ALD). We measured serum K18-M65 levels and assessed their ability to predict early ALD. High levels of K18-M65 characterized AUD patients with early ALD, while levels in the minimal ALD group were similar to those in healthy controls. K18-M65 levels distinguished minimal liver disease from early ALD (AUROC = 0.8704; p < 0.0001) with an optimal cutoff at 265.9 U/L. K18-M65 levels strongly correlated with transaminases and predicted early ALD (OR 25.81; 95% CI 3.166-336.1; p < 0.0001), controlled attenuation parameter, and liver stiffness independently from transaminases and other potential confounders. K18-M65 levels did not discriminate between fibrosis and steatohepatitis but correlated with histological signs of hepatocellular injury and inflammation (all p < 0.05). The K18-M65 cutoff detected early ALD in the validation cohort with high accuracy (sensitivity 86.67%, specificity 96.67%) and a very high positive likelihood ratio (28.6; 95% CI 4.14-197.73). Serum K18-M65 levels can be used as a biomarker to detect early ALD stages with excellent predictive value.

Immunomodulation of neutrophil granulocyte functions by bacterial polyphosphates.

Polyphosphates are highly conserved, linear polymers of monophosphates that reside in all living cells. Bacteria produce long chains containing hundreds to thousands of phosphate units, which can interfere with host defense to infection. Here, we report that intratracheal long-chain polyphosphate administration to C57BL/6J mice resulted in the release of proinflammatory cytokines and influx of Ly6G+ polymorphonuclear neutrophils in the bronchoalveolar lavage fluid causing a disruption of the physiologic endothelial-epithelial small airway barrier and histologic signs of lung injury. Polyphosphate-induced effects were attenuated after neutrophil depletion in mice. In isolated murine neutrophils, long-chain polyphosphates modulated cytokine release induced by lipopolysaccharides (LPS) from Gram-negative bacteria or lipoteichoic acid from Gram-positive bacteria. In addition, long-chain polyphosphates induced immune evasive effects in human neutrophils. In detail, long-chain polyphosphates downregulated CD11b and curtailed the phagocytosis of Escherichia coli particles by neutrophils. Polyphosphates modulated the migration capacity by inducing CD62L shedding resulting in CD62Llow and CD11blow neutrophils. The release of IL-8 induced by LPS was also significantly reduced. Pharmacologic blockade of PI3K with wortmannin antagonized long-chain polyphosphate-induced effects on LPS-induced IL-8 release. In conclusion, polyphosphates govern immunomodulation in murine and human neutrophils, suggesting polyphosphates as a therapeutic target for bacterial infections to restore innate immune defense.

Partial decellularization eliminates immunogenicity in tracheal allografts.

There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long-segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea. Recent advances in tissue engineering have led to the idea of partial decellularization that allows for the creation of tracheal scaffolds that supports tracheal epithelial formation while preserving mechanical properties. However, the ability of partial decellularization to eliminate graft immunogenicity remains unknown, and understanding the immunogenic properties of partially decellularized tracheal grafts (PDTG) is a critical step toward clinical translation. Here, we determined that tracheal allograft immunogenicity results in epithelial cell sloughing and replacement with dysplastic columnar epithelium and that partial decellularization creates grafts that are able to support an epithelium without histologic signs of rejection. Moreover, allograft implantation elicits CD8+ T-cell infiltration, a mediator of rejection, while PDTG did not. Hence, we establish that partial decellularization eliminates allograft immunogenicity while creating a scaffold for implantation that can support spatially appropriate airway regeneration.

Inactivation of the gene encoding procalcitonin prevents antibody-mediated arthritis.

Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca-/-), lacking PCT (n = 15), and wild-type (WT) mice(n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, whileCalca-deficiency preserved bone integrity. The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA.

Leser–Trelat sign in cosmetologist’s practice

LeserTrelat syndrome (eruptive seborrheic keratosis) is an unusial paraneoplastic dermatosis characterized by sudden appearance of seborrheic keratomas on the skin and a progressive increase of their number. This condition was first described in 1901 by the German surgeon E. Leser and the French surgeon U. Trelat. It occurs with the same frequency in both men and women aged 40+. The etiology and pathogenesis have not been studied in detail, however, there is evidence that the development of the syndrome may be associated with stimulation of the epidermal growth factor, which leads to stimulation of keratinocytes. The manifestation of the syndrome is usually start at the same time with cancer development, mostly it can be combained with adenocarcinoma of the gastrointestinal tract (47.7%), with intestinal carcinoma (32%), with lymphoproliferative diseases (21%), less often with malignant neoplasms of the lungs, breast, prostate.&#x0D; The clinical picture of the LeserTrelat sign is characterized by the sudden appearance оf seborrheic keratomas, which have typical clinical and histological signs. The most typical localization of seborrheic keratosis are back and chest (76%), limbs (18%), face (21%), abdomen (15%), neck (13%), armpits (6%), inguinal folds (3%). Keratosis can appear rapidly, over several months or even weeks. The rapid appearance of multiple seborheic keratomas may precede or develop with the oncological process in the internal organs.&#x0D; Treatment is carried out at the same time with the establishment and treatment of the underlying disease and consists in removing the largest keratomas by destructive methods (surgical excision, radiowave method, cryodestruction, electrocoagulation).&#x0D; The prognosis is favorable if paraneoplastic process was early detected.&#x0D; The article describes clinical cases of multiple seborrheic keratosis and the tactics of examining this group of patients.

Growth-Restricted Fetuses and Offspring Reveal Adverse Sex-Specific Metabolic Responses in Preeclamptic Mice Expressing Human sFLT1.

Fetal adaptations to harmful intrauterine environments due to pregnancy disorders such as preeclampsia (PE) can negatively program the offspring's metabolism, resulting in long-term metabolic changes. PE is characterized by increased circulating levels of sFLT1, placental dysfunction and fetal growth restriction (FGR). Here we examine the consequences of systemic human sFLT1 overexpression in transgenic PE/FGR mice on the offspring's metabolic phenotype. Histological and molecular analyses of fetal and offspring livers as well as examinations of offspring serum hormones were performed. At 18.5 dpc, sFLT1 overexpression resulted in growth-restricted fetuses with a reduced liver weight, combined with reduced hepatic glycogen storage and histological signs of hemorrhages and hepatocyte apoptosis. This was further associated with altered gene expression of the molecules involved in fatty acid and glucose/glycogen metabolism. In most analyzed features males were more affected than females. The postnatal follow-up revealed an increased weight gain of male PE offspring, and increased serum levels of Insulin and Leptin. This was associated with changes in hepatic gene expression regulating fatty acid and glucose metabolism in male PE offspring. To conclude, our results indicate that sFLT1-related PE/FGR in mice leads to altered fetal liver development, which might result in an adverse metabolic pre-programming of the offspring, specifically targeting males. This could be linked to the known sex differences seen in PE pregnancies in human.

MP41-13 QUANTITATIVE ASSESSMENT OF MESENCHYMAL DIFFERENTIATION FOR METASTATIC RISK PREDICTION OF CLEAR CELL RENAL CARCINOMA (CCRCC)

You have accessJournal of UrologyCME1 Apr 2023MP41-13 QUANTITATIVE ASSESSMENT OF MESENCHYMAL DIFFERENTIATION FOR METASTATIC RISK PREDICTION OF CLEAR CELL RENAL CARCINOMA (CCRCC) Daniel Vilchez, Bodong Zhang, Alejandro Sanchez, Deepika Sirohi, Tolga Tasdizen, and Beatrice Knudsen Daniel VilchezDaniel Vilchez More articles by this author , Bodong ZhangBodong Zhang More articles by this author , Alejandro SanchezAlejandro Sanchez More articles by this author , Deepika SirohiDeepika Sirohi More articles by this author , Tolga TasdizenTolga Tasdizen More articles by this author , and Beatrice KnudsenBeatrice Knudsen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003279.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Epithelial-to-mesenchymal transition (EMT) results in poor prognosis sarcomatoid and rhabdoid histologic growth patterns (HGP) of ccRCC. However, only ∼15% of metastatic cases reveal areas of sarcomatoid/rhabdoid differentiation in the primary tumor. We questioned whether a computer can learn salient features of EMT that are associated with risk of metastatic progression across all HGPs of ccRCC. METHODS: The project uses 410 digital H&E slides of ccRCC. We incorporated a novel co-training approach into a machine learning model (MLM) and trained the model to distinguish epithelial (nested) and mesenchymal (sarcomatoid, rhabdoid) HGPs in a Utah cohort. The trained MLM is applied to the TCGA KIRC cohort (n=360) with annotated regions of nested, tubulo-papillary, low grade-spindle, sarcomatoid and rhabdoid HGPs for which the hazard ration of metastatic progression was published. For each case, the MLM outputs a mesenchymal-differentiation (DP-MD) score on a scale of 0 to 1 where closer to 1 is higher likelihood of EMT. RESULTS: A unique machine learning / AI model was developed to quantify sarcomatoid differentiation in ccRCC with no obvious histologic signs of mesenchymal morphology. H&E stains were used as separate inputs of a contrastive co-training model (H/E-CCTM) to force the learning of mesenchymal features. The inclusion of a semi-supervised learning component improved the accuracy of predicting mesenchymal differentiation by >4% over other state-of-the-art co-training algorithms and performed equally well when trained on 10% versus 100% of labeled cancer data. Sarcomatoid, low grade spindle and rhabdoid cases received average DP-MD scores of 0.91, 0.97 and 0.83, respectively in a held-out test set, while cases with nested morphology, including expansile, and high nuclear to cytoplasmic ratio averaged DP-MD scores of 0.08. Tubulo-papillary HGPs without obvious mesenchymal features obtained an average DP-MD score of 0.49. CONCLUSIONS: Computer-assisted morphometric analysis can be used to quantify mesenchymal differentiation and has the potential to improve the prediction of metastatic risk in ccRCC and the selection of patients for adjuvant treatment after nephrectomy. Source of Funding: Huntsman Cancer Foundation, NIH P30CA042014 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e560 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Vilchez More articles by this author Bodong Zhang More articles by this author Alejandro Sanchez More articles by this author Deepika Sirohi More articles by this author Tolga Tasdizen More articles by this author Beatrice Knudsen More articles by this author Expand All Advertisement PDF downloadLoading ...

Biphasic Interpositional Allograft for Rotator Cuff Repair Augmentation Is Safe in an Ovine Model

This study is a preclinical histological assessment of a biphasic acellular interpositional cancellous allograft in an ovine model of rotator cuff repair (RCR) designed to better understand its safety profile and effects on tendon healing after rotator cuff repair. Thirty skeletally mature sheep with clinically normal shoulders with an artificially created degenerative infraspinatus tendon (IST) tear were randomized to control and treatment groups. Animals were euthanized at 3-weeks, 6-weeks, and 12-weeks. After gross dissection, rotator cuff specimens were fixed with formalin and polymerized for sectioning and staining. Blinded histological scores evaluated inflammatory cell infiltrates, signs of degradation, particulate debris, collagen arrangement, neo-vascularization, and enthesis qualitative measures. There were no treatment specimens that exhibited histological signs of a significant infection, inflammatory infiltrate, or foreign body reaction such as granuloma or fibrous capsule formation. Histological scores in all categories were not significantly different at all time points, including the primary endpoint mean cumulative inflammatory score (control: 3.66 ± 1.21 versus treated: 4.33 ± 1.51, p = 0.42), when comparing the treatment and control RCR groups. In general, the degree of tendon healing and host tissue response was essentially equivalent between the two groups with observation of low overall levels of inflammation and progressive improvements in collagen organization, reduced tenocyte activity, and fibrocartilaginous enthesis reformation. This histological study demonstrated the use of a biphasic interpositional allograft for rotator cuff repair augmentation in an ovine model does not generate an inflammatory response or foreign body reaction. Use of the biphasic interpositional allograft resulted in a histological profile that was essentially equivalent to that of a standard RCR at 3-, 6-, and 12-week post-operative timepoints. These findings suggest that a biphasic interpositional allograft is safe for further clinical investigation in humans before broader clinical application. Patch augmentation of RCR is a popular technique that has shown clinical success in improving the likelihood of a successful repair in patients at elevated risk for retear. Newer augmentation technologies are being developed to address the biology at the interface between the bone and soft tissue where failure typically occurs.

An Evaluation of the Efficacy of Systemic Immune-Inflammation Index in Predicting Enterobius-Associated Appendicitis Preoperatively.

Objective Our study aimed to retrospectively evaluate Enterobius-associated appendicitis cases and compare them with acute appendicitis cases in terms of parameters such as the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP)-to-lymphocyte ratio (CLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). We primarily aimed to evaluate the utility of SIIin the differential diagnosis of Enterobius-associated appendicitis. Methods The appendectomy specimens of pediatric patients who were operated on for acute appendicitisbetween June 2016 and August 2022 were retrospectively evaluated. Enterobius-associated appendicitis cases wereincluded for analysis. All patients were evaluated regarding age, gender, blood count, surgery, and pathology reports. Pathology reports were evaluated for the presence of histological signs of acute appendicitis. The patients were classified into an Enterobius-associated appendicitis group and a regular acute appendicitis group. CRP, white blood cell (WBC), red cell distribution width (RDW),neutrophils, lymphocytes, NLR, monocytes, eosinophils, platelet (PLT), PLR, CLR, and SII values were compared between the two groups. Results Eleven cases of Enterobius-associated appendicitis were identified out of 430 total cases (2.55%) examined. The mean age of the group with acute appendicitis was 12.83 ±3.16 years, while the mean age of the group with Enterobius-associated appendicitis was 8.55 ±2.54 years. There was no statistically significant difference in terms of CRP, WBC, RDW, lymphocytes, neutrophils, NLR, monocytes, eosinophils, PLT, PLR, and CLR values between the two groups (p>0.05). However, when the SII values of the participants were analyzed, it was observed that the SII values of the participants in the regular appendicitis group were significantly higher than those of the participants in the Enterobius group (p<0.05). Among the 11Enterobius-associated appendicitis patients, seven appendectomy specimens revealed no inflammation and were regarded as negative appendectomy (63.63%). Conclusion This is the first study to demonstrate the utility of preoperative SII evaluation in Enterobius-associated appendicitis. SII is a simple, easy-to-calculate indicator of Enterobius-associated appendicitis and aids in the preoperative differential diagnosis of acute appendicitis.

SEC22B inhibition attenuates colorectal cancer aggressiveness and autophagic flux under unfavorable environment

Autophagy has bidirectional functions in cancer by facilitating cell survival and death in a context-dependent manner. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a large family of proteins essential for numerous biological processes, including autophagy; nevertheless, their potential function in cancer malignancy remains unclear. Here, we explored the gene expression patterns of SNAREs in tissues of patients with colorectal cancer (CRC) and discovered that SEC22B expression, a vesicle SNARE, was higher in tumor tissues than in normal tissues, with a more significant increase in metastatic tissues. Interestingly, SEC22B knockdown dramatically decreased CRC cell survival and growth, especially under stressful conditions, such as hypoxia and serum starvation, and decreased the number of stress-induced autophagic vacuoles. Moreover, SEC22B knockdown successfully attenuated liver metastasis in a CRC cell xenograft mouse model, with histological signs of decreased autophagic flux and proliferation within cancer cells. Together, this study posits that SEC22B plays a crucial role in enhancing the aggressiveness of CRC cells, suggesting that SEC22B might be an attractive therapeutic target for CRC.

Hereditary renal tumor syndromes.

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

Alpha-2-macroglobulin is involved in the occurrence of early-onset pre-eclampsia via its negative impact on uterine spiral artery remodeling and placental angiogenesis

BackgroundPre-eclampsia (PE) is one of the leading causes of maternal and fetal morbidity/mortality during pregnancy, and alpha-2-macroglobulin (A2M) is associated with inflammatory signaling; however, the pathophysiological mechanism by which A2M is involved in PE development is not yet understood.MethodsHuman placenta samples, serum, and corresponding clinical data of the participants were collected to study the pathophysiologic mechanism underlying PE. Pregnant Sprague–Dawley rats were intravenously injected with an adenovirus vector carrying A2M via the tail vein on gestational day (GD) 8.5. Human umbilical artery smooth muscle cells (HUASMCs), human umbilical vein endothelial cells (HUVECs), and HTR-8/SVneo cells were transfected with A2M-expressing adenovirus vectors.ResultsIn this study, we demonstrated that A2M levels were significantly increased in PE patient serum, uterine spiral arteries, and feto-placental vasculature. The A2M-overexpression rat model closely mimicked the characteristics of PE (i.e., hypertension in mid-to-late gestation, histological and ultrastructural signs of renal damage, proteinuria, and fetal growth restriction). Compared to the normal group, A2M overexpression significantly enhanced uterine artery vascular resistance and impaired uterine spiral artery remodeling in both pregnant women with early-onset PE and in pregnant rats. We found that A2M overexpression was positively associated with HUASMC proliferation and negatively correlated with cell apoptosis. In addition, the results demonstrated that transforming growth factor beta 1 (TGFβ1) signaling regulated the effects of A2M on vascular muscle cell proliferation described above. Meanwhile, A2M overexpression regressed rat placental vascularization and reduced the expression of angiogenesis-related genes. In addition, A2M overexpression reduced HUVEC migration, filopodia number/length, and tube formation. Furthermore, HIF-1α expression was positively related to A2M, and the secretion of sFLT-1 and PIGF of placental origin was closely related to PE during pregnancy or A2M overexpression in rats.ConclusionsOur data showed that gestational A2M overexpression can be considered a contributing factor leading to PE, causing detective uterine spiral artery remodeling and aberrant placental vascularization.

Cervical spinal cord injury leads to injury and altered metabolism in the lungs.

High-cervical spinal cord injury often disrupts respiratory motor pathways and disables breathing in the affected population. Moreover, cervically injured individuals are at risk for developing acute lung injury, which predicts substantial mortality rates. While the correlation between acute lung injury and spinal cord injury has been found in the clinical setting, the field lacks an animal model to interrogate the fundamental biology of this relationship. To begin to address this gap in knowledge, we performed an experimental cervical spinal cord injury (N = 18) alongside sham injury (N = 3) and naïve animals (N = 15) to assess lung injury in adult rats. We demonstrate that animals display some early signs of lung injury two weeks post-spinal cord injury. While no obvious histological signs of injury were observed, the spinal cord injured cohort displayed significant signs of metabolic dysregulation in multiple pathways that include amino acid metabolism, lipid metabolism, and N-linked glycosylation. Collectively, we establish for the first time a model of lung injury after spinal cord injury at an acute time point that can be used to monitor the progression of lung damage, as well as identify potential targets to ameliorate acute lung injury.

Lésions iatrogènes du tube digestif vues par le pathologiste

The number of drugs available to clinicians, especially targeted therapies, grows continuously. Some drugs are known to cause frequent digestive adverse effects, which may affect the gastro-intestinal tract in a diffuse or localized manner. Some treatments may leave relatively pathognomonic deposits, but histological lesions of iatrogenic origin are mostly non-specific. The diagnostic and etiological approach is often complex because of these non-specific aspects and also because (1) a single type of drug may cause different histological lesions, (2) different drugs may cause identical histological lesions, (3) the patient may receive different drugs, and (4) drug-induced lesions may mimic other pathological entities such as inflammatory bowel disease, celiac disease, or graft versus host disease. The diagnosis of iatrogenic gastrointestinal tract injury therefore requires close anatomic-clinical correlation. The iatrogenic origin can only be formally established if the symptomatology improves when the incriminating drug is stopped. This review aims to present the different histological patterns of gastrointestinal tract iatrogenic lesions, the potentially incriminate drugs, as well as the histological signs to look for in order to help the pathologist to distinguish an iatrogenic injury from another pathology of the gastrointestinal tract.

The Evaluation Retinal Toxicity of Intravitreal Infliximab Injection

Objective To evaluate toxicity of varying doses of Infliximab injecting intravitreally in rabbits. Infliximab, an FDA approved anti-inflammatory drug for Rheumatoid arthritis and Crohn’s disease. It has been reported as an alternative or adjunct drug to chronic recurrent uveitis especially Behcet’s disease, Diabetic retinopathy and PVR Materials and Methods Twenty New Zeland albino rabbits were used for this study and divided into five groups (n=4 each). ARVO guidelines were followed in treatment of animals. The rabbits were injected intravitreally with, 0.125mg 0.250mg, 0.500mg, 1.25mg or 2.5mg Infliximab in 0.1 ml in one eye and 0.1 ml saline solution was used in the contralateral eye. All the animals were examined using indirect ophthalmoscopy and slit-lamp biomicroscopic examination before intravitreal injection and at days 1,7 and 14. An ERG was performed before any treatment and at day 14. On day 14 the animals were euthanized. Histological preparations of the enucleated eyes were examined for retinal toxicity. Results We found no retinal toxicity up to 1.25mg groups according to ERG results and Histological signs. 1of 4 eyes in the 2.5mg group had some significant decrease in Electroretinogram and histological toxicity signs. Conclusions Infliximab injection up to 1.25 mg is nontoxic to the rabbit’s retina. Intravitreal injected Infliximab may be a useful treatment for Uveitis especially Behcet’s disease, Diabetic retinopathy, Age Related Macular Degeneration and Proliferative Vitreoretinopathy.