Neointimal myofibroblasts contribute to maintaining Th1/Tc1 and Th17/Tc17 inflammation in giant cell arteritis.

Vascular smooth muscle cells (VSMCs) have been shown to play a role in the pathogenesis of giant cell arteritis (GCA) through their capacity to produce chemokines recruiting T cells and monocytes in the arterial wall and their ability to migrate and proliferate in the neointima where they acquire a myofibroblast (MF) phenotype, leading to vascular stenosis. This study aimed to investigate if MFs could also impact T-cell polarization. Confocal microscopy was used to analyze fresh fragments of temporal artery biopsies (TABs). Healthy TAB sections were cultured to obtain MFs, which were then treated or not with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and analyzed by immunofluorescence and RT-PCR. After peripheral blood mononuclear cells and MFs were co-cultured for seven days, T-cell polarization was analyzed by flow cytometry. In the neointima of GCA arteries, we observed a phenotypic heterogeneity among VSMCs that was consistent with a MF phenotype (α-SMA+CD90+desmin+MYH11+) with a high level of STAT1 phosphorylation. Co-culture experiments showed that MFs sustain Th1/Tc1 and Th17/Tc17 polarizations. The increased Th1 and Tc1 polarization was further enhanced following the stimulation of MFs with IFN-γ and TNF-α, which induced STAT1 phosphorylation in MFs. These findings correlated with increases in the production of IL-1ß, IL-6, IL-12 and IL-23 by MFs. Our study showed that MFs play an additional role in the pathogenesis of GCA through their ability to maintain Th17/Tc17 and Th1/Tc1 polarizations, the latter being further enhanced in case of stimulation of MF with IFN-γ and TNF-α.

Allelic heterogeneity in a patient with postzygotic MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

A case of mosaic MTOR-associated hemimegalencephaly and hypomelanosis of Ito, died at 33 probably because of sudden unexpected death in epilepsy. Assessment of the variant allele fraction (VAF) in different tissues postmortem showed high variability not correlated with clinical features, representing the most detailed assessment of VAFs in different tissues to date.

Early prenatal diagnosis of causative homozygous variants in ASCC1 in a fetus with cystic hygroma and additional homozygous variants of unknown significance associated with a neurological phenotype not visible in early gestation: Dual diagnosis or not?

A consanguineous couple was referred at 10 weeks of gestation (WG) for prenatal genetic investigations due to isolated cystic hygroma. Prenatal trio exome sequencing identified causative homozygous truncating variants in ASCC1 previously implicated in spinal muscular atrophy with congenital bone fractures. Prenatal manifestations in ASCC1 can usually include hydramnios, fetal hypo-/akinesia, arthrogryposis, contractures and limb deformities, hydrops fetalis and cystic hygroma. An additional truncating variant was identified in CSPP1 associated with Joubert syndrome. Presentations in CSPP1 include cerebellar and brainstem malformations with vermis hypoplasia and molar tooth sign, difficult to visualize in early gestation. A second pregnancy was marked by the recurrence of isolated increased nuchal translucency at 10 + 2 WG. Sanger prenatal diagnosis targeted on ASCC1 and CSPP1 variants showed the presence of the homozygous familial ASCC1 variant. In this case, prenatal exome sequencing analysis is subject to a partial ASCC1 phenotype and an undetectable CSPP1 phenotype at 10 weeks of gestation. As CSPP1 contribution is unclear or speculative to a potentially later in pregnancy or postnatal phenotype, it is mentioned as a variant of uncertain significance. The detection of pathogenic or likely pathogenic variants involved in severe disorders but without phenotype-genotype correlation because the pregnancy is in the early stages or due to prenatally undetectable phenotypes, will encourage the clinical community to define future practices in molecular prenatal reporting.

[Contribution of connected prescriptions (NetSIG) for the management of molecular pathology exams]. / Apport de la prescription connectée (NetSIG) dans la prise en charge et la gestion des examens de pathologie moléculaire.

INTRODUCTION: This study describes our experience implementing a connected prescription software (NetSIG, Terascop) for molecular pathology exams. MATERIAL AND METHODS: NetSIG was set up for liquid biopsies and tissue testing. After registration and activation of regional pathology laboratories, NetSIG was implemented for external then internal prescriptions. RESULTS: NetSIG allows users to follow up on all prescriptions on the website, to interact through messages and to consult reports after validation. External set up was quick (3-4 months) and comprehensive (>70%). Prescriptions were made by physicians or more often by secretaries or referring pathologists. Internal prescriptions were made by pathologists then registered in NetSIG by our secretaries. This deployment strategy has resulted in very good completeness of prescriptions (>90%). DISCUSSION AND CONCLUSION: Connected prescriptions made this complex circuit more fluid and facilitated the redistribution of different administrative and technical tasks. The number of phone calls decreased sharply. Half of the prescriptions were made by pathologists and half by oncologists (physicians or secretaries). The mean dearchiving duration for blocks was one day. Mean forwarding of blocks was 2.5 days. Mean turnaround time was 8 days for targeted techniques and 13 days for Next Generation Sequencing. Physicians appreciated the interactivity of the software and the fact that they could consult it on a smartphone.

Intestinal Norovirus Binding Patterns in Nonsecretor Individuals.

Human norovirus (HuNoV) infection is associated with an active FUT2 gene, which characterizes the secretor phenotype. However, nonsecretor individuals are also affected by HuNoV infection although in a lesser proportion. Here, we studied GII.3, GII.4, and GII.17 HuNoV interactions in nonsecretor individuals using virus-like particles (VLPs). Only GII.4 HuNoV specifically interacted with nonsecretor saliva. Competition experiments using histo-blood group antigen (HBGA)-specific monoclonal antibodies (MAbs) demonstrate that GII.4 VLPs recognized the Lewis a (Lea) antigen. We also analyzed HuNoV VLP interactions on duodenum tissue blocks from healthy nonsecretor individuals. VLP binding was observed for the three HuNoV genotypes in 10 of the 13 individuals, and competition experiments demonstrated that VLP recognition was driven by an interaction with the Lea antigen. In 3 individuals, binding was restricted to either GII.4 alone or GII.3 and GII.17. Finally, we performed a VLP binding assay on proximal and distal colon tissue blocks from a nonsecretor patient with Crohn's disease. VLP binding to inflammatory tissues was genotype specific since GII.4 and GII.17 VLPs were able to interact with regenerative mucosa, whereas GII.3 VLP was not. The binding of GII.4 and GII.17 HuNoV VLPs was linked to Lea in regenerative mucosae from the proximal and distal colon. Overall, our data clearly showed that Lea has a pivotal role in the recognition of HuNoV in nonsecretors. We also showed that Lea is expressed in inflammatory/regenerative tissues and interacts with HuNoV in a nonsecretor individual. The physiological and immunological consequences of such interactions in nonsecretors have yet to be elucidated. IMPORTANCE Human norovirus (HuNoV) is the main etiological agent of viral gastroenteritis in all age classes. HuNoV infection affects mainly secretor individuals where ABO(H) and Lewis histo-blood group antigens (HBGAs) are present in the small intestine. Nonsecretor individuals, who only express Lewis (Le) antigens, are less susceptible to HuNoV infection. Here, we studied the interaction of common HuNoV genotypes (GII.3, GII.4, and GII.17) in nonsecretor individuals using synthetic viral particles. Saliva binding assays showed that only GII.4 interacted with nonsecretor saliva via the Lewis a (Lea) antigen Surprisingly, the three genotypes interacted with nonsecretor enterocytes via the Lea antigen on duodenal tissue blocks, which were more relevant for HuNoV/HBGA studies. The Lea antigen also played a pivotal role in the recognition of GII.4 and GII.17 particles by inflammatory colon tissue from a nonsecretor Crohn's disease patient. The implications of HuNoV binding in nonsecretors remain to be elucidated in physiological and pathological conditions encountered in other intestinal diseases.

Deep learning automation of MEST-C classification in IgA nephropathy.

BACKGROUND: Although the MEST-C classification is among the best prognostic tools in immunoglobulin A nephropathy (IgAN), it has a wide interobserver variability between specialized pathologists and others. Therefore we trained and evaluated a tool using a neural network to automate the MEST-C grading. METHODS: Biopsies of patients with IgAN were divided into three independent groups: the Training cohort (n = 42) to train the network, the Test cohort (n = 66) to compare its pixel segmentation to that made by pathologists and the Application cohort (n = 88) to compare the MEST-C scores computed by the network or by pathologists. RESULTS: In the Test cohort, >73% of pixels were correctly identified by the network as M, E, S or C. In the Application cohort, the neural network area under the receiver operating characteristics curves were 0.88, 0.91, 0.88, 0.94, 0.96, 0.96 and 0.92 to predict M1, E1, S1, T1, T2, C1 and C2, respectively. The kappa coefficients between pathologists and the network assessments were substantial for E, S, T and C scores (kappa scores of 0.68, 0.79, 0.73 and 0.70, respectively) and moderate for M score (kappa score of 0.52). Network S and T scores were associated with the occurrence of the composite survival endpoint (death, dialysis, transplantation or doubling of serum creatinine) [hazard ratios 9.67 (P = .006) and 7.67 (P < .001), respectively]. CONCLUSIONS: This work highlights the possibility of automated recognition and quantification of each element of the MEST-C classification using deep learning methods.

Automated evaluation with deep learning of total interstitial inflammation and peritubular capillaritis on kidney biopsies.

BACKGROUND: Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients' kidney prognoses and facilitate therapeutic management. METHODS: We used a convolutional neural network to evaluate those criteria on kidney biopsies. A total of 423 kidney samples from various diseases were included; 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. RESULTS: The precision, recall and F-score for leukocyte detection were, respectively, 81%, 71% and 76%. Regarding peritubular capillaries detection the precision, recall and F-score were, respectively, 82%, 83% and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82, respectively, all P < .0001). The areas under the receiver operating characteristics curves for the prediction of pathologists' Banff total inflammation (ti) and peritubular capillaritis (ptc) scores were respectively all above 0.94 and 0.86. The kappa coefficients between the visual and the neural networks' scores were respectively 0.74, 0.78 and 0.68 for ti ≥1, ti ≥2 and ti ≥3, and 0.62, 0.64 and 0.79 for ptc ≥1, ptc ≥2 and ptc ≥3. In a subgroup of patients with immunoglobulin A nephropathy, the inflammation severity was highly correlated to kidney function at biopsy on univariate and multivariate analyses. CONCLUSION: We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology.

High-density lipoprotein infusion protects from acute graft-versus-host disease in experimental allogeneic hematopoietic cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram-negative bacteria are well-known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein-mediated transport to the liver (i.e., the so-called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL-deficient (Apoa1tm1Unc ) recipient mice developed exacerbated aGVHD. Repeated administration of HDL isolated from human plasma significantly decreased the mortality and the severity of aGVHD. While the potential role of HDL in scavenging circulating LPS was examined in this study, it appears that HDL plays a more direct immunomodulatory role by limiting or controlling aGVHD. Notably, HDL infusion mitigated liver aGVHD by diminishing immune infiltration (e.g., interferon-γ-secreting CD8+ T cells and non-resident macrophages), systemic and local inflammation (notably cholangitis). Hence, our results revealed the interest of HDL-based therapies in the prevention of aGVHD.

Mucosal-associated invariant T cells in Giant Cell Arteritis.

This study aimed to assess the implication of mucosal-associated invariant T (MAIT) cells in GCA. Blood samples were obtained from 34 GCA patients (before and after 3 months of treatment with glucocorticoids (GC) alone) and compared with 20 controls aged >50 years. MAIT cells, defined by a CD3+CD4-TCRγδ-TCRVα7.2+CD161+ phenotype, were analyzed by flow cytometry. After sorting, we assessed the ability of MAIT cells to proliferate and produce cytokines after stimulation with anti CD3/CD28 microbeads or IL-12 and IL-18. MAIT were stained in temporal artery biopsies (TAB) by confocal microscopy. MAIT cells were found in the arterial wall of positive TABs but was absent in negative TAB. MAIT frequency among total αß-T cells was similar in the blood of patients and controls (0.52 vs. 0.57%; P = 0.43) and not modified after GC treatment (P = 0.82). Expression of IFN-γ was increased in MAIT cells from GCA patients compared to controls (44.49 vs. 32.9%; P = 0.029), and not modified after 3 months of GC therapy (P = 0.82). When they were stimulated with IL-12 and IL-18, MAIT from GCA patients produced very high levels of IFN-γ and displayed a stronger proliferation compared with MAIT from controls (proliferation index 3.39 vs. 1.4; P = 0.032). In GCA, the functional characteristics of MAIT cells are modified toward a pro-inflammatory phenotype and a stronger proliferation capability in response to IL-12 and IL-18, suggesting that MAIT might play a role in GCA pathogenesis. Our results support the use of treatments targeting IL-12/IL-18 to inhibit the IFN-γ pathway in GCA.

Heamatological malignancies in giant cell arteritis: a French population-based study.

OBJECTIVES: An increased risk of haematological malignancies (HM) has been reported in GCA patients. Our study aimed to investigate the incidence and the type of HM occurring in GCA. METHODS: All patients with GCA and HM living in Côte d'Or (France) were identified by crossing data from the RHEMCO (Registre des Hémopathies Malignes de Côte d'Or) and those having a positive temporal artery biopsy between 1 January 2001 and 31 December 2018. RESULTS: Among 276 biopsy-proven GCA patients, 14 HM were identified in 12 patients (4.3%). In comparison with the general population aged >50 y, the incidence of myeloid HM and myeloproliferative syndromes were increased in GCA patients [standardized incidence ratios (SIR) = 2.71 and 5.16, respectively], with a specific increase in men with GCA (SIR = 4.82 and 9.04, respectively) but not in women. In addition, the study of SIR depending on the chronology between GCA and HM diagnoses suggests that there was an increased risk of developing GCA in men but not in women, after a diagnosis of myeloid HM (SIR = 9.56), especially if it was a MPS (SIR = 17.56). CONCLUSIONS: Our study shows a particular epidemiology of HM in GCA patients, which is characterized by an increased incidence of myeloid HM, especially MPS, in male GCA patients. The chronology of the diagnoses of GCA and HM raises the hypothesis that clonal hematopoiesis may be implicated in some cases of GCA.

Chronic kidney disease linked to SARS-CoV-2 infection: a case report.

BACKGROUND: The recent COVID-19 pandemic has raised concerns about patient diagnosis and follow-up of chronically ill patients. Patients suffering from chronic illnesses, concomitantly infected by SARS-CoV-2, globally tend to have a worse prognosis and poor outcomes. Renal tropism and acute kidney injury following SARS-CoV-2 infection has recently been described in the literature, with elevated mortality rates. Furthermore, patients with pre-existing chronic kidney disease, infected by SARS-CoV-2, should be monitored carefully. Here, we report the case of a 69-year-old patient with splenic marginal zone lymphoma, suffering from longstanding chronic kidney disease following SARS-CoV-2 infection. CASE PRESENTATION: A 69-year-old male patient previously diagnosed with pulmonary embolism and splenic marginal zone lymphoma (Splenomegaly, Matutes 2/5, CD5 negative and CD23 positive), was admitted to the hospital with shortness of breath, fever and asthenia. A nasopharyngeal swab test was performed in addition to a CT-scan, which confirmed SARS-CoV-2 infection. Blood creatinine increased following SARS-CoV-2 infection at 130 µmol/l, with usual values at 95 µmol/l. The patient was discharged at home with rest and symptomatic medical treatment (paracetamol and hydration), then readmitted to the hospital in August 2020. A kidney biopsy was therefore conducted as blood creatinine levels were abnormally elevated. Immunodetection performed in a renal biopsy specimen confirmed co-localization of SARS-CoV2 nucleocapsid and protease 3C proteins with ACE2, Lewis x and sialyl-Lewis x antigens in proximal convoluted tubules and podocytes. Co-localization of structural and non-structural viral proteins clearly demonstrated viral replication in proximal convoluted tubules in this chronically ill patient. Additionally, we observed the co-localization of sialyl-Lewis x and ACE2 receptors in the same proximal convoluted tubules. Reverse Transcriptase-Polymerase Chain Reaction test performed on the kidney biopsy was negative, with very low Ct levels (above 40). The patient was finally readmitted to the haematology department for initiation of chemotherapy, including CHOP protocol and Rituximab. CONCLUSIONS: Our case emphasizes on the importance of monitoring kidney function in immunosuppressed patients and patients suffering from cancer following SARS-CoV-2 infection, through histological screening. Further studies will be required to decipher the mechanisms underlying chronic kidney disease and the putative role of sialyl-Lewis x and HBGA during SARS-CoV-2 infection.

[Contribution and limits of lean management in the organization and working of a pathology department]. / Apports et limites du lean management dans l'organisation et le fonctionnement d'un service de Pathologie.

INTRODUCTION: In order to validate our strategy of continuous improvement and to identify new ways to increase performance, an evaluation of all the procedures was conducted in our department using the principles of lean management. MATERIAL AND METHODS: Lean-6-sigma methodology (Gemba Walk, Value StreamMapping, spaghetti diagram, Kaizen workshop and priorization matrix) was used to analyze the procedures of the conventional and molecular sectors, and to identify bottlenecks, actions without added value and solutions. RESULTS: The audit identified bottlenecks in pre-analytical (registration), analytical (cytology, immunohistochemistry, sequencing, pathologists) and post-analytical processes (absence of secretaries, delivery of reports by mail). It underlined a suboptimal flow of people and materials, the heavy impact of an increasing work load (8%/year) in reception and microscopy even though we had outsourced, and an often critical work place schedule for technicians which prevent them from achieving tasks without added value (quality control, validation of methods and protocols) or even daily tasks (cutting, immunohistochemistry). After completing the 72 actions aimed at managing overproduction, improving working conditions and developing new activities, turn-around time was partially under control and the automation process was well advanced. DISCUSSION AND CONCLUSION: The audit validated our strategy of continuous improvement and advanced the standardization of our working conditions. Even if the turn-around time for reports was shortened, the audit initiated a positive medical and technical dynamic that should help us to implement the next steps of our reorganization (automation and extension of the department).

Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes.

PRDM16 (positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074-3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non-compaction (LVNC) with a PRDM16 variant. The third-trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly. Endocardial fibroelastosis was associated with non-compaction of the myocardium of the left ventricle. Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16. ES also identified two rare variants of unknown significance, according to the American College of Medical Genetics and Genomics guidelines, in the titin gene (TTN): a de novo missense p.(Lys14773Asn) variant and a c.33043+5A>G variant inherited from the mother. Along with the PRDM16 de novo probably pathogenic variant, TTN VOUS variants could possibly contribute to the severity and early onset of the cardiac phenotype. Because of the genetic heterogeneity of cardiomyopathies, large panels or even ES could be considered as the main approaches for the molecular diagnosis, particularly in fetal presentations, where multiple hits seem to be common.

Sudden Infant Death Associated with Rhinovirus Infection.

A less than one-month-old infant with symptoms of rhinitis died unexpectedly in his sleep. He was not born prematurely and had no known underlying disease. Cerebrospinal fluid, nasopharyngeal and lung samples, and rectal swab were found to be positive for subgroup A rhinovirus, while the blood was negative. This case highlights the important finding that the rhinovirus, a common pathogen associated with upper respiratory tract infections, can sometimes, as the only pathogen, lead to complications such as a cerebrospinal infection and be involved in the sudden infant death syndrome (SIDS). Vigilance is necessary in case of viral infections in the infant's environment, and measures of hygiene and protection must be encouraged in order to reduce the risk of the SIDS.

Recognition of intraglomerular histological features with deep learning in protocol transplant biopsies and their association with kidney function and prognosis.

Background: The Banff Classification may not adequately address protocol transplant biopsies categorized as normal in patients experiencing unexplained graft function deterioration. This study seeks to employ convolutional neural networks to automate the segmentation of glomerular cells and capillaries and assess their correlation with transplant function. Methods: A total of 215 patients were categorized into three groups. In the Training cohort, glomerular cells and capillaries from 37 patients were manually annotated to train the networks. The Test cohort (24 patients) compared manual annotations vs automated predictions, while the Application cohort (154 protocol transplant biopsies) examined predicted factors in relation to kidney function and prognosis. Results: In the Test cohort, the networks recognized histological structures with Precision, Recall, F-score and Intersection Over Union exceeding 0.92, 0.85, 0.89 and 0.74, respectively. Univariate analysis revealed associations between the estimated glomerular filtration rate (eGFR) at biopsy and relative endothelial area (r = 0.19, P = .027), endothelial cell density (r = 0.20, P = .017), mean parietal epithelial cell area (r = -0.38, P < .001), parietal epithelial cell density (r = 0.29, P < .001) and mesangial cell density (r = 0.22, P = .010). Multivariate analysis retained only endothelial cell density as associated with eGFR (Beta = 0.13, P = .040). Endothelial cell density (r = -0.22, P = .010) and mean podocyte area (r = 0.21, P = .016) were linked to proteinuria at biopsy. Over 44 ± 29 months, 25 patients (16%) reached the primary composite endpoint (dialysis initiation, or 30% eGFR sustained decline), with relative endothelial area, mean endothelial cell area and parietal epithelial cell density below medians linked to this endpoint [hazard ratios, respectively, of 2.63 (P = .048), 2.60 (P = .039) and 3.23 (P = .019)]. Conclusion: This study automated the measurement of intraglomerular cells and capillaries. Our results suggest that the precise segmentation of endothelial and epithelial cells may serve as a potential future marker for the risk of graft loss.

Case Report: Giant insulinoma, a very rare tumor causing hypoglycemia.

Insulinomas, with an incidence of 4 cases per million individuals per year, remain amongst the most frequent functional neuroendocrine tumors. The usual diameter of insulinomas usually remains under 3 cm of major axis. However, 44 exceptional cases of "giant insulinomas", have been reported worldwide, generally exceeding 9 cm in major axis. In this article, we report the case of a 38-year-old woman whom suffered from chronic hypoglycemia despite treatment with diazoxide. Abdominal CT-scan revealed a 88 x 73 mm mass located at the tail of the pancreas. Following surgical excision, histopathological analysis confirmed G1 neuroendocrine tumor, with focal cytoplasmic expression of insulin in tumor cells. After a 16-month follow-up period, the patient didn't address any specific complaint, and no disease recurrence and/or metastasis were observed. A 68Ga-DOTATATE-PET scan was performed 6 months after surgery, which came back normal. Genetic evaluation has not been performed in our patient. The physiopathology of giant insulinomas remain unexplained, however with possible relationship with type 1 multiple endocrine neoplasia, sporadic somatic YY1 mutations and possible transformation of bulky non-functional pancreatic neuroendocrine tumors to a functional phenotype, with slow insulin secretion. While giant insulinomas remain rare in the literature, multicentric genetic analysis of tumor samples might reveal unique features of this rare subtype of neuroendocrine pancreatic tumors. Insulinomas of large size tend to have greater malignancy and higher rates of invasiveness. Careful follow-up, especially for liver and lymph node metastases, must be performed using functional imaging techniques to avoid disease relapse.

Biomechanical properties of 3D printable material usable for synthetic personalized healthy human aorta.

With the development of three-dimensional (3D) printing, 3D-printed products have been widely used in medical fields, such as plastic surgery, orthopedics, dentistry, etc. In cardiovascular research, 3D-printed models are becoming more realistic in shape. However, from a biomechanical point of view, only a few studies have explored printable materials that can represent the properties of the human aorta. This study focuses on 3D-printed materials that might simulate the stiffness of human aortic tissue. First, the biomechanical properties of a healthy human aorta were defined and used as reference. The main objective of this study was to identify 3D printable materials that possess similar properties to the human aorta. Three synthetic materials, NinjaFlex (Fenner Inc., Manheim, USA), FilasticTM (Filastic Inc., Jardim Paulistano, Brazil), and RGD450+TangoPlus (Stratasys Ltd.©, Rehovot, Israel), were printed in different thicknesses. Uniaxial and biaxial tensile tests were performed to compute several biomechanical properties, such as thickness, stress, strain, and stiffness. We found that with the mixed material RGD450+TangoPlus, it was possible to achieve a similar stiffness to healthy human aorta. Moreover, the 50-shore-hardness RGD450+TangoPlus had similar thickness and stiffness to the human aorta.

Human monocyte-derived suppressive cells (HuMoSC) for cell therapy in giant cell arteritis.

Introduction: The pathogenesis of Giant Cell Arteritis (GCA) relies on vascular inflammation and vascular remodeling, the latter being poorly controlled by current treatments. Methods: This study aimed to evaluate the effect of a novel cell therapy, Human Monocyte-derived Suppressor Cells (HuMoSC), on inflammation and vascular remodeling to improve GCA treatment. Fragments of temporal arteries (TAs) from GCA patients were cultured alone or in the presence of HuMoSCs or their supernatant. After five days, mRNA expression was measured in the TAs and proteins were measured in culture supernatant. The proliferation and migration capacity of vascular smooth muscle cells (VSMCs) were also analyzed with or without HuMoSC supernatant. Results: Transcripts of genes implicated in vascular inflammation (CCL2, CCR2, CXCR3, HLADR), vascular remodeling (PDGF, PDGFR), angiogenesis (VEGF) and extracellular matrix composition (COL1A1, COL3A1 and FN1) were decreased in arteries treated with HuMoSCs or their supernatant. Likewise, concentrations of collagen-1 and VEGF were lower in the supernatants of TAs cultivated with HuMoSCs. In the presence of PDGF, the proliferation and migration of VSMCs were both decreased after treatment with HuMoSC supernatant. Study of the PDGF pathway suggests that HuMoSCs act through inhibition of mTOR activity. Finally, we show that HuMoSCs could be recruited in the arterial wall through the implication of CCR5 and its ligands. Conclusion: Altogether, our results suggest that HuMoSCs or their supernatant could be useful to decrease vascular in flammation and remodeling in GCA, the latter being an unmet need in GCA treatment.

Temporal Artery Vascular Diseases.

In the presence of temporal arteritis, clinicians often refer to the diagnosis of giant cell arteritis (GCA). However, differential diagnoses should also be evoked because other types of vascular diseases, vasculitis or not, may affect the temporal artery. Among vasculitis, Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is probably the most common, and typically affects the peri-adventitial small vessel of the temporal artery and sometimes mimics giant cell arteritis, however, other symptoms are frequently associated and more specific of ANCA-associated vasculitis prompt a search for ANCA. The Immunoglobulin G4-related disease (IgG4-RD) can cause temporal arteritis as well. Some infections can also affect the temporal artery, primarily an infection caused by the varicella-zoster virus (VZV), which has an arterial tropism that may play a role in triggering giant cell arteritis. Drugs, mainly checkpoint inhibitors that are used to treat cancer, can also trigger giant cell arteritis. Furthermore, the temporal artery can be affected by diseases other than vasculitis such as atherosclerosis, calcyphilaxis, aneurysm, or arteriovenous fistula. In this review, these different diseases affecting the temporal artery are described.

Case report: Umbilical vessel aneurysm thrombosis and factor V Leiden mutation leading to fetal demise.

Complicated pregnancies are nowadays a major public health concern, with possible lethality or sequelae both for the mother and the fetus. Blood coagulation disorders (including antiphospholipid syndrome, factor V Leiden mutation and antithrombin deficiency) and hypertensive gestational disorders are very well-known contributors of complicated pregnancies with poor fetal outcome, such as intrauterine growth retardation (IUGR) and fetal demise. Less commonly, vascular malformations of the placenta can also potentially lead to serious complications such as IUGR and fetal death. These malformations include hypercoiled umbilical cord, umbilical cord knot, umbilical cord varix, umbilical cord arterial or venous aneurysm, and velamentous insertion of the umbilical cord potentially leading to Benckiser's hemorrhage. Here, we report the case of a 29-year-old Gravida 2 Para 0 mother with previous history of stillbirth and smoking, admitted to the obstetrics department for the absence of fetal movement at 38 weeks of amenorrhea (WA). First-trimester and second-trimester routine ultrasounds were otherwise normal. Ultrasound performed at 38 WA revealed a 83 × 66 × 54 mm cystic heterogenous mass at the umbilical cord insertion. After delivery, fetal and placental pathology as well as maternal blood testing were performed. Fetal pathology was otherwise normal, except for diffuse congestion and meconial overload suggesting acute fetal distress. Fetal karyotype was normal (46 XX). Placental pathology revealed an umbilical artery aneurysm (UAA) at the base of the insertion of the umbilical cord, lined with a CD34+ CD31+ endothelium. After dissection, the aneurysm was filled with hemorrhagic debris, indicating aneurysm thrombosis. Histopathology revealed associated maternal vascular malperfusion (MVM) and increased peri-villous fibrin (IPF). Maternal blood tests revealed heterozygous factor V Leiden mutation, without other associated auto-immune conditions (such as antiphospholipid syndrome). Umbilical artery aneurysms remain extremely rare findings in the placenta, with <20 reported cases. Umbilical artery aneurysms have tendency to be located at the base of the insertion of the placenta, and lead to fetal demise in more than 60% of cases, mainly due to aneurysmal thrombosis, hematoma, possible vascular compression and/or rupture. Umbilical vessel aneurysms can be associated with trisomy 18 or 13. In our case, the association of factor V Leiden mutation, a hypercoagulable state, with UAA could explain massive thrombosis of the aneurysmal lumen and sudden fetal demise. Further consideration of current guidelines for surveillance and management of UAA would allow appropriate planned delivery in maternal care settings.