Publications by authors named "Natalie Patey"

29 Publications

  • Page 1 of 1

FcγRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus.

Blood 2020 Dec;136(25):2933-2945

Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Québec, QC, Canada.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (ICs) in organs and tissues. The expression of FcγRIIA by human platelets, which is their unique receptor for immunoglobulin G antibodies, positions them to ideally respond to circulating ICs. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE remain unknown. Here, we evaluated the involvement of FcγRIIA in the course of SLE and platelet activation. In patients with SLE, levels of ICs are associated with platelet activation. Because FcγRIIA is absent in mice, and murine platelets do not respond to ICs in any existing mouse model of SLE, we introduced the FcγRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcγRIIA expression by bone marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcγRIIA-expressing and nonexpressing mice, but enrichment for type I interferon response gene changes was specifically observed in the FcγRIIA mice. Moreover, circulating platelets were degranulated and were found to interact with neutrophils in FcγRIIA-expressing lupus mice. FcγRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be used to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcγRIIA in nephritis and in platelet activation in SLE.
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http://dx.doi.org/10.1182/blood.2020004974DOI Listing
December 2020

Mesenchymal chondrosarcoma of the orbit masquerading as a hemophilic pseudotumor.

Orbit 2020 Aug 24:1-4. Epub 2020 Aug 24.

Department of Ophthalmology, Université de Montreal , Montreal, Quebec, Canada.

An 11-year-old boy presented with a lesion of the right orbit that was thought to be a hemophilic pseudotumor. Excisional biopsy revealed an unexpected diagnosis of mesenchymal chondrosarcoma. Both mesenchymal chondrosarcoma and hemophilic pseudotumor of the orbit are exceedingly rare. To the best of our knowledge, this is the first reported case of orbital mesenchymal chondrosarcoma masquerading as hemophilic pseudotumor.
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http://dx.doi.org/10.1080/01676830.2020.1812093DOI Listing
August 2020

FcγRIIA expression aggravates nephritis and increases platelet activation in systemic lupus erythematosus in mice.

Blood 2020 Aug 7. Epub 2020 Aug 7.

CHU de Quebec, Quebec, Quebec, Canada.

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease characterized by deposits of immune complexes (IC) in organs and tissues. The expression of FcγRIIA by human platelets, which is their unique receptor for IgG antibodies, positions them to ideally respond to circulating IC. Whereas chronic platelet activation and thrombosis are well-recognized features of human SLE, the exact mechanisms underlying platelet activation in SLE are still unknown. Here, we evaluated the involvement of FcγRIIA in the course of SLE and platelet activation. In SLE patients, levels of IC are associated with platelet activation. As FcγRIIA is absent in mice and murine platelets do not respond to IC in any existing mouse model of SLE, we introduced the FcγRIIA (FCGR2A) transgene into the NZB/NZWF1 mouse model of SLE. In mice, FcγRIIA expression by bone-marrow cells severely aggravated lupus nephritis and accelerated death. Lupus onset initiated major changes to the platelet transcriptome, both in FcγRIIA-expressing and non-expressing mice, but an enrichment for type-I interferon response gene changes was specifically observed in the FcγRIIA mice. Moreover, circulating platelet were degranulated and were found interacting with neutrophils in FcγRIIA expressing lupus mice. FcγRIIA expression in lupus mice also led to thrombosis in lungs and kidneys. The model recapitulates hallmarks of human SLE and can be utilized to identify contributions of different cellular lineages in the manifestations of SLE. The study further reveals a role for FcγRIIA in nephritis and in platelet activation in SLE.
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http://dx.doi.org/10.1182/blood.2020004974DOI Listing
August 2020

Clinical relevance of membrane attack complex deposition in children with IgA nephropathy and Henoch-Schönlein purpura.

Pediatr Nephrol 2020 05 13;35(5):843-850. Epub 2020 Jan 13.

Department of Pathology, CHU Sainte Justine, 3175 Chemin Côte Sainte Catherine, Montréal, Québec, H3T 1C5, Canada.

Background: IgA nephropathy (IgAN) and Henoch-Schönlein purpura are common glomerular disorders in children sharing the same histopathologic pattern of IgA deposits within the mesangium, even if their physiopathology may be different. Repeated exposure to pathogens induces the production of abnormal IgA1. The immune complex deposition in the renal mesangium in IgAN or potentially in small vessels in Henoch-Schönlein purpura induces complement activation via the alternative and lectin pathways. Recent studies suggest that levels of membrane attack complex (MAC) in the urine might be a useful indicator of renal injury. Because of the emerging availability of therapies that selectively block complement activation, the aim of the present study is to investigate whether MAC immunostaining might be a useful marker of IgA-mediated renal injury.

Methods: We conducted immunohistochemistry analysis of the MAC on renal biopsies from 67 pediatric patients with IgAN and Henoch-Schönlein purpura. We classified their renal biopsies according to the Oxford classification, retrieved symptoms, biological parameters, treatment, and follow-up.

Results: We found MAC expression was significantly related to impaired renal function and patients whose clinical course required therapy. MAC deposits tend to be more abundant in patients with decreased glomerular filtration rate (p = 0.02), patients with proteinuria > 0.750 g/day/1.73 m, and with nephrotic syndrome. No correlation with histological alterations was observed.

Conclusions: We conclude that MAC deposition could be a useful additional indicator of renal injury in patients with IgAN and Henoch-Schönlein purpura, independent of other indicators.
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http://dx.doi.org/10.1007/s00467-019-04445-xDOI Listing
May 2020

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers.

JAMA Netw Open 2019 04 5;2(4):e192906. Epub 2019 Apr 5.

Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Québec, Canada.

Importance: Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-to-treat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases.

Objective: To assess the feasibility of identifying potentially actionable mutations using next-generation sequencing-based assays in a clinically relevant time frame.

Design, Setting, And Participants: This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board.

Main Outcomes And Measures: Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies.

Results: A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken.

Conclusions And Relevance: Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, including targeted therapy and clinically relevant information of diagnostic, prognostic, and monitoring significance.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487576PMC
April 2019

Severe Acute Kidney Injury and Multiple Organ Failure in a 17-Day-Old Newborn: When Pathology Makes the Difference.

Can J Kidney Health Dis 2018 6;5:2054358118804834. Epub 2018 Oct 6.

Division of Nephrology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, QC, Canada.

Rationale: Acute tubulointerstitial nephritis (ATIN) in children is most commonly due to allergic drug reactions. In neonates, diagnosis of ATIN is clinically suspected and a kidney biopsy is not routinely performed.

Presenting Concern: A 17-day-old newborn presented with vomiting and dehydration, along with anuric acute kidney injury, severe electrolyte disturbances, hypocomplementemia, and thrombocytopenia. Abdominal ultrasound revealed bilateral nephromegaly and hepatosplenomegaly. The patient was promptly started on intravenous (IV) fluid and broad-spectrum antibiotics. His electrolyte disturbances were corrected as per standard guidelines. The rapid progressive clinical deterioration despite maximal treatment and the unclear etiology influenced the decision to proceed to a kidney biopsy. Histopathological findings revealed diffuse interstitial edema with a massive polymorphic cellular infiltrate and destruction of tubular structures, consistent with severe ATIN. Elements of thrombotic microangiopathy (TMA) were observed.

Diagnosis: The clinical presentation combined with imaging and histopathological findings was suggestive of ATIN caused by a severe acute bacterial pyelonephritis.

Intervention: Methylprednisolone pulses followed by oral prednisolone were administered. Antibiotics were continued for 10 days. The patient was kept on invasive mechanical ventilation and on peritoneal dialysis for 12 days.

Outcome: His condition stabilized following steroid pulses. His renal function progressively improved, and renal replacement therapy was weaned off. His renal ultrasound normalized. He has maintained a normal blood pressure, urinalysis, and renal function over the past 5 years.

Novel Finding: This case reports a severe presentation of acute bacterial pyelonephritis in a neonate. It highlighted the involvement of complement activation in severe infectious process. Histopathological findings of ATIN and TMA played a crucial role in understanding the physiopathology and severity of the disease.
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http://dx.doi.org/10.1177/2054358118804834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174648PMC
October 2018

Caspase-3 Is a Pivotal Regulator of Microvascular Rarefaction and Renal Fibrosis after Ischemia-Reperfusion Injury.

J Am Soc Nephrol 2018 07 20;29(7):1900-1916. Epub 2018 Jun 20.

Research Centre, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada;

Ischemia-reperfusion injury (IRI) is a major risk factor for chronic renal failure. Here, we characterize the different modes of programmed cell death in the tubular and microvascular compartments during the various stages of IRI-induced AKI, and their relative importance to renal fibrogenesis. We performed unilateral renal artery clamping for 30 minutes and contralateral nephrectomy in wild-type mice (C57BL/6) or caspase-3 mice. Compared with their wild-type counterparts, caspase-3 mice in the early stage of AKI had high urine cystatin C levels, tubular injury scores, and serum creatinine levels. Electron microscopy revealed evidence of tubular epithelial cell necrosis in caspase-3 mice, and immunohistochemistry showed upregulation of the necroptosis marker receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in renal cortical sections. Western blot analysis further demonstrated enhanced levels of phosphorylated RIPK3 in the kidneys of caspase-3 mice. In contrast, caspase-3 mice had less microvascular congestion and activation in the early and extension phases of AKI. In the long term (3 weeks after IRI), caspase-3 mice had reduced microvascular rarefaction and renal fibrosis, as well as decreased expression of -smooth muscle actin and reduced collagen deposition within peritubular capillaries. Moreover, caspase-3 mice exhibited signs of reduced tubular ischemia, including lower tubular expression of hypoxia-inducible factor-1 and improved tubular injury scores. These results establish the pivotal importance of caspase-3 in regulating microvascular endothelial cell apoptosis and renal fibrosis after IRI. These findings also demonstrate the predominant role of microvascular over tubular injury as a driver of progressive renal damage and fibrosis after IRI.
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http://dx.doi.org/10.1681/ASN.2017050581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050936PMC
July 2018

Apple peel polyphenols reduce mitochondrial dysfunction in mice with DSS-induced ulcerative colitis.

J Nutr Biochem 2018 07 21;57:56-66. Epub 2018 Mar 21.

Research Centre, CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada, H3T 1C5; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada, H3T 1C5; Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec, Quebec, Canada, G1V 0A6; Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4. Electronic address:

Inflammatory bowel diseases (IBDs) are multifaceted and relapsing immune disorders, which necessitate long-term dependence on powerful drugs. As the use of natural product-based therapies has emerged as a promising intervention, the present study aimed to further characterize dried apple peel powder (DAPP) mechanisms of action and evaluate the preventive and curative effects of DAPP on mitochondrial functions in a murine model. Induction of intestinal inflammation in mice is performed by oral administration of the dextran sodium sulfate (DSS) at 2.5% for 10 days. Doses of DAPP (200 or 400 mg/kg/day) were administered by gavage for 10 days pre- and 1 day after colitis induction simultaneously with DSS treatment for a period of 10 days. The preventive (200 mg/kg/day) and therapeutic (400 mg/kg/day) doses of DAPP limited DSS-induced histological lesions, improved macroscopic parameters and attenuated clinical signs. DAPP at the same conditions reduced massive infiltration of inflammatory cells and concomitantly displayed a robust potential of counteracting inflammation and oxidative stress in DSS mice. Moreover, DAPP partially restored mitochondrial abnormalities related to size, density, redox homeostasis, fatty acid β-oxidation, ATP synthesis, apoptosis and regulatory mitochondrial transcription factors. Our findings demonstrate the preventive and therapeutic impact of DAPP on experimental colitis while underlying the role of mitochondria. They also suggest that this natural DAPP product may represent an interesting candidate for further studies on the prevention/treatment of IBD.
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http://dx.doi.org/10.1016/j.jnutbio.2018.03.008DOI Listing
July 2018

NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.

Genes Chromosomes Cancer 2018 06 28;57(6):311-319. Epub 2018 Mar 28.

Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.

The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (∼10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60%-70% of cases and include RBM15-MKL1, CBFA2T3-GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners. We report a novel NUP98-BPTF fusion in an infant presenting with primary refractory AMKL. In this NUP98r, the C-terminal chromatin recognition modules of BPTF, a core subunit of the NURF (nucleosome remodeling factor) ATP-dependent chromatin-remodeling complex, are fused to the N-terminal moiety of NUP98, creating an in frame NUP98-BPTF fusion, with structural homology to NUP98-KDM5A. The leukemic blasts expressed two NUP98-BPTF splicing variants, containing one or two tandemly spaced PHD chromatin reader domains. Our study also identified an unreported wild type BPTF splicing variant encoding for 2 PHD domains, detected both in normal cord blood CD34 cells and in leukemic blasts, as with the fly BPTF homolog, Nurf301. Disease course was marked by rapid progression and primary chemoresistance, with ultimately significant tumor burden reduction following treatment with a clofarabine containing regimen. In sum, we report 2 novel NUP98-BPTF fusion isoforms that contribute to refine the NUP98r subgroup of pediatric AMKL. Multicenter clinical trials are critically required to determine the frequency of this fusion in AMKL patients and explore innovative treatment strategies for a disease still plagued with poor outcomes.
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http://dx.doi.org/10.1002/gcc.22532DOI Listing
June 2018

Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.

Genet Med 2018 07 26;20(7):745-753. Epub 2017 Oct 26.

CHU Sainte-Justine, Montreal, Quebec, Canada.

Purpose: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies.

Methods: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia.

Results: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort.

Conclusion: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.
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http://dx.doi.org/10.1038/gim.2017.173DOI Listing
July 2018

H Syndrome: A Rare Genodermatosis Imaged With 18F-FDG PET/CT.

Clin Nucl Med 2018 Jan;43(1):36-37

H syndrome (OMIM 612391) is an extremely rare autosomal recessive genodermatosis, characterized by extensive skin infiltration. We report a case imaged with F-FDG PET/CT.
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http://dx.doi.org/10.1097/RLU.0000000000001896DOI Listing
January 2018

[All large necrotic and hemorrhagic kidney tumors in children are not necessarily malignant: A case of a 7-month-old child].

Ann Pathol 2017 Dec 21;37(6):474-478. Epub 2017 Nov 21.

Département de pathologie, CHU Sainte-Justine, 3175, côte-de-Sainte-Catherine, H3T 1C5 Montréal, Canada.

We report the case of a large tumor in the left kidney with necrotic and hemorrhagic features in a 7-month-old child, which was clinically and radiologically suggestive of a nephroblastoma. The tumor was a nodular mass measuring 8cm in diameter occupying two thirds of the kidney and presenting areas of necrosis and hemorrhage. No capsular rupture or renal sinus infiltration were found. Adjacent renal parenchyma appeared mascroscopically normal. Histologically, the tumor showed a strictly tubulopapillary architectural pattern with numerous psammomas. The initial hypothesis was a purely epithelial nephroblastoma. However, this hypothesis was rejected due to some immunohistochemical and histological characteristics and the final diagnosis was a metanephric adenoma. Metanephric adenoma is an exceptionally rare benign renal tumor in children. However, pathologists need to keep it in mind because simple surgical excision is curative.
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http://dx.doi.org/10.1016/j.annpat.2017.10.002DOI Listing
December 2017

Disrupted apical exocytosis of cargo vesicles causes enteropathy in FHL5 patients with Munc18-2 mutations.

JCI Insight 2017 Jul 20;2(14). Epub 2017 Jul 20.

Division of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria.

Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5-associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied. Morphology of duodenal sections was analyzed by electron and fluorescence microscopy. Small intestinal enterocytes and organoid-derived monolayers displayed the subcellular characteristics of MVID. For the analyses of Munc18-2-dependent SNARE-protein interactions, a Munc18-2 CaCo2-KO model cell line was generated by applying CRISPR/Cas9 technology. Munc18-2 is required for Slp4a/Stx3 interaction in fusion of cargo vesicles with the apical plasma membrane. Cargo trafficking was investigated in patient biopsies, patient-derived organoids, and the genome-edited model cell line. Loss of Munc18-2 selectively disrupts trafficking of certain apical brush-border proteins (NHE3 and GLUT5), while transport of DPPIV remained unaffected. Here, we describe the molecular mechanism how the loss of function of Munc18-2 leads to cargo-selective mislocalization of brush-border components and a subapical accumulation of cargo vesicles, as it is known from the loss of polarity phenotype in MVID.
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http://dx.doi.org/10.1172/jci.insight.94564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518552PMC
July 2017

Apple peel polyphenols: a key player in the prevention and treatment of experimental inflammatory bowel disease.

Clin Sci (Lond) 2016 12 14;130(23):2217-2237. Epub 2016 Sep 14.

Research Centre, CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada, H3T 1C5

Diets rich in fruits and vegetables may reduce oxidative stress (OxS) and inflammation via several mechanisms. These beneficial effects may be due to their high polyphenol content. The aims of the present study are to evaluate the preventive and therapeutic aspects of polyphenols in dried apple peel powder (DAPP) on intestinal inflammation while elucidating the underlying mechanisms and clinical benefits. Induction of intestinal inflammation in mice was performed by oral administration of the inflammatory agent dextran sulfate sodium (DSS) at 2.5% for 10 days. Physiological and supraphysiological doses of DAPP (200 and 400 mg/kg/day respectively) were administered by gavage for 10 days pre- and post-DSS treatment. DSS-mediated inflammation caused weight loss, shortening of the colon, dystrophic detachment of the epithelium, and infiltration of mono- and poly-morphonuclear cells in the colon. DSS induced an increase in lipid peroxidation, a down-regulation of antioxidant enzymes, an augmented expression of myeloperoxidase (MPO) and cyclooxygenase-2 (COX-2), an elevated production of prostaglandin E2 (PGE2) and a shift in mucosa-associated microbial composition. However, DAPP normalized most of these abnormalities in preventive or therapeutic situations in addition to lowering inflammatory cytokines while stimulating antioxidant transcription factors and modulating other potential healing pathways. The supraphysiological dose of DAPP in therapeutic situations also improved mitochondrial dysfunction. Relative abundance of Peptostreptococcaceae and Enterobacteriaceae bacteria was slightly decreased in DAPP-treated mice. In conclusion, DAPP exhibits powerful antioxidant and anti-inflammatory action in the intestine and is associated with the regulation of cellular signalling pathways and changes in microbiota composition. Evaluation of preventive and therapeutic effects of DAPP may be clinically feasible in individuals with intestinal inflammatory bowel diseases.
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http://dx.doi.org/10.1042/CS20160524DOI Listing
December 2016

Can Monitoring Fetal Intestinal Inflammation Using Heart Rate Variability Analysis Signal Incipient Necrotizing Enterocolitis of the Neonate?

Pediatr Crit Care Med 2016 Apr;17(4):e165-76

1Department of Obstetrics-Gynaecology, CHU Sainte-Justine Research Centre, l'Universite de Montréal, Montréal, QC, Canada. 2Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montréal, QC, Canada. 3Dynamical Analysis Laboratory, Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, ON, Canada. 4Department of Clinical Sciences, Faculty of veterinary medicine, Université de Montréal, St-Hyacinthe, QC, Canada. 5Division of Pathology, CHU Sainte-Justine, Montréal, QC, Canada. 6Dynamical Analysis Laboratory, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. 7Centre de recherche en reproduction animale, l'Université de Montréal, St-Hyacinthe, QC, Canada. 8Department of Neurosciences, l'Université de Montréal, Montreal, QC, Canada.

Objective: Necrotizing enterocolitis of the neonate is an acute inflammatory intestinal disease that can cause necrosis and sepsis. Chorioamnionitis is a risk factor of necrotizing enterocolitis. The gut represents the biggest vagus-innervated organ. Vagal activity can be measured via fetal heart rate variability. We hypothesized that fetal heart rate variability can detect fetuses with incipient gut inflammation.

Design: Prospective animal study.

Setting: University research laboratory.

Subjects: Chronically instrumented near-term fetal sheep (n = 21).

Measurements And Main Results: Animals were surgically instrumented with vascular catheters and electrocardiogram to allow manipulation and recording from nonanesthetized animals. In 14 fetal sheep, inflammation was induced with lipopolysaccharide (IV) to mimic chorioamnionitis. Fetal arterial blood samples were drawn at selected time points over 54 hours post lipopolysaccharide for blood gas and cytokines (interleukin-6 and tumor necrosis factor-α enzymelinked immunosorbent assay). Fetal heart rateV was quantified throughout the experiment. The time-matched fetal heart rate variability measures were correlated to the levels of interleukin-6 and tumor necrosis factor-α. Upon necropsy, ionized calcium binding adaptor molecule 1+ (Iba1+), CD11c+ (M1), CD206+ (M2 macrophages), and occludin (leakiness marker) immunofluorescence in the terminal ileum was quantified along with regional Iba1+ signal in the brain (microglia). Interleukin-6 peaked at 3 hours post lipopolysaccharide accompanied by mild cardiovascular signs of sepsis. At 54 hours, we identified an increase in Iba1+ and, specifically, M1 macrophages in the ileum accompanied by increased leakiness, with no change in Iba1 signal in the brain. Preceding this change on tissue level, at 24 hours, a subset of nine fetal heart rate variability measures correlated exclusively to the Iba+ markers of ileal, but not brain, inflammation. An additional fetal heart rate variability measure, mean of the differences of R-R intervals, correlated uniquely to M1 ileum macrophages increasing due to lipopolysaccharide.

Conclusions: We identified a unique subset of fetal heart rate variability measures reflecting 1.5 days ahead of time the levels of macrophage activation and increased leakiness in terminal ileum. We propose that such subset of fetal heart rate variability measures reflects brain-gut communication via the vagus nerve. Detecting such noninvasively obtainable organ-specific fetal heart rate variability signature of inflammation would alarm neonatologists about neonates at risk of developing necrotizing enterocolitis and sepsis. Clinical validation studies are required.
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http://dx.doi.org/10.1097/PCC.0000000000000643DOI Listing
April 2016

Revisiting Pathological Criteria for Earlier Diagnosis of Coeliac Disease.

J Pediatr Gastroenterol Nutr 2016 05;62(5):734-8

*Département de Pathologie †Unité de Recherche clinique appliquée ‡Département de Gastroentérologie Hépatologie et Nutrition §Département de Biochimie, CHU Sainte-Justine, Montréal, QC, Canada.

Objectives: The diagnosis of coeliac disease (CD) remains sometimes difficult because the histological criteria are not fully met. The aim of this study was to refine histological diagnostic criteria of CD.

Methods: One hundred seventy-five duodenal bulb D1 (n = 79) and duodenal D2 (n = 96) biopsies of 96 patients with CD (58 girls, mean age 7 years), 135 normal D2 biopsies (69 girls, mean age 12 years), and 64 D2 biopsies of other digestive disorders (DDs) (39 girls, mean age 13 years) obtained from children during a period of 4 years were reviewed.

Results: Interobserver agreement was greater for the classification of Corazza-Villanacci than for Marsh-Oberhuber (κ = 0.812 vs κ = 0.409, respectively). Between 40 and 70 intraepithelial lymphocytes (IELs) per 100 epithelial cells (ECs), 32% of patients were CD, whereas 50% had other DD. Above 70 IELs per 100 EC, 53% were CD, and only 6% had other DD. In CD, IELs were significantly located above EC nuclei compared with other DD, (12 IELs/100 EC vs 2 IELs/100 EC, respectively). In 21% of CD cases, D2 were normal and the diagnosis could only be made on D1. Finally, 6% of CD cases showed isolated increase of IELs in D1 without architectural modification.

Conclusions: D1 allowed diagnosis of CD in 21% of cases and IEL >70 per 100 EC correlated strongly with CD. Between 40 and 70 IELs per 100 EC, CD is very likely but other DD must be considered. Finally, the preferential localisation of IELs above EC nuclei favours CD, and increased IEL in D1 may be the sole abnormality.
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http://dx.doi.org/10.1097/MPG.0000000000001026DOI Listing
May 2016

Isolated thymic Langerhans cell histiocytosis discovered on F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT).

Pediatr Radiol 2015 Nov 9;45(12):1870-3. Epub 2015 Jul 9.

Pathology, CHU Sainte-Justine, Montréal, Canada.

The thymic infiltration in young patients with multisystemic Langerhans cell histiocytosis and its radiologic features are well known. However, isolated thymic disease has seldom been reported in the literature. We report the case of a 10-month-old child admitted for fever of unknown origin. Whole-body F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) was performed to identify a focus of infection. It demonstrated an unusual aspect of the thymus, which led to further investigation and revealed isolated infiltration of the thymus by Langerhans cell histiocytosis. The patient was treated accordingly and is now disease free. As evaluation of Langerhans cell histiocytosis patients with F-18 FDG PET/CT is becoming more frequent, it is important to be aware of the scintigraphical characteristics of thymic Langerhans cell histiocytosis.
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http://dx.doi.org/10.1007/s00247-015-3409-6DOI Listing
November 2015

Conserved Telomere Length in Human Ectopic Thyroids: An Argument Against Premature Differentiation Causing Arrested Migration.

Thyroid 2015 Sep 3;25(9):1050-4. Epub 2015 Aug 3.

1 Endocrinology Service and Research Center, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal , Montreal, Canada .

Background: In humans, the cause of arrested migration of the median thyroid anlage resulting in an ectopic sublingual gland is unknown. These ectopic glands have a normal follicular architecture but their thyrotropin-induced growth is insufficient, leading to congenital hypothyroidism in the vast majority of affected subjects. We hypothesized that arrested migration is due to premature differentiation [reflected by decreased telomere length (TL)], as observed in neural tube defects in mice.

Methods: Absolute TL and telomerase reverse transcriptase (hTERT) expression was measured in four ectopic and six orthotopic thyroids. TL was measured by quantitative polymerase chain reaction of genomic DNA, whereas hTERT expression was measured by quantitative polymerase chain reaction of total RNA.

Results: The mean±standard deviation TL (in kilobases per diploid genome) was 140.45±40.07 in ectopic and 97.50±30.48 in orthotopic thyroids (p=0.12). Expression of hTERT was quiescent in both ectopic and orthotopic thyroids.

Conclusions: Compared with orthotopic thyroids, TL shortening is not observed in ectopic thyroid tissues and, consequently, no compensatory hTERT expression was measured. This makes premature differentiation an unlikely cause of arrested migration and it suggests, indirectly, that ectopic thyroids are not at higher risk of cancer than orthotopic thyroids.
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http://dx.doi.org/10.1089/thy.2015.0204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746059PMC
September 2015

A case of C3 glomerulonephritis successfully treated with eculizumab.

Pediatr Nephrol 2015 Jun 22;30(6):1033-7. Epub 2015 Mar 22.

Department of Pediatrics, Division of Nephrology, CHU Sainte Justine and University of Montreal, 3175 Côte Sainte Catherine, H3T1C5, Montreal, QC, Canada.

Background: C3 glomerulonephritis (C3GN) is a rare form of glomerulopathy that is characterized by predominant C3 deposits. Eculizumab, a humanized monoclonal C5 antibody, has recently emerged as a treatment option for C3GN. We report a C3GN patient successfully treated with eculizumab.

Case Diagnosis/treatment: A 5-year-old boy who presented with proteinuria, hematuria, high ASO titers, and low C3 levels was initially diagnosed with post-streptococcal GN. His first kidney biopsy confirmed this diagnosis, but complement investigations identified three alternative pathway dysregulation factors: C3 nephritic factor, complement factor I heterozygous mutation (I398L), and anti-factor H autoantibodies (4,500 AU/ml). A second biopsy performed 11 months after initial presentation (nephrotic range proteinuria) showed a C3GN suggestive of isolated C3 deposits. Despite the use of intensive immunosuppressive therapy (rituximab, corticosteroids, mycophenolate), nephrotic-range proteinuria persisted and a third kidney biopsy showed the same C3GN pattern with more endocapillary proliferation. The serum C5b-9 level was elevated. Eculizumab was initiated and resulted in a significant decline of proteinuria (5.3 to 1.3 g/day) and an improvement in pathologic features. A transient interruption of eculizumab resulted in a rapid rise in proteinuria to 9.3 g/day, which decreased to 0.8 g/day after resumption of treatment.

Conclusions: The administration of anti-C5 antibodies may represent a valuable therapeutic option in patients with C3GN.
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http://dx.doi.org/10.1007/s00467-015-3061-2DOI Listing
June 2015

Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort.

Medicine (Baltimore) 2014 Dec;93(29):e327

From the Department of Microbiology, Infectiology and Immunology, University of Montreal, Montreal, Canada (IF, EH, FLD); Department of Microbiology and Immunology, CHU Sainte-Justine, Montreal, Canada (IF, FLD); CHU Sainte-Justine Research Center, Montreal, Canada (IF, NP, EH, HD, FLD); Department of Pathology and Cell Biology, CHU Sainte-Justine and University of Montreal, Montreal, Canada (NP); Department of Paediatrics, University of Montreal, Montreal, Canada (VM, EH, HD, FLD); Division of Gastroenterology, Hepatology and Nutrition, CHU Sainte-Justine, Montreal, Canada (VM); Histology Facility, IRIC, University of Montreal, Montreal, Montreal, Canada (MB); Medical Genetics Service, University of Sherbrooke, Sherbrooke, Canada (BM); and Division of Rheumatology, Immunology and Allergology, CHU Sainte-Justine Montreal, Canada (EH, HD, FLD).

Hereditary multiple intestinal atresia (HMIA) is a rare cause of intestinal obstruction in humans associated with a profound combined immune deficiency. Deleterious mutations of the tetratricopeptide repeat domain-7A (TTC7A) gene lead to HMIA, although the mechanism(s) causing the disease in TTC7A deficiency has (have) not yet been clearly identified. To evaluate the consequences of TTC7A deficiency, we studied the morphology of several organs from HMIA patients at different developmental stages, as well as the expression of the TTC7A protein. We performed histological and immunohistochemical analyses on biopsies and autopsies of 6 patients and 1 fetus with HMIA. Moreover, we characterized for the first time the expression of the TTC7A protein by immunostaining it in several organs from control (including fetal samples), infants, and 1 fetus with HMIA. Besides the gastrointestinal tract, HMIA disease was associated with morphological alterations in multiple organs: thymus, lung, spleen, and liver. Moreover, we demonstrated that normal TTC7A protein was expressed in the cytoplasm of epithelial cells of the intestine, thymus, and pancreas. Surprisingly, altered TTC7A protein was highly expressed in tissues from patients, mainly in the epithelial cells. We have established that HMIA associated with a TTC7A defect is characterized by multiorgan impairments. Overall, this report suggests that TTC7A protein is critical for the proper development, preservation, and/or function of thymic and gastrointestinal epithelium.
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http://dx.doi.org/10.1097/MD.0000000000000327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602622PMC
December 2014

Assessment of correlation between p16INK4a staining, specific subtype of human papillomavirus, and progression of LSIL/CIN1 lesions: first comparative study.

Am J Clin Pathol 2014 Jul;142(1):104-10

From the Department of Pathology,

Objectives: To study and compare the effectiveness of p16(INK4a) staining and specific human papillomavirus (HPV) subtypes as a prognostic marker in cervical intraepithelial neoplasia grade 1 (CIN1; low-grade squamous intraepithelial lesions).

Methods: Sixty-four cervical samples diagnosed as CIN1 and stained with p16(INK4a), with HPV status assessed by polymerase chain reaction-direct sequencing.

Results: Of the 34 p16(INK4a)-negative biopsy specimens, 26 regressed, seven persisted, and one progressed. Of the 20 p16(INK4a) diffusely positive biopsy specimens, seven regressed, eight persisted, and five progressed. Ten biopsy specimens stained positive only in the lower one-third of the sample, of which seven regressed and three persisted. p16(INK4a) diffusely positive CIN1 lesions were associated with only high-risk HPV subtypes, with the exception of one HPV-negative biopsy specimen. Three different high-risk HPV subtypes and one low-risk HPV subtype (HPV66) were identified in the six CIN1 lesions that progressed.

Conclusions: There is a significant relationship between p16(INK4a) immunostaining and follow-up (P = .002). p16(INK4a)-negative specimens or positivity in the lower one-third of CIN1 lesions seldom progress to a CIN2-3 lesion.
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http://dx.doi.org/10.1309/AJCPBX74QXCPXIKKDOI Listing
July 2014

Diagnostic utility of molecular and cytogenetic analysis in lipoblastoma: a study of two cases and review of the literature.

Histopathology 2014 Apr 17;64(5):731-40. Epub 2014 Jan 17.

Department of Pathology, CHU Sainte Justine, Montreal, QC, Canada.

Aims: Lipoblastoma is a benign neoplasm of embryonic white fat tissue that results from the proliferation of primitive adipocytes, in which histological features can be ambiguous. In order to discriminate between lipoblastoma and other lipogenic and lipomatous tumours, we studied chromosomal alterations and protein expression in two cases of lipoblastoma in infants.

Methods And Results: Standard cytogenetic analysis, fluorescence in-situ hybridization, array comparative genomic hybridization and Western blotting allowed us to demonstrate the presence of chromosome abnormalities involving the 8q11-13 region containing the pleomorphic adenoma gene 1 (PLAG1), which are classically reported in lipoblastoma, and aberrant expression of PLAG1.

Conclusions: This report illustrates two different tumorigenic pathways implicating PLAG1 in lipoblastoma: amplification through multiple copies of a small marker chromosome derived from chromosome 8, and a paracentric inversion of the long arm of chromosome 8. Both these anomalies induced aberrant expression of PLAG1, emphasizing the role of PLAG1 in tumorigenesis. The aberrant expression of PLAG1 protein has been hypothesized, but this is the first report to demonstrate its occurrence in lipoblastoma.
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http://dx.doi.org/10.1111/his.12317DOI Listing
April 2014

Prenatal diagnosis of femoral-facial syndrome: report of two cases.

Birth Defects Res A Clin Mol Teratol 2013 Dec 19;97(12):770-3. Epub 2013 Nov 19.

Department of Pathology, Sainte-Justine Hospital, Montréal, Canada.

Background: Femoral-facial syndrome (FFS), also known as femoral hypoplasia-unusual facial syndrome (FHUFS) is a rare disorder, which has been more frequently described in females. Only a few cases diagnosed prenatally have been reported so far in the literature. FFS is characterized by femoral hypoplasia and various facial abnormalities, which can be associated with a variety of other malformations

Cases: In this report, we present two male fetuses which were diagnosed with FFS after detection of short femora, micrognathia, and other anomalies by ultrasonography at the age of 14 and 16 weeks, respectively. The sonographic findings were confirmed at autopsy. The differential diagnosis of FFS with other disorders characterized by hypoplastic femora is discussed

Conclusion: FFS represents a severe condition; hence, the importance of an early prenatal diagnosis, especially in light of offering counseling for affected parents.
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http://dx.doi.org/10.1002/bdra.23201DOI Listing
December 2013

A study of calretinin in Hirschsprung pathology, particularly in total colonic aganglionosis.

J Pediatr Surg 2013 May;48(5):1037-43

Department of Pediatric Surgery, CHU Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada, H3C 1C5.

Introduction: Calretinin, a calcium-binding protein, has been reported to be an important new marker in Hirschsprung's disease (HD). The aim is to study the diagnostic value of Calretinin in total colonic aganglionosis (TA), prematurity, and superficial biopsy when nerve hyperplasia may not be accessed by ACE activity.

Methods: Records of patients diagnosed with HD at our institution from 1985 to 2010 were studied and patients with TA identified. We examined tissue samples from those TA, partial colectomies for HD, biopsies for suspicion of HD, and rectal tissue from aborted fetuses. Immunohistochemical analysis of Calretinin was compared with ACE gold standard method in all cases.

Results: In the majority of the cases, the diagnosis was ascertained by ACE activity and Calretinin staining. However, in 9 cases, the diagnosis was possible with Calretinin staining but not with ACE: in 4 TA because of the absence of nerve hyperplasia, and in 5 cases because the biopsies were too superficial to examine the nerve hyperplasia. In addition, Calretinin was expressed in the gut as early as 22 gestational weeks.

Conclusion: The use of Calretinin staining may be superior to ACE activity, particularly in the context of TA, superficial biopsies, and prematurity, allowing earlier diagnosis.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.02.026DOI Listing
May 2013

Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia.

J Med Genet 2013 May 19;50(5):324-9. Epub 2013 Feb 19.

Centre de Recherche du CHU Ste-Justine, University of Montreal, Montreal, Quebec, Canada

Background: Congenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype. A genetic basis for MIA is likely. We had previously ascertained a cohort of patients of French-Canadian origin, most of whom were deceased as infants or in utero. The goal of the study was to identify the molecular basis for the disease in the patients of this cohort.

Methods: We performed whole exome sequencing on samples from five patients of four families. Validation of mutations and familial segregation was performed using standard Sanger sequencing in these and three additional families with deceased cases. Exon skipping was assessed by reverse transcription-PCR and Sanger sequencing.

Results: Five patients from four different families were each homozygous for a four base intronic deletion in the gene TTC7A, immediately adjacent to a consensus GT splice donor site. The deletion was demonstrated to have deleterious effects on splicing causing the skipping of the attendant upstream coding exon, thereby leading to a predicted severe protein truncation. Parents were heterozygous carriers of the deletion in these families and in two additional families segregating affected cases. In a seventh family, an affected case was compound heterozygous for the same 4bp deletion and a second missense mutation p.L823P, also predicted as pathogenic. No other sequenced genes possessed deleterious variants explanatory for all patients in the cohort. Neither mutation was seen in a large set of control chromosomes.

Conclusions: Based on our genetic results, TTC7A is the likely causal gene for MIA.
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http://dx.doi.org/10.1136/jmedgenet-2012-101483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625823PMC
May 2013

Inflammatory bowel disease and T cell lymphopenia in G6PC3 deficiency.

J Clin Immunol 2013 Apr 20;33(3):520-5. Epub 2012 Nov 20.

Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada.

Purpose: G6PC3 deficiency presents as a complex and heterogeneous syndrome that classically associates severe congenital neutropenia with cardiac and urogenital developmental defects. Here we investigate the findings of T cell lymphopenia and inflammatory bowel disease in a child with G6PC3 deficiency due to compound heterozygous mutations in intron 3 (c.IVS3-1 G>A) and exon 6 (c.G778G/C; p.Gly260/Arg).

Methods: Histological examination was conducted on all biopsy specimens. Immunophenotyping and lymphocyte proliferation assays were performed. Immunoglobulin levels and vaccine responses were measured.

Results: The patient showed persistent global T cell lymphopenia, with only 8 to 13 % of thymic naive CD31(+)CD45RA(+) cells among CD4 T cells (normal range 27-60 %). Proliferation assays and vaccine responses were within normal limits. The gastrointestinal inflammatory lesions were very closely related to those of glycogen storage disease type 1b, with a Crohn's-like appearance but without granuloma or increased cryptic abscesses. The gastrointestinal disease responded to infliximab therapy. These findings were associated with a polyclonal hypergammaglobuliemia G.

Conclusion: G6PC3 deficiency may present with inflammatory bowel disease and T cell lymphopenia. The diagnosis should thus be considered in a patient with chronic congenital neutropenia and gastrointestinal symptoms. Patients with confirmed disease should also undergo T cell phenotyping to rule out cellular immunodeficiency.
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http://dx.doi.org/10.1007/s10875-012-9833-6DOI Listing
April 2013

Therapeutic efficacy of cord blood-derived mesenchymal stromal cells for the prevention of acute graft-versus-host disease in a xenogenic mouse model.

Stem Cells Dev 2012 Jul 21;21(10):1616-26. Epub 2011 Oct 21.

CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Quebec, Canada.

Human mesenchymal stromal cells (MSCs) have been successfully utilized for the treatment of refractory graft-versus-host disease (GvHD). Despite the large number of in vitro and in vivo models developed for clarifying their immunomodulatory properties, the mechanism of action of MSCs remains elusive and their efficacy controversial. Here, we tested the ability of cord blood-derived MSCs to alleviate the symptoms of GvHD induced by the injection of human peripheral blood mononuclear cells into NOD/SCID/γc(-) mice. In this in vivo xeno-GvHD model, we demonstrate that a single MSC injection is able to inhibit GvHD in terms of clinical signs and related mortality. We also show that in this model MSCs act by both immunomodulating T-cells and fostering recovery after irradiation. The translational impact of these findings could provide a reliable preclinical model for studying the efficacy, dosage, and time of administration of human MSCs for the prevention of acute GvHD.
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http://dx.doi.org/10.1089/scd.2011.0413DOI Listing
July 2012

[Juvenile xanthogranuloma of the nasal cavity].

Ann Pathol 2010 Oct 8;30(5):374-7. Epub 2010 Oct 8.

Département de biologie et pathologie cellulaire, hôpital Sainte-Justine, CHU Sainte-Justine, 3175, chemin Côte-Ste-Catherine, Montréal, QC H3T 1C5, Canada.

JXG is a benign lesion of unknown incidence. It is the most frequent type of non-langerhans histiocytosis with a median age of 2 years. It usually presents as isolated cutaneous lesions. Multiple lesions, especially over the head and neck, may occur. The skin lesions tend to regress slowly with time. Extra-cutaneous and visceral involvements have been observed, the most common site being the eye. When the lesions are numerous, they may persist, hence the need for treatment with corticosteroids or chemotherapy. Histologically, the lesion consists of histiocytes admixed with an inflammatory infiltrate of variable density. The lesions are initially monomorphic and very cellular, progressively enriched with multinucleated giant cells of Touton and foamy cells, followed by spindle cells. We report an 8-year old girl with JXG of early type without multinucleated and foamy cells. This case presented as a tumour in the inferior meatus of nasal cavity, clinically simulating a rhabdomyosarcoma. This atypical clinical and histological presentation with benign evolution should be recognized since it requires only local treatment.
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http://dx.doi.org/10.1016/j.annpat.2010.07.013DOI Listing
October 2010

Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients.

Gastroenterology 2010 Jul 17;139(1):249-58. Epub 2010 Mar 17.

Division of Gastroenterology, Department of Pediatrics, Centre Hospitalier Universitaire Ste-Justine, Montréal, Quebec, Canada.

Background & Aims: In adults, irritable bowel syndrome (IBS) and functional dyspepsia (FD) are chronic conditions that often start during childhood. We investigated mucosal serotonin (5-HT) signaling in children with the idea that data from subjects with a shorter history may improve our understanding of underlying pathophysiological mechanisms.

Methods: Ninety-eight children undergoing gastroscopy or colonoscopy were studied prospectively. Biopsy specimens were evaluated for inflammation, enterochromaffin cell numbers, 5-HT content, and messenger RNA (mRNA) levels for the synthetic enzyme, tryptophan hydroxylase 1, and the serotonin transporter (SERT) were assessed by quantitative real-time reverse-transcription polymerase chain reaction.

Results: Data from 12 children with IBS and 17 with FD were compared with age-matched controls (12 with rectal biopsies and 12 with gastric biopsies) and with subjects with organic disorders. In patients with FD, a small number of immune cells were observed in the gastric mucosa in half of the patients, but no abnormalities with respect to the 5-HT pathway were identified. In patients with IBS, no differences were detected between patients and controls regarding intraepithelial lymphocytes and CD3+ cells in the lamina propria although all patients showed at least a slight inflammatory infiltrate. In the IBS samples, higher 5-HT content (P < .01) and lower SERT mRNA (P < .05) were detected as compared with controls. Severe inflammation in the colonic mucosa had a high impact on 5-HT signaling with a significant decrease in enterochromaffin cells (P < .01) and 5-HT content (P < .01) and a high SERT mRNA expression (P < .01).

Conclusions: These results confirm the role of 5-HT signaling in IBS in children and argue against such a role in FD.
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http://dx.doi.org/10.1053/j.gastro.2010.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902614PMC
July 2010