Publications by authors named "Helene Decaluwe"

26 Publications

  • Page 1 of 1

Association of outcomes in acute flaccid myelitis with identification of enterovirus at presentation: a Canadian, nationwide, longitudinal study.

Lancet Child Adolesc Health 2020 11;4(11):828-836

SickKids Research Institute, Neuroscience and Mental Health Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM.

Methods: In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score.

Findings: 58 children with AFM (median age 5·1 years, IQR 3·8-8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV-) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1-9·5 vs EDSS 4·0, IQR 3·0-6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0-7·4 vs EDSS 3·0, IQR 1·5-4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0-7·0 vs EDSS 3·0, IQR 1·0-4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0-6·9 vs EDSS 2·5 IQR 0·3-3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037).

Interpretation: Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM.

Funding: None.
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http://dx.doi.org/10.1016/S2352-4642(20)30176-0DOI Listing
November 2020

Microbiota stimulation generates LCMV-specific memory CD8 T cells in SPF mice and determines their TCR repertoire during LCMV infection.

Mol Immunol 2020 08 17;124:125-141. Epub 2020 Jun 17.

Population Biology Unit, CNRS URA 196, Institut Pasteur, Paris 75015, France; INSERM, U1151, CNRS, UMR8253, Institut Necker Enfants Malades, Université Paris Descartes, Paris 75015, France. Electronic address:

Both mouse and human harbour memory phenotype CD8 T cells specific for antigens in hosts that have not been previously exposed to these antigens. The origin and the nature of the stimuli responsible for generation of CD44 CD8 T cells in specific pathogen-free (SPF) mice remain controversial. It is known that microbiota plays a crucial role in the prevention and resolution of systemic infections by influencing myelopoiesis, regulating dendritic cells, inflammasome activation and promoting the production of type I and II interferons. By contrast, here we suggest that microbiota has a direct effect on generation of memory phenotype CD44GP33CD8 T cells. In SPF mice, it generates a novel GP33CD44CD8 T cell sub-population associating the properties of innate and genuine memory cells. These cells are highly enriched in the bone marrow, proliferate rapidly and express immediate effector functions. They dominate the response to LCMV and express particular TCRβ chains. The sequence of these selected TCRβ chains overlaps with that of GP33CD8 T cells directly selected by microbiota in the gut epithelium of SPF mice, demonstrating a common selection mechanism in gut and peripheral CD8 T cell pool. Therefore microbiota has a direct role in priming T cell immunity in SPF mice and in the selection of TCRβ repertoires during systemic infection. We identify a mechanism that primes T cell immunity in SPF mice and may have a major role in colonization resistance and protection from infection.
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http://dx.doi.org/10.1016/j.molimm.2020.05.012DOI Listing
August 2020

Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.

Blood Adv 2019 11;3(21):3307-3321

Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.

Acute megakaryoblastic leukemia (AMKL) represents ∼10% of pediatric acute myeloid leukemia cases and typically affects young children (<3 years of age). It remains plagued with extremely poor treatment outcomes (<40% cure rates), mostly due to primary chemotherapy refractory disease and/or early relapse. Recurrent and mutually exclusive chimeric fusion oncogenes have been detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene rearrangements, most commonly NUP98-KDM5A. Human models of NUP98-KDM5A-driven AMKL capable of faithfully recapitulating the disease have been lacking, and patient samples are rare, further limiting biomarkers and drug discovery. To overcome these impediments, we overexpressed NUP98-KDM5A in human cord blood hematopoietic stem and progenitor cells using a lentiviral-based approach to create physiopathologically relevant disease models. The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions. Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient mice led to multiple subtypes of leukemia, including AMKL, that phenocopy human disease phenotypically and molecularly. The integrative molecular characterization of synthetic and patient NUP98-KDM5A AMKL samples revealed SELP, MPIG6B, and NEO1 as distinctive and novel disease biomarkers. Transcriptomic and proteomic analyses pointed to upregulation of the JAK-STAT signaling pathway in the model AMKL. Both synthetic models and patient-derived xenografts of NUP98-rearranged AMKL showed in vitro therapeutic vulnerability to ruxolitinib, a clinically approved JAK2 inhibitor. Overall, synthetic human AMKL models contribute to defining functional dependencies of rare genotypes of high-fatality pediatric leukemia, which lack effective and rationally designed treatments.
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http://dx.doi.org/10.1182/bloodadvances.2019030981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855103PMC
November 2019

Common gamma chain cytokines and CD8 T cells in cancer.

Semin Immunol 2019 04;42:101307

Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. Electronic address:

Overcoming exhaustion-associated dysfunctions and generating antigen-specific CD8 T cells with the ability to persist in the host and mediate effective long-term anti-tumor immunity is the final aim of cancer immunotherapy. To achieve this goal, immuno-modulatory properties of the common gamma-chain (γ) family of cytokines, that includes IL-2, IL-7, IL-15 and IL-21, have been used to fine-tune and/or complement current immunotherapeutic protocols. These agents potentiate CD8 T cell expansion and functions particularly in the context of immune checkpoint (IC) blockade, shape their differentiation, improve their persistence in vivo and alternatively, influence distinct aspects of the T cell exhaustion program. Despite these properties, the intrinsic impact of cytokines on CD8 T cell exhaustion has remained largely unexplored impeding optimal therapeutic use of these agents. In this review, we will discuss current knowledge regarding the influence of relevant γ cytokines on CD8 T cell differentiation and function based on clinical data and preclinical studies in murine models of cancer and chronic viral infection. We will restate the place of these agents in current immunotherapeutic regimens such as IC checkpoint blockade and adoptive cell therapy. Finally, we will discuss how γ cytokine signaling pathways regulate T cell immunity during cancer and whether targeting these pathways may sustain an effective and durable T cell response in patients.
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http://dx.doi.org/10.1016/j.smim.2019.101307DOI Listing
April 2019

Restored immune cell functions upon clearance of senescence in the irradiated splenic environment.

Aging Cell 2019 08 31;18(4):e12971. Epub 2019 May 31.

Centre de recherche du CHU Ste-Justine, Montreal, Quebec, Canada.

Some studies show eliminating senescent cells rejuvenate aged mice and attenuate deleterious effects of chemotherapy. Nevertheless, it remains unclear whether senescence affects immune cell function. We provide evidence that exposure of mice to ionizing radiation (IR) promotes the senescent-associated secretory phenotype (SASP) and expression of p16 in splenic cell populations. We observe splenic T cells exhibit a reduced proliferative response when cultured with allogenic cells in vitro and following viral infection in vivo. Using p16-3MR mice that allow elimination of p16 -positive cells with exposure to ganciclovir, we show that impaired T-cell proliferation is partially reversed, mechanistically dependent on p16 expression and the SASP. Moreover, we found macrophages isolated from irradiated spleens to have a reduced phagocytosis activity in vitro, a defect also restored by the elimination of p16 expression. Our results provide molecular insight on how senescence-inducing IR promotes loss of immune cell fitness, which suggest senolytic drugs may improve immune cell function in aged and patients undergoing cancer treatment.
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http://dx.doi.org/10.1111/acel.12971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612633PMC
August 2019

18F-Flurodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT) findings in children with encephalitis and comparison to conventional imaging.

Eur J Nucl Med Mol Imaging 2019 Jun 12;46(6):1309-1324. Epub 2019 Mar 12.

Division of Nuclear Medicine, Department of Medical Imaging, Centre Hospitalier Universitaire Sainte-Justine, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, Québec, H3T 1C5, Canada.

Purpose: FDG PET/CT is emerging as a new tool for the evaluation of acute encephalitis (AE). However, to date, there are no exclusively pediatric studies on the use of FDG PET for suspected AE. The objective of this study was to compare qualitative and quantitative brain PET to conventional brain imaging in a cohort of children, and to identify patterns of metabolic abnormalities characteristic of AE.

Methods: This retrospective study included 34 children imaged with PET/CT, CT and magnetic resonance imaging (MRI). The positivity rate of all three imaging modalities was measured. Besides visual assessment, quantification of relative regional brain metabolism (RRBM) was performed and compared to a database of normal pediatric brains.

Results: Fourteen subjects had a clinical diagnosis of autoimmune encephalitis (AIE) or encephalitis of unknown origin (EX), six of anti-N-methyl-D-aspartate receptor (anti-NMDAr) encephalitis, three of Hashimoto's encephalopathy, three of neurolupus and eight had other subtypes of encephalitis. Quantitative PET was abnormal in 100% of cases, visually assessed PET in 94.1% of subjects, MRI in 41.2% and CT in 6.9%. RRBM quantification demonstrated multiple hyper and hypo metabolic cortical regions in 82.3% of subjects, exclusively hypermetabolic abnormalities in 3%, and exclusively hypometabolic abnormalities in 14.7%. The basal ganglia were hypermetabolic in 26.5% of cases on visual assessment and in 58.8% of subjects using quantification.

Conclusion: In our pediatric population FDG PET was more sensitive than conventional imaging for the detection of AE, and basal ganglia hypermetabolism was frequently encountered.
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http://dx.doi.org/10.1007/s00259-019-04302-xDOI Listing
June 2019

SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery.

Blood 2018 10 28;132(17):1737-1749. Epub 2018 Aug 28.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with , , or defects and was significantly better compared with patients with or mutations. Patients with or mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4 and CD4CD45RA cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4 cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.
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http://dx.doi.org/10.1182/blood-2018-03-840702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202916PMC
October 2018

B-cell differentiation and IL-21 response in SCID patients after hematopoietic stem cell transplantation.

Blood 2018 06 4;131(26):2967-2977. Epub 2018 May 4.

Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA.

Allogeneic hematopoietic stem cell transplant (HSCT) typically results in donor T-cell engraftment and function in patients with severe combined immunodeficiency (SCID), but humoral immunity, particularly when using donors other than matched siblings, is variable. B-cell function after HSCT for SCID depends on the genetic cause, the use of pre-HSCT conditioning, and whether donor B-cell chimerism is achieved. Patients with defects in or undergoing HSCT without conditioning often have poor B-cell function post-HSCT, perhaps as a result of impairment of IL-21 signaling in host-derived B cells. To investigate the effect of pre-HSCT conditioning on B-cell function, and the relationship of in vitro B-cell function to clinical humoral immune status, we analyzed 48 patients with SCID who were older than 2 years after HSCT with donors other than matched siblings. T follicular helper cells (T) developed in these patients with kinetics similar to healthy young children; thus, poor B-cell function could not be attributed to a failure of T development. In vitro differentiation of B cells into plasmablasts and immunoglobulin secretion in response to IL-21 strongly correlated with the use of conditioning, donor B-cell engraftment, freedom from immunoglobulin replacement, and response to tetanus vaccine. Patients receiving immunoglobulin replacement who had normal serum immunoglobulin M showed poor response to IL-21 in vitro, similar to those with low serum IgM. In vitro response of B cells to IL-21 may predict clinically relevant humoral immune function in patients with SCID after HSCT.
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http://dx.doi.org/10.1182/blood-2017-10-809822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024640PMC
June 2018

Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease.

Front Immunol 2017 26;8:1167. Epub 2017 Sep 26.

Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada.

Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI) and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.
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http://dx.doi.org/10.3389/fimmu.2017.01167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622950PMC
September 2017

Quality of Life, Treatment Beliefs, and Treatment Satisfaction in Children Treated for Primary Immunodeficiency with SCIg.

J Clin Immunol 2017 Jul 8;37(5):496-504. Epub 2017 Jun 8.

Sainte-Justine UHC, 3175, Chemin de la Côte Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.

Despite the development of subcutaneous treatment, children and adolescents with primary immunodeficiency (PID) are vulnerable to a lower quality of life (QoL) than non-clinical participants. Comparisons have been offered in rare reports with limited sample sizes. No description is available of treatment beliefs and treatment satisfaction with standard tools. The objective of this study was to describe a large sample of patients with pediatric PID on QoL, treatment beliefs and satisfaction, and identify perceived benefits and issues of treatment both in children and parents. A mail-back survey was conducted in 60 patients with PID treated with subcutaneous Ig and their parents from a clinic in Montreal (QC, Canada). We used the standardized tools to assess for QoL levels, beliefs of necessity and concerns with treatment, and dimensions of satisfaction. We collected and coded perceived benefits and issues through open-ended questions. We found lower QoL in children with PID than in healthy non-clinical participants (median d = 0.40) and similar QoL levels to children with cancer (median d = 0.12). Participants considered their treatment as less necessary and able to control the illness and less convenient than patients with other conditions. Children were more prone to consider the treatment as convenient (69 vs. 47% p = .028) but reported more discomfort (24 vs. 10% p = .043) than parents. Results suggest a lower-than-expected QoL in pediatric PID. Aspects of the illness and treatment are probably unclear to patients and their families, as necessity beliefs were lower than expected. Educational strategies should be developed and assessed to address this issue.
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http://dx.doi.org/10.1007/s10875-017-0409-3DOI Listing
July 2017

A Novel PGM3 Mutation Is Associated With a Severe Phenotype of Bone Marrow Failure, Severe Combined Immunodeficiency, Skeletal Dysplasia, and Congenital Malformations.

J Bone Miner Res 2017 Sep 26;32(9):1853-1859. Epub 2017 Jun 26.

Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada.

Congenital disorders of glycosylation (CDGs) affect multiple systems and present a broad spectrum of clinical features, often including skeletal dysplasia. Exome sequencing has led to the identification of new CDG genes. Immune and skeletal phenotypes associated with mutations in PGM3, encoding a protein that converts N-acetyl-glucosamine-6-phosphate into N-acetyl-glucosamine-1-phosphate, were recently reported. Through exome sequencing, we identified a novel homozygous mutation (c.1135T>C; p.Phe379Leu) in PGM3 in two siblings with bone marrow failure, severe combined immunodeficiency, renal and intestinal malformations, and a skeletal dysplasia resembling Desbuquois dysplasia. Severe respiratory compromise secondary to lung hypoplasia and pulmonary hypertension, and intestinal obstruction led to their demise. We thus report the most severe phenotype described so far associated with PGM3 mutations. This CDG should be considered in the presence of skeletal dysplasia associated with severe immunodeficiency. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3173DOI Listing
September 2017

IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection.

Proc Natl Acad Sci U S A 2016 09 29;113(37):E5444-53. Epub 2016 Aug 29.

Cytokines and Adaptive Immunity Laboratory, Sainte-Justine University Hospital Research Center, Montreal, QC, Canada H3T 1C5; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3C 3J7; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada H3T 1C5

Exhaustion of CD8(+) T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain-dependent cytokines, on CD8(+) T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor β (IL2Rβ) chain is selectively maintained on CD8(+) T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections. Its expression correlates with exhaustion severity and identifies terminally exhausted CD8(+) T cells both in mice and humans. Genetic ablation of the IL2Rβ chain on CD8(+) T cells restrains inhibitory receptor induction, in particular 2B4 and Tim-3; precludes terminal differentiation of highly defective PD-1(hi) effectors; and rescues memory T-cell development and responsiveness to IL-7-dependent signals. Together, we ascribe a previously unexpected role to IL-2 and IL-15 as instigators of CD8(+) T-cell exhaustion during chronic viral infection.
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http://dx.doi.org/10.1073/pnas.1604256113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027416PMC
September 2016

Primary Immune Deficiency Treatment Consortium (PIDTC) update.

J Allergy Clin Immunol 2016 08 22;138(2):375-85. Epub 2016 Apr 22.

Pediatric Immunology and Pediatrics, Mother and Child Ste-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a collaboration of 41 North American centers studying therapy for rare primary immune deficiency diseases (PIDs), including severe combined immune deficiency (SCID), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD). An additional 3 European centers have partnered with the PIDTC to study CGD. Natural history protocols of the PIDTC analyze outcomes of treatment for rare PIDs in multicenter longitudinal retrospective, prospective, and cross-sectional studies. Since 2009, participating centers have enrolled more than 800 subjects on PIDTC protocols for SCID, and enrollment in the studies on WAS and CGD is underway. Four pilot projects have been funded, and 12 junior investigators have received fellowship awards. Important publications of the consortium describe the outcomes of hematopoietic cell transplantation for SCID during 2000-2009, diagnostic criteria for SCID, and the pilot project of newborn screening for SCID in the Navajo Nation. The PIDTC Annual Scientific Workshops provide an opportunity to strengthen collaborations with junior investigators, patient advocacy groups, and international colleagues. Funded by the National Institute of Allergy and Infectious Diseases and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, the PIDTC has recently received renewal for another 5 years. Here we review accomplishments of the group, projects underway, highlights of recent workshops, and challenges for the future.
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http://dx.doi.org/10.1016/j.jaci.2016.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986691PMC
August 2016

Cytokines and persistent viral infections.

Cytokine 2016 06 20;82:4-15. Epub 2016 Feb 20.

Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology and Immunology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada; Immunology and Rheumatology Division, Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. Electronic address:

Intracellular pathogens such as the human immunodeficiency virus, hepatitis C and B or Epstein-Barr virus often cause chronic viral infections in humans. Persistence of these viruses in the host is associated with a dramatic loss of T-cell immune response due to functional T-cell exhaustion. Developing efficient immunotherapeutic approaches to prevent viral persistence and/or to restore a highly functional T-cell mediated immunity remains a major challenge. During the last two decades, numerous studies aimed to identify relevant host-derived factors that could be modulated to achieve this goal. In this review, we focus on recent advances in our understanding of the role of cytokines in preventing or facilitating viral persistence. We concentrate on the impact of multiple relevant cytokines in T-cell dependent immune response to chronic viral infection and the potential for using cytokines as therapeutic agents in mice and humans.
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http://dx.doi.org/10.1016/j.cyto.2016.02.006DOI Listing
June 2016

IL-2 and IL-15 regulate CD8+ memory T-cell differentiation but are dispensable for protective recall responses.

Eur J Immunol 2015 Dec 2;45(12):3324-38. Epub 2015 Nov 2.

Cytokines and Adaptive Immunity Laboratory, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.

The ability to mount effective secondary responses is a cardinal feature of memory CD8(+) T cells. An understanding of the factors that regulate the generation and recall capacities of memory T cells remains to be ascertained. Several cues indicate that two highly related cytokines, IL-2 and IL-15, share redundant functions in this process. To establish their combined roles in memory CD8(+) T-cell development, maintenance, and secondary responses, we compared the outcome of adoptively transferred IL2Rβ(+/-) or IL2Rβ(-/-) CD8(+) T cells after an acute viral infection in mice. Our results demonstrate that both IL-2 and IL-15 signals condition the differentiation of primary and secondary short-lived effector cells by altering the transcriptional network governing lineage choices. These two cytokines also regulate the homeostasis of the memory T-cell pool, with effector memory CD8(+) T cells being the most sensitive to these two interleukins. Noticeably, the inability to respond to both cytokines limits the proliferation and survival of primary and secondary effectors cells, whereas it does not preclude potent cytotoxic functions and viral control either initially or upon rechallenge. Globally, these results indicate that lack of IL-2 and IL-15 signaling modulates the CD8(+) T-cell differentiation program but does not impede adequate effector functions.
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http://dx.doi.org/10.1002/eji.201546000DOI Listing
December 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

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

Ataxia-telangiectasia presenting with a novel immunodeficiency.

Pediatr Neurol 2012 May;46(5):322-4

Division of Neurology, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, Quebec, Canada.

Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity.
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http://dx.doi.org/10.1016/j.pediatrneurol.2012.02.027DOI Listing
May 2012

Safety and efficacy of rituximab in severe juvenile dermatomyositis: results from 9 patients from the French Autoimmunity and Rituximab registry.

J Rheumatol 2011 Jul 15;38(7):1436-40. Epub 2011 Jun 15.

Department of Pediatric Immunology and Rheumatology, Paris Descartes University, AP-HP, Necker Hospital, Paris, France.

Objective: To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients.

Methods: We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry.

Results: Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients.

Conclusion: This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with severe JDM.
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http://dx.doi.org/10.3899/jrheum.101321DOI Listing
July 2011

Gamma(c) deficiency precludes CD8+ T cell memory despite formation of potent T cell effectors.

Proc Natl Acad Sci U S A 2010 May 3;107(20):9311-6. Epub 2010 May 3.

Cytokines and Lymphocyte Development Unit, Institut Pasteur, Paris F-75015, France.

Several cytokines (including IL-2, IL-7, IL-15, and IL-21) that signal through receptors sharing the common gamma chain (gamma(c)) are critical for the generation and peripheral homeostasis of naive and memory T cells. Recently, we demonstrated that effector functions fail to develop in CD4(+) T cells that differentiate in the absence of gamma(c). To assess the role of gamma(c) cytokines in cell-fate decisions that condition effector versus memory CD8(+) T cell generation, we compared the response of CD8(+) T cells from gamma(c)(+) or gamma(c)(-) P14 TCR transgenic mice after challenge with lymphocytic choriomeningitis virus. The intrinsic IL-7-dependent survival defect of gamma(c)(-) naive CD8(+) T cells was corrected by transgenic expression of human Bcl-2. We demonstrated that although gamma(c)-dependent signals are dispensable for the initial expansion and the acquisition of cytotoxic functions following antigenic stimulation, they condition the terminal proliferation and differentiation of CD8(+) effector T cells (i.e., KLRG1(high) CD127(low) short-lived effector T cells) via the transcription factor, T-bet. Moreover, the gamma(c)-dependent signals that are critical for memory T cell formation are not rescued by Bcl2 overexpression. Together, these data reveal an unexpected divergence in the requirement for gamma(c) cytokines in the differentiation of CD4(+) versus CD8(+) cytotoxic T lymphocytes.
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http://dx.doi.org/10.1073/pnas.0913729107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889085PMC
May 2010

Epitope specificity and relative clonal abundance do not affect CD8 differentiation patterns during lymphocytic choriomeningitis virus infection.

J Virol 2009 Nov 2;83(22):11795-807. Epub 2009 Sep 2.

INSERM, U591, Faculté de Médecine Descartes Paris 5, Paris, France.

To evaluate the impact of immunodominance on CD8 T-cell properties, we compared the functional properties of dominant and subdominant populations in the response to lymphocytic choriomeningitis virus (LCMV). To improve functional discrimination, in addition to the usual tests of phenotype and function, we used a sensitive technique that allows the screening of all CD8 effector genes simultaneously in single cells. Surprisingly, these methods failed to reveal a major impact of clonal dominance in CD8 properties throughout the response. Aiming to increase clonal dominance, we examined high-frequency transferred P14 T-cell receptor transgenic (TCR Tg) cells. Under these conditions LCMV is cleared faster, and accordingly we found an accelerated response. However, when Tg and endogenous cells were studied in the same mice, where they should be subjected to the same antigen load, they showed overlapping properties, and the presence of P14 cells did not modify endogenous responses to other LCMV epitopes or a perturbed immunodominance hierarchy in the memory phase. Using allotype-labeled Tg cells, we found that during acute infection up to 80% downregulated their TCR and were undetectable by tetramer binding, and that tetramer-negative and tetramer-positive cells had very different features. Since Tg cells are not available to evaluate immune responses in humans and, in many cases, are not available from the mouse, the tetramer-based evaluation of early immune responses in most situations of high viremia may be incomplete and biased.
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http://dx.doi.org/10.1128/JVI.01402-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772677PMC
November 2009

Long-term outcome after hematopoietic stem cell transplantation of a single-center cohort of 90 patients with severe combined immunodeficiency.

Blood 2009 Apr 23;113(17):4114-24. Epub 2009 Jan 23.

Unité d'Immuno-Hématologie et Rhumatologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for severe combined immunodeficiency (SCID). Detailed assessment of the long-term outcome of HSCT, ie, the occurrence of clinical events and the quality and stability of immune reconstitution, is now required. We performed a single-center retrospective analysis of the long-term outcome of HSCT in 90-patient cohort followed for between 2 and 34 years (median, 14 years). Clinical events and immune reconstitution data were collected. Almost half the patients have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papilloma virus (HPV) infections, and a requirement for nutritional support. With the notable exception of severe HPV infection, these complications tend to become less common 15 years later after HSCT. A multivariate analysis showed that the occurrence of these events correlated with non-genoidentical donors, diagnosis of Artemis SCID, and quality of immune reconstitution. In most cases, HSCT enables long-term survival with infrequent sequelae. However, the occurrence of relatively late-onset complications is a concern that requires specific means of prevention and justifies careful patient follow-up.
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http://dx.doi.org/10.1182/blood-2008-09-177923DOI Listing
April 2009

IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gammaR1-deficient hosts.

PLoS Med 2008 Jan;5(1):e26

Laboratoire de Génétique Humaine des Maladies Infectieuses, INSERM, U550, Paris, France.

Background: Interferon-gamma receptor 1 (IFN-gammaR1) deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation (HSCT) is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-gammaR1 deficiency.

Methods And Findings: We demonstrated that HSCT with cells from a syngenic C57BL/6 Ifngr1+/+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL/6 Ifngr1-/- recipients. However, Ifngr1-/- mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rejected HSCT. Like infected IFN-gammaR1-deficient humans, infected Ifngr1-/- mice displayed very high serum IFN-gamma levels before HSCT. The administration of a recombinant IFN-gamma-expressing AAV vector to Ifngr1-/- naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1-/- x Ifng-/- double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-gamma depletion in infected Ifngr1-/- mice in vivo allowed subsequent engraftment.

Conclusions: High serum IFN-gamma concentration is both necessary and sufficient for graft rejection in IFN-gammaR1-deficient mice, inhibiting the development of heterologous, IFN-gammaR1-expressing, haematopoietic cell lineages. These results confirm that IFN-gamma is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN-gammaR1-deficient patients through IFN-gamma depletion from the blood. They further raise the possibility that depleting IFN-gamma may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor.
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http://dx.doi.org/10.1371/journal.pmed.0050026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2214797PMC
January 2008

Rabies in a nine-year-old child: The myth of the bite.

Can J Infect Dis 2002 Mar;13(2):121-5

Pediatric Intensive Care Unit, Department of Pediatrics.

A nine-year-old boy died from rabies encephalitis caused by a rabies virus variant associated with insectivorous bats. The patient was most likely infected in the Laurentian Mountains of western Quebec, but neither the patient nor his parents remembered any direct contact with an animal. The diagnosis was made seven days after the start of symptoms. After examining the most recent cases of rabies in North America, it is obvious that rabies following bat exposure can occur without history of a documented bite. The present case report emphasizes that the general public and medical care providers need better information about the risks associated with exposure to bats.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2094861PMC
http://dx.doi.org/10.1155/2002/475909DOI Listing
March 2002

gamma(c) cytokines provide multiple homeostatic signals to naive CD4(+) T cells.

Eur J Immunol 2007 Sep;37(9):2606-16

Cytokines and Lymphoid Development Unit, Immunology Department, Institut Pasteur, Paris, France.

Cytokines signaling through receptors sharing the common gamma chain (gamma(c)), including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, are critical for the generation and peripheral homeostasis of B, T and NK cells. To identify unique or redundant roles for gamma(c) cytokines in naive CD4(+) T cells, we compared monoclonal populations of CD4(+) T cells from TCR-Tg mice that were gamma(c) (+), gamma(c) (-), CD127(-/-) or CD122(-/-). We found that gamma(c) (-) naive CD4(+) T cells failed to accumulate in the peripheral lymphoid organs and the few remaining cells were characterized by small size, decreased expression of MHC class I and enhanced apoptosis. By over-expressing human Bcl-2, peripheral naive CD4(+) T cells that lack gamma(c) could be rescued. Bcl-2(+) gamma(c) (-) CD4(+) T cells demonstrated enhanced survival characteristics in vivo and in vitro, and could proliferate normally in vitro in response to antigen. Nevertheless, Bcl-2(+) gamma(c) (-) CD4(+) T cells remained small in size, and this phenotype was not corrected by enforced expression of an activated protein kinase B. We conclude that gamma(c) cytokines (primarily but not exclusively IL-7) provide Bcl-2-dependent as well as Bcl-2-independent signals to maintain the phenotype and homeostasis of the peripheral naive CD4(+) T cell pool.
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http://dx.doi.org/10.1002/eji.200737234DOI Listing
September 2007

Procalcitonin in children with Escherichia coli O157:H7 associated hemolytic uremic syndrome.

Pediatr Res 2006 Apr;59(4 Pt 1):579-83

Department of Pediatrics, Intensive Care Medicine, Sainte-Justine Hospital, University of Montreal, Canada, H3T-1C5.

Shiga toxin producing Escherichia coli (STEC) are noninvasive enteric pathogens that may cause hemorrhagic colitis (HC) and diarrhea-associated hemolytic uremic syndrome (D+ HUS). We hypothesized that development of D+ HUS is associated with increased serum procalcitonin (PCT) levels. PCT was measured by an immunoluminometric assay in 113 patients. Concentrations of PCT were different in normal controls, disease control groups (rotavirus enteritis, HC due to non-STEC pathogens, chronic renal failure), and children with uncomplicated O157:H7 HC or D+ HUS. Children with D+ HUS showed higher PCT levels than those with uncomplicated O157:H7 HC, and increased concentrations were noted in cases requiring peritoneal dialysis. Severely increased concentrations were observed in children with D+ HUS on d 5 or 6 after the onset of enteritis, whereas serial measurements in those with uncomplicated O157:H7 HC remained within the normal range throughout the first week of illness. PCT was correlated with serum concentrations of lipopolysaccharide (LPS)-binding protein and serum levels of alanine aminotransferase. Using two separate sets of real-time PCR primers, we were unable to detect elevated PCT mRNA transcripts in nonadherent undifferentiated (monocytic) or differentiated (macrophage-like) THP-1 cells stimulated with purified Shiga toxin-1 and/or LPS. Our data show that serum levels of PCT are associated with the severity of illness in children with D+ HUS. Further studies are needed to determine the role of PCT in the pathogenesis of thrombotic microangiopathy associated to childhood D+ HUS.
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http://dx.doi.org/10.1203/01.pdr.0000203100.45658.d5DOI Listing
April 2006