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Find video protocols related to scientific articles indexed in Pubmed.
High-resolution CT can differentiate between alloimmune and nonalloimmune lung disease early after hematopoietic cell transplantation.
AJR Am J Roentgenol
PUBLISHED: 08-23-2014
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The purpose of this study was to develop a simple semiquantitative high-resolution CT (HRCT) scoring system to differentiate alloimmune-mediated lung syndromes (allo-LS) from other lung diseases early after hematopoietic cell transplantation. Allo-LS should be differentiated from other abnormalities, such as infections and toxicity, because they are life threatening and require prompt and specific treatment.
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Transplantation in inborn errors of metabolism: current considerations and future perspectives.
Br. J. Haematol.
PUBLISHED: 07-30-2014
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Inborn errors of metabolism (IEM) comprise an assorted group of inherited diseases, some of which are due to disordered lysosomal or peroxisomal function and some of which might be improved following haemopoietic cell transplantation (HCT). In these disorders, the onset in infancy or early childhood is typically accompanied by rapid deterioration, resulting in early death in the more severe phenotypes. Timely diagnosis and immediate referral to an IEM specialist are essential steps in optimal management. Treatment recommendations are based on the diagnosis, its phenotype, rate of progression, prior extent of disease, family values and expectations and the risks and benefits associated with available therapies, including HCT. International collaborative efforts are of utmost importance in determining outcomes of therapy for these rare diseases, and have improved those outcomes significantly over recent decades. This discussion focusses on HCT in IEM, providing an international perspective on progress, limitations, and future directions.
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Early Umbilical Cord Blood-Derived Stem Cell Transplantation Does Not Prevent Neurological Deterioration in Mucopolysaccharidosis Type III.
JIMD Rep
PUBLISHED: 06-26-2014
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Mucopolysaccharidosis type III (MPS III), or Sanfilippo disease, is a neurodegenerative lysosomal storage disease (LSD) caused by defective lysosomal degradation of heparan sulfate (HS). No effective disease-modifying therapy is yet available. In contrast to some other neuronopathic LSDs, bone marrow-derived hematopoietic stem cell transplantation (HSCT) fails to prevent neurological deterioration in MPS III patients. We report on the 5-year outcome of early transplantation, i.e., before onset of clinical neurological disease, in combination with the use of umbilical cord blood-derived hematopoietic stem cells (UCBT), in two MPS III patients. Both patients had a normal developmental quotient at the time of UCBT. One patient had a combination of mutations predicting a classical severe phenotype (MPS IIIA), and one patient (MPS IIIB) had mutations predicting a very attenuated phenotype. Transplantation was uncomplicated with full engraftment of donor cells in both.Both patients showed progressive neurological deterioration with regression of cognitive skills and behavioral disturbances during 5 years after successful UCBT, comparable to the natural history of patients with the same combination of mutations. The concentration of HS in CSF in the patient with the attenuated phenotype of MPS IIIB 2 years after UCBT was very high and in the range of untreated MPS III patients.We conclude that the course of cognitive development, behavioral problems, and absence of biochemical correction in CSF demonstrate the absence of relevant effect of UCBT in MPS III patients, even when performed before clinical onset of CNS disease.
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A novel Fc?RIIa Q27W gene variant is associated with common variable immune deficiency through defective Fc?RIIa downstream signaling.
Clin. Immunol.
PUBLISHED: 06-25-2014
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We identified a novel Q27W Fc?RIIa variant that was found more frequently in common variable immunodeficiency (CVID) or CVID-like children. We analyzed the possible functional consequence of the Q27W Fc?RIIa mutation in human cells. We used peripheral blood mononuclear cells from Q27W Fc?RIIa patients and healthy controls, and cultured cells that overexpress the Q27W and common Fc?RIIa variants. The Q27W Fc?RIIa mutation does not disrupt Fc?RIIa surface expression in peripheral blood mononuclear cells. Mononuclear cells express multiple Fc?R, precluding careful analysis of Q27W Fc?RIIa functional deviation. For functional analysis of Fc?RIIa function, we therefore overexpressed the Q27W Fc?RIIa and common Fc?RIIa variant in IIA1.6 cells that are normally deficient in Fc?R. We show that Fc?RIIa triggering-induced signaling is obstructed, as measured by both decrease in calcium flux and defective MAPK phosphorylation. In conclusion, we here describe a novel Q27W Fc?RIIa variant that causes delayed downstream signaling. This variant may contribute to CVID.
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Pain: a prevalent feature in patients with mucopolysaccharidosis. Results of a cross-sectional national survey.
J. Inherit. Metab. Dis.
PUBLISHED: 06-12-2014
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While clinical observations suggest that many patients with mucopolysaccharidosis (MPS) experience chronic pain, few studies have assessed its extent and impact. We therefore investigated its prevalence in patients with all types of MPS in the Netherlands. We also examined the association between pain and health related quality of life (HRQoL) and other clinical variables.
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Will Post-Transplantation Cell Therapies for Pediatric Patients Become Standard of Care?
Biol. Blood Marrow Transplant.
PUBLISHED: 03-17-2014
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Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant disorders, some critical obstacles remain to be overcome, including relapse, engraftment failure, graft-versus-host disease (GVHD), and infection. Harnessing the immune system to induce a graft-versus-tumor effect or rapidly restore antiviral immunity through the use of donor lymphocyte infusion (DLI) has been remarkably successful in some settings. Unfortunately, however, the responses to DLI can be variable, and GVHD is common. Thus, manipulations to minimize GVHD while restoring antiviral immunity and enhancing the graft-versus-tumor effect are needed to improve outcomes after allogeneic HSCT. Cellular therapies, defined as treatment modalities in which hematopoietic or nonhematopoietic cells are used as therapeutic agents, offer this promise for improving outcomes post-HSCT. This review presents an overview of the field for pediatric cell therapies in the transplant setting and discusses how we can broaden applicability beyond phase I.
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Perioperative complications in patients diagnosed with mucopolysaccharidosis and the impact of enzyme replacement therapy followed by hematopoietic stem cell transplantation at early age.
Paediatr Anaesth
PUBLISHED: 01-22-2014
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Mucopolysaccharidoses (MPS) are hereditary storage diseases; airway management typically worsens in these patients with the progression of the disease.
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Dendritic Cell Therapy in an Allogeneic-Hematopoietic Cell Transplantation Setting: An Effective Strategy toward Better Disease Control?
Front Immunol
PUBLISHED: 01-01-2014
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Hematopoietic cell transplantation (HCT) is a last treatment resort and only potentially curative treatment option for several hematological malignancies resistant to chemotherapy. The induction of profound immune regulation after allogeneic HCT is imperative to prevent graft-versus-host reactions and, at the same time, allow protective immune responses against pathogens and against tumor cells. Dendritic cells (DCs) are highly specialized antigen-presenting cells that are essential in regulating this balance and are of major interest as a tool to modulate immune responses in the complex and challenging phase of immune reconstitution early after allo-HCT. This review focuses on the use of DC vaccination to prevent cancer relapses early after allo-HCT. It describes the role of host and donor-DCs, various vaccination strategies, different DC subsets, antigen loading, DC maturation/activation, and injection sites and dose. At last, clinical trials using DC vaccination post-allo-HCT and the future perspectives of DC vaccination in combination with other cancer immunotherapies are discussed.
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Towards evidence-based dosing regimens in children on the basis of population pharmacokinetic pharmacodynamic modelling.
Arch. Dis. Child.
PUBLISHED: 12-19-2013
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When growing up, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of drugs change, which may alter the effect of drugs. To ensure optimal drug efficacy and safety in paediatric care, PK and PD relationships of drugs need to be explored in children. This article presents an outline on performing a population PK/PD study and translating these results into rational dosing regimens, with the development and prospective evaluation of PK/PD derived evidence-based dosing regimen being discussed. Examples on amikacin, morphine and busulfan are provided, showing how PK(/PD) modelling not only led to optimization and individualization in paediatric clinical care for the specific drugs but also to insight in maturation of organ systems involved. It is shown that the latter results can subsequently be used as a basis for dosing of other drugs eliminated through the same pathway. Ultimately, these efforts should lead to predictable drug efficacy and safety across all age groups.
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Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric HCT: maintaining efficacy with less toxicity.
Biol. Blood Marrow Transplant.
PUBLISHED: 09-27-2013
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Busulfan (Bu) is used as a myeloablative agent in conditioning regimens prior to allogeneic haematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, the outcomes may be optimized by replacing cyclophosphamide (Cy) +/- Melphalan (Mel) with fludarabine (Flu). Therefore we compared the outcomes in two consecutive cohorts of HCT patients with either a non-malignant HCT indication, a myeloid malignancy or lymphoid malignancy with a contraindication for total body irradiation (TBI). 64 children received Flu+Bu targeted to 80-95mg*h/L (2009-2012) and 50 children received Bu targeted to 74-80mg*h/L + Cy (2005-2008). In the latter group Mel was added in myeloid malignancies (n=12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI (2005-2012). Estimated two year survival and event free survival were 82% and 78% in FluBu and 78% and 72% in BuCy(Mel), respectively (NS). Lower toxicity was noted after FluBu compared to BuCy(Mel): Acute-(non-infectious) lung injury (16% vs. 36%: P=0.007), VOD (3% vs. 28%: P=0.003), cGvHD (9% vs 26%, P=0.047), Adenovirus- (3% vs 32% P=0.001) and HHV6-reactivation (21% vs 44%, P=0.005). Furthermore, the median duration of neutropenia was 11 in FluBu compared to 22 in BuCy(Mel) (P<0.001) and less transfusions were given. In conclusion, Flu(160mg/m2) with targeted myeloablative Bu (90mg*h/L) was less toxic and equally effective compared to BuCy(Mel), in patients with similar HCT indications.
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Improvement of white matter changes on neuroimaging modalities after stem cell transplant in metachromatic leukodystrophy.
JAMA Neurol
PUBLISHED: 04-24-2013
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We sought to illustrate improvement of cerebral white matter changes in metachromatic leukodystrophy after treatment with hematopoietic stem cell transplant (HSCT).
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Hemorrhagic cystitis in a cohort of pediatric transplantations: incidence, treatment, outcome, and risk factors.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-17-2013
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Hemorrhagic cystitis (HC) can be a severe complication in hematopoietic stem cell transplantation (HSCT). To identify risk factors and etiology and to improve treatment, a number of factors were analyzed retrospectively in a cohort of 74 consecutive pediatric HSCTs between 2007 and 2009 in a single institution. The 74 transplantations were done in 67 children. Potential risk factors for HC were age, gender, underlying disease, ablative conditioning, graft-versus-host disease prophylaxis, unrelated donor, stem cell source, conditioning regime, acute graft-versus-host disease and cytomegalovirus reactivation. Fourteen patients developed HC (19%). In all but 4 cases (71%), HC appeared after engraftment. Severity was assessed as grade 1 in 1, grade 2 in 8, and grade 3 in 5 cases. In 79% of the patients with HC, urine samples showed BK virus. This may provide guidance for future prevention policies. In 11 children, treatment included forced hydration, spasmolytics, and bladder irrigation. Three children required cystoscopy, intravesical therapy and/or antiviral therapy. Statistical analysis revealed age over six years to be a risk factor for the development of HC. We conclude that current conditioning regimens lead to a still considerable incidence of HC in pediatric HSCT, necessitating the evaluation of screening protocols and preventive measures.
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Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning.
Blood
PUBLISHED: 03-14-2013
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We report transplantation outcomes of 258 children with Hurler syndrome (HS) after a myeloablative conditioning regimen from 1995 to 2007. Median age at transplant was 16.7 months and median follow-up was 57 months. The cumulative incidence of neutrophil recovery at day 60 was 91%, acute graft-versus-host disease (GVHD) (grade II-IV) at day 100 was 25%, and chronic GVHD and 5 years was 16%. Overall survival and event-free survival (EFS) at 5 years were 74% and 63%, respectively. EFS after HLA-matched sibling donor (MSD) and 6/6 matched unrelated cord blood (CB) donor were similar at 81%, 66% after 10/10 HLA-matched unrelated donor (UD), and 68% after 5/6 matched CB donor. EFS was lower after transplantation in 4/6 matched unrelated CB (UCB) (57%; P = .031) and HLA-mismatched UD (41%; P = .007). Full-donor chimerism (P = .039) and normal enzyme levels (P = .007) were higher after CB transplantation (92% and 98%, respectively) compared with the other grafts sources (69% and 59%, respectively). In conclusion, results of allogeneic transplantation for HS are encouraging, with similar EFS rates after MSD, 6/6 matched UCB, 5/6 UCB, and 10/10 matched UD. The use of mismatched UD and 4/6 matched UCB was associated with lower EFS.
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Pleconaril-resistant chronic parechovirus-associated enteropathy in agammaglobulinaemia.
Antivir. Ther. (Lond.)
PUBLISHED: 06-21-2011
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A 14 year old common variable immunodeficiency patient developed severe protein-losing enteropathy. A chronic enteral infection with human parechovirus type 1 and norovirus was diagnosed. Treatment strategies aimed at virus eradication and providing supportive care were ineffective. The antipicornavirus agent pleconaril did not have any effect on viral replication. Symptoms improved on immunosuppressive therapy, suggesting infection-related immune dysregulation in an immunocompromised host.
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A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13-4 function.
Pediatr Blood Cancer
PUBLISHED: 02-11-2011
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UNC13D, encoding the protein munc13-4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13-4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D.
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Does high-resolution CT has diagnostic value in patients presenting with respiratory symptoms after hematopoietic stem cell transplantation?
Eur J Radiol
PUBLISHED: 01-03-2011
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Hematopoietic stem cell transplantation (SCT) can be complicated by a variety of live-threatening infectious and non-infectious pulmonary complications. The management of these complications is critically dependent on the most probable diagnosis, which is in part based on imaging work-up.
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How I treat adenovirus in hematopoietic stem cell transplant recipients.
Blood
PUBLISHED: 09-13-2010
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Adenovirus (AdV) infections are very common in the general pediatric population. The delayed clearance in young persons imposes a threat to immunocompromised patients after hematopoietic stem cell transplantation (HSCT), who can reactivate the virus, resulting in life-threatening disseminated disease. Although a definitive cure requires adequate immune reconstitution, 2 approaches appear to be feasible and effective to improve the outcomes of AdV infections. Strict monitoring with AdV quantitative polymerase chain reaction followed by preemptive treatment with low-dose (1 mg/kg) cidofovir 3 times a week, is effective in most cases to bridge the severely immunocompromised period shortly after HSCT, with acceptable toxicity rates. For centers who have the access, AdV-specific cytotoxic T cells can be the other important cornerstone of anti-AdV therapy with promising results so far. Methods to positively influence the reconstitution of the immune system after HSCT and optimizing new and currently available cellular immunotherapies will make HSCT safer against the threat of AdV infection/reactivation and associated disease.
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Adenovirus DNA positivity in nasopharyngeal aspirate preceding hematopoietic stem cell transplantation: a very strong risk factor for adenovirus DNAemia in pediatric patients.
Clin. Infect. Dis.
PUBLISHED: 10-23-2009
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Human adenovirus (HAdV)-positive nasopharyngeal aspirate preceding hematopoietic stem cell transplantation was prospectively analyzed in 62 patients. By multivariate Cox proportional hazard models, HAdV-positive nasopharyngeal aspirate was the only predictor for HAdV DNAemia after hematopoietic stem cell transplantation (P < .001). HAdV DNAemia was a predictor for alloreactive disease. Early detection and intervention might help to prevent HAdV disease after hematopoietic stem cell transplantation.
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Life-threatening human herpes virus-6 infection in early childhood: presenting symptom of a primary immunodeficiency?
Pediatr Crit Care Med
PUBLISHED: 03-07-2009
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To report two previously healthy children with a life-threatening course of human herpes virus type 6 (HHV-6) infection and prolonged pediatric intensive care treatment.
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Risk factor analysis of outcomes after unrelated cord blood transplantation in patients with hurler syndrome.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-29-2009
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Allogeneic stem cell transplantation (SCT) is considered effective in preventing disease progression in patients with Hurler syndrome (HS). Unrelated umbilical cord blood (UCB) grafts are suggested as an alternative to bone marrow (BM) or peripheral blood stem cells (PBSC). We studied 93 HS patients receiving an UCB graft to analyze risk factors for outcomes. The median time from diagnosis to transplant was 4.6 months, median follow-up was 29 months, and median number of nucleated CB cells infused was 7.6 x 10(7)/kg. Most of the patients received 1 or 2 HLA disparate grafts, and the most frequently used conditioning regimen was cyclophosphamide + busulfan (Bu/Cy). All patients received anti-T cell antibody. At post transplant day +60, the cumulative incidence of neutrophil engraftment was 85%. A younger age at transplant and a higher CD34(+) dose at infusion were favorably associated with engraftment. With the exception of 2 patients, all engrafted patients achieved full and sustained donor chimerism. The 3-year event-free survival (EFS) and 3-year overall survival (OS) rates were 70% and 77%, respectively. In a multivariate analyses, use of Bu/Cy and a shorter interval from diagnosis to transplant were predictors for improved EFS rate (82% for patients transplanted within 4.6 months after diagnosis compared to 57% for the rest). Improved outcomes from early transplantation and immediate availability of CB unit lead us to conclude that CB transplantation is a beneficial option, which should be considered expediently for children with HS.
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Association between busulfan exposure and outcome in children receiving intravenous busulfan before hematologic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-27-2009
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Busulfan, combined with therapeutic drug monitoring-guided dosing, is associated with higher event-free survival (EFS) rates due to fewer graft failures/relapses and lower toxicity. The optimal target area under the curve (AUC) and dosing schedule of intravenous busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) remain unclear, however. We conducted a retrospective analysis of the association between busulfan exposure and clinical outcome in 102 children age 0.2 to 21 years who received busulfan 1 or 4 times daily before undergoing HSCT (46 malignant and 56 nonmalignant indications). EFS and overall survival after a median of 2 years of follow-up were 68% and 72%, respectively. EFS was optimal when the exposure of busulfan (AUC) was 78 mg x h/L (95% confidence interval=74 to 82 mg x h/L). Acute graft-versus-host disease (aGVHD) grade II-IV occurred more frequently with greater busulfan exposure. The addition of melphalan was an independent risk factor; melphalan use combined with high busulfan exposure (AUC >74 mg x h/L) was associated with high incidences of aGVHD (58%), veno-occlusive disease (66%), and mucositis grade III-IV (26%). Dosing frequency (1 or 4 times daily) was not related to any outcome. In conclusion, dose targeting of busulfan to a narrow therapeutic range was found to increase EFS in children. Adding melphalan to optimal busulfan exposure is associated with a high incidence of toxicity.
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Fc? receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells.
Blood
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The reactivation of human cytomegalovirus (HCMV) poses a serious health threat to immune compromised individuals. As a treatment strategy, dendritic cell (DC) vaccination trials are ongoing. Recent work suggests that BDCA-3(+) (CD141(+)) subset DCs may be particularly effective in DC vaccination trials. BDCA-3(+) DCs had however been mostly characterized for their ability to cross-present antigen from necrotic cells. We here describe our study of human BDCA-3(+) DCs in elicitation of HCMV-specific CD8(+) T-cell clones. We show that Fcgamma-receptor (Fc?R) antigen targeting facilitates antigen cross-presentation in several DC subsets, including BDCA-3(+) DCs. Fc?R antigen targeting stimulates antigen uptake by BDCA-1(+) rather than BDCA-3(+) DCs. Conversely, BDCA-3(+) DCs and not BDCA-1(+) DCs show improved cross-presentation by Fc?R targeting, as measured by induced release of IFN? and TNF by antigen-specific CD8(+) T cells. Fc?R-facilitated cross-presentation requires antigen processing in both an acidic endosomal compartment and by the proteasome, and did not induce substantial DC maturation. Fc?RII is the most abundantly expressed Fc?R on both BDCA-1(+) and BDCA-3(+) DCs. Furthermore we show that BDCA-3(+) DCs express relatively more stimulatory Fc?RIIa than inhibitory Fc?RIIb in comparison with BDCA-1(+) DCs. These studies support the exploration of Fc?R antigen targeting to BDCA-3(+) DCs for human vaccination purposes.
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Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children.
Biol. Blood Marrow Transplant.
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The severity of complications of allogeneic hematopoietic stem cell transplantation (HSCT) is governed mainly by the status of immune reconstitution. In this study, we investigated differences in immune reconstitution with different cell sources and the association between the kinetics of immune reconstitution and mortality. Immunophenotyping was performed every 2 weeks in children who had undergone HSCT between 2004 and 2008 at University Medical Center Utrecht. Lymphocyte reconstitution in the first 90 days after HSCT was studied in relation to mortality in 3 HSCT groups: matched sibling bone marrow (BM) recipients (35 patients), unrelated BM recipients (32 patients), and unrelated cord blood recipients (36 patients). The median age of recipients was 5.9 years (range, 0.1-21 years). The nature and speed of T cell, B cell, and natural killer (NK) cell reconstitution were highly dependent on the cell source. In the first 90 days after HSCT, faster B cell and NK cell reconstitution and delayed T cell reconstitution were shown in unrelated cord blood recipients compared with matched sibling BM and unrelated BM recipients. Of the lymphocyte subsets investigated, a large number of NK cells and a more rapid CD4(+) immune reconstitution over time, resulting in sustained higher CD4(+) counts, were the only predictors of a lower mortality risk in all cell sources. The final model showed that during the first 90 days, patients with an area under the CD4(+) cell receiver- operating curve of >4,300 cells/day and no peak in CD4(+) cell counts had the highest likelihood of survival (hazard ratio for mortality, 0.2; 95% confidence interval, 0.06-0.5). Our data indicate that CD4(+) kinetics may be used to identify patients at greatest risk for mortality early after HSCT.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.