PubMed Health⌕ Search

Biomedical subjects

N Wulffraat

Publications and source records attributed to N Wulffraat.

At least 19 recordsLinked to original sources
PubMed2006

Haematopoietic cell transplantation (HCT) in combination with enzyme replacement therapy (ERT) in patients with Hurler syndrome.

Hurler syndrome (MPS 1H) is the severe form of mucopolysaccharidosis type 1 (MPS 1). Haematopoietic cell transplantation (HCT) is the treatment of choice, but carries a high incidence of graft failure and morbidity. The use of enzyme replacement therapy (ERT) might improve the clinical signs and symptoms before HCT, resulting in less transplantation-related complications. Moreover, clearance of glycosaminoglycans (GAG's) from the bone marrow might improve engraftment. Twenty-two patients with MPS 1H received one or more HCT procedures in combination with ERT. One patient with severe cardiomyopathy improved significantly after ERT. All children were in a relatively good clinical condition before HCT. Of patients 59, 82 and 86% were alive and engrafted after one, two and three HCT procedures, respectively. Two patients died after repetitive HCT. No serious ERT-infusion-related toxicity occurred. ERT with HCT was well tolerated. Neither a positive nor a negative effect on the number of patients who are alive and engrafted after receiving ERT before HCT as compared to a historic cohort was noted. However, patients in a poor clinical condition before HCT might benefit from ERT.

Child, Preschool↗
PubMed2005

PRINTO/PRES international website for families of children with rheumatic diseases: www.pediatric-rheumatology.printo.it.

OBJECTIVE: To prepare a website for families and health professionals containing up to date information about paediatric rheumatic diseases (PRD). METHODS: Firstly, paediatric rheumatology centres and family self help associations were surveyed to characterise current clinical practice of physicians providing care for children with PRD, research activities, and training facilities of each centre. Secondly, international consensus was reached on the content of the website. Finally, the website was developed and the texts translated. RESULTS: The web page contains three main sections: (a) description for families of the characteristics of 15 PRD; (b) list of paediatric rheumatology centres; (c) contact information for family self help associations. A version for 45 countries in 52 languages (with another three in progress) is now available on the web. 291 surveys from 171 centres and 102 family associations were received from 42 countries. The median proportion of time spent in paediatric practice in the centres examined was 100%, with 70% of this time dedicated to paediatric rheumatology. 90% of the centres were willing to perform clinical trials in the future. CONCLUSIONS: The PRINTO/PRES website provides a well defined and competent set of information about PRD, with appropriate multiple translated versions and easy web navigational direction.

Child↗
PubMed2005

The importance of identifying a back-up donor for unrelated stem cell transplantation.

The importance of identifying a back-up donor, once a primary suitable unrelated stem cell donor has been found, is often underestimated. Transplant centres erroneously count on the unrelated volunteer donors to be willing, available and medically fit for actual donation. According to our data, which includes 502 unrelated donor work-up procedures performed for 425 Dutch patients between 1987 and 2002, one of 11 work-ups ended in the primary requested donor failing to donate. Of all donor-related cancellations (N=46), 78% of the procedures were deferred due to medical reasons and 22% due to nonmedical reasons. Most of the donors deferred for medical reasons were female (P=0.005). In 50% of the cases for which a back-up donor was already identified, the patients were transplanted with a delay of less then 2 weeks; when no back-up donor was available, the median delay increased to 18 weeks. We strongly encourage implementing a search for at least one back-up donor in the primary search. Identifying a back-up donor can save precious time and complicated logistic rescheduling.

Female↗
PubMed2004

Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients.

The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group conducted a survey to obtain information about the frequency, presentation, and treatment of mycobacterial infection (MBI) in stem cell transplant (SCT) recipients. Among 29 centers, MBI was diagnosed in 0.79% of 1513 allogeneic and 0.23% of 3012 autologous SCT recipients during 1994-1998 a median of 160 days after transplantation. The mean interval between first symptoms and diagnosis was 29 days and was still longer for patients with atypical MBI or recipients of corticosteroid therapy. The prevalence of MBI was highest among those who received matched unrelated or mismatched STCs from related donors. Of 31 patients, 20 had tuberculosis, 8 had atypical MBI, and 3 had diagnoses based on histological findings only. Five patients (16%) died, all of whom had received an allogeneic SCT. Because of the increased numbers of unmatched donors and transplantation programs in countries with a high prevalence of tuberculosis, constant vigilance is required to early detect MBI in SCT recipients.

Adolescent↗
PubMed2004

Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention.

Veno-occlusive disease (VOD) of the liver is a complication observed particularly in patients undergoing hematopoietic stem cell transplantation (HSCT). Defibrotide (DF) is a polydeoxyribonucleotide with aptameric activity on endothelium. We evaluated in a retrospective analysis the efficacy of DF in pediatric patients developing hepatic VOD after HSCT.A total of 45 patients between 0.2 and 20 years (median age: 8.2 years) with hepatic VOD were treated with DF: 22 patients (49%) met risk criteria for severe or progressive disease and 23 (51%) for moderately severe and mild disease. The median duration of DF treatment was 17 days. In all, 34 patients (76%) achieved complete response (CR) with a survival rate of 64% at day 100. CR rate in patients with severe disease was 50% with long-term survival of 36%. The average DF dose in the CR group was 45 mg/kg/day and in the no responder (NR) group 27 mg/kg/day. The use of additional drugs besides DF to treat VOD made no difference in the outcome compared to DF alone. The average interval from diagnosis to start of DF was 1 day in the CR and 5.5 days in NR group. In multivariate analysis, early intervention remained the only significant factor for a CR.

Adolescent↗
PubMed2003

LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as gamma chain (gamma(c)) deficiency] in 9 out of 10 patients by retrovirus-mediated gamma(c) gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with gammadelta+ or alphabeta+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Visual loss in uveitis of childhood.

AIMS: To investigate the manifestations and severity of uveitis in children and to identify the risk and specific causes of blindness in this population. METHODS: Retrospective study of data of 123 consecutive patients examined with active uveitis and the onset of ocular disease before the age of 16 years. Numerous variables were assessed including age and sex distribution, laboratory data, the presence of systemic diseases, onset and course of ocular inflammation, clinical features and complications, therapeutic strategies and their outcomes, final visual acuity, and characteristics associated with poor visual outcome. RESULTS: Systemic disease was observed in 36/123 patients (29%), with juvenile idiopathic arthritis being the most frequent (25/123, 20%). Toxoplasma retinochoroiditis was diagnosed in 12/23 patients with posterior uveitis (52%; 10% of all with uveitis). Severe intraocular inflammation required systemic drugs in 57 (46%) patients. Ocular complications were observed in 93 patients (76%), of which the most common was cataract (43/123, 35%). Intraocular surgery was required in 35 patients (28%; in total 75 procedures). Three patients (2%) became legally blind and an additional 20/121 (17%) had one legally blind eye caused by uveitis. The most frequent causes of blindness were chorioretinal scars in the macular area and glaucoma in contrast with cystoid macular oedema (CMO) in adults. CONCLUSIONS: Uveitis in childhood is a potentially blinding disease, in the majority of patients characterised by a chronic course and a high complication rate.

Adolescent↗
PubMed2001

Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome.

Omenn syndrome (OS) is an inherited disorder characterized by an absence of circulating B cells and an infiltration of the skin and the intestine by activated oligoclonal T lymphocytes, indicating that a profound defect in the lymphoid developmental program could be accountable for this condition. Inherited mutations in either the recombination activating genes RAG1 or RAG2, resulting in partial V(D)J recombinase activity, were shown to be responsible for OS. This study reports on the characterization of new RAG1/2 gene mutations in a series of 9 patients with OS. Given the occurrence of the same mutations in patients with T-B-severe combined immune deficiency or OS on 3 separate occasions, the proposal is made that an additional factor may be required in certain circumstances for the development of the Omenn phenotype. The nature of this factor is discussed.

DNA Nucleotidyltransferases↗
PubMed2001

Recognition and management of scleroderma in children.

Juvenile scleroderma is a rare disease of childhood. The 2 main forms are localised and systemic scleroderma, although the pathogenesis of both forms is still unclear. The main clinical characteristic is the presence of skin sclerosis. Localised scleroderma can be divided into 3 different subtypes: morphoea, linear scleroderma and 'coup de sabre' lesions. The incidence is 0.2 to 0.4 per 100,000. 25 to 40% of patients are rheumatoid factor positive and 23 to 67% antinuclear antibody positive. An increased number of eosinophils occur in 31% of patients. Systemic sclerosis is an even rarer disease; approximately 10% of patients evolve the disease before the age of 18 years. The clinical presentation and disease course differ from the adult disease. This is reflected in the much better outcome. With regard to therapeutic options, there is still no gold standard for either form of the disease.

Child, Preschool↗
PubMed2001

Autologous stem cell transplantation for pediatric rheumatic diseases.

The National Institute of Allergy and Infectious Disease, National Institutes of Health, convened a workshop entitled The Next Step: Protocol Development for Autologous Stem Cell Transplantation for Pediatric Rheumatic Disease, June 2000, co-chaired by Drs. Karyl Barron and Carol Wallace. The goal of the workshop was to focus on the scientific rationale for stem cell transplantation therapy in the pediatric diseases, unique aspects of this therapy in the pediatric rheumatic diseases, transplantation issues and options, regulatory issues, and development of a DNA repository for these diseases.

Child↗
PubMed2000

Stress induces increases in IL-6 production by leucocytes of patients with the chronic inflammatory disease juvenile rheumatoid arthritis: a putative role for alpha(1)-adrenergic receptors.

Juvenile rheumatoid arthritis (JRA) is characterized by chronic inflammation of the joints. In the present study we demonstrate that exposure of JRA patients to a noradrenergic stressor (cold pressor test) results in enhanced LPS-induced IL-6 production by peripheral blood cells of these patients. Healthy, age-matched controls had the same rise in norepinephrine, but do not respond with changes in IL-6 production after exposure to the cold pressor test. Moreover, PBMC of patients with JRA express mRNA encoding alpha(1)-adrenergic receptors (AR), predominantly of the alpha(1d)-AR subtype. In contrast, we could not detect mRNA encoding for alpha(1)-AR in PBMC of healthy controls. The results of this study suggest that expression of alpha(1)-AR mRNA in PBMC during chronic inflammation is associated with altered responses of the immune system to stress.

Acute Disease↗
PubMed2000

Two genes are responsible for Griscelli syndrome at the same 15q21 locus.

Griscelli syndrome is a rare autosomal recessive disease characterized by pigment dilution, variable cellular immunodeficiency, and an acute phase of uncontrolled T lymphocyte and macrophage activation. We previously mapped the disease locus to 15q21 and showed that a MyoVa gene (HGMW-approved symbol MYO5A) defect leads to Griscelli syndrome. We report a second MyoVa mutation in a new patient, confirming this first finding. However, in four other Griscelli syndrome patients analyzed, the MYOVA protein is expressed, and no mutation can be detected in the MyoVa gene coding sequence, even in the alternatively spliced region for which exon-intron boundaries were characterized. Linkage analysis performed in 15 Griscelli families thus far studied confirms the first localization. However, fine haplotype analysis in three families strongly suggests the existence of a second gene at the same locus for Griscelli syndrome less than 7.3 cM distant from the MyoVa gene.

Alternative Splicing↗
PubMed2000

Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.

Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region. Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D15S1003 and D15S962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with GS. Unlike MYO5A, the GTP-binding protein RAB27A appears to be involved in the control of the immune system, as all patients with RAB27A mutations, but none with the MYO5A mutation, developed HS. In addition, RAB27A-deficient T cells exhibited reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells did not. RAB27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis.

B-Lymphocytes↗
PubMed1999

Autologous haemopoietic stem-cell transplantation in four patients with refractory juvenile chronic arthritis.

BACKGROUND: Autologous haemopoietic stem-cell transplantation (AHSCT) had been described as a possible treatment for severe autoimmune disease refractory to conventional treatment. We report the first four children with severe forms of juvenile chronic arthritis (JCA) treated with AHSCT. METHODS: We studied three children with systemic JCA and one child with polyarticular JCA. Unprimed bone marrow was taken 1 month before AHSCT. T-cell depletion of the graft was done with CD2 and CD3 antibodies. We used a preparative regimen of antithymocyte globulin (20 mg/kg), cyclophosphamide (200 mg/kg) and low-dose total body irradiation (4 Gy). Methotrexate and cyclosporin were stopped before AHCST, prednisone was tapered after 2 months. FINDINGS: Our patients showed a drug-free follow-up of 6-18 months with a marked decrease in joint swelling, pain, and morning stiffness. Erythrocyte sedimentation rate, C-reactive protein, and haemoglobin returned to almost normal values within 6 weeks. Despite T-cell depletion there was a rapid immune reconstitution in three out of four children. Two patients developed a limited varicella zoster virus eruption, which was treated by aciclovir. INTERPRETATION: AHSCT for severe JCA was well tolerated and induced a remission of disease in four children with JCA that was resistant to conventional treatment. Prolonged prednisone-free growth catch-up and general well-being is a major therapeutic gain in such children. The actual follow-up is too short, however, for us to conclude that these children are completely cured of their disease.

Arthritis, Juvenile↗
PubMed1999

Resting energy expenditure and nutritional status in children with juvenile rheumatoid arthritis.

OBJECTIVE: Undernutrition is frequently encountered in children with juvenile rheumatoid arthritis (JRA). We assessed resting energy expenditure (REE) in relation to nutritional status and body composition in patients with JRA. METHODS: We selected 33 children (age 6 to 18 yrs) with JRA (13 oligoarticular, 10 polyarticular, 10 systemic JRA) and 17 controls matched for age and sex. Nutritional status was assessed for height, weight, and fat-free mass (FFM), and REE was measured with indirect calorimetry. RESULTS: Nutritional status in the patients with systemic JRA was diminished compared to the controls for height (140 vs. 159 cm; p<0.01) and FFM (28 vs. 38 kg; p = 0.03). Oligo and polyarticular patients with JRA had normal height and FFM. No significant differences existed in crude REE among the groups. However, after correcting REE for body weight and FFM, the patients with systemic JRA, compared to controls, had 18% higher REE per kg body weight (159 vs. 134 kJ/kg/day; p<0.01) and 21% higher REE per kg FFM (196 vs. 162 kJ/kg/day; p<0.01). Oligo and polyarticular JRA patients had 8% increased values for REE per kg body weight or FFM, but these differences were not statistically significant. CONCLUSION: Patients with systemic JRA show stunting, low FFM, and a significantly increased REE when nutritional status is taken into account. These data suggest that assessment of individual energy requirements should include correction for fat-free mass in the treatment of malnutrition in patients with systemic JRA.

Adolescent↗
PubMed1996

Functional alpha 1-adrenergic receptors on leukocytes of patients with polyarticular juvenile rheumatoid arthritis.

During the last decade it has been shown that the central nervous system can influence the immune system. In healthy individuals, catecholamines can inhibit the production of pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) via interaction with beta 2-adrenergic receptors. In contrast, we show here that catecholamines can stimulate the production of the interleukin-6 (IL-6) in children with the chronic inflammatory disease polyarticular juvenile rheumatoid arthritis (JRA). The induction of IL-6 is mediated by triggering of alpha 1-adrenergic receptors on peripheral blood leucocytes of the patients with polyarticular JRA. Functional alpha 1-adrenergic receptors are absent on leukocytes of normal donors and on leukocytes of patients with the oligoarticular form of the disease.

Adolescent↗
PubMedDate not supplied

Primary ciliary dyskinesia: ciliary activity.

In primary ciliary dyskinesia (PCD) the cilia of the respiratory tract are immotile or they show an incoordinate, abnormal beating pattern. Consequently, mucociliary clearance is lacking. Most patients with PCD have ultrastructural abnormalities in their cilia. In some patients, however, the ciliary ultrastructure is completely normal. In this study a semi-quantitative scoring method is described for studying ciliary motility in biopsies of nasal mucosa. For every cell the frequency, coordination and amplitude of the ciliary beat are scored. Thereafter, a total score of ciliary activity per cell can be calculated. This method is simple and has proved to be reproducible. By using this scoring method the presence of a PCD can be established with certainty, whether the ciliary ultrastructure is abnormal or not. In patients with a normal ciliary ultrastructure the cilia have a rather high beating frequency (vibration). By scoring the ciliary motility in mucosal biopsies, the time-consuming electronmicroscopic investigation of the cilia is no longer necessary in most patients.

Adolescent↗