PubMed Health⌕ Search

Biomedical subjects

W Friedrich

Publications and source records attributed to W Friedrich.

At least 37 records · Page 2Linked to original sources
PubMed2000

Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk.

ZAP-70-deficient patients present with nonfunctional CD4+ T cells in the periphery. We find that a subset of primary ZAP-70-deficient T cells, expressing high levels of the related protein-tyrosine kinase Syk, can proliferate in vitro. These cells (denoted herein as Syk(hi)/ZAP-70(-) T cells) provide a unique model in which the contribution of Syk to TCR-mediated responses can be explored in a nontransformed background. Importantly, CD3-induced responses, such as tyrosine phosphorylation of cellular substrates (LAT, SLP76, and PLC-gamma1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Syk(hi)/ZAP-70(-) T cells. However, Syk(hi)/ZAP-70(-) T cells differ from control T cells with respect to the T cell antigen receptor (TCR)-mediated activation of the MAPK cascades: extracellular signal-regulated kinase activity and recruitment of the JNK and p38 stress-related MAPK pathways are diminished. This distinct phenotype of Syk(hi)/ZAP-70(-) T cells is associated with a profound decrease in CD3-mediated interleukin 2 secretion and proliferation relative to control T cells. Thus, ZAP-70 and Syk appear to play distinct roles in transducing a TCR-mediated signal.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Ultrasonic surfactant nebulization with different exciting frequencies.

Intratracheal bolus instillation of natural lung surfactant is the treatment of choice in neonatal respiratory distress syndrome and an increasing part in adults' therapy. For reasons of hemodynamics, surfactant distribution and efficiency the application mode should be improved. Nebulization seems to have some advantages but its technical realization is difficult. The aim of the present study was to investigate if ultrasonic nebulization with exciting frequencies higher than 2.8 MHz can improve the efficiency of surfactant nebulization without changing the surface-active properties of the material. Exciting frequencies of 1.7, 3.3 and 4.0 MHz were used to produce a surfactant aerosol. The phospholipid content in the liquefied aerosol and particle size distinctly dropped with higher frequencies. The surface activity was not altered in the produced aerosol and neither in the surfactant remaining in the nebulizer. Although possible, ultrasonic nebulization of surfactant suspensions is ineffective because of a striking decrease in phospholipid content.

Aerosols↗
PubMed2000

Retrovirus-mediated transduction of primary ZAP-70-deficient human T cells results in the selective growth advantage of gene-corrected cells: implications for gene therapy.

Humans lacking the ZAP-70 protein tyrosine kinase present with an absence of CD8+ T cells and defective CD4+ T cells in the periphery. This severe combined immunodeficiency is fatal unless treated by allogeneic bone marrow transplantation. However, in the absence of suitable marrow donors, the development of alternative forms of therapy is desirable. Because lymphocytes are long-lived, it is possible that introduction of the wild-type ZAP-70 gene into CD4+ ZAP-70-deficient T cells will restore their immune function in vivo. Initial investigations evaluating the feasibility of gene therapy for ZAP-70 deficiency were performed using HTL V-I-transformed lymphocytes. Although transformation was useful in circumventing problems associated with the maintenance of ZAP-70-deficient T cells and low gene transfer levels, the presence of HTL V-I precluded any biological studies. Here, we investigated a retrovirus-mediated approach for the correction of primary T cells derived from two ZAP-70-deficient patients. Upon introduction of the wild-type ZAP-70 gene, TCR-induced MAPK activation, IL-2 secretion and proliferation were restored to approximately normal levels. Importantly, this gain-of-function was associated with a selective growth advantage of gene-corrected cells, thereby indicating the feasibility of a gene therapy-based strategy.

Cell Division↗
PubMed1999

Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European group for bone marrow transplantation and the european society for immunodeficiency.

We analyzed the outcomes of 214 HLA non-identical T-cell-depleted bone marrow transplantations (BMTs), performed in 178 consecutive patients for treatment of severe combined immunodeficiencies (SCID). Patients were treated in 18 European centers between 1981 and March 1995. SCID variants, that is, absence of T and B lymphocytes (B-) or absence of T cells with presence of B lymphocytes (B+) were found to have a major influence on outcome. The disease-free survival was significantly better for patients with B+ SCID (60%) as compared with patients with B- SCID (35%) (P =.002), with a median follow-up of 57 months and 52 months, respectively. Other factors associated with a poor prognosis were the presence of a lung infection before BMT (odds ratio = 2.47 [1.99-2.94]) and the use of monoclonal antibodies for T-cell depletion of the graft (odds ratio = 1.67 [1. 18-2.15]). Additional factors influencing outcome were age at BMT (<6 months) and period during which BMT was performed. Better results were achieved after 1991. Reduced survival of patients with B- SCID was associated with a higher incidence of early deaths from infection, a diminished rate of marrow engraftment, a trend to a higher incidence of chronic graft-versus-host disease, and slower kinetics of T/B immune function development. In both groups of patients, the use of busulfan (8 mg/kg total dose) and cyclophosphamide (200 mg/kg total dose) as a conditioning regimen provided the best cure rate (74% for patients with B+ SCID and 43% for patients with B- SCID, respectively), although results were not statistically significantly different from other regimens. This retrospective analysis should lead to the design of adapted measures to the performance of HLA non-identical BMT in patients with distinct SCID conditions.

Age Factors↗
PubMed1999

Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-gamma-receptor (IFNgammaR1) deficiency: mutational analysis and evaluation of therapeutic options.

We describe the history of a girl with interferon-gamma-receptor (IFNgammaR1) deficiency and studies performed to identify the molecular and clinical characteristics of this recently discovered disorder. This is the first report of a child from Northern Europe with IFNgammaR1 deficiency. The patient, now 7 years old, first presented with swelling and reddening at the Bacille Calmette-Guerin (BCG) vaccination site, swelling of lymph nodes, hepatomegaly, and an unusually severe varicella rash at the age of 4 months. At that time, she was diagnosed with BCG histiocytosis without typical granuloma formation and was treated with antituberculous agents. During the clinical course of her illness, several different types of atypical mycobacteria and (for the first time in an IFNgammaR1-deficient patient) Listeria monocytogenes were detected. Flow cytometric analysis showed that the patient's monocytes could not bind a monoclonal antibody specific for the IFNgamma-receptor. Our analysis of mRNA derived from the alpha-chain (IFNgammaR1) gene of this receptor revealed deletions of 173 bp and 4 bp in cDNA sequences originating from individual alleles. The 173 bp deletion was located between nucleotide positions 200 and 372, exactly matching those of exon 3, and the 4 bp deletion was located between nucleotide positions 561 and 564 of the coding region of the cDNA. Analysis of genomic DNA revealed the presence of a G to T transition at the 5'end of the splice consensus sequence of intron 3, which explains the absence of exon 3. The other allele carried the 4-base-pair deletion (ACTC) at nucleotide positions 15-18 of exon 5. Twelve months after an allo\geneic bone marrow transplantation, the patient had clinically improved.

Alleles↗
PubMed1999

Definition of a critical T cell threshold for prevention of GVHD after HLA non-identical PBPC transplantation in children.

The aim of this study was to reduce the rate of graft failure after HLA non-identical stem cell transplantation by using G-CSF mobilized CD34+ peripheral blood progenitor cells (PBPC), either in combination with bone marrow or as single grafts. To prevent GVHD, PBPC were highly purified, resulting in a 5 to 6 log T cell depletion. In additon to T cell depletion no further GVHD prophylaxis was used. We transplanted 23 pediatric patients with life-threatening malignant or non-malignant hematological disorders, who had no available matched donor. Engraftment was obtained in 18 of 21 evaluable patients. Five patients developed acute GVHD of grade II and III, which became chronic in four cases and was fatal in four. The use of highly purified PBPC allowed the exact quantification of residual T cells in the grafts and a strict correlation between the residual T cell load and the development of GVHD was observed: patients with GVHD had received numbers of T cells between 8 and 20 x 104/kg, whereas patients without GVHD were grafted with T cell numbers ranging from 0.7 to 6.0 x 104/kg. We therefore clearly demonstrate that a residual T cell content of <5 x 104/kg is safe for prevention of GVHD after HLA non-identical PBPC transplantation in children.

Adolescent↗
PubMed1999

Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).

X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.

Carrier Proteins↗
PubMed1999

Child sexual behavior inventory: A Dutch-speaking normative sample.

OBJECTIVES: To describe normative sexual behavior in Dutch-speaking children; to assess the frequencies of different types of sexual behaviors reported in children by their parents; to analyze the relation of these sexual behaviors to demographic, personal, familial, and general behavioral variables; and to compare the Dutch-speaking sample with American samples. METHOD: Nine hundred seventeen children (2-12 years of age), screened to exclude sexual abuse, were rated by their caregiver via parent report consisting of the translated Dutch version of the Child Sexual Behavior Inventory, the Child Behavior Checklist, a life event checklist, and a questionnaire assessing family nudity and parental attitudes regarding sexuality. RESULTS: Frequencies of a wide variety of sexual behaviors for 2- to 5-, 6- to 9-, and 10- to 12-year-old children are presented. Sexual behavior was found to be related to the child's age, maternal education, family nudity, and parental attitudes toward sexuality. The positive relation to general behavioral problems was confirmed. Findings were primarily similar to previously published American studies. CONCLUSION: Our study confirms that sexual behavior in children is varied and related to developmental, personal, and familial factors. The relative frequency of the wide variety of sexual behaviors in a Dutch-speaking normative sample is comparable to American samples.

Age Factors↗
PubMed1998

Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients.

We have performed a retrospective analysis of the development of T- and B-cell functions after HLA-nonidentical T-cell-depleted bone marrow transplantation (BMT) performed in 193 patients with severe combined immunodeficiency (SCID) at 18 European centers between December 1982 and December 31, 1993. One hundred sixteen of 193 patients were alive with evidence of engraftment 6 months after BMT. Development of T-cell function occurred earlier than B-cell function and was achieved more frequently up to the time of last follow-up. The median time to achieve normal T-cell function was 8.7 months, whereas the median time to achieve normal B-cell function was 14.9 months. Twenty-four patients died later than 6 months post-BMT, mainly due to chronic graft-versus-host disease (cGVHD) and/or viral infection. Absence of T-cell reconstitution 6 months after BMT, unlike absence of B-cell reconstitution, was associated with a poor outcome. Two additional factors were associated with a poor outcome: presence of cGVHD 6 months after BMT and B- SCID versus B+ SCID. However, two of these three factors remained as significant prognostic factors in a multivariate analysis: the absence of T-cell function and the presence of cGVHD 6 months after BMT. Analysis of the factors influencing the development of immune reconstitution showed that T- and B-cell functions occurred earlier and more frequently in B+ SCID versus B- SCID patients. Acute GVHD was associated with a slower development of T-cell function at 6 months, and cGVHD had a negative influence on the development of T-cell function afterwards, but neither acute nor chronic GVHD was found to influence the development of B-cell function. Once engraftment occurred, whether patients had or had not received Busulfan in the conditioning regimen did not influence the kinetics and quality of T-cell function development. In a multivariate study, two factors were found to influence the T-cell function 6 months after BMT: type of SCID and acute GVHD. The results of this retrospective analysis should lead to new protocols adapted to SCID disease, considering that disease-related as well as BMT-related parameters influence the development of immune function and thereby long-term outcome after HLA-nonidentical T-cell-depleted BMT.

B-Lymphocytes↗
PubMed1998

Mutations in the gene for the common gamma chain (gammac) in X-linked severe combined immunodeficiency.

X-linked severe combined immunodeficiency (XSCID) constitutes a disorder of the immune system caused by mutations in the gene encoding the common gamma chain (gammac), a subunit of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors, which are necessary for lymphocyte development and function. In this study the IL2RG gene of 31 patients with severe combined immunodeficiency (SCID) was examined by nonradioactive single-strand conformation polymorphism and sequence analysis. Among the 11 patients with XSCID, ten different mutations were identified in the IL2RG gene, including eight novel mutations. Ninety percent of the mothers of the XSCID patients are carriers of the mutated allele. One patient showed low numbers of B-cells, a striking deviation from the classical B-cell-positive and T-cell-negative phenotype.

B-Lymphocytes↗
PubMed1998

The stable microbubble test on tracheal aspirate samples from newborn babies for diagnosis of surfactant deficiency and/or surfactant malfunction.

For predicting the risk of respiratory distress syndrome (RDS), lung surfactant in amniotic fluid can be assessed by observation of stable microbubbles (< 15 microns diameter). It was investigated if the stable microbubble test (MT) developed on amniotic fluid could be applied on tracheal aspirate samples (TA) obtained from newborn infants. Forty-four TA from 29 newborn infants without pulmonary diseases (group 1) and 65 TA from 21 newborn infants with respiratory insufficiency (group 2) were analyzed by the MT for predicting surfactant deficiency and/or surfactant malfunction. Ten microbubbles/ mm2 was defined as cutoff value of the MT. A specificity of 90% and a sensitivity of 52% was obtained with this cutoff value. A much lower rate of false negative results (sensitivity 91%) was noted after surface tension measurement of TA. The sensitivity of the MT (52%) does not encourage the use of the MT on TA.

Cohort Studies↗
PubMed1998

Bone marrow transplantation in congenital immunodeficiency diseases.

Bone Marrow transplantation (BMT) is the treatment of choice in a large number of primary immunodeficiencies, for which this treatment is potentially curative. BMT needs to be considered as soon as possible after diagnosis because these disorders usually run an unpredictable course and may be rapidly fatal. Beside conventional HLA-matched donor BMT, there is growing and increasingly favourable experience with alternative, in particular HLA-haploidentical donors. In this review, current results of BMT are presented.

Bone Marrow Transplantation↗
PubMed1998

Mobilization and collection of allogeneic peripheral blood progenitor cells for transplantation.

A median dose of 11 (6-17) microg G-CSF per kg and day was given to 96 (49 female, 47 male) healthy family donors in order to mobilize and to collect peripheral blood progenitor cells (PBPC) for allogeneic transplantation. Donor age was 36 (17-76) years. The leukocytes of the donors increased to 46 (12-115) x 10(9)/l on days 4-6 of G-CSF treatment with a median of 71 (2-657) CD34+ cells per microl, respectively. Female and older donors seem to have a lower response to G-CSF. About 32% of the donors suffered from side-effects of G-CSF requiring analgetics. A total of 197 stem cell aphereses were performed using the COBE Spectra cell separator. Median apheresis time was 225 (118-300) min processing 11.8 (5.7-20) l blood, collecting 5.3 (1.7-14.9) x 10(10) nucleated cells and containing 0.7 (0.1-3.7)% CD34+ cells. Severe citrate toxicity occurred in 5% of the donors. Retransfusion of autologous platelets post apheresis was necessary in 16% of the donors because of a platelet count <80 x 10(9)/l. An insufficient number of stem cells was collected in four female donors due to a very poor response to G-CSF. In conclusion, the collection of allogeneic G-CSF-mobilized PBPC is safe and effective. One or two aphereses were sufficient in 91% of the donors to achieve >4 x 10(6) CD34+ cells per kg. In 4% of the donors an additional bone marrow harvest or the use of an alternative donor was necessary because of a poor mobilization.

Adolescent↗
PubMed1997

Serum bone alkaline phosphatase is superior to plasma levels of bone matrix proteins for assessment of bone metabolism in patients receiving renal transplants.

The plasma concentrations of two bone matrix proteins (osteocalcin, osteonectin) were monitored in 56 samples from 14 patients receiving renal transplants and the values compared with serum bone alkaline phosphatase mass concentrations and osteotropic hormone levels (parathyroid hormone, calcitriol). There were no significant changes in the concentrations of plasma osteonectin at any time after transplantation, as compared with the values before transplantation (P > 0.1). None of the plasma samples showed osteonectin levels above the reference interval. There was a weak but significant relationship between platelet counts and plasma osteonectin levels (r = +0.322; P < 0.05). Osteocalcin showed a marked decrease of the values 1 week following transplantation as compared with the values before transplantation without further change of the values 1 and 3 months after transplantation (P > 0.5) whereas 3 months after transplantation bone alkaline phosphatase levels were higher than before transplantation (P < 0.05). Multiple regression analysis (performed with data from 42 samples obtained after transplantation) revealed serum creatinine as an independent predictor of plasma osteocalcin whereas serum calcitriol was an independent predictor of serum bone alkaline phosphatase (P < 0.05). No correlation was observed between serum calcitriol/plasma parathyroid hormone on the one hand and plasma osteocalcin on the other (P > 0.05). After transplantation there was a lack of correlation between serum bone alkaline phosphatase mass concentrations and plasma osteocalcin values (P > 0.05). In conclusion, serum bone alkaline phosphatase should be preferred to bone matrix proteins for the assessment of bone metabolism in patients receiving renal transplants: (a) bone alkaline phosphatase-but not osteocalcin-is significantly correlated with calcitriol and adequately reflects increased bone formation after renal transplantation; (b) interpretation of osteocalcin values is severely hampered by their strong correlation with serum creatinine concentrations; (c) plasma osteonectin determinations are not useful for monitoring bone formation.

Adult↗
PubMed1997

Calculation of residence times and radiation doses using the standard PC software Excel.

We developed a program which aims to facilitate the calculation of radiation doses to single organs and the whole body. IMEDOSE uses Excel to include calculations, graphical displays, and interactions with the user in a single general-purpose PC software tool. To start the procedure the input data are copied into a spreadsheet. They must represent percentage uptake values of several organs derived from measurements in animals or humans. To extrapolate these data up to seven half-lives of the radionuclide, fitting to one or two exponentional functions is included and can be checked by the user. By means of the approximate time-activity information the cumulated activity or residence times are calculated. Finally these data are combined with the absorbed fraction doses (S-values) given by MIRD pamphlet No. 11 to yield radiation doses, the effective dose equivalent and the effective dose. These results are presented in a final table. Interactions are realized with push-buttons and drop-down menus. Calculations use the Visual Basic tool of Excel. In order to test our program, biodistribution data of fluorine-18 fluorodeoxyglucose were taken from the literature (Meija et al., J Nucl Med 1991; 32:699-706). For a 70-kg adult the resulting radiation doses of all target organs listed in MIRD 11 were different from the ICRP 53 values by 1%+/-18% on the average. When the residence times were introduced into MIRDOSE3 (Stabin, J Nucl Med 1996; 37:538-546) the mean difference between our results and those of MIRDOSE3 was -3%+/-6%. Both outcomes indicate the validity of the present approach.

Adult↗
PubMed1997

German consensus on immunogenetic donor search for transplantation of allogeneic bone marrow and peripheral blood stem cells.

In Germany allotransplantation of bone marrow or peripheral blood stem cells is presently performed by 34 different teams operating more or less independently. Thus, strategies of immunogenetic donor search, use of the various tissue typing techniques and policy on acceptable HLA mismatches in related and unrelated settings may vary considerably from one transplant centre to another. This paper summarises the results of the first German consensus meeting on immunogenetic donor search for bone marrow/peripheral blood stem cell grafting. The main goal of the participating transplant physicians and immunogeneticists was to define national standards for the above issues.

Bone Marrow Transplantation↗