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Biomedical subjects

W Friedrich

Publications and source records attributed to W Friedrich.

At least 19 recordsLinked to original sources
PubMed2006

Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide.

Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder of osteoclast function, which can be reversed by hematopoietic stem cell transplantation (SCT). We observed a high incidence of hepatic veno-occlusive disease (VOD) in transplanted patients and explored the prevention of this complication by using defibrotide (DF) as a prophylaxis. Twenty children with MIOP were consecutively transplanted in our center between 1996 and 2005. Eleven of these patients were transplanted between 1996 and 2001 and experienced an overall incidence of VOD of 63.6% (7/11). VOD was severe in three patients and one patient succumbed to VOD-related multi-organ failure. Owing to this very high incidence of VOD, DF prophylaxis was initiated in nine patients consecutively transplanted between 2001 and 2005. In this group, only one patient (11.1%) was diagnosed with moderate VOD. We report here a very high risk in patients with MIOP to develop VOD after transplantation. Prophylactic DF was implemented in our current transplant protocol and reduced the VOD rate significantly in this high-risk population.

Female↗
PubMed2004

Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis.

This report describes eight infants who developed acute severe pulmonary arterial hypertension (PAH) at days -2 to +89 after allogeneic stem cell transplantation (SCT) for malignant infantile osteopetrosis (MIOP). They were taken from a total of 28 children (frequency 29%) transplanted for this disease at three institutions between 1996 and 2002. Typical presentations were acute dyspnoea, hypoxia and brady/tachycardia usually in the absence of fever, crepitations or other evidence of infection. Six patients (75%) required assisted ventilation and five (62%) died. There was clinical or pathological evidence of veno-occlusive disease (VOD) in three children, but absence of VOD in the remaining five suggests that a separate disease process may be responsible for the PAH. Responses to nitric oxide (NO), defibrotide (DF), nicardipine and steroids in varying combinations were disappointing. Three children showed sustained improvement after administration of epoprostenol (EP, prostacyclin) in conjunction with NO and/or DF and remain well and free of PAH 25, 31 and 32 months post-transplant. PAH must therefore be excluded in any child who becomes acutely breathless after SCT for osteopetrosis.

Antihypertensive Agents↗
PubMed2003

Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report.

A retrospective analysis was made of 122 children who had received an allogeneic haematopoietic stem cell transplantation (HSCT) for autosomal recessive osteopetrosis between 1980 and 2001. The actuarial probabilities of 5 years disease free survival were 73% for recipients of a genotype HLA-identical HSCT (n=40), 43% for recipients of a phenotype HLA-identical or one HLA-antigen mismatch graft from a related donor (n=21), 40% for recipients of a graft from a matched unrelated donor (n=20) and 24% for patients who received a graft from an HLA-haplotype-mismatch related donor (n=41). In the latter group, a trend towards improvement was achieved at the end of the study period (17% before 1994, 45% after 1994, P=0.11). Causes of death after HSCT were graft failure and early transplant-related complications. Severe visual impairment was present in 42% of the children before HSCT. Conservation of vision was better in children transplanted before the age of 3 months. Final height was related to height at the time of HSCT and better preserved in children transplanted early. Most children attended regular school or education for the visually handicapped. At present, HSCT is the only curative treatment for autosomal recessive osteopetrosis and should be offered as early as possible.

Body Height↗
PubMed2003

Long-term remission of APL with a second allogeneic BMT after CNS relapse following HLA-identical allogeneic BMT.

Second allogeneic bone marrow transplantation (BMT) for AML relapsing after an initial BMT has a poor prognosis, with a probability of a 2-y disease-free survival below 30 per cent, caused both by treatment-related mortality (TRM) and high relapse rate. While TRM is most likely due to heavy pretreatment, AML relapse after BMT may be due to resistant disease or to a poor graft-versus-leukaemia (GvL) effect of the transplant. The degree of GvL may depend on individual donor/recipient immunoreactivity. In most published cases of second allogeneic BMT, both transplants were performed from the same donor. Here, we describe a patient who was first transplanted for acute promyelocytic leukaemia (APL) (AML FAB M3v) from his HLA-identical brother and received intensive immunotherapy including donor lymphocytes and IL2. He remained free from GvHD >I degrees, but developed CNS relapse. After a second BMT from another HLA-identical brother, he spontaneously developed GvHD III degrees, and has now been disease free for nearly 3 years. In this patient, long-term remission of AML relapsing after BMT was achieved by combining remission induction using an individual chemotherapy protocol with a second BMT from an alternative matched related donor and transient GvHD III degrees, which probably conferred a GVL effect.

Bone Marrow Transplantation↗
PubMed2003

Chronic cutaneous sclerodermoid graft-versus-host disease: evaluation by 20-MHz sonography.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is an immunological disorder frequently occurring as a late consequence of allogeneic bone marrow transplantation. Two variants, cutaneous lichenoid and sclerodermoid, have been described, based on clinical and histopathological examinations. It is, however, difficult to determine non-invasively the degree of cutaneous GVHD in vivo. Ultrasonographic methods have recently provided us with the means for objective and non-invasive monitoring of the dynamics of many chronic skin diseases. AIM, PATIENTS AND METHODS: In five patients with chronic cutaneous sclerodermoid GVHD skin thickness was measured with a 20-MHz B-mode ultrasound scanner (DUB 20S, taberna pro medicum, Lüneburg, Germany) in a clinically well-defined target skin lesion. Additionally cutaneous GVHD was assessed histologically before and after treatment. RESULTS: In all patients before treatment the corium of sclerotic skin was thicker than the corresponding areas of healthy skin. The skin thickness was increased from 45% to 83%. In the subcutaneous tissue proper echo-rich reflexes were prominent, representing the correlate of subcutaneous fibrotic trabeculae. In all patients ultrasonographic evidence of regression was shown (decrease of skin thickness by 18-83%). Moreover, it was demonstrated that quantitative assessment of skin thickness is feasible. CONCLUSIONS: In this paper we describe the detailed sonographic features of cutaneous sclerodermoid GVHD for the first time. As the method is simple and non-invasive, repeated examinations are possible. This provides the basis for monitoring treatment effects and efficient follow-up in these chronically progressive clinical conditions after bone marrow transplantation.

Adolescent↗
PubMed2002

Reticular dysgenesis: HLA non-identical bone marrow transplants in a series of 10 patients.

Reticular dysgenesis is a very rare congenital immunodeficiency classified within the severe combined immunodeficiencies (SCID) and characterized by impairment of both lymphoid and myeloid cell development. We report our experience in 10 patients with RD, treated between 1979 and 1999 with HLA-haploidentical hematopoietic stem cell transplantation (HSCT). All children but one were symptomatic within the first days of their lives. Five patients required two HSCT. Five patients received conditioning therapy with busulfan (16 mg/kg) and cyclophosphamide. Three of them are alive and well with myeloid and T and B cell lymphoid reconstitution, whereas two patients died (one chronic graft-versus-host disease, one pneumonitis). Transplantation without or with other conditioning regimens in the other five cases led to absent or incomplete engraftment and none of these cases survived. These results demonstrate the mandatory need for intensive conditioning before haploidentical HSCT in RD to achieve full lymphoid and myeloid engraftment.

Bone Marrow Transplantation↗
PubMed2002

Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe.

The Accreditation Sub-Committee of the EBMT regularly publishes special reports on current practice of haemopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders. Major changes have occurred since the last report in 1998. Haemopoietic stem cell transplantation today includes allogeneic and autologous stem cells derived from bone marrow, peripheral blood and cord blood. With reduced intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged, such as autoimmune disorders and AL amyloidosis for autologous, and solid tumours for allogeneic transplants. Other indications, such as autologous transplantation for breast cancer have been challenged. An updated report with revised tables and operating definitions is presented here.

Adult↗
PubMed2001

Transplacentally acquired maternal T lymphocytes in severe combined immunodeficiency: a study of 121 patients.

A study in 121 infants with severe combined immunodeficiency (SCID) was performed to determine the prevalence of an engraftment by transplacentally acquired maternal T cells and to explore clinical and immunological findings related to this abnormality. Each newly diagnosed patient with SCID presenting with circulating T cells was evaluated for chimerism by performing selective HLA typing of T cells and non-T cells. In patients with engraftment, maternal T cells were characterized phenotypically and functionally, and results were correlated with clinical findings in the patients. Maternal T cells were detected in the circulation in 48 patients; these cells ranged from fewer than 100/microL in 14 cases to more than 2000/microL in 4 cases (median, 415/microL). Clinical signs of graft-versus-host disease (GVHD) were absent in 29 patients. In the other cases, manifestations of GVHD were present, involving the skin and in 14 cases also the liver. Skin GVHD was mild in 8 patients. In these patients, as well as in patients with no signs of GVHD, maternal T cells were predominantly CD8(+) and, with one exception, failed to respond to mitogen stimulation. In 9 patients, manifestations of skin GVHD were prominent. T cells in these cases were predominantly CD4(+) and responded, with one exception, to mitogen stimulation. In 8 of the cases with prominent skin GVHD, the underlying SCID variant was characterized by the absence of B cells. In this study, further understanding is provided of a phenomenon that is responsible for the significant heterogeneity of clinical and immunological findings in SCID.

Cells, Cultured↗
PubMed2001

Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.

Chloride channels play important roles in the plasma membrane and in intracellular organelles. Mice deficient for the ubiquitously expressed ClC-7 Cl(-) channel show severe osteopetrosis and retinal degeneration. Although osteoclasts are present in normal numbers, they fail to resorb bone because they cannot acidify the extracellular resorption lacuna. ClC-7 resides in late endosomal and lysosomal compartments. In osteoclasts, it is highly expressed in the ruffled membrane, formed by the fusion of H(+)-ATPase-containing vesicles, that secretes protons into the lacuna. We also identified CLCN7 mutations in a patient with human infantile malignant osteopetrosis. We conclude that ClC-7 provides the chloride conductance required for an efficient proton pumping by the H(+)-ATPase of the osteoclast ruffled membrane.

Adenosine Triphosphatases↗
PubMed2001

V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.

Alleles↗
PubMed2001

Successful HLA-identical bone marrow transplantation in a patient with PNP deficiency using busulfan and fludarabine for conditioning.

PNP deficiency is an autosomal recessive metabolic disorder characterized by severe combined immunodeficiency and by complex neurological symptomatology including ataxia, developmental delay and spasticity. Patients usually die in the first or second decade of life due to recurrent infections. The only curative treatment is bone marrow transplantation (BMT). We describe a 22-month-old girl who underwent BMT from her HLA-identical brother. Conditioning consisted of busulfan and fludarabine only, resulting in low toxicity and prompt engraftment. At 18 months after BMT, the girl has developed normal immunological functions, and her neurological status has improved.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Eradication of a dysfunctional HLA-haploidentical T cell system by a second HLA-identical BMT.

A 12-year-old boy treated for SCID at 1 month of age by HLA-haploidentical BMT developed a lymphoproliferative disease of unknown etiology at the age of 9 years characterized by sustained, marked elevation of circulating CD8+ donor T cells and by diffuse infiltration of the liver by CD8+ T cells. Because of progressive liver disease, the patient underwent a second BMT from a younger HLA-matched sister. This treatment induced an effective graft-versus-graft reaction and led to complete replacement of the HLA-nonidentical, dysfunctional T cell system, resolution of the hepatopathy and full reconstitution of T and B cell functions.

Bone Marrow Transplantation↗
PubMed2001

Disturbed surface properties in preterm infants with pneumonia.

Congenital pneumonia in preterm infants is often associated with respiratory insufficiency requiring mechanical ventilation. This study was performed to show whether pneumonia in these infants is associated with an inhibition or deficiency of surfactant. The ratio of lecithin and sphingomyelin (L/S ratio) and minimal surface tension were determined in pharyngeal aspirates from 90 term born infants (healthy) and in tracheal aspirates from preterm infants with wet lung (n = 13), congenital pneumonia (n = 21) and respiratory distress syndrome (RDS) (n = 90). The L/S ratio was lower (p < 0.0001) in the RDS group (8.6) when compared with healthy (48.6), wet lung (42.9) and pneumonia (28.9). Surface tension was higher (p < 0.001) in RDS (37 mN/m) and pneumonia (33.7) when compared with healthy (22.9) or wet lung (21.2). For infants with RDS, L/S ratio <16.5 detects surfactant deficiency with 96% specificity and 70% sensitivity, surface tension >29 mN/m represents surfactant inhibition (specificity 97%, sensitivity 92%). Using these cut-off values in infants with pneumonia, 81% had a sufficient amount of surfactant but only 21% of infants with pneumonia had appropriate surface tension. Our study shows that lung effluent of respiratory insufficient infants with pneumonia, who need mechanical ventilation, has disturbed surface properties despite a sufficient amount of surfactant. In these infants, surfactant substitution could be beneficial.

Case-Control Studies↗
PubMed2001

The impact of social change on child mental health in Eastern Europe.

The transition of the Eastern European countries in the past 12 years from totalitarian, communist societies to democratic societies has had a broad impact on children's mental health, both positively and negatively. This transition has not been without economic difficulties. All countries in the region experienced a significant deterioration of output that has affected the availability of commodities and services. Although recovery has been achieved in some Eastern European countries and is in progress in other countries, reversal of the cutbacks in allocations to necessary services that protect children and families may take longer to achieve. Movement toward a free market economy and greater individualism also has focused attention away from the role of society to protect and provide care for its citizens, especially the most vulnerable. On the positive side, mental health, as a concept for children and adults, comes to be appreciated only in a society that values and safeguards individual rights. Democratic process within the family, the depoliticization of mental illness, the passage of laws assuring basic children's rights, services for and public awareness about children abuse, reforms in education, the proliferation of mental health clinics and support centers, and the resumption of training of mental health professionals all set a tone to first consider, then assure, the positive development of children's mental health.

Adolescent↗
PubMed2000

Similar pattern of thymic-dependent T-cell reconstitution in infants with severe combined immunodeficiency after human leukocyte antigen (HLA)-identical and HLA-nonidentical stem cell transplantation.

Donor T cells after stem cell transplantation reconstitute by 2 different pathways: by expansion from grafted, mature T cells and by intrathymic maturation from progenitor cells. This study characterized thymic-dependent reconstitution of CD4(+) T cells following different transplant modalities in patients with severe combined immunodeficiency (SCID). Three groups of patients were studied: one group after transplantation from human leukocyte antigen (HLA)-identical siblings with unmanipulated grafts without conditioning, a second group after transplantation from HLA-nonidentical parents with T-cell-depleted grafts without preconditioning, and a third group with prior conditioning. Reconstitution of the T-cell compartment was monitored by determining the expression of CD45 isoforms by developing CD4(+) cells in the peripheral blood and in discriminating expanded (CD45RO(+)) and newly generated (CD45RA(+)) T cells. Concomitantly, changes in the size of the thymus were evaluated sequentially by ultrasonography. Reconstitution of CD4(+)CD45RA(+) cells was delayed in all patients for several months, including patients after HLA-identical transplantation, and was always paralleled by normalization of the size of the thymus. No engraftment of donor progenitor cells was observed, as studied in one patient transplanted without conditioning. CD4(+)CD45RO(+) cells were detected early after transplantation only in patients given unmanipulated grafts. The study showed that thymic-dependent T-cell maturation in these patients with SCID runs an autonomous course, independent of graft manipulation, of major HLA disparities, and of whether conditioning is used or not. In addition, thymic maturation may not require engraftment of donor-derived CD34(+) cells in the marrow. (Blood. 2000;96:4344-4349)

Adolescent↗
PubMed2000

Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis.

Although the gene defects for several mouse mutants with severe osteopetrosis are known, the genes underlying human infantile malignant recessive osteopetrosis remain elusive. Osteopetrosis is thought to be caused by a defect in osteoclast function. These cells degrade bone material in a tightly sealed extracellular compartment that is acidified by a vacuolar (V)-type H(+)-ATPase. Genes encoding components of the acidification machinery are candidate genes for osteopetrosis. In five of ten patients with infantile malignant osteopetrosis, we now demonstrate five different mutations in OC116, the gene encoding the a3 subunit of the V-ATPase from osteoclasts. Two independent patients were homozygous for mutations that predict a total loss of function by severely truncating the protein. By affecting a splice site, another homozygous mutation deletes 14 amino acids within the N-terminus, which interacts with other subunits of the proton pump. On the other hand, in four patients no mutations were found, and one patient from a consanguineous family did not show homozygosity at the OC116 locus, suggesting that mutations in at least one different gene may underlie osteopetrosis. Our work shows that mutations in the gene encoding the a3 subunit of the proton pump are a rather common cause of infantile osteopetrosis and suggests that this disease is genetically heterogeneous.

Amino Acid Sequence↗
PubMed2000

Surfactant protein SP-B counteracts inhibition of pulmonary surfactant by serum proteins.

In addition to the primary surfactant deficiency in newborns with respiratory distress syndrome (RDS), in the later course of RDS substantial protein leakage into the alveolar spaces can occur by damage to the alveolocapillary membrane. Acute lung injury results in surfactant dysfunction due in part to inhibition by serum proteins. The aim of this study was to investigate the influence of SP-B on the inhibitory effects of albumin (alb) and fibrinogen (fib) on the surface activity of pulmonary surfactant, using a) surface tension measurement with the pulsating bubble surfactometer in suspensions and b) in surfactant films applying the hypophase exchanger. After hypophase exchange a preformed film of Survanta is very resistant to the inhibitory activity of alb or fib. The surface tensions of suspensions are significantly higher (p <0.001) than the surface tensions of preformed surfactant films if alb or fib were added, e.g., 42 (41 to 43) mN/m vs. 21 (19 to 22) mN/m for Survanta with 20 mg alb/ml. After additional supplementation of Survanta with SP-B the surface activity of Survanta/1% SP-B films did not show inhibition by fib (2 mg/ml), (surface tension 8 (4 to 13) mN/m). These results indicate that SP-B can play an important role to protect the pulmonary surfactant film from inactivation by serum proteins.

Fibrinogen↗