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Biomedical subjects

P Imbach

Publications and source records attributed to P Imbach.

At least 19 recordsLinked to original sources
PubMed2006

Childhood ITP: 12 months follow-up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS).

BACKGROUND: Acute and chronic idiopathic thrombocytopenic purpura (ITP) is traditionally based on the duration of thrombocytopenia at the cut-off point of 6 months after diagnosis. Registry I evaluated the diagnosis, definition, management, and follow-up of childhood ITP. This report focuses on children with thrombocytopenia persisting more than 6 months. PROCEDURE: Data were collected by questionnaires to the physicians caring for children with ITP, at diagnosis, 6, and 12 months later. Data were compared regarding initial features and follow-up with emphasis on children with persistent thrombocytopenia, and those with ITP who recovered their platelet counts between 7 and 12 months from diagnosis. RESULTS: At 12 months from diagnosis, 79 of 308 (25.6%) evaluable children recovered from ITP and 229 had ongoing ITP. Children with recovered ITP were younger than children with ongoing ITP (P = 0.043) and exhibited a lower frequency of bleeding symptoms during the first 6 months after diagnosis (P = 0.018). Frequency of hospitalization, bone marrow aspiration, and drug treatment differed regionally. CONCLUSIONS: The high rate of recovery from ITP between 7 to 12 months demonstrates, that the cut-off point of 6 months for the definition of chronic ITP does not adequately differentiate chronic from acute ITP. The majority of children with ITP have variable time to recovery with gradual improvement of platelet counts and disappearance of bleeding signs. ITP is a heterogeneous disorder with a diverse natural history and diverse pattern of treatment response.

Acute Disease↗
PubMed2004

[Idiopathic thrombocytopenic purpura in children].

In children the rate of acute, transient ITP is much higher than the chronic form of ITP. Often acute childhood ITP is a para- or postinfectious event. Pathophysiologically bleeding symptoms mainly depend on the ratio between normal or increased platelet production and early destruction of platelets. The management of ITP has to be focused on the individual bleeding symptoms rather than to the platelet count (see staging system). Today's treatments are directed against the disturbed immune response. As recent guidelines and surveys demonstrate opinion based recommendations have to be challenged by evidence based clinical research in ITP (see www.unibas.ch/itpbasel).

Acute Disease↗
PubMed2003

Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences.

One of the most relevant concerns in long-term survivors of paediatric acute lymphoblastic leukaemia (ALL) is the development of neuropsychological sequelae. The majority of the published studies report on patients treated with chemotherapy and prophylactic central nervous system (CNS) irradiation, little is known about the outcome of patients treated with chemotherapy-only regimens. Using the standardised clinical and neuropsychological instruments of the SPOG Late Effects Study, the intellectual performance of 132 paediatric ALL patients treated with chemotherapy only was compared to that of 100 control patients surviving from diverse non-CNS solid tumours. As a group, ALL and solid tumour survivors showed normal and comparable intellectual performances (mean global IQ 104.6 in both groups). The percentage of patients in the borderline range (global IQ between 70 and 85) was comparable and not higher as expected (10% cases and 13% controls, expected 16%). Only 2 (2%) of the former ALL and 1 (1%) of the solid tumour patients were in the range of mental retardation (global IQ<70). Former known risk factors described in children treated with prophylactic CNS irradiation, like a younger age at diagnosis of ALL and female gender, remained valid in chemotherapy-only treated patients. The abandonment of prophylactic CNS irradiation and its replacement by a more intensive systemic and intrathecal chemotherapy led to a reduction, but not the disappearance of late neuropsychological sequelae.

Adolescent↗
PubMed2001

A new structural class of selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

We describe the identification and in vitro characterization of a series of 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the 20S proteasome. Our initial SAR data demonstrate that the 2-aminobenzylstatine core structure can effectively serve as the basis for designing potent, selective and non-covalent inhibitors of the chymotrypsin-like activity of the 20S proteasome.

Amino Acids↗
PubMed2001

Modeling of the binding mode of a non-covalent inhibitor of the 20S proteasome. Application to structure-based analogue design.

The 2-aminobenzvlstatine derivative I is a 20S proteasome inhibitor of a novel chemical type identified by high throughput screening. The compound specifically inhibits the chymotrypsin-like catalytic activity of the human proteasome with an IC50 value in the micromolar range. Using the crystal structure of the yeast proteasome, we modeled the structure of the human proteasome in complex with 1. As one of the first applications of the model in our oncology programme targeting the proteasome, we designed an analogue of the inhibitor having enhanced stacking/hydrophobic interactions with the enzyme. One order of magnitude in inhibitory potency was gained.

Amino Acids↗
PubMed2001

Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura: a pilot study.

Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.

Case-Control Studies↗
PubMed2000

[Single and double high-dose chemotherapy with autologous stem cell transplantation in children with advanced solid tumors: first experiences].

The disease-free survival of children with malignant disorders has increased impressively over the last three decades due to better understanding of tumour biology and the resultant improvement in diagnosis and therapy. Children with advanced and relapsed solid tumours, such as brain tumour, alveolar rhabdomyosarcoma, Ewing's sarcoma, or neuroblastoma, have not benefited from this progress. The concept of myeloablative high-dose chemotherapy (HDT) is based on the observation that certain cytostatic drugs have a steep linear dose-response curve, and thus escalating the dose may increase the tumour cell kill. The interest in HDT intensified when autologous stem cells mobilised from the peripheral blood became available, in view of the possibility of increasing the cell dose, which correlates directly with the time period of haematopoietic recovery and thus reduces therapy-associated toxicity. The aim of the study was to evaluate the feasibility of single or double HDT by autologous peripheral blood stem cell transplantation (PBSCT) after each cycle in children, and to obtain pilot data for future prospective clinical trials. 11 children aged between 2.8 and 17.2 years with brain tumours, soft tissue sarcomas, germ-cell tumours and neuroblastomas were analysed over a 2-year-period. 7 of the 11 children are in complete remission 2+ and 24+ months after HDT, 3 died of progressive disease and one child died of therapy-associated complications. The median hospital stay was 29.5 (22-104) days. An absolute neutrophil granulocyte count of 0.5 x 10(9)/l was achieved after a median stay of 11 days and a platelet count of > 20 x 10(9)/l independent of platelet transfusions was achieved after 11 days. Painful stomatitis leading to total parenteral nutrition (9 children) and intravenous morphine therapy (6 children) was the most serious toxicity. Single or double HDT with autologous PBSCT after each cycle is feasible in children and offers basic data for conducting phase III paediatric clinical studies.

Adolescent↗
PubMed2000

Structure-based design of potent CDK1 inhibitors derived from olomoucine.

Cyclin-dependent kinase 1 (CDK1), an enzyme participating in the regulation of the cell cycle, constitutes a possible target in the search for new antitumor agents. Starting from the purine derivative olomoucine and following a structure-based approach, potent inhibitors of this enzyme were rapidly identified. The molecular modeling aspects of this work are described.

Amino Acid Sequence↗
PubMed2000

Ethnicity and environment may affect the phenotype of immune thrombocytopenic purpura in children.

Little is known about the influence of environmental and ethnic factors on the epidemiology of immune thrombocytopenic purpura (ITP). Therefore we compared the initial presentation and condition after 6 mo in 90 Vietnamese and 89 German and Swiss children with newly diagnosed ITP. Data from the two cohorts were collected within the same time period. No differences in age and sex were observed between the Asian and European cohorts, but significant differences between initial platelet count, the occurrence of dry versus wet bleeding symptoms, and infection preceding the onset of ITP were found. Children who had chronic ITP also differed with respect to platelet count and postinfectious state, but not initial bleeding type. In addition, chronic ITP occurred more often than expected with a male to female ratio of 1.2 in Vietnam and 2 in Germany and Switzerland. The data support the potential influence of environmental or ethnic factors on the different aspects of ITP, and point to the need for further epidemiologic investigations.

Asian People↗
PubMed1998

[Establishing an umbilical cord blood bank for unrelated allogenic stem cell transplantation].

We report the establishment of a cord-blood bank in a routine hematological laboratory. Cord-blood collection was performed with placenta in utero by a trained team and immediately sent to the cord-blood bank. There, 6.8 ml cord-blood was used for analysis of nucleated cell counts, counts of CD34-positive cells, CFU's, complete HLA-typing, ABO and Rhesus blood groups, bacteriologic cultures and serology for HIV 1 and 2, HbsAg, HVC, CMV, syphilis and toxoplasmosis. The cord-blood collection was frozen and conserved at -192 degrees C. From each cord-blood vials of DNA, viable cells and plasma were cryopreserved. Between June 1997 and April 1998, 54 cord-bloods were collected. 40 of them were cryo-preserved, and 14 discarded because of low cell counts. The median volume was 109 ml with 1.4 x 10(9) nucleated cells. The in vitro capacity of proliferation of the cord-blood correlated well with the absolute counts of CD34-positive cells (r = 0.93), moderately with the relative counts of CD34 (r = 0.68) as well as the nucleated cells (r = 0.70), poorly with the volume (r = 0.44). Three of the 40 (7.5%) cord-blood products contained a bacterial contamination. This study shows that a cord-blood bank can be organised in a routine hematological laboratory, which is familiar with transplantation products. However, the procedure is time consuming, expensive and requires a highly qualified team and specialised technical equipment.

Blood Banks↗
PubMed1998

Neonatal platelet physiology and pathophysiology.

Platelets contribute to primary haemostatic events and are closely linked to plasmatic coagulation. Their function is highly dependent not only on their number but also on their integral physiology. In comparison with adults or children, the haemostasis of newborn infants, although physiological, is characterized by a reduced functional reserve capacity leading to the rapid occurrence of bleeding disorders especially in the presence of additional risk factors such as prematurity, asphyxia, or infection. Morphological and biochemical differences reflect an immature cellular stage which results in platelet hyporeactivity and contributes to the reduced capacity of the neonatal haemostatic system. Additionally acquired and inherited platelet disorders markedly affect platelet function. Hence assessment of neonatal platelet physiology may supply important information, however, no adequate screening tests are currently available, and technical difficulties of blood sampling limit the value of laboratory testing. Evaluation of the neonatal platelet function is highly dependent on individual laboratory results and it is advisable to perform complex diagnostic procedures with the collaboration of specialists experienced in neonatal haematology. With the advent of new technology such as platelet flow cytometry more adequate tools are available, although still reserved for specialized laboratories, thus awaiting their clinical significance. The role of maternal influences on neonatal platelet function must be always considered. Thus, neonatal platelet physiology and pathophysiology is complex and require more studies and experience.

Blood Platelet Disorders↗
PubMed1998

Management of children with acute and chronic immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is divided in an acute and chronic form based on the duration of the disease. Persistence of thrombocytopenia for more than 6 months defines chronic ITP. The disease occurs in both children and adults with acute ITP as the predominant form of childhood and chronic ITP occurring in approximately 20% of children and almost all adult patients. The diagnostic procedures and the therapeutic consequences are discussed with respect to the many open and unresolved questions recently identified by a panel of pediatric and adult hematologists on behalf of The American Society of Hematology. Research activities with identification of priorities are important to better understand the disease resulting in an optimal evidence-based management of children and adults with ITP.

Acute Disease↗
PubMed1998

Chronic immune thrombocytopenic purpura in childhood.

Immune thrombocytopenic purpura (ITP) is a bleeding disorder and is traditionally divided in acute and chronic forms based on the duration of the disease. Chronic ITP is characterized by a persistence of thrombocytopenia for more than 6 months. Ten to 20% of children with ITP and almost all adults will develop the chronic condition. Pathophysiology of chronic ITP suggests an autoimmune process and a dysregulated immune response. There are no risk factors to predict the clinical course of ITP. Controlled clinical trials are needed to clarify many diagnostic and therapeutic aspects of chronic ITP, as recently stated by a panel of pediatric and adult hematologists on behalf of The American Society of Hematology (ASH). In this article, we will focus on pathophysiological, diagnostic, and management aspects of chronic childhood ITP.

Child↗
PubMed1998

Immune thrombocytopenic purpura ITP.

Immune thrombocytopenic purpura ITP is characterized by early platelet destruction due to an imbalanced immune response. In acute ITP, a transient increase of HLA-DR molecules has been detected while in individuals with chronic ITP, in addition, increased serum concentrations of IL-2 and other cytokines reflecting in vivo T-cell activation have been observed. Clinically, the hemorrhagic manifestation of ITP rather than the platelet count should define the indication for active intervention. In a staging system a patient with stage III has bleeding signs and platelet counts below 10 or 20 x 10(9)/L and needs treatment, a patient with stage II should be treated on an individual level (prevention of bleeding) and a patient with stage I (no bleeding, platelet count above 50 x 10(9)/L) should be observed only.

Adolescent↗
PubMed1997

International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies.

Platelet-associated and plasma autoantibodies against platelet glycoproteins (GP) have been demonstrated in patients with autoimmune thrombocytopenia (AITP) using various methods. Eight laboratories in seven countries participated in this international study to evaluate the interlaboratory agreement using glycoprotein-specific immunoassays for these autoantibodies. The participating laboratories received blind samples of frozen washed platelets and plasma from 22 normal donors and 22 AITP patients. Platelet-associated and plasma autoantibodies against GPIIb-IIIa and GPIb-IX were measured by MAIPA, immunobead assay or modified antigen capture assay. Of the control samples, 96.0% and 97.2% of all results for platelet-associated and plasma autoantibodies to GPIIb-IIIa/ GPIb-IX, respectively, were negative. The mean variation coefficient of the control samples of platelet-associated and plasma autoantibodies was 89.5% (range 11.1-272.9%) and 46.5% (range 21.0-78.0%), respectively. In 20/22 patient samples, platelet-associated autoantibodies to either glycoprotein were noted by at least two laboratories. The mean degree of agreement in these samples was 74.0%. There was a significant correlation in the individual antibody measurements between all laboratories (Kendall coefficient of concordance 0.60 and 0.38, P < 0.001; Spearman rank order test, range of correlation coefficient 52.3-94.0% and 42.2-85.0%, P < 0.05, for anti-GPIIb-IIIa and anti-GPIb-IX, respectively). In contrast, plasma autoantibodies to either glycoprotein were noted by at least two laboratories in only 13/22 patient samples. Moreover, the degree of agreement was poor (50.1%) and a significant correlation was noted between only six pairs of laboratories. We conclude that methods used in this study yield good interlaboratory agreement in measuring platelet-associated autoantibodies against GPIIb-IIIa and GPIb-IX. In contrast, poor agreement was found in detecting plasma autoantibodies to the same glycoproteins.

Autoantibodies↗