Biomedical subjects

Amos Toren

Publications and source records attributed to Amos Toren.

25 records · Page 2Linked to original sources

PubMed2003

Diffuse alveolar hemorrhage following allogeneic bone marrow transplantation in children.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a frequent life-threatening complication of bone marrow transplantation (BMT) in adults. This noninfectious pulmonary disorder is rarely reported following BMT in neonates and children. STUDY OBJECTIVES: To review the clinical features and course of children who underwent allogeneic BMT and developed DAH in the posttransplant period. DESIGN: A retrospective 6-year chart review. SETTING: Pediatric ICU in a university hospital. PATIENTS AND INTERVENTIONS: At total of 138 children who had undergone allogeneic BMT for nonmalignant (n = 66) or malignant (n = 72) diseases. MEASUREMENTS AND RESULTS: Six of 138 children (4.3%) aged 2 months to 10 years (male/female ratio, 1:1) developed DAH. Each had a fulminant course with rapidly developing severe respiratory failure, mandating mechanical ventilation within 24 h following symptom onset. They were all treated with methylprednisolone, 6 mg/kg/d for 3 days. Only one child survived, and there have been no sequelae at 2 years post-BMT. Four children died of respiratory causes, and one died of multiorgan failure. CONCLUSIONS: DAH is a potentially fatal respiratory complication that should be included early in the differential diagnosis of acute respiratory failure in children following allogenic BMT for both malignant and nonmalignant diseases. Therapy with high doses of steroids apparently do not affect the course of the disease.

Anti-Inflammatory Agents↗

PubMed2002

Combined analysis of morphology and fluorescence in situ hybridization in follow-up of minimal residual disease in a child with Philadelphia-positive acute lymphoblastic leukemia.

The past decade has brought new technologies to the study of minimal residual disease (MRD) in leukemia. Each of them has limitations and is far from being accurate. Recently, a new multiparametric cell scanning system (Duet) was introduced to the field of MRD detection. This system has the advantage of automatically scanning large numbers of cells and performing combined analysis of morphology and fluorescence in situ hybridization (FISH) on the same cell. We used this system to characterize the lineage and degree of maturation of the cells carrying the minor m-BCR/ABL fusion, in a follow-up of an 8-year-old boy with Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL). The boy was treated using a high-risk protocol and was closely monitored with FISH analysis for cells carrying the m-BCR/ABL fusion. Consecutive analysis along 2.5 years from remission showed 0.2-4.5% m-BCR/ALB(+) cells in the peripheral blood (PB), which is within the accepted background range for this method. The combined analysis found that all the m-BCR/ABL(+) cells were mature lymphocytes. Because mature lymphocytes have a long life span in the circulation, this finding supports the fact that the patient is in remission. Moreover, since mature differentiated cells have a low proliferative capacity, there is a low risk for relapse.

Cell Division↗

PubMed2002

A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1.

p53 exerts its tumor suppressor effects by activating genes involved in cell growth arrest and programmed cell death. The p53 target genes inducing growth arrest are well defined whereas those inducing apoptosis are not fully characterized. Proapoptotic activity of p53 was shown to involve several genes like Bax, Noxa and Puma, which may function in the release of cytochrome c from the mitochondria. Cytochrome c associates with Apaf-1 and caspase 9 to form the apoptosome. Genetic and cellular data indicate that Apaf-1 deficiency abrogates the apoptotic effect of p53 and substitutes for p53 loss in promoting tumor formation. Here we show that Apaf-1, the mammalian homologue of C. elegans CED4, is a direct target of p53 as demonstrated by gel shift analysis of the target site sequence in the presence of p53 and by Apaf-1 promoter-luciferase assays. We also show that the p53 activation of the Apaf-1 luciferase construct can be enhanced by the putative tumor suppressor gene product, Zac-1, a transcription factor that has previously been shown to inhibit cell proliferation. Furthermore, we demonstrate that Zac-1 is a possible direct target of p53 since the sequence upstream to the first coding exon of Zac-1 contains a p53 recognition site and the luciferase construct containing this region is activated by p53. These results suggests the existence of a tightly controlled self amplifying mechanism of transcriptional activation leading to apoptosis by p53.

Animals↗

PubMed2002

MAP kinase activation by mu opioid receptor in cord blood CD34(+)CD38(-) cells.

OBJECTIVE: Opioid receptor expression and function traditionally have been studied in neuronal cells and recently in mature lymphoid cells; however, little is known about their possible functions in hematopoietic stem cells (CD34(+) cells). We studied the expression of the mu receptor on CD34(+) cells and assessed the signal transduction cascade it induces. MATERIALS AND METHODS: Mu-receptor expression on cord blood (CB) and peripheral blood (PB) CD34(+) cells was studied by microarrays, immunostaining, and fluorescence-activated cell sorting analysis. Signal transduction by the mu receptor was studied through Western blots and kinase assay of enkephalin-activated CB CD34(+) cells. Apoptotic, differentiation, and proliferation responses following mu-receptor activatioSn were studied by annexin V assay and inverted microscopy. RESULTS: A prominent difference in gene expression, in favor of CB compared to PB CD34(+) cells, was observed in the mu-receptor gene. This receptor was mainly expressed on the CB CD34(+)CD38(-) subpopulation. A MAP kinase signal transduction cascade was shown to be induced through activation of this receptor by enkephalin or morphine. CONCLUSIONS: We showed for the first time that the mu receptor is expressed on immature CB stem cells and that its activation by enkephalin or morphine induces a MAP kinase signal transduction cascade. Because the MAP kinase cascade is known to elicit proliferation and differentiation responses, these findings suggest a possible role of endogenous enkephalins in hematopoietic stem cell proliferation and differentiation and may lead to therapeutic applications of opiates in CB stem cell expansion and neuronal differentiation.

ADP-ribosyl Cyclase↗

PubMed2002

Predictors of outcome in the pediatric intensive care units of children with malignancies.

PURPOSE: Children with malignancies in whom life-threatening complications develop are traditionally considered as having a grim prognosis. Clinical predictors of short-term outcome for rational triage to pediatric intensive care units (PICU) were retrospectively assessed. PATIENTS AND METHODS: The records of 94 children consecutively admitted to the PICU at the authors' institution between January 1989 and January 1999 were reviewed, and predictors of 30-day mortality rates were delineated using stepwise logistic regression. RESULTS: The children's mean age was 7.3 years (range, 2-21). Their diseases included hematologic malignancies 45 (48%), extracranial solid tumors 21 (22%), and intracranial tumors 28 (30%). The overall 30-day survival rate was 66%. Mortality was highest among children admitted for respiratory failure (40%). High mortality was also found for those with circulatory collapse (33.3%) and neurologic deterioration (31%). The admitting pediatric risk of mortality score (PRISM) among the survivors was 6.6 +/- 1.3, compared with 15.2 +/- 3 among nonsurvivors (P < 0.01). The number of organ system failures was higher among the nonsurvivors on admission (P < 0.001). The need for ventilatory or inotropic support corresponded to worse outcome (P < 0.001 or P < 0.01, respectively). Overall, 36 (38%) of the children had sepsis during their PICU stay, with a mortality rate of 50% compared with 24% among nonseptic children (P < 0.01). Sepsis present on admission was later correlated with the development of organ system failure (P < 0.01). CONCLUSIONS: New trends in therapeutic approaches to children with malignancies can clearly improve outcome. The high (66%) survival rate justifies policy of early admission to the PICU of children in whom signs of multiorgan involvement start to develop, as reflected by high PRISM and the need for ventilatory or inotropic support. Further refinement of reliable clinical predictors of survival will enable better triage of these children to the PICU for possible prevention of systemic complications and reduction of mortality rates.

Adolescent↗

PubMed2002

Stem-cell transplantation for primary immunodeficiencies.

Until further improvement in gene therapy is achieved, stem-cell transplantation is still the main option for cure of patients with primary immunodeficiency diseases. Performing the transplant in early infancy before severe infections and organ damage develop has the highest chance for success. The remarkable progress that has been achieved in understanding these disorders has made it possible to identify most of the genetic abnormalities. This enables an early transplant immediately after birth or even in utero. However, the optimal approach for stem-cell transplantation in children with immunodeficiency has yet to be determined. The non-myeloablative protocols increasingly used in recent years have the potential for immune reconstitution without considerable toxicity, but the experience is still limited. A better understanding of the specific immune dysfunction and the exact degree of residual immunity may enable the tailoring of the most appropriate conditioning regimen for each patient so that engraftment will be ensured with little morbidity.

Hematopoietic Stem Cell Transplantation↗

PubMedDate not supplied

Role of 18F-FDG PET/CT in staging and follow-up of lymphoma in pediatric and young adult patients.

OBJECTIVE: To assess the role of 18F-Fluorodeoxyglucose (18F-FDG) PET/CT in pediatric patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). MATERIALS AND METHODS: 31 patients, mean age 12.9 +/- 5.1, HD (n = 24), and NHL (n = 7) underwent 18F-FDG PET/CT at diagnosis (n = 31 studies) and later in the course of the disease (n = 75 studies). The findings of PET/CT were correlated with diagnostic CT and clinical follow-up. RESULTS: PET/CT findings resulted in a change of disease staging in 10 patients (32.3%), upstaging in 7 (22.6%) and downstaging in 3 (9.6%). On a lesion analysis, 164 disease sites were detected by PET/CT of which 38 were overlooked by DCT. At mid-treatment, PET was negative in 28 out of 31 patients (90%) with negative predictive value of 96% as all latter patients except for 1, were disease free (mean 15.4 +/- 8.8 months). The positive predictive value of persistent increased 18F-FDG uptake was 100% as 3 patients with latter findings had active disease. On the CT part, 76 residual masses were identified in 22 patients. Increased 18F-FDG uptake was detected in 11 masses in 4 patients who had active disease. Remaining 65 PET negative masses were false positive findings. The positive predictive value of residual CT mass was 14%. CONCLUSIONS: PET/CT is associated with change in staging in approximately 1 out of 3 pediatric patients with HD and NHL. When used for monitoring response to treatment, a negative study is associated with disease-free period, even when residual mass is detected. A positive PET study indicates residual malignant disease.

Adolescent↗