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Biomedical subjects

C Peters

Publications and source records attributed to C Peters.

At least 37 records · Page 2Linked to original sources
PubMed2001

Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia.

In order to compare the outcomes of unrelated umbilical cord blood transplants (UCBTs) or bone marrow transplants, 541 children with acute leukemia (AL) transplanted with umbilical cord blood (n = 99), T-cell-depleted unrelated bone marrow transplants (T-UBMT) (n = 180), or nonmanipulated (UBMT) (n = 262), were analyzed in a retrospective multicenter study. Comparisons were performed after adjustment for patient, disease, and transplant variables. The major difference between the 3 groups was the higher number in the UCBT group of HLA mismatches (defined by serology for class I and molecular typing for DRB1). The donor was HLA mismatched in 92% of UCBTs, in 18% of UBMTs, and in 43% of T-UBMTs (P <.001). Other significant differences were observed in pretransplant disease characteristics, preparative regimens, graft-versus-host disease (GVHD) prophylaxis, and number of cells infused. Nonadjusted estimates of 2-year survival and event-free survival rates were 49% and 43%, respectively, in the UBMT group, 41% and 37% in the T-UBMT group, and 35% and 31% in the UCBT group. After adjustment, differences in outcomes appeared in the first 100 days after the transplantation. Compared with UBMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR] = 0.37; 95% confidence interval [95CI]: 0.27-0.52; P <.001), increased 100 day transplant-related mortality (HR = 2.13; 95CI: 1.20-3.76; P <.01) and decreased acute graft-versus-host disease (aGVHD) (HR = 0.50; 95CI: 0.34-0.73; P <.001). T-UBMT recipients had decreased aGVHD (HR = 0.25; 95CI: 0.17-0.36; P <.0001) and increased risk of relapse (HR = 1.96; 95CI: 1.11-3.45; P =.02). After day 100 posttransplant, the 3 groups achieved similar results in terms of relapse. Chronic GVHD was decreased after T-UBMT (HR = 0.21; 95CI: 0.11-0.37; P <.0001) and UCBT (HR = 0.24; 95CI: 0.01-0.66; P =.002), and overall mortality was higher in T-UBMT recipients (HR = 1.39; 95CI: 0.97-1.99; P <.07). In conclusion, the use of UCBT, as a source of hematopoietic stem cells, is a reasonable option for children with AL lacking an acceptably matched unrelated marrow donor.

Analysis of Variance↗
PubMed2001

Cathepsin S regulates the expression of cathepsin L and the turnover of gamma-interferon-inducible lysosomal thiol reductase in B lymphocytes.

Loading of antigenic peptide fragments on major histocompatibility complex class II molecules is essential for generation of CD4(+) T cell responses and occurs after cathepsin-mediated degradation of the invariant chain chaperone molecule. Cathepsins are expressed differentially in antigen presenting cells, and mice deficient in cathepsin S or cathepsin L exhibit severely impaired antigen presentation in peripheral lymphoid organs and the thymus, respectively. To determine whether these defects are due solely to the block in invariant chain cleavage, we used cathepsin-deficient B cells to examine the role of cathepsins S and B in the degradation of other molecules important in the class II presentation pathway. Our data indicate that neither cathepsin S nor B is critical for H-2M degradation or processing of precursor gamma-interferon-inducible lysosomal thiol reductase (GILT) to a mature thiol reductase, but suggest a role for cathepsin S in the turnover of mature GILT and in regulating levels of mature cathepsin L protein in B cells. Despite the presence of mature cathepsin L protein, no enzyme activity could be detected in B cells or dendritic cells. These experiments suggest a novel mechanism by which these functionally important enzymes may be regulated.

Animals↗
PubMed2001

Measurement of CP-violating asymmetries in B0 decays to CP eigenstates.

We present measurements of time-dependent CP-violating asymmetries in neutral B decays to several CP eigenstates. The measurement uses a data sample of 23x10(6) Upsilon(4S)-->BbarB decays collected by the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we find events in which one neutral B meson is fully reconstructed in a CP eigenstate containing charmonium and the flavor of the other neutral B meson is determined from its decay products. The amplitude of the CP-violating asymmetry, which in the standard model is proportional to sin2beta, is derived from the decay time distributions in such events. The result is sin2beta = 0.34+/-0.20 (stat)+/-0.05 (syst).

Journal Article↗
PubMed2001

Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion.

SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) and Rab-GTPases, together with their cofactors, mediate the attachment step in the membrane fusion of vesicles. But how bilayer mixing--the subsequent core process of fusion--is catalysed remains unclear. Ca2+/calmodulin controls this terminal process in many intracellular fusion events. Here we identify V0, the membrane-integral sector of the vacuolar H+-ATPase, as a target of calmodulin on yeast vacuoles. Between docking and bilayer fusion, V0 sectors from opposing membranes form complexes. V0 trans-complex formation occurs downstream from trans-SNARE pairing, and depends on both the Rab-GTPase Ypt7 and calmodulin. The maintenance of existing complexes and completion of fusion are independent of trans-SNARE pairs. Reconstituted proteolipids form sealed channels, which can expand to form aqueous pores in a Ca2+/calmodulin-dependent fashion. V0 trans-complexes may therefore form a continuous, proteolipid-lined channel at the fusion site. We propose that radial expansion of such a protein pore may be a mechanism for intracellular membrane fusion.

Calmodulin↗
PubMed2001

Oral busulfan pharmacokinetics and engraftment in children with Hurler syndrome and other inherited metabolic storage diseases undergoing hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is the only treatment for selected inherited metabolic storage diseases (IMSD); a significant shortcoming is failure to achieve donor-derived engraftment. This study was undertaken to determine whether busulfan pharmacokinetics (BU PK) are altered in children with IMSD and whether BU concentrations are important in achieving engraftment. BU samples were obtained from 39 IMSD children, including 20 children with Hurler syndrome, undergoing HCT. Patients received oral BU (40 mg/m(2)/dose x 8 doses), cyclophosphamide (60 mg/kg/day x 2 doses) and TBI (750 cGy in one fraction) as a preparative regimen. Median (range) oral clearance corrected for bioavailability (Cl/F in ml/min/kg), area under the curve (AUC in ng min/ml) and BU plasma concentration (Cp in ng/ml) with the fourth dose were 5.2 (2.1-11.4), 318 294 (112 893-640 995) and 950 (314-1780), respectively. Children < 3 years of age had lower AUC and Cp but higher Cl/F (P < or = 0.03). BU Cp (P = 0.06) or marrow cell dose (P = 0.32) was not different in Hurler syndrome compared to other IMSD. A median BU Cp of 959 and 831 ng/ml was achieved in children with full and failed early engraftment, respectively. There was no difference in early and late engraftment between children with Hurler and other IMSD. In conclusion, we found no significant association between engraftment, marrow cell dose and BU exposure when combined with CY and TBI in children with IMSD.

Administration, Oral↗
PubMed2001

Allogeneic bone marrow transplantation-mediated transfer of specific immunity against Toxocara canis associated with excessive IgE.

A girl with myelodysplastic syndrome (RAEB-T) received HLA-identical bone marrow from her younger brother after myeloablative treatment with busulfan and cyclophosphamide. After bone marrow transplantation, fever, exanthema, pruritus, and a pulmonary infiltrate were treated symptomatically. Bacterial cultures remained negative. Leukocyte engraftment began on day 10, and all blood cell populations proved to be of donor origin on FISH analysis. Increasing IgE levels (21 000 U/ml) on day 14 after BMT, positive RAST, specific IgG-antibodies, and missing Toxocara (T.) canis antigens in the recipient indicated donor-derived seroconversion. Before BMT, the recipient had been negative for T. canis in routine parasitological screening, and the donor proved to be positive for T. canis antibody by ELISA. This report suggests that the transfer of IgE immunity in the absence of detectable antigens may be responsible for IgE-mediated symptoms consistent with toxocara infection and confirms the need for parasite screening in donor medical examinations.

Adoptive Transfer↗
PubMed2001

Influence of transplantation regimen on prognostic significance of high-level minimal residual disease before allogeneic stem cell transplantation in children with ALL.

High MRD levels before transplantation in children receiving T cell-depleted unrelated grafts for relapsed ALL were associated with a 100% relapse risk. We report on two children with relapsed ALL who underwent non T cell-depleted BMT from unrelated donors. Despite a high residual tumor load pre- transplant and the occurrence of only aGVHD grade I, they are still in second complete remission 2.7 and 5.2 years after transplantation, respectively. Thus, we propose that the transplant regimens influence the prognostic significance of high MRD levels pre-BMT.

Burkitt Lymphoma↗
PubMed2001

A multi-institutional analysis of laparoscopic orchidopexy.

OBJECTIVE: To combine and analyse the results from centres with a large experience of laparoscopy for the impalpable testis with small series, to determine the expected success rate for laparoscopic orchidopexy. METHODS: A questionnaire was distributed to participating paediatric urologists; each contributor retrospectively reviewed the clinical charts for their cases of therapeutic laparoscopy for an impalpable testis, detailing 36 variables for each patient. The data were collated centrally into a computerized database. For inclusion, the testis was intra-abdominal (including 'peeping' at the internal ring) at laparoscopic examination, was not managed through an open approach and did not undergo orchidectomy. Three surgical groups were assessed, with success defined as lack of atrophy and intrascrotal position: group 1, primary laparoscopic orchidopexy; group 2, a one-stage Fowler-Stephens (F-S) orchidopexy; and group 3, a two-stage F-S orchidopexy. RESULTS: Data were gathered from 10 centres in the USA, covering the period 1990-1999; 252 patients representing 310 testes were included and overall, 15.2% were lost to follow-up. There was no significant difference between success rates in the larger and smaller series. Atrophy occurred in 2.2% of 178 testes, 22.2% of 27 testes and 10.3% of 58 testes in groups 1-3, respectively. Testes were not in a satisfactory scrotal position in 0.6%, 7.4% and 1.7% of groups 1-3, respectively. The mean follow-up for each group was 7.7, 8.6 and 20.0 months, respectively. The overall success for all groups was 92.8% (97.2% group 1; 74.1% group 2; 87.9% group 3), with an atrophy rate of 6.1%. CONCLUSION: Laparoscopic orchidopexy for the intra-abdominal testis, in both large and small series, can be expected to have a success rate higher than that historically ascribed to open orchidopexy. Within this series, single-stage F-S laparoscopic orchidopexy resulted in a significantly higher atrophy rate than the two-stage repair. However, when considering both F-S approaches, the laparoscopic approach gave greater success than previously reported for the same open approaches. Despite the weaknesses inherent in a retrospective unrandomized study, we conclude that laparoscopic orchidopexy is, if not the procedure of choice, an acceptable and successful approach to the impalpable undescended testicle.

Child, Preschool↗
PubMed2001

Serial granulocytapheresisunder daily administration of rHuG-CSF: effects on peripheral blood counts, collection efficiency, and yield.

BACKGROUND: An option for treatment of severe infections in neutropenic patients is the transfusion of granulocytes from donors stimulated with rHuG-CSF. The schedule of rHuG-CSF-stimulated granulocyte donations and the quality of the components remain controversial. This study was done with the intention of ensuring daily granulocyte support with therapeutic cell numbers, while keeping the patients' allogeneic exposure as low as possible. STUDY DESIGN AND METHODS: Granulocyte collection with multiple consecutive leukapheresis procedures under daily rHuG-CSF administration and with hydroxyethyl starch as sedimenting agent were prospectively studied. Complete blood counts of the donors, collection yield, and efficiency were analyzed. RESULTS: Products (n = 259) from 76 donors were examined. The median peripheral blood WBC and neutrophil counts were 28.1 g per L and 24.1 g per L, respectively, and they were significantly higher on Day 5 of collections than on Days 1 to 3. Platelet counts and Hb levels decreased steadily. Collection yields increased over time from 4.9 to 6.7 x 10(10) neutrophils. Side effects of cytokines and aphereses did not exceed World Health Organization grade II status. CONCLUSION: Repetitive daily rHuG-CSF administration-even under daily leukapheresis procedures-results in a continuing increase in WBC and neutrophil levels and thus leads to increased collection yields. Side effects are tolerable, although Hb and platelet levels should be monitored closely.

Adolescent↗
PubMed2001

Towards specific functions of lysosomal cysteine peptidases: phenotypes of mice deficient for cathepsin B or cathepsin L.

The lysosomal cysteine peptidases cathepsin B and cathepsin L are abundant and ubiquitously expressed members of the papain family, and both enzymes contribute to the terminal degradation of proteins in the lysosome. However, there is accumulating evidence for specific functions of lysosomal proteases in health and disease. The generation of 'knock out' mouse strains that are deficient in lysosomal proteases provides a valuable tool for evaluation of existing hypotheses and gaining new insights into the in vivo functions of these proteases. In this minireview, we summarise and discuss the findings obtained by analysis of mice that are devoid of cathepsin B or cathepsin L. In brief, cathepsin L appears to be critically involved in epidermal homeostasis, regulation of the hair cycle, and MHC class II-mediated antigen presentation in cortical epithelial cells of the thymus. Cathepsin B plays a major role in pathological trypsinogen activation in the early course of experimental pancreatitis and contributes significantly to TNF-alpha induced hepatocyte apoptosis.

Animals↗
PubMed2001

The chemical biology of Ras lipidation.

In this review, we summarize the successful interplay between three disciplines, organic synthesis, biophysics and cell biology, in the study of protein lipidation and its relevance to targeting of proteins to the plasma membrane of cells in molecular detail. Highlighting the example of the Ras proteins, we show how the development of new synthetic methodologies paved the road to the synthesis of lipidated peptides and--by a combination of chemical and molecular biological techniques--lipidated proteins as molecular tools. We further give an overview of the results of the biophysical properties and biological activities of the molecules synthesized by means of this interdisciplinary approach. This successful combination of different disciplines led to a better understanding of the selective targeting of Ras and related lipoproteins to the plasma membrane.

Animals↗
PubMed2000

Imidovanadium(v) complexes as reaction partners for kinetically stabilized phosphaalkynes: synthesis of 1,2,4-azaphosphavanada(v)-cyclobutenes, 1,3,5-triphosphabenzenes, and 1H-1,2,4-azadiphospholes.

Cycloaddition reactions of the kinetically stabilized phosphaalkynes 1 with the imidovanadium(v) trihalides 9 furnish the 1,2,4-azaphosphavanada(v)cyclobutenes 10. The stability of these novel metallacyclic compounds depends solely on the substitutents of the imido unit. Thus, the imidovanadium(v) species 9 with tertiary alkyl groups on the N atom form stable addition products with 1 while in the cases of compounds 9 with a lower degree of substitution at N (primary and secondary alkyl groups) the primarily formed adducts 10 undergo irreversible decomposition to afford the 1H-1,2,4-azadiphospholes 13. Reactions of an excess of the phosphaaalkyne 1 with the vanadium complexes 9 furnish the corresponding triphosphabenzenes 8 in good yields (36-68%). A catalytic reaction course has been demonstrated for the all-tert-butyl system 1a/9a in which the metallacyclic species 10a serves as the catalytically active species. Poisoning of the catalyst leads to a second reaction pathway, which results in formation of the azatetraphosphaquadricyclanes 16. By means of the stepwise use of different phosphaalkynes 1a,b this methodology provides the first access to the differently substituted triphosphabenzenes through cyclotrimerization.

Journal Article↗
PubMed2000

Successful stem cell transplantation following orthotopic liver transplantation from the same haploidentical family donor in a girl with hemophagocytic lymphohistiocytosis.

The case of a 4-month-old girl with familial hemophagocytic lymphohistiocytosis is described. The patient underwent stem cell transplantation from her haploidentical mother 2 months after receiving a living-related liver transplant from the same donor for acute hepatic failure. Conditioning regimen consisted of 16 mg/kg busulfan, 200 mg/kg cyclophosphamide, 10 mg/kg thiothepa, and antithymocyte globulin. Myeloid engraftment occurred on day +10, but CD3(+) cells of recipient origin remained. To convert the T-cell chimerism, the patient received donor lymphocyte infusion on day +43, and subsequently the allelic pattern changed to complete donor genotype on day +57. Four months after stem cell transplantation the patient is disease free, with complete donor chimerism in bone marrow and stable hepatic graft function without any immunosuppressive therapy. (Blood. 2000;96:3997-3999)

Behavior Therapy↗
PubMed2000

Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons.

Cathepsin D-deficient (CD-/-) mice have been shown to manifest seizures and become blind near the terminal stage [approximately postnatal day (P) 26]. We therefore examined the morphological, immunocytochemical, and biochemical features of CNS tissues of these mice. By electron microscopy, autophagosome/autolysosome-like bodies containing part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles were demonstrated in the neuronal perikarya of CD-/- mouse brains after P20. Autophagosomes and granular osmiophilic deposits were detected in neurons at P0 but were few in number, whereas they increased in the neuronal perikarya within days after birth. Some large-sized neurons having autophagosome/autolysosome-like bodies in the perikarya appeared in the CNS tissues, especially in the thalamic region and the cerebral cortex, at P17. These lysosomal bodies occupied the perikarya of almost all neurons in CD-/- mouse brains obtained from P23 until the terminal stage. Because these neurons exhibited autofluorescence, it was considered that ceroid lipofuscin may accumulate in lysosomal structures of CD-/- neurons. Subunit c of mitochondrial ATP synthase was found to accumulate in the lysosomes of neurons, although the activity of tripeptidyl peptidase-I significantly increased in the brain. Moreover, neurons near the terminal stage were often shrunken and possessed irregular nuclei through which small dense chromatin masses were scattered. These results suggest that the CNS neurons in CD-/- mice show a new form of lysosomal accumulation disease with a phenotype resembling neuronal ceroid lipofuscinosis.

Action Potentials↗