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C Peters

Publications and source records attributed to C Peters.

At least 19 recordsLinked to original sources
PubMed1996

Targeted disruption of the arylsulfatase B gene results in mice resembling the phenotype of mucopolysaccharidosis VI.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase B (ASB), which is involved in degradation of dermatan sulfate and chondroitin 4-sulfate. A MPS VI mouse model was generated by targeted disruption of the ASB gene. Homozygous mutant animals exhibit ASB enzyme deficiency and elevated urinary secretion of dermatan sulfate. They develop progressive symptoms resembling those of MPS VI in humans. Around 4 weeks of age facial dysmorphia becomes overt, long bones are shortened, and pelvic and costal abnormalities are observed. Major alterations in bone formation with perturbed cartilaginous tissues in newborns and widened, perturbed, and persisting growth plates in adult animals are seen. All major parenchymal organs show storage of glycosaminoglycans preferentially in interstitial cells and macrophages. Affected mice are fertile and mortality is not elevated up to 15 months of age. This mouse model will be a valuable tool for studying pathogenesis of MPS VI and may help to evaluate therapeutical approaches for lysosomal storage diseases.

Animals↗
PubMed1996

Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery.

We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.

Adolescent↗
PubMed1996

Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome.

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

Bone Marrow Transplantation↗
PubMed1996

Ten-year experience with the artificial urinary sphincter in children.

PURPOSE: To assess the efficacy of the artificial urinary sphincter survival and continence were first evaluated 5 years ago. We now evaluated the effects of the artificial urinary sphincter more than a decade after implantation. MATERIALS AND METHODS: Before 1985 an artificial urinary sphincter was implanted in 22 male and 14 female consecutive patients 4 to 30 years old (median age 12). In addition, between 1985 and 1990, 18 other children underwent artificial urinary sphincter implantation. Results of both series were compared. RESULTS: Of the 25 sphincters in the original series that were functioning after 5 years 1 was removed and 2 patients were lost to followup, resulting in 22 functioning implants (61% of the patients). Mean survival time of the prostheses was 12.1 years and average followup for functioning sphincters was 13.7 years. There was no statistically significant difference in artificial urinary sphincter survival between the original group at 5 years and the second group treated after 1985. Of the patients in both groups with sphincters in place 32 of 39 (82%) were dry. Augmentation cystoplasty was performed in 9 of 18 patients (50%) in the second series (5 preoperatively and 4 postoperatively) compared to 10 of 36 (28%) in the original series at 5 years (3 preoperatively and 7 postoperatively). Renal failure developed in 6 patients from both series. CONCLUSIONS: The artificial urinary sphincter is a durable long-term solution for children with intractable incontinence. Long-term surveillance of the urinary tract is mandatory because of the potential for renal failure in patients who have bladder hypertonicity after placement of the device.

Adolescent↗
PubMed1996

Identification, expression, and biochemical characterization of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients.

Maroteaux-Lamy syndrome, or mucopolysaccharidosis type VI (MPS-VI), is a lysosomal storage disorder characterized by the defective degradation of dermatan sulfate due to the deficiency of N-acetylgalactosamine-4-sulfatase (4S). The clinical severity of MPS-VI ranges in a continuum from mildly affected to severely affected patients. Mutations in MPS-VI patient samples were identified by chemical cleavage and direct DNA sequencing of PCR products derived from patient cDNA. Five amino acid substitutions were identified (T92M, R95Q, Y210C, H393P, and L498P), individually introduced into the wild-type 4S cDNA by site-directed in vitro mutagenesis, and transfected into Chinese hamster ovary cells. Three of the five mutations (R95Q, Y210C, and H393P) were observed in >1 of 25 unrelated MPS-VI patients; however, the mutations were not found in 20 control individuals. The residual 4S activity and protein (biochemical phenotype) were determined for each mutant in order to confirm their identity as mutations and to dissect the contribution of each mutant allele to the overall clinical phenotype of the patient. For each patient, the combined biochemical phenotypes of the two 4S mutant alleles demonstrated a good correspondence with the observed clinical phenotype (with the possible exception of a patient who was a compound heterozygote for T92M and L498P). This preliminary correspondence between genotype and the phenotype in MPS-VI may, with further refinement, contribute to the assessment of therapeutic approaches for MPS-VI patients.

Adolescent↗
PubMed1996

Alcohol risk assessment and intervention for family physicians. Project of the College of Family Physicians of Canada.

At-risk and problem drinkers (excluding those with severe dependency) are estimated to be 20% of the Canadian population. With minimal training family physicians can effectively manage patients with alcohol problems. The Alcohol Risk Assessment and Intervention Project of the College of Family Physicians of Canada has developed materials and training for family physicians to use in helping their patients reduce the risks of alcohol-related harm.

Alcoholism↗
PubMed1995

The first reported outbreak of diarrheal illness associated with Cyclospora in the United States.

OBJECTIVE: To investigate and characterize the epidemiology of a diarrheal outbreak associated with a potentially new pathogen, Cyclospora species (previously referred to as Cyanobacteria [blue-green algae]-like bodies). DESIGN: Three retrospective cohort studies supported by laboratory studies, environmental investigation, and community surveillance. SETTING: A hospital in Chicago. PARTICIPANTS: Housestaff physicians and hospital administrative staff. MEASUREMENTS: Identification of clinical features associated with illness and potential risks for acquisition of infection. RESULTS: Illness was characterized by watery diarrhea, abdominal cramping, decreased appetite, and low-grade fever. Symptoms typically occurred in a distinctive cycle of remissions and exacerbations lasting up to several weeks. Stool cultures and examinations for known ova and parasites were negative. Microscopic examination of stool specimens from 11 ill persons showed many spherical bodies, 8 to 10 microns in diameter, that were identified as Cyclospora organisms. The organisms disappeared by 9 weeks after onset of illness in the 7 patients from whom follow-up specimens were obtained. Epidemiologic studies implicated tap water from a physicians' dormitory as the most likely source of the outbreak. Environmental investigation suggested that stagnant water in a storage tank may have contaminated the water supply after a pump failure. CONCLUSIONS: This is the first reported outbreak of diarrhea associated with Cyclospora in the United States. Cyclospora may be a human enteric pathogen able to produce bouts of acute and relapsing diarrhea, and it should be considered in assessments of patients with unexplained, prolonged diarrheal illness.

Adult↗
PubMed1995

Two site-directed mutations abrogate enzyme activity but have different effects on the conformation and cellular content of the N-acetylgalactosamine 4-sulphatase protein.

The sulphatase family of enzymes have regions of sequence similarity, but relatively little is known about either the structure-function relationships of sulphatases, or the role of highly conserved amino acids. The sequence of amino acids CTPSR at position 91-95 of 4-sulphatase has been shown to be highly conserved in all of the sequenced sulphatase enzymes. The cysteine at amino acid 91 of 4-sulphatase was selected for mutation analysis due to its potential role in either the active site, substrate-binding site or part of a key structural domain of 4-sulphatase and due to the absence of naturally occurring mutations in this residue in mucopolysaccharidosis type VI (MPS VI) patients. Two mutations, C91S and C91T, altering amino acid 91 of 4-sulphatase were generated and expressed in Chinese hamster ovary cells. Biochemical analysis of protein from a C91S cell line demonstrated no detectable 4-sulphatase enzyme activity but a relatively normal level of 4-sulphatase polypeptide (180% of the wild-type control protein level). Epitope detection, using a panel of ten monoclonal antibodies, demonstrated that the C91S polypeptide had a similar immunoreactivity to wild-type 4-sulphatase, suggesting that the C91S substitution does not induce a major structural change in the protein. Reduced catalytic activity associated with normal levels of 4-sulphatase protein have not been observed in any of the MPS VI patients tested and all show evidence of structural modification of 4-sulphatase protein with the same panel of antibodies [Brooks, McCourt, Gibson, Ashton, Shutter and Hopwood (1991) Am. J. Hum. Genet. 48, 710-719]. The loss of enzyme activity without a detectable protein conformation change suggests that Cys-91 may be a critical residue in the catalytic process. In contrast, analysis of protein from a C91T cell line revealed low levels of catalytically inactive 4-sulphatase polypeptide (0.37% of the wild-type control protein level) which had missing or masked epitopes, suggesting an altered protein structure or conformation. Subcellular fractionation studies of the C91T cell line demonstrated a high proportion of 4-sulphatase polypeptide content in organelles characteristic of microsomes. The aberrant intracellular localization and the reduced cellular content of 4-sulphatase polypeptide was consistent with the observed structural modification leading to retention and degradation of the protein within an early vacuolar compartment.

Animals↗
PubMed1995

Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis. Application to the analysis of the nonlinear elimination kinetics of erythropoietin in adult humans.

The disposition-decomposition analysis (DDA) methodology enables isolation of the overall elimination and distribution effects in pharmacokinetics and facilitates analysis which focuses on drug elimination kinetics and does not require a specific structured modeling of drug distribution processes. A computer algorithm enables a curve fitting and a kinetic estimation by integration of the convolution type integrodifferential equation in the DDA. The approach is demonstrated in an analysis of the nonlinear disposition kinetics of erythropoietin (Epo) in 10 healthy, adult human subjects who each received 10, 100, and 500 U/kg i.v. bolus doses of Epo. The nonlinearity is analyzed according to a Michaelis-Menten type nonlinear elimination function, considering simultaneous fitting to the data from all three doses in each subject. The simultaneous fittings produced estimates of the Michaelis-Menten parameters (mean, % cv) Vm (901 mU/mL/h, 19.4%) and km (4814 mU/mL, 24.6%). A linear clearance parameter is defined as the asymptotic clearance value approached when the drug level decreases toward zero. The degree of nonlinearity reached from various dosings was quantified in terms of a clearance ratio which is defined as the ratio between the linear clearance and the clearance estimated for the maximum drug concentration encountered at the given dose level. The subjects showed very little nonlinearity at the 10 U/kg dosing with a mean clearance ratio of 1.07 (2.1% CV) A statistically significant increase in the degree of nonlinearity was observed in the Epo elimination kinetics as the dosing level was increased to 100 and 500 U/kg, reaching clearance ratios of 1.66 (14% CV) and 4.33 (27% CV), respectively. A zero value for the global elimination rate parameter in all 30 dosings indicates that Epo's elimination is entirely accounted for by nonlinear pathway(s).

Adult↗
PubMed1995

Ovine bone marrow extracellular matrix and soluble protein extraction: fetuin amino terminus microheterogeneity.

In this article, the authors describe a new method using phosphate-buffered saline for the initial extraction of extracellular matrix (ECM) and soluble proteins from hematologic tissues. Direct comparisons between this method and previously reported methods demonstrate superior total protein yields with the novel technique in a fraction of the time for these ovine hematologic tissues: bone marrow, marrow aspirate, spleen, liver, and blood. Analysis by one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis and silver staining demonstrate comparable protein patterns with this method and a previously reported method. This method also successfully extracts the ECM glycoproteins fibronectin and laminin as well as the proteoglycan, chondroitin sulfate from marrow. These findings are demonstrated by Western and dot blotting. Bone marrow ECM and soluble proteins extracted by the novel method stimulate myeloid progenitor growth in a methylcellulose assay. Using an assay for elastase inhibitory capacity, the authors demonstrate that alpha 1-proteinase inhibitor, the principal inhibitor of neutrophil elastase, is present and that its activity is preserved in bone marrow samples extracted with this team's method. In contrast, very low total protein yields are obtained with the method used previously to recover hemonectin, a rabbit bone marrow ECM granulocytic cytoadhesion molecule. This team's novel procedure, which extracts ECM and soluble proteins from small samples of tissue in a rapid, efficient, and reproducible manner, greatly enhances the analysis of these proteins from tissue culture, animal, and human clinical samples. In addition, with purification by chromatofocusing chromatography and molecular sieving gel electrophoresis, N-terminal amino acid sequencing could be performed on a developmentally regulated marrow protein with biochemical properties similar to those of hemonectin and the plasma protein fetuin. The authors propose that this novel technique be used for the initial extraction of ECM and soluble proteins from hematologic tissues and that subsequent, definitive recovery of insoluble proteins be accomplished using previously reported, though less efficient, methods.

Amino Acid Sequence↗
PubMed1995

Remote telemetry: new twists for old technology.

Availability of telemetry beds was increased cost-effectively by providing telemetry on medical/surgical units with remote monitoring at designated critical care areas. Guidelines were developed for patient selection, education, clinical policy and procedure. A two-hour inservice was completed by all medical/surgical nurses and after a pilot study the system was implemented on three medical/surgical units.

Cost-Benefit Analysis↗
PubMed1995

The role of macrophage receptors in adhesion and uptake of Leishmania mexicana amastigotes.

Amastigotes of the protozoan parasite Leishmania proliferate in phagolysosomes of mammalian macrophages. Propagation of the infection is considered to occur by host-cell rupture and uptake of released parasites by uninfected macrophages. In this study, the kinetics of binding of L mexicana mexicana amastigotes to COS cells and to COS cells transfected with three different macrophage receptors (FcRII-B2, receptor for the Fc-domain of immunoglobulins; CR3, complement type 3 receptor and the mannose receptor) is compared to the rate of adhesion to peritoneal macrophages. Amastigotes isolated from macrophages cultivated in vitro bind with slow, sigmoid kinetics to COS cells expressing either of the three receptors, or to peritoneal macrophages. In contrast, amastigotes isolated from mouse lesions bind with rapid, hyperbolic kinetics to COS cells expressing the Fc receptor or to peritoneal macrophages but with slow, sigmoid kinetics to COS cells expressing the CR3 or the mannose receptor. As shown by immunofluorescence experiments, lesion-derived amastigotes contain host-derived immunoglobulins (Ig) but no complement component 3 at their surface. It is concluded that amastigotes contain no intrinsic ligand at their surface, which enables high-affinity interactions with macrophages. Opsonization by specific Ig may be of relevance in vivo because firstly, in cryosections of mouse lesions extracellular amastigotes containing surface Ig can be detected and, secondly, B cell-deficient mice reconstituted with parasite-specific Ig show a modest increase in the rate of lesion development. In addition, it is shown that amastigotes are internalized by COS cells and grow in large parasitophorous vacuoles similar to those observed in macrophages.

Adhesiveness↗
PubMed1995

Haemostasis activation markers in plasma of patients with benign and malignant gynaecological tumours: a pilot study.

Coagulation and fibrinolysis activation have been investigated in fifty-eight women with recently detected gynaecological tumours. Twenty-six were benign and 32 malignant: of the last group nine patients had metastases. A control group consisted of 31 age-matched healthy women. Prothrombin fragment 1 + 2, thrombin-antithrombin III and D-dimer were measured. The median values of all analytes were significantly higher in the malignant tumour group, but not in the benign tumour group, as compared to the control group. The group of patients with a gynaecological tumour and metastases differed from the non-metastasized tumour group in prothrombin fragment 1 + 2, thrombin-antithrombin III and D-dimer. In the non-metastasized malignant tumour group solely prothrombin fragment 1 + 2 was significantly higher than in the benign tumour group. Coagulation and fibrinolysis predominating as can be derived from the elevated D-dimer/thrombin-antithrombin III and D-dimer/prothrombin fragment 1 + 2 ratios. The studied constituents do not enable a differentiation between the benign and malignant processes. However, as the differences of these values in both malignant tumour groups were significant, this might be used to trace the existence of metastases in gynaecological tumours. Investigation of these analytes in several specific types of gynaecological tumours might be clinically relevant.

Biomarkers, Tumor↗
PubMed1995

Immune thrombocytopenia and elemental mercury poisoning.

Three cases of severe mercury toxicity occurring within a family are reported. Two cases of thrombocytopenia occurred in this family and represent the second such report in the literature of an association between elemental mercury toxicity and thrombocytopenia. Three of the children presented with a combination of dermatologic and neurologic manifestations reminiscent of acrodynia or pink disease. Each of the four children in this family were treated with dimercaptosuccinic acid. The hazard of vacuuming spilled mercury and appropriate clean-up procedures are described.

Adolescent↗
PubMed1995

Isolated extramedullary relapse in children with acute lymphoblastic leukemia: a comparison between treatment results of chemotherapy and bone marrow transplantation. BFM Relapse Study Group.

The purpose of this study was to determine the therapeutic efficacy of different treatment strategies, namely chemotherapy, allogeneic and autologous bone marrow transplantation (BMT), for extramedullary relapse of acute lymphoblastic leukemia (ALL) in children in second or subsequent remission. Between 1983 and 1993, 165 patients up to 19 years of age with extramedullary relapse of ALL were registered in the multicenter ALL-REZ BFM trials. One hundred and thirty four children received chemotherapy only; 17 children were grafted from HLA-identical sibling donors 152 days (46-392 days) after diagnosis of relapse, and 14 children underwent autologous BMT after a median time of 137 (range 23-300) days. Event-free survival (EFS) at 5 years was 0.47 +/- 0.05 for patients receiving chemotherapy: 0.76 +/- 0.07 for late, 0.33 +/- 0.08 for early and 0.33 +/- 0.07 for very early relapsed patients. Sixty five patients are in complete remission (CR), 61 patients relapsed, 5 died from therapy related complications, 2 patients in CR were lost to follow-up and one patient developed a second malignancy. For patients who had undergone BMT, EFS at 5 years was 0.36 +/- 0.10 without significant difference between autologous BMT (8 of 14 in CR, 6 relapsed) and allogeneic BMT (6 of 17 in CR, 4 died of acute toxicity, and 7 relapsed).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗