Biomedical subjects

C Peters

Publications and source records attributed to C Peters.

At least 73 records · Page 4Linked to original sources

PubMed2000

New roles for glial cell line-derived neurotrophic factor and neurturin: involvement in hair cycle control.

Glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN), and their receptors, GDNF family receptor alpha-1 (GFRalpha-1) and GDNF family receptor alpha-2 (GFRalpha-2), are critically important for kidney and nervous system development. However, their role in skin biology, specifically in hair growth control, is as yet unknown. We have studied expression and function of GDNF, neurturin, GFRalpha-1, and GFRalpha-2 in murine skin during the cyclic transformation of the hair follicle (HF) from its resting state (telogen) to active growth (anagen) and then through regression (catagen) back to telogen. GDNF protein and GFRalpha-1 messenger RNA are prominently expressed in telogen skin, which lacks NTN and GFRalpha-2 transcripts. Early anagen development is accompanied by a significant decline in the skin content of GDNF protein and GFRalpha-1 transcripts. During the anagen-catagen transition, GDNF, GFRalpha-1, NTN, and GFRalpha-2 transcripts reach maximal levels. Compared with wild-type controls, GFRalpha-1 (+/-) and GFRalpha-2 (-/-) knockout mice show a significantly accelerated catagen development. Furthermore, GDNF or NTN administration significantly retards HF regression in organ-cultured mouse skin. This suggests important, previously unrecognized roles for GDNF/GFRalpha-1 and NTN/GFRalpha-2 signaling in skin biology, specifically in the control of apoptosis-driven HF involution, and raises the possibility that GFRalpha-1/GFRalpha-2 agonists/antagonists might become exploitable for the treatment of hair growth disorders that are related to abnormalities in catagen development.

Animals↗

PubMed2000

The overactive bladder in childhood: long-term results with conservative management.

PURPOSE: Idiopathic detrusor overactivity has not been thoroughly investigated and its natural history remains largely anecdotal. Bladder overactivity resulting from a neurogenic, anatomical or medical condition has been well described. Therefore, we assessed the long-term results of conservative treatment of children with idiopathic symptomatic refractory detrusor instability. MATERIALS AND METHODS: We reviewed the records of 58 patients who had an isolated finding of uninhibited contractions on urodynamics performed for refractory enuresis and daytime wetting between 1988 and 1994. Study exclusion criteria were chronic urinary tract infection, neurological lesion, anatomical abnormality of the lower urinary tract and less than 12 months of followup. RESULTS: Of the 30 children who met our study inclusion criteria 26 (87%) had complete (21) or significant (5) symptom resolution. Average time to resolution was 2.7 years (range 0.2 to 6.6). Patients with a 50% to 90% bladder capacity expected for age were more likely to benefit from therapy than those with a bladder capacity outside of this range. Age and gender were not significant predictors of resolution although girls were more likely to have resolution than boys. CONCLUSIONS: Idiopathic detrusor instability is amenable to conservative management in the majority of patients during a prolonged period. We advocate thorough urological and urodynamic evaluation to identify idiopathic detrusor instability as an etiology of enuresis and daytime wetting in complicated cases.

Adolescent↗

PubMed2000

Administration of recombinant human granulocyte-macrophage colony-stimulating factor to children undergoing allogeneic marrow transplantation: a prospective, randomized, double-masked, placebo-controlled trial.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to 40 pediatric patients undergoing partially matched related, or closely matched unrelated, allogeneic marrow transplants. This trial was set up in a prospective, randomized, double-masked, placebo-controlled manner to establish if the administration of GM-CSF to such patients enhanced neutrophil recovery in this allogeneic transplant setting. The GM-CSF group had a significantly shorter time to neutrophil recovery to > 500 x 10(9) cells/L (15 days) than the placebo group (p = 0.0036). In addition, the GM-CSF group had a significantly shorter neutrophil recovery time to > 1,000 x 10(9) cells/L (18 days) than the placebo group (p = 0.0053). The primary objective of this study was met by showing that GM-CSF enhanced neutrophil recovery in this allogeneic setting. However, within the study group of patients, there was no effect of GM-CSF on the incidence or severity of graft-vs.-host disease (GvHD), one of the secondary end-points of the study. With regard to the other secondary end-points, there was no effect of GM-CSF on marrow cellularity, duration of systemic antibiotics given for real infections or as prophylaxis to prevent infections, risk of significant infections (as defined by systemic culture of virus, fungus, or bacteria), and duration or cost of hospitalization, platelet recovery, and nutritional support. With the secondary end-points, it will be necessary to study larger numbers of pediatric patients to identify differences that are small in this study group. In conclusion, GM-CSF can be safely administered to children with few, if any, significant side-effects. Additional work remains to facilitate earlier discharge of patients and decreased antibiotic usage, to offset the cost of using a neutrophil growth factor.

Adolescent↗

PubMed2000

Genome-wide, large-scale production of mutant mice by ENU mutagenesis.

In the post-genome era, the mouse will have a major role as a model system for functional genome analysis. This requires a large number of mutants similar to the collections available from other model organisms such as Drosophila melanogaster and Caenorhabditis elegans. Here we report on a systematic, genome-wide, mutagenesis screen in mice. As part of the German Human Genome Project, we have undertaken a large-scale ENU-mutagenesis screen for dominant mutations and a limited screen for recessive mutations. In screening over 14,000 mice for a large number of clinically relevant parameters, we recovered 182 mouse mutants for a variety of phenotypes. In addition, 247 variant mouse mutants are currently in genetic confirmation testing and will result in additional new mutant lines. This mutagenesis screen, along with the screen described in the accompanying paper, leads to a significant increase in the number of mouse models available to the scientific community. Our mutant lines are freely accessible to non-commercial users (for information, see http://www.gsf.de/ieg/groups/enu-mouse.html).

Animals↗

PubMed2000

Pulmonary cytolytic thrombi: a newly recognized complication of stem cell transplantation.

Over the past 5 years we have recognized a new pulmonary complication of hematopoietic stem cell transplantation (HSCT) associated with fever and pulmonary nodules termed 'pulmonary cytolytic thrombi' (PCT). Retrospective analysis of medical and radiographic records and pathologic material from 13 HSCT recipients with PCT and a review of the Blood and Marrow Transplant Database for all patients with radiographic evidence of pulmonary nodules or who underwent open-lung biopsy from 1 January 1993 to 31 December 1998 (n = 1228) were performed. The median age of patients with PCT was 11.9 years (range, 1.3-29.7 years). All patients developed fever at a median of 72 days (range, 8-343 days) post transplant, followed by pulmonary nodules on chest CT. Eleven patients were receiving therapy for active GVHD (acute, grades I-IV (n = 10); extensive chronic (n = 1)). Biopsy of the pulmonary nodules revealed a unique pattern of necrotic, basophilic thromboemboli with amorphous material suggestive of cellular breakdown products. This was descriptively labeled 'pulmonary cytolytic thrombi'. Immunohistochemical staining revealed entrapped leukocytes and disrupted endothelium, but was negative for histiocytes. Cultures and immunohistochemical stains were negative for infectious agents. Empiric therapy included systemic corticosteroids (n = 9) and amphotericin (n = 7). Nine patients survive with resolution of PCT at a median follow-up of 1.5 years. Bone Marrow Transplantation (2000) 25, 293-300.

Adolescent↗

PubMed2000

Measurements from normal umbilical cord blood of four lysosomal enzymatic activities: alpha-L-iduronidase (Hurler), galactocerebrosidase (globoid cell leukodystrophy), arylsulfatase A (metachromatic leukodystrophy), arylsulfatase B (Maroteaux-Lamy).

Umbilical cord blood (UCB) has received increasing attention as a source of unrelated hematopoietic stem cells for transplantation. Lysosomal diseases have been effectively treated and normal enzymatic activity has occurred subsequent to engraftment using UCB. The use of donor cells with normal amounts of enzyme, rather than those from carriers whose level may be 50% or less, is an obvious goal. The frequency of such heterozygotes varies from 1:10 to 1:140 or lower depending upon the disease at issue. We assayed the levels of lysosomal enzymes in normal UCB in random samples as well as those used for transplantation. We measured the following enzymatic activities: alpha-l-iduronidase (Hurler), galactocerebrosidase (globoid cell leuko- dystrophy) and arylsulfatase A (metachromatic leukodystrophy). For the latter, levels of activity in UCB are comparable to those found in adult blood. In the case of arylsulfatase B (Maroteaux-Lamy) a level lower than adult level was found. An informed choice by the transplanting physician based on the activity of the relevant enzyme in the UCB donor will provide a better opportunity for an improved prognosis for more complete correction of the recipient's primary disease. Bone Marrow Transplantation (2000) 25, 541-544.

Adult↗

PubMed2000

Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome).

Hunter syndrome is an X-linked metabolic storage disorder arising from deficiency of iduronate sulfatase enzyme activity. Despite the successful use of hematopoietic cell transplantation for a variety of lysosomal and peroxisomal storage diseases, limited benefit occurs following transplantation in either the severe or mild forms of Hunter syndrome. A brief ethical commentary is provided on the case of a boy with mucopolysaccharidosis IIB (ie the mild form) who received an unrelated umbilical cord blood transplant to improve his future quality of life. Bone Marrow Transplantation (2000).

Anemia, Hemolytic, Autoimmune↗

PubMed2000

Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: a single centre experience and review of the literature.

Juvenile myelomonocytic leukaemia (JMML) is a rare paediatric disease and allogeneic stem cell transplantation is the only curative approach. The roles of pretransplant treatment, conditioning regimen and graft-versus-host disease (GVHD) are still unclear. Eleven children with JMML underwent allogeneic BMT in our institution. Donors were matched unrelated (n = 6) matched siblings (n = 4) and one mismatch family donor. Transplant-related mortality (TRM) was 36%. Three patients relapsed after transplantation. Two of three patients with relapse are in continuous remission after donor lymphocyte infusion or second BMT, respectively. To evaluate the role of pretransplant treatment, conditioning regimen and GVHD, we have summarised our series with other published single centre reports and give an overview on a total of 65 patients with JMML who underwent allogeneic BMT. No significant correlation between pretransplant treatment, conditioning regimen and TRM could be observed. Overall relapse rate is high (47%). TBI is associated with a significantly higher relapse rate (P = 0.012). Other conditioning modalities, intensive chemotherapy and splenectomy prior to stem cell transplantation do not seem to have a significant impact on relapse rate. Patients with or without GVHD showed no significant difference in relapse rate (58% vs 45%). In the event of relapse after transplantation withdrawal of immunosuppression, donor lymphocyte infusion or second transplant was successful in 6/11 patients. Graft-versus-leukaemia effect seems to play an essential role in bone marrow transplantation for JMML.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

Statement of current majority practices in graft-versus-host disease prophylaxis and treatment in children.

Great variations exist in the prophylaxis and treatment of GVHD in children undergoing allogeneic stem cell transplantation (SCT). The EBMT Working Party Paediatric Diseases (EBMT-WP PD) and the International BFM Study Group--Subcommittee Bone Marrow Transplantation (IBFM-SG), aimed at evaluating current local standards in the prevention and treatment of GVHD and steps which can be taken to achieve a uniform policy for the individual methods. Several conferences with their members assessed practices which are mainly applied or under investigation in children and identified where additional information is needed. For prevention of GVHD, the majority of the paediatric centres prefer CsA +/- MTX. Addition of folinic acid to MTX was considered for reduction of side-effects. During treatment of acute GVHD most centres administer prednisolone and whole blood level-adjusted CsA as medications of first choice. In cases of poor or no response to this therapy, additional immunosuppressive agents such as ATG, mycophenolate-mofetile and tacrolimus are being increasingly used. The treatment of chronic GVHD usually consists of various combinations of prednisolone and CsA. In severe cases, extracorporeal photopheresis, psoralene-UVA (PUVA) and thalidomide are administered.

Adolescent↗

PubMed2000

Wolman disease successfully treated by bone marrow transplantation.

Wolman disease is characterized by severe diarrhea and malnutrition leading to death during infancy. Lysosomal acid lipase deficiency is the cause of the symptoms and signs. It is inherited in an autosomal recessive manner. All Wolman disease patients have adrenal gland calcification. Previous therapeutic attempts have failed to provide remission. We report successful long-term bone marrow engraftment in a patient with Wolman disease resulting in continued normalization of peripheral leukocyte lysosomal acid lipase enzyme activity. Diarrhea is no longer present. Now, at 4 years of age, this patient is gaining developmental milestones. Cholesterol and triglyceride levels are normal. Liver function is normal. This is the first long-term continued remission reported for Wolman disease.

Bone Marrow Transplantation↗

PubMed2000

The pharmacokinetics of caudal ropivacaine 0.2% in children. A study of infants aged less than 1 year and toddlers aged 1-5 years undergoing inguinal hernia repair.

This study evaluates the pharmacokinetics of ropivacaine in children after caudal epidural injection. Twenty male children undergoing inguinal hernia repair were enrolled after ethics committee approval and informed parental consent, and were grouped according to age (10 'infants' aged less than 1 year and 10 'toddlers' aged 1-5 years). After induction of general anaesthesia, caudal epidural injection using ropivacaine 0.2% 1 ml.kg-1 was performed. Plasma concentrations of ropivacaine in the first 2 h after injection were determined by reversed-phase high-pressure liquid chromatography. Caudal blockade with ropivacaine 2 mg.ml-1 resulted in mean (SD) peak plasma concentrations of 0.73 [0.27] microg.ml-1 in infants and 0.49 [0.21] microg.ml-1 in toddlers (p < 0.01). Maximum plasma concentrations occurred after a median [range] period of 60 [15-90] min and 52.5 [30-120] min in infants and toddlers, respectively. Two infants (weighing 3.8 and 5.0 kg) showed the highest individual maximum plasma concentrations: 1.31 and 1.11 microg.ml-1. No clinical signs of local anaesthetic toxicity were observed. The results of the present investigation suggest that, from a pharmacokinetic point of view, caudal blockade using ropivacaine 0. 2% 1 ml.kg-1 can be regarded as a safe technique in children, i.e. in infants as well as in toddlers.

Amides↗

PubMed2000

Molecular organization, expression and chromosomal localization of the mouse pronapsin gene.

Napsins have been identified only very recently as new aspartic proteinases of the pepsin family. Isolation, sequencing and functional analysis of the mouse genomic locus indicates that the organization of the pronapsin gene into nine exons is identical to that of other mammalian aspartic proteinase precursors, including pepsinogen. However, the additional C-terminal residues, which are a distinguishing feature of napsins, are encoded within exon 9 and not within an additional exon. Quantitation of pronapsin mRNA using RT-PCR indicates that the gene is transcribed in lung, kidney and spleen but not in heart. Regulation of gene expression was not influenced by the extent of CpG methylation but depended on the recognition of potential binding motifs in the promoter region by specific transcription factors such as YY-1. The single copy of the mouse pronapsin gene was located on chromosome 7. In humans, there are two pronapsin genes and, based on the mouse information, preliminary structures were deduced for these from sequences in the human genome databases. They appear to be located together on chromosome 19.

Amino Acid Sequence↗

PubMed2000

Antidepressant treatment and neural plasticity.

The use of psychopharmacologic agents in children is complicated by several factors. One important neurobiologic consideration is the relationship of the effect of the medication to ongoing brain development. Although available data are inadequate to address this issue directly, a review of ancillary data suggests that there are theoretical reasons to exercise prudence in prescribing psychopharmacologic agents. For example, the effects of serotonin on neuronal plasticity suggest that agents that can alter serotonergic function may alter neuronal wiring. Although this can occur in any brain, it may be of particular importance in a developing nervous system. The consequences of these induced changes are not clear. Animal studies on the effect of long-term antidepressant administration in immature pups may begin to answer some of the clinical concerns of these observations.

Animals↗

PubMed2000

Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling.

Lysosomal cysteine proteinases of the papain family are involved in lysosomal bulk proteolysis, major histocompatibility complex class II mediated antigen presentation, prohormone processing, and extracellular matrix remodeling. Cathepsin L (CTSL) is a ubiquitously expressed major representative of the papain-like family of cysteine proteinases. To investigate CTSL in vivo functions, the gene was inactivated by gene targeting in embryonic stem cells. CTSL-deficient mice develop periodic hair loss and epidermal hyperplasia, acanthosis, and hyperkeratosis. The hair loss is due to alterations of hair follicle morphogenesis and cycling, dilatation of hair follicle canals, and disturbed club hair formation. Hyperproliferation of hair follicle epithelial cells and basal epidermal keratinocytes-both of ectodermal origin-are the primary characteristics underlying the mutant phenotype. Pathological inflammatory responses have been excluded as a putative cause of the skin and hair disorder. The phenotype of CTSL-deficient mice is reminiscent of the spontaneous mouse mutant furless (fs). Analyses of the ctsl gene of fs mice revealed a G149R mutation inactivating the proteinase activity. CTSL is the first lysosomal proteinase shown to be essential for epidermal homeostasis and regular hair follicle morphogenesis and cycling.

Alopecia↗

PubMed2000

Upper airway complications in children after bone marrow transplantation.

OBJECTIVE: To describe the upper and lower airway complications in children during bone marrow transplantation (BMT). STUDY DESIGN: Review of medical records of patients requiring airway intervention during BMT over a 4-year period. RESULTS: During the 4-year period, 832 pediatric BMTs were performed. Of these, 87 patients (10.5%) required mechanical ventilation. Patients had intubation for a mean of 79 days (range, -7-638 d) after BMT. Patients received mechanical ventilation for a mean of 12 days (range, 1-85 d). Duration of ventilation was significantly longer in patients with difficult intubation; in these 54 patients there were 64 intubations. Of these intubations, 19 (30%) were difficult. These difficult intubations occurred in 16 (30%) patients. Patients with Hurler syndrome and congenital immunodeficiencies had significantly more difficult intubations than children with leukemia. The incidence of complications causing difficult intubation were difficulty visualizing cords, because of the presence of blood (63%); difficulty visualizing cords, because of edema (19%); anatomically narrowed airway (13%); limited neck extension (13%); and limited jaw opening (6%). The resulting mortality rate was 82% in children requiring intubation. Survivors were significantly younger than nonsurvivors. CONCLUSIONS: Pediatric BMT has become increasingly more common. Airway management is rarely required during the engraftment phase, but when intervention is required, it is often difficult, particularly in the nonleukemic child, and may require the skills of an otolaryngologist. Representative cases are presented, and management is discussed.

Adolescent↗

PubMed2000

Exonic variants of the GABA(B) receptor gene and panic disorder.

The enhancement of GABAergic neurotransmission has been closely linked to antipanic drug efficacy. This is the first study to investigate a putative association of exonic sequence variants of the human GABA(B) receptor 1 (GABA(B)R1) gene and susceptibility to panic disorder. Three DNA sequence variants in exons 1a1, 7 and 11 were assessed by polymerase chain reaction-based restriction fragment length polymorphism in a case-control study among patients with panic disorder with and without agoraphobia (DSM III-R criteria) and blood donors. There was no indication of an increased vulnerability to panic disorder or agoraphobia with respect to the allelic variants under study.

Agoraphobia↗

PubMed2000

Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis.

Autodigestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. The mechanism responsible for the intrapancreatic activation of digestive zymogens is unknown, but a recent hypothesis predicts that a redistribution of lysosomal cathepsin B (CTSB) into a zymogen-containing subcellular compartment triggers this event. To test this hypothesis, we used CTSB-deficient mice in which the ctsb gene had been deleted by targeted disruption. After induction of experimental secretagogue-induced pancreatitis, the trypsin activity in the pancreas of ctsb(-/-) animals was more than 80% lower than in ctsb(+/+) animals. Pancreatic damage as indicated by serum activities of amylase and lipase, or by the extent of acinar tissue necrosis, was 50% lower in ctsb(-/-) animals. These experiments provide the first conclusive evidence to our knowledge that cathepsin B plays a role in intrapancreatic trypsinogen activation and the onset of acute pancreatitis.

Acute Disease↗

PubMed2000

Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c.

TNF-alpha-induced apoptosis is thought to involve mediators from acidic vesicles. Cathepsin B (cat B), a lysosomal cysteine protease, has recently been implicated in apoptosis. To determine whether cat B contributes to TNF-alpha-induced apoptosis, we exposed mouse hepatocytes to the cytokine in vitro and in vivo. Isolated hepatocytes treated with TNF-alpha in the presence of the transcription inhibitor actinomycin D (AcD) accumulated cat B in their cytosol. Further experiments using cell-free systems indicated that caspase-8 caused release of active cat B from purified lysosomes and that cat B, in turn, increased cytosol-induced release of cytochrome c from mitochondria. Consistent with these observations, the ability of TNF-alpha/AcD to induce mitochondrial release of cytochrome c, caspase activation, and apoptosis of isolated hepatocytes was markedly diminished in cells from CatB(-/-) mice. Deletion of the CatB gene resulted in diminished liver injury and enhanced survival after treatment in vivo with TNF-alpha and an adenovirus construct expressing the IkappaB superrepressor. Collectively, these observations suggest that caspase-mediated release of cat B from lysosomes enhances mitochondrial release of cytochrome c and subsequent caspase activation in TNF-alpha-treated hepatocytes.

Animals↗