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Biomedical subjects

G Peters

Publications and source records attributed to G Peters.

At least 109 records · Page 6Linked to original sources
PubMed1998

[Therapy of febrile neutropenia episodes in systemic hematologic illnesses with new once daily ceftriaxone administration].

In this open label prospective multicenter trial, 420 patients with neutropenia < 1000/microliter, fever > 38.5 degrees C and hematological malignancies were treated with ceftriaxone. Acute leukemia (n = 238) and high-grade lymphoma patients (n = 182) from 35 centers were enrolled. Between February 1992 and January 1996, patients were treated with 2 g ceftriaxone i.v. per day either as monotherapy (n = 135), or in combination with aminoglycosides (n = 235), glycopeptides (n = 37), or other antimicrobial agents (n = 13). Patients' median age was 54 years (range 15 to 97) with a median Karnofsky-performance-score of 6.0. The median neutrophil counts were 400/microliter. Fever was of unknown origin (FUO) in 268 (63.8%) of patients. Clinically defined infections (CDI) were diagnosed in 152 (36.2%) cases, including 74 (17.8%) episodes with pneumonia. Response to the initial approach with ceftriaxone was observed in 56.2% of febrile episodes, including 93 (68.8%) treatment courses with ceftriaxone alone. Concerning defervescence of fever ceftriaxone monotherapy was successful as compared to ceftriaxone in combination. Analysis revealed a low risk characterized by higher neutrophil counts (> or = 500/microliter; p < 0.0001), better Karnofsky-performance-score (> or = 7; p = 0.01), duration of neutropenia (< or = 5 days; p = 0.008) from start of antimicrobial treatment and duration of neutropenia per cycle (< or = 10 days; p = 0.0016). At the end of the observation, an overall response was obtained in 88.3% of the patients (n = 371) without statistical difference between patients treated with ceftriaxone alone or in combination. Once daily ceftriaxone either alone or in combination was effective in patients with hematological malignancies. Monotherapy was effective in a low risk group characterized by neutrophil counts (> or = 500/microliter), a Karnofsky-performance-score (> or = 7) and a duration of neutropenia (< or = 5 days) at the commencement of treatment.

Acute Disease↗
PubMed1997

Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins.

The passage of mammalian cells through the restriction point into the S phase of the cell cycle is regulated by the activities of Cdk4 and Cdk6 complexed with the D-type cyclins and by cyclin E/Cdk2. The activities of these holoenzymes are constrained by CDK inhibitory proteins. The importance of the restriction point is illustrated by its deregulation in many tumour cells and upon infection with DNA tumour viruses. Here we describe the properties of cyclins encoded by two herpesviruses, herpesvirus saimiri (HVS) which can transform blood lymphocytes and induce malignancies of lymphoid origin in New World primates, and human herpesvirus 8 (HHV8) implicated as a causative agent of Kaposi's sarcoma and body cavity lymphomas. Both viral cyclins form active kinase complexes with Cdk6 that are resistant to inhibition by the CDK inhibitors p16(Ink4a), p21Cip1 and p27Kip1. Furthermore, ectopic expression of a viral cyclin prevents G1 arrest imposed by each inhibitor and stimulates cell-cycle progression in quiescent fibroblasts. These results suggest a new mechanism for deregulation of the cell cycle and indicate that the viral cyclins may contribute to the oncogenic nature of these viruses.

3T3 Cells↗
PubMed1997

Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status.

Viral transformation of mouse and human fibroblasts has very different effects on the composition of cyclin-dependent kinase (Cdk) complexes. In human cells transformed by the large T-antigen of simian virus 40 (SV40 T-Ag) and human tumour cell lines that lack a functional retinoblastoma gene product (pRb) no cyclin D1-Cdk4 complexes can be detected because all the available Cdk4 is associated with the Cdk-inhibitor p16INK4a. In contrast, SV40-transformed mouse cells and fibroblasts from Rh1-nullizygous mouse embryos contain normal levels of cyclin D1-Cdk4 complexes. To investigate this species difference, we have compared the biochemical properties and expression of mouse p16INK4a with that of its human counterpart. There is a marked increase in p16 RNA and protein levels as primary embryo fibroblasts approach their finite lifespan in culture, but mouse p16 expression does not appear to be influenced by the status of pRb. Transformed or spontaneously immortalized mouse cells therefore do not achieve the very high levels of p16 characteristic of pRb-negative human cell lines. We suggest that these differences may be related to the different frequencies with which mouse and human cells can be immortalized in culture.

3T3 Cells↗
PubMed1997

Left ventricular assist device infection is associated with increased mortality but is not a contraindication to transplantation.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used as a bridge to transplantation. Infection is a frequent and major complication associated with the use of these devices, however, the correlation of infection and outcome has not yet been evaluated in a prospective fashion. METHODS AND RESULTS: Twenty-five patients (24 male, 1 female) with end-stage cardiac failure and resulting organ dysfunction were included. Patients were bridged with the Novacor N100 portable LVAD (median duration of support, 55 days) and were evaluated prospectively by device surface cultures on explantation, molecular typing of isolates, and correlation of infection with survival to transplant. Twelve (48%) of 25 patients had LVAD infection as defined by recovery of multiple isolates of identical genotype from the device surface. Whereas only 5 (42%) of 12 patients with LVAD infection survived until transplantation, 11 (85%) of 13 patients without infection were successfully transplanted (P < .05). Death of the 7 patients with proven LVAD infection was associated with multiple organ failure or other signs of acute infection. CONCLUSIONS: LVAD infection is associated with a significantly decreased survival probability. It does not preclude successful bridging but rather may pose an indication for urgent transplantation.

Adult↗
PubMed1997

Cdk2-dependent phosphorylation of Id2 modulates activity of E2A-related transcription factors.

The helix-loop-helix (HLH) protein Id2 is thought to affect the balance between cell growth and differentiation by negatively regulating the function of basic-helix-loop-helix (bHLH) transcription factors. Id2 acts by forming heterodimers that are unable to bind to specific (E-box) DNA sequences. Here we show that this activity can be overcome by phosphorylation of a serine residue within a consensus target site for cyclin-dependent kinases (Cdks). In vitro, Id2 can be phosphorylated by either cyclin E-Cdk2 or cyclin A-Cdk2 but not by cyclin D-dependent kinases. Analogous phosphorylation occurs in serum-stimulated human diploid fibroblasts at a time in late G1 consistent with the appearance of active cyclin E-Cdk2. The phosphorylation of Id2 in these cells correlates with the restoration of a distinct E-box-dependent DNA-binding complex, suggesting that the levels of this complex are modulated by both the abundance and phosphorylation status of Id2. These data provide a link between cyclin-dependent kinases and bHLH transcription factors that may be critical for the regulation of cell proliferation and differentiation.

3T3 Cells↗
PubMed1997

[Bone lengthening osteotomy in malunited clavicular fracture].

Most fractures of the clavicle heal well with nonoperative treatment. On rare occasions, malunited clavicular fractures are associated with a pattern of disability that includes not only pain but also functional or neurovascular impairment. In these cases, clavicular osteotomy and correction of the deformity should be considered. In four patients with a malunited fracture of the clavicle following nonoperative treatment, we performed a clavicular osteotomy for deformity. In all four patients the clavicular fracture healed with shortening associated with pain and ipsilateral glenohumeral dysfunction. The deformity was not associated with neurovascular dysfunction. In preoperative X-ray studies, the shortening of the malunited clavicle was between 0.9 and 2.2 cm in comparison to the contralateral clavicle. All patients underwent an extension osteotomy of the clavicle with interposition of an autogenous iliac crest bone graft. The follow-up was 1-4 years postoperatively. The functional outcome was evaluated using the Constant-Murley and the UCLA score. All patients had immediate pain relief following osteotomy and correction of the deformity. The shoulder function rapidly improved, and the functional outcome was good in three out of the four patients. If there is associated functional impairment in malunited clavicular fractures, extension osteotomy combined with autogenous bone grafting may produce predictably good results.

Adult↗
PubMed1997

Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface.

Biofilm formation on a polymer surface which involves initial attachment and accumulation in multilayered cell clusters (intercellular adhesion) is proposed to be the major pathogenicity factor in Staphylococcus epidermidis foreign-body-associated infections. We have characterized two distinct classes of biofilm-negative Tn917 mutants in S. epidermidis affected in initial attachment (class A) or intercellular adhesion (class B). mut1 (class A mutant) lacks five surface-associated proteins with molecular masses of 120, 60, 52, 45 and 38 kDa and could be complemented by transformation with a 16.4 kb wild-type DNA fragment. The complemented mutant was able to attach to a polystyrene surface, to form a biofilm, and produced all of the proteins missing from mut1. Subcloning experiments revealed that the 60 kDa protein is sufficient for initial attachment. Immunofluorescence microscopy using an antiserum raised against the 60 kDa protein showed that this protein is located at the cell surface. DNA-sequence analysis of the complementing region revealed a single open reading frame which consists of 4005 nucleotides and encodes a deduced protein of 1335 amino acids with a predicted molecular mass of 148kDa. The amino acid sequence exhibits a high similarity (61% identical amino acids) to the atl gene product of Staphylococcus aureus, which represents the major autolysin; therefore the open reading frame was designated atlE. By analogy with the S. aureus autolysin, AtlE is composed of two bacteriolytically active domains, a 60 kDa amidase and a 52 kDa glucosaminidase domain, generated by proteolytic processing. The 120 kDa protein missing from mut1 presumably represents the unprocessed amidase and glucosaminidase domain after proteolytic cleavage of the signal- and propeptide. The 45 and 38kDa proteins are probably the degradation products of the 60 and 52 kDa proteins, respectively. Additionally, AtlE was found to exhibit vitronectin-binding activity, indicating that AtlE plays a role in binding of the cells not only to a naked polystyrene surface during early stages of adherence, but also to plasma protein-coated polymer surfaces during later stages of adherence. Our findings provide evidence for a new function of an autolysin (AtlE) in mediating the attachment of bacterial cells to a polymer surface, representing the prerequisite for biofilm formation.

Adhesins, Bacterial↗
PubMed1997

Interaction of von Willebrand factor with Staphylococcus aureus.

Intravascular infection due to Staphylococcus aureus requires colonization of subendothelium in the presence of shear forces. von Willebrand factor (VWF) is a large multimeric glycoprotein playing a key role in platelet adhesion to subendothelium. To determine whether VWF may also play a role in adhesion of S. aureus to endovascular sites, binding of VWF to S. aureus and adhesion of S. aureus to VWF-adsorbed substrates was examined. Binding isotherms revealed a dose-dependent reaction of purified VWF with S. aureus Cowan 1 as well as VWF binding to other S. aureus strains. On solid phase, VWF showed saturable adsorption kinetics to polymethylmethacrylate and promoted S. aureus adhesion up to 67-fold in a trypsin-sensitive reaction. Similar adhesion promotion was observed when recombinant VWF was used. These results show that VWF interacts with S. aureus in suspension and promotes S. aureus adhesion to surfaces, suggesting a role of VWF in the pathogenesis of intravascular S. aureus infections.

Bacterial Adhesion↗
PubMed1997

Germline mutations of the CDKN2 gene in UK melanoma families.

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.

Adult↗
PubMed1997

A 140-kilodalton extracellular protein is essential for the accumulation of Staphylococcus epidermidis strains on surfaces.

Two distinct pathogenic mechanisms, adhesion to polymer surfaces and subsequent accumulation of sessile bacterial cells, are considered important pathogenic steps in foreign body infections caused by Staphylococcus epidermidis. By using mitomycin mutagenesis, we have recently generated a mutant, strain M7, from S. epidermidis RP62A which is unaffected in adhesion but deficient in accumulation on glass or polystyrene surfaces and lacks a 115-kDa extracellular protein (designated the 140-kDa antigen; F. Schumacher-Perdreau, C. Heilmann, G. Peters, F. Götz, and G. Pulverer, FEMS Microbiol. Lett. 117:71-78, 1994). To evaluate the role of this protein in accumulation, we harvested extracellular proteins from S. epidermidis RP62A grown on dialysis membranes placed over chemically defined medium, purified the protein by using ion-exchange chromatography, determined its N-terminal amino acid sequence, and raised antiserum in rabbits. The antibody recognized only a single band in a Western immunoblot of the crude extracellular extract. With the microtiter biofilm test, antiserum at a dilution of < or =1:1,000 blocked accumulation of RP62A up to 98% whereas preimmune serum did not. The 140-kDa antigen was found only in extracellular products from bacteria grown under sessile conditions. Of 58 coagulase-negative clinical isolates, 32 strains were 140-kDa antigen positive and produced significantly larger amounts of biofilm than the 26 strains that were 140-kDa antigen negative. The 140-kDa protein appears to be biochemically and functionally unrelated to any previously described factors associated with biofilm formation. Thus, the 140-kDa antigen, referred to as accumulation-associated protein, may be a factor essential in S. epidermidis accumulation and, due to its immunogenicity, may allow the development of novel immunotherapeutic strategies for prevention of foreign body infection.

Amino Acid Sequence↗
PubMed1997

A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persists intracellularly.

Although small-colony variants (SCVs) of Staphylococcus aureus have been recognized for many years, this phenotype has only recently been related to persistent and recurrent infections. Clinical S. aureus SCVs are frequently auxotrophic for menadione or hemin, two compounds involved in the biosynthesis of the electron transport chain elements menaquinone and cytochromes, respectively. While this observation as well as other biochemical characteristics of SCVs suggests a link between electron-transport-defective strains and persistent infections, the strains examined thus far have been genetically undefined SCVs. Therefore, we generated a stable mutant in electron transport by interrupting one of the hemin biosynthetic genes, hemB, in S. aureus by inserting an ermB cassette into hemB. We isolated a hemB mutant, due to homologous recombination, by growth at a nonpermissive temperature and selection for erythromycin resistance. This mutant showed typical characteristics of clinical SCVs, such as slow growth, decreased pigment formation, low coagulase activity, reduced hemolytic activity, and resistance to aminoglycosides. Additionally, the mutant was able to persist within cultured endothelial cells due to decreased alpha-toxin production. Northern and Western blot analyses showed that expression of alpha-toxin and that of protein A were markedly reduced, at both the mRNA and the protein level. The SCV phenotype of the hemB mutant was reversed by growth with hemin or by complementation with intact hemB. Hence, a defect in the electron transport system allows S. aureus SCVs to resist aminoglycosides and persist intracellularly.

Aminoglycosides↗
PubMed1997

Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation.

The functions of basic helix-loop-helix (bHLH) transcription factors in activating differentiation-linked gene expression and in inducing G1 cell cycle arrest are negatively regulated by members of the Id family of HLH proteins. These bHLH antagonists are induced during a mitogenic signalling response, and they function by sequestering their bHLH targets in inactive heterodimers that are unable to bind to specific gene regulatory (E box) sequences. Recently, cyclin E-Cdk2- and cyclin A-Cdk2-dependent phosphorylation of a single conserved serine residue (Ser5) in Id2 has been shown to occur during late G1-to-S phase transition of the cell cycle, and this neutralizes the function of Id2 in abrogating E-box-dependent bHLH homo- or heterodimer complex formation in vitro (E. Hara, M. Hall, and G. Peters, EMBO J. 16:332-342, 1997). We now show that an analogous cell-cycle-regulated phosphorylation of Id3 alters the specificity of Id3 for abrogating both E-box-dependent bHLH homo- or heterodimer complex formation in vitro and E-box-dependent reporter gene function in vivo. Furthermore, compared with wild-type Id3, an Id3 Asp5 mutant (mimicking phosphorylation) is unable to promote cell cycle S phase entry in transfected fibroblasts, whereas an Id3 Ala5 mutant (ablating phosphorylation) displays an activity significantly greater than that of wild-type Id3 protein. Cdk2-dependent phosphorylation therefore provides a switch during late G1-to-S phase that both nullifies an early G1 cell cycle regulatory function of Id3 and modulates its target bHLH specificity. These data also demonstrate that the ability of Id3 to promote cell cycle S phase entry is not simply a function of its ability to modulate bHLH heterodimer-dependent gene expression and establish a biologically important mechanism through which Cdk2 and Id-bHLH functions are integrated in the coordination of cell proliferation and differentiation.

Animals↗
PubMed1997

A new device for monitoring gastric pH in free-ranging animals.

An autonomous stomach probe for the measurement of gastric pH and temperature in free-ranging animals is presented. The probe was successfully deployed in four species of penguins and measured pH for periods of up to 10 days under fluctuating pressure conditions. The resolution of pH was better than 0.1 pH units, and the absolute accuracy was on average better than 0.25 pH units for deployment in Pygoscelis penguins and better than 0.1 pH units in Spheniscus penguins. Stomach pH in chickrearing penguins was highly flexible, with values ranging from below pH 2 to virtually neutral, allowing the birds to adjust the rate of digestion to the prevailing demands.

Animals↗
PubMed1997

Regulation and function of the cyclin-dependent kinase inhibitor p16CDKN2.

Many human tumours show perturbations of a pathway that includes the D-cyclins, their associated cyclin-dependent kinases, and specific kinase inhibitors. The focal point of this pathway is the product of the retinoblastoma tumour suppressor gene, pRb, which imposes a block on G1 phase progression. Thus, the major role of the cyclin D-dependent kinases is to overcome this block by initiating the phosphorylation of pRb. Excessive activity of this pathway is likely to lead to excessive cell proliferation. Conversely, accumulation of the inhibitors is associated with the cessation of cell division.

Carrier Proteins↗