Biomedical subjects
G Peters
Publications and source records attributed to G Peters.
[Evaluation of anti-streptolysin O titers].
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[Comparison of extra renal potassium management in hypertensive, diabetic and normal subjects].
BACKGROUND: Sodium and potassium ions are involved in the regulation of blood pressure and the genesis of hypertension. AIM: To assess internal potassium balance, as a measure of sodium pump activity, in subjects with essential hypertension and diabetic patients. PATIENTS AND METHODS: Eleven hypertensive subjects, 5 non-insulin-dependent diabetics and 16 age matched controls were studied. An acute oral load of 0.8 mEq/Kg body weight of KCl was administered and blood samples were drawn every 30 min thereafter, until 120 min, to measure plasma K+ levels. Urinary K+ excretion during this period was also measured. In eight hypertensive patients, the test was repeated after two week of supplementation with 60 mEq/day of KCl. The maximal increase in plasma potassium levels and the time required to achieve the maximum concentration was recorded. RESULTS: All patients had normal serum creatinine levels. Mean fasting blood glucose of diabetic patients was 133 +/- 15.1 mg/dl. No difference between patients and controls in maximal increase plasma potassium increase, was observed. In hypertensive patients the lapse to achieve the maximal potassium concentration was longer than in controls. After the period of potassium supplementation in hypertensive patients, there was a significant increase in basal plasma K+ levels and the temporal pattern of plasma potassium increase was similar to that of controls. Between 63 and 68% of retained K+ load was translocated to the intracellular space at 120 min in all study groups. CONCLUSIONS: Internal potassium balance is not significantly altered in subjects with essential hypertension or in non-insulin-dependent diabetics.
Cyclin D1 and prognosis in human breast cancer.
We have used immunohistochemical staining to assess the expression of cyclin D1 in formalin-fixed sections of 345 breast carcinomas, dating back 20 years. Clinical follow-up data were available on all patients. Approximately 50% of the tumours showed excessive nuclear staining for cyclin D1 as compared with normal epithelium. Some tumours showed strong cytoplasmic staining in the absence of nuclear staining, and around 25% of the tumours were judged to be negative for nuclear cyclin D1. Contrary to expectations, moderate/strong staining for cyclin D1 was associated with improved relapse-free and overall survival relative to patients whose tumours stained weakly or negatively. Conversely, tumours that were considered negative for cyclin D1 staining had an adverse prognosis, and the poor outcome was further accentuated if the tumours were also oestrogen receptor-negative. A possible explanation for our findings is that tumours in which cyclin D1 levels are abnormally low may have sustained mutations in other genes, such as RBI and that it is this abnormality that has the more significant impact on survival from breast cancer.
Regulation of phosphorylation of deoxycytidine and 2',2'-difluorodeoxycytidine (gemcitabine); effects of cytidine 5'-triphosphate and uridine 5'-triphosphate in relation to chemosensitivity for 2',2'-difluorodeoxycytidine.
Deoxycytidine kinase(dCK) and deoxycytidine deaminase (dCDA) are two key enzymes in the activation and inactivation, respectively, of deoxycytidine and its antiviral and anticancer analogues. One purpose of this study was to determine whether or not the deoxycytidine-converting activity of both enzymes would correlate with growth inhibition by 2',2'-difluorodeoxycytidine (dFdC), a deoxycytidine analogue with established antitumour activity in solid tumours. Another aim of this work was to determine the effects of normal nucleotides on dCK. dCK and dCDA activities were measured with both deoxycytidine and dFdC as substrates in 5 solid tumour cell lines, but no correlation with cellular sensitivity to dFdC was found with either substrate. The normal dCK activities with deoxycytidine as substrate varied between 0.8 and 13 nmol/hr/10(6) cells. The activities determined with dFdC as substrate were remarkably similar in all 5 cell lines (1.1-1.6 nmol/hr/10(6) cells). dCDA activities varied considerably with both substrates (20-30 fold). Because dFdC markedly affected intracellular concentrations of cytidine 5'-triphosphate (CTP) and uridine 5'-triphosphate (UTP), we studied their effect on deoxycytidine-and dFdC-phosphorylating activities in 3 cell lines (i.e., A2780, WiDr and C26-10) with similar dCK activity but major differences in dFdC sensitivity, 1 mM CTP inhibited deoxycytidine phosphorylation (at 230 muM) by 20-30% in A2780 and C26-10 cells, but increased that of WiDr cells by approximately 70%. CTP did not++ affect dFdC phosphorylation (at 230 muM) in A2780 cells, but did increase it by 40% in WiDr cells. At 1 and 10 muM of deoxycytidine the effects of CTP on dCK activity in A2780, C26-10 and WiDr cells were less pronounced. 1mM UTP enhanced deoxycytidine phosphorylation at 230 muM in WiDr cells by approximately 40%, whereas dFdC phosphorylation was increased 40% by UTP in C26-10 cells but decreased by 70-80% in WiDr cells. UTP caused a more pronounced increase in dCK activity at 1 and 10 muM deoxycytidine in C26-10 cells, but provoked a higher inhibition in A2780 and WiDr Cells at 10 muM. Because of these complex results, dCK kinetics were studied in greater detail. Biphasic kinetics for deoxycytidine were observed in all 3 cell lines, with Km values of 23.2 and 0.4 muM for A2780 cells, 15.9 and 1.5 muM for C26-10 cells, and 27.2 and 0.9 muM for WiDr cells. In all 3 cell lines, adenosine 5'-triphosphate (ATP) was the optimal phosphate donor, as compared to CTP and UTP. In conclusion, the efficiency of dCK (Vmax/Km ratio) seems to correlate with accumulation of dFdCTP, the active metabolite of dFdC, and with cellular sensitivity. UTP and CTP, which are seriously affected in cells exposed to dFdC, display varying effects in these solid tumour cell lines. Both activation and inhibition have been observed; the physiologically low CTP pools and the relatively minor effect on dCK in A2780 cells seem to favour dFdC phosphorylation in these cells, which are the most sensitive.
Ultrasound for diagnosis of apophyseal injuries.
Avulsion injuries of the apophysis is a problem in young athletes. A correct diagnosis is necessary for establishing the appropriate treatment and the rehabilitation program. However, it is often difficult to distinguish between a simple muscle strain and an avulsion fracture. The X-ray examination is helpful only when an ossification center of the apophysis exists. Ultrasonography is considered the suitable diagnostic tool for these cases. From June 1988 to June 1993, 243 young athletes were seen with an anamnestic and clinically suspected apophyseal injury of the lower extremity. In all cases X-ray examination and ultrasound examination were performed. In 80 cases the diagnosis was confirmed by X-ray examination and in 97 by ultrasonography. Four criteria were defined for the sonographic examination: (a) a hypoechogenic zone, (b) increased distance to the apophysis, (c) dislocation of the apophysis, and (d) mobility of the apophysis on dynamic examination. These criteria are correlated to (a) edema, (b) lysis, (c) avulsion, and (d) unstable avulsion of the apophysis. Ultrasonography is a proven technique for the detection of apophyseal injuries. In comparison to X-ray examination, it has the advantages of no radiation exposure, early detection even without ossification center, and dynamic examination.
A four-year prospective study on microbial ecology of explanted prosthetic hips in 52 patients with "aseptic" prosthetic joint loosening.
The bacteriology of explanted prosthetic hips and surrounding soft tissue was studied in 52 patients undergoing surgical revision for joint loosening. In a prospective four-year study, positive bacterial cultures were recorded in 34 (76%) patients. Coagulase-negative staphylococci were the predominant isolates, and 11 patients (33%) had more than three organisms isolated, 7 (20%) had two only, and 11 (33%) had one species. Among the 23 patients from whom specimens from all 11 predetermined anatomic sites were cultured, the highest frequency of positive cultures (52% and 47%) came from the shaft and capsular tissue, respectively. Organisms were less frequently recovered from the cement and acetabulum (13% and 4%, respectively). Using molecular typing in eight patients with paired isolates of the same species, clonal identity was found in four. An additional patient underwent a second revision for loosening 17 months after the first revision and the same clone of Staphylococcus epidermidis was isolated on both occasions.
Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer.
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In-vitro activity of RP 59500, a new semisynthetic injectable pristinamycin against staphylococci.
We compared the in vitro activity of RP 59500, a new streptogramin, with that of vancomycin and ciprofloxacin against 130 strains of S. aureus and 117 strains of coagulase-negative staphylococci, using the agar dilution method. The antistaphylococcal activity of RP 59500 was similar to that of vancomycin. All staphylococcal strains were inhibited by < or = 2 micrograms/mL, including 61 methicillin-resistant S. aureus, 28 methicillin-resistant S. epidermidis and 23 methicillin-resistant S. haemolyticus strains. In contrast to ciprofloxacin, the in vitro activity of RP 59500 as well as of vancomycin remained almost unchanged, irrespective of the resistance phenotype for methicillin.
In-vitro activity of ofloxacin, levofloxacin and D-ofloxacin against staphylococci.
The in-vitro activity of levofloxacin was compared with ofloxacin and D-ofloxacin against 130 isolates of Staphylococcus aureaus and 117 isolates of coagulase-negative staphylococci, using the agar dilution method. In general, levofloxacin was equally active or up to fourfold more active than ofloxacin against all staphylococci, including 61 methicillin-resistant S. aureus. In contrast, D-ofloxacin showed little activity against all isolates tested.
Micrococcus luteus as a cause of recurrent bacteremia.
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Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence.
p16CDKN2 specifically binds to and inhibits the cyclin-dependent kinases CDK4 and CDK6, which function as regulators of cell cycle progression in G1 by contributing to the phosphorylation of the retinoblastoma protein (pRB). Human cell lines lacking functional pRB contain high levels of p16 RNA and protein, suggesting a negative feedback loop by which pRB might regulate p16 expression in late G1. By a combination of nuclear run-on assays and promoter analyses in human fibroblasts expressing a temperature-sensitive simian virus 40 T antigen, we show that p16 transcription is affected by the status of pRB and define a region in the p16 promoter that is required for this response. However, the effect is not sufficient to account for the differences in p16 RNA levels between pRB-positive and -negative cells. Moreover, p16 RNA is extremely stable, and the levels do not change appreciably during the cell cycle. Primary human fibroblasts express very low levels of p16, but the RNA and protein accumulate in late-passage, senescent cells. The apparent overexpression of p16 in pRB-negative cell lines is therefore caused by at least two factors: loss of repression by pRB and an increase in the number of population doublings.
Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.
Altered expression or function of the p16CDKN2 tumor suppressor gene on chromosome 9p21 occurs in a wide range of human tumors, and mutations in the gene have been shown to segregate with familial predisposition to malignant melanoma. We have used a variety of assays to examine the functional properties of tumor-associated alleles, including eight premature termination mutants, eight missense mutants, and three isoforms of p16 initiated at different amino-terminal methionine codons. The amino- and carboxy-terminal domains of the protein, outside the ankyrin-like repeats, appeared to be dispensable, but the majority of the premature termination mutations led to loss of function. Of the missense mutations tested, four displayed clear loss of function whereas two behaved like the wild type under all conditions tested. The remaining two mutations, a G-to-W mutation at position 101 (Gl01W) and V126D, both of which are associated with familial melanoma, were found to be temperature sensitive for binding to Cdk4 and Cdk6 in vitro, for inhibiting cyclin D1-Cdk4 in a reconstituted pRb-kinase assay, and for increasing the proportion of G1-phase cells following transfection. These findings clarify previous disparities and argue strongly that p16CDKN2 is a bona fide tumor suppressor associated with familial melanoma.
Epidemiology, control and treatment of methicillin-resistant Staphylococcus aureus.
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[Primary arthrodesis of the knee joint].
Because of progressive development in the field of knee arthroplasty, currently there are fewer indications for primary knee arthrodesis. Primary knee arthrodesis is indicated in acute or chronic infections in which conservative treatment has failed, monoarticular arthritis in young patients if total knee replacement is not suitable, unstable knee joints caused by poliomyelitis or other neuromuscular disease, neuropathic joint disease, in salvage of the extremities with tumors of the distal femur and proximal tibia, and to obtain length in femur dysplasia. The operation technique with a modified Charnley compression fixator is described. Fifteen patients (100%) treated by this double-frame fixator have had a solid arthrodesis 13.6 weeks after surgery. We found 5 pin infections and had to reset 2 Steinmann pins.
Perturbation of cell cycle regulators in human cancer.
Progression through the mammalian cell cycle requires the sequential activation of a series of cyclin dependent kinases. The activity of these kinases is regulated at several levels and the current challenge is to determine how the various signal transduction pathways are linked to the cell cycle machinery. An obvious focus is the so-called restriction point in late G1, and current evidence suggests that this is in part determined by the phosphorylation of the retinoblastoma protein (Rb) by the cyclin D dependent kinases, CDK4 and CDK6. Downstream targets of Rb, such as the E2F1 transcription factor, can promote cell cycle progression, whereas inhibitors of CDK4 and CDK6, such as p16CDKN2a, can block G1 progression. Many human tumours have been shown to have chromosomal abnormalities that directly affect components of this pathway, resulting in either the functional inactivation of p16 or Rb or the excessive activity of cyclin D1 or CDK4. Each of these lesions is likely to lead to unrestrained proliferation, and as they form part of a common pathway, they are generally mutually exclusive. Inhibitors of this pathway therefore have considerable promise as therapeutic agents.
[Is the NIDEP-Study suitable in the assessment and appraisal of nosocomial infections in Germany?].
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Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors.
p16INK4a and p15INK4b are cell cycle regulators that specifically bind to and inhibit the cyclin D-dependent kinases, cdk4 and cdk6. Because these genes undergo frequent deletions and/or mutations in various human cancers, we examined the status and expression of the cognate mouse cdk inhibitors in a panel of 29 cell lines, as well as in 12 primary tumors, representing different stages of mouse skin carcinogenesis. Deletion of p16INK4a and/or p15INK4b was seen in 8 of 10 cell lines derived from spindle carcinomas, the most advanced stage of skin carcinogenesis. Five showed deletion of both genes, and three had independent deletions of p16INK4a or p15INK4b, but in those retaining p16INK4a, expression of the protein was not detected. By contrast, none of 19 more differentiated squamous cell lines exhibited such deletions. In several cases, primary tumor DNA was available, and two spindle tumors showed the same deletion pattern as observed in the corresponding cell lines. In apparent contrast, comparison of two clonally related squamous and spindle cell lines derived from a single carcinoma showed unusually high levels of p16INK4a and p15INK4b only in the invasive spindle cells. Therefore, deletion or altered regulation of p16INK4a and p15INK4b occur concomitantly with the loss of differentiation associated with the late spindle stage of tumor progression in mouse skin.