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Biomedical subjects

P Meyer

Publications and source records attributed to P Meyer.

At least 19 recordsLinked to original sources
PubMed1995

The transformation booster sequence from Petunia hybrida is a retrotransposon derivative that binds to the nuclear scaffold.

The transformation booster sequence (TBS) from Petunia hybrida enhances transformation frequencies in P. hybrida, Nicotiana tabacum and Zea mays. TBS also stimulates homologous inter- and intramolecular recombination in P. hybrida, the molecular basis for this stimulation is not known. We investigated whether TBS contains sequence elements that might contribute to the stimulation of recombination and whether its recombinogenic potential reflects a biological function of TBS. We identified a scaffold attachment region (SAR) within TBS and analysed its distribution in the genome and its homologies to other genomic sequences. A 516 bp subfragment of TBS binds to the nuclear scaffold. The sequence of the TBS-SAR fragment shows strong homologies to retroviral elements from plants, suggesting that TBS is an inactive derivative of a retrovirus that still promotes DNA recombination.

Base Sequence↗
PubMed1995

Risk stratification in unstable angina. Prospective validation of the Braunwald classification.

OBJECTIVES: To validate the Braunwald classification of unstable angina as a predictor of in-hospital cardiac complications; to determine which factors of the Braunwald classification contributed significantly to this prediction; and to devise a method of combining these predictive factors into an overall odds ratio for complications. DESIGN: A validation cohort of consecutive patients followed prospectively for in-hospital cardiac complications including myocardial infarction and death. SETTING: A community-based academic medical center. PATIENTS: A total of 393 patients admitted consecutively to the coronary care and intermediate care units with unstable angina. MAIN OUTCOME MEASURES: Major cardiac complications including death, myocardial infarction, congestive heart failure, cardiogenic shock, and severe ventricular dysrhythmias. RESULTS: Multiple logistic regression analysis identified four clinical factors used in the Braunwald classification that predicted the in-hospital occurrence of major cardiac complications: (1) myocardial infarction within less than 14 days (odds ratio [OR], 5.72; 95% confidence interval [CI], 1.92 to 16.97); (2) need for intravenous nitroglycerin (OR, 2.33; 95% CI, 1.31 to 4.17); (3) lack of beta-blocker or calcium channel blocker prior to admission (OR, 3.83; 95% CI, 1.55 to 9.42); and (4) baseline ST depression (OR, 2.81; 95% CI, 1.45 to 5.47). Two other clinical factors, diabetes and age, were also significant predictors. Validation of this model using parametric and nonparametric bootstrap techniques revealed excellent agreement between the CIs for adjusted ORs derived from the multiple logistic regression and those derived from the bootstrap. CONCLUSIONS: The classification of unstable angina proposed by Braunwald includes four factors that predict risk of major in-hospital cardiac complications. Specific factors used in this classification can be combined with diabetes and age to better stratify risk of major cardiac complications in this disorder using a simpler model.

Age Factors↗
PubMed1995

Effects of calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in porcine ciliary arteries.

Calcium channel blockers are increasingly used in ophthalmology, for instance in patients with visual field defects caused by vasospasm. Endothelin is a new vasoactive peptide which also has been implicated in hypoperfusion of the ophthalmic circulation. This study investigated the effects of the calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in isolated porcine ciliary arteries (diameter 200-250 microns). Isolated porcine ciliary arteries were suspended in myograph systems filled with modified Krebs-Ringer solution (37 degrees C; 95% O2/5% CO2) for isometric tension recording. Endothelin-1 (10(-12) -10(-7) M) induced potent concentration-dependent contractions of porcine ciliary arteries (PD50 = 8.3 +/- 0.1; n = 7). Lacidipine (10(-5) -10(-7) M) and nifedipine (10(-5) M) significantly reduced the contractions and decreased the sensitivity to endothelin-1 as compared to control (P < 0.03). On the other hand, endothelium-dependent relaxations to bradykinin (10(-10) -10(-6) M) and endothelium-independent relaxations to sodium nitroprusside (10(-10) -10(-4) M) remained unaffected by the calcium channel blocker. These findings demonstrate that in porcine ciliary arteries, the calcium channel blockers selectively inhibit endothelin-1-induced contractions, while leaving endothelium-dependent and endothelium-independent relaxations unaffected. This property of calcium channel blockers may contribute to the clinical efficacy of this class of drugs in patients with ocular vasospasms.

Animals↗
PubMed1995

Effects of signal peptide mutations on processing of Bacillus stearothermophilus alpha-amylase in Escherichia coli.

Bacillus stearothermophilus alpha-amylase has a signal peptide typical for proteins exported by Gram-positive bacteria. There is only one signal peptidase processing site when the protein is exported from the original host, but when it is exported by Escherichia coli, two alternative sites are utilized. Site-directed mutagenesis was used to study the processing in E. coli. Processing sites for 13 B. stearothermophilus alpha-amylases carrying mutations in their signal peptide were determined. Processing of the signal peptide was remarkably tolerant to mutations, because switching between the alternative sites was possible. The length and the sequence of the region between the hydrophobic core and the cleavage site was crucial for determining the choice of the processing site. Some mutations more distal to the cleavage site also affected the site preference.

Amino Acid Sequence↗
PubMed1995

Prostate-specific antigen levels in patients receiving long-term dialysis.

OBJECTIVE: To investigate the effect, if any, of renal failure upon prostate-specific antigen (PSA) levels and the validity of PSA estimation as a marker of prostatic disease in renal failure. PATIENTS AND METHODS: PSA was measured in 65 men (median age 67 years, range 39-84) on regular haemodialysis and 37 men (median age 70 years, range 42-77) on continuous ambulatory peritoneal dialysis (CAPD). Patients with a PSA level > 4 ng/mL underwent prostatic biopsy guided by transrectal ultrasonography. RESULTS: There was no evidence of an artefactual elevation of PSA attributable solely to renal failure. All eight patients with a PSA level > 4 ng/mL had prostatic disease. CONCLUSION: PSA measurements in patients with end-stage renal failure treated by dialysis remain a useful marker of prostatic disease.

Adult↗
PubMed1995

Treatment with propionic and butyric acid enhances expression variegation and promoter methylation in plant transgenes.

Two phenotypic marker genes (A1 and GUS) were employed to monitor the influence of small chain fatty acids on transgene expression in petunia and tobacco. In plants homozygous with respect to the A1 transgene, which normally carry red flowers due to A1 expression, fatty acid treatment induced a range of variegated and white pigmentation patterns which persisted for several months after terminating the treatment. The inhibitory effect was clearly less pronounced for heterozygous plants of the same transgenic line. In all cases the reduction of transgene activities correlated with an increase in transgene promoter methylation. Contrary to evidence reported for mammals and Drosophila, we do not observe an increase in gene expression, but an enhancement of DNA methylation and epigenetic variegation. The inhibition of transgene activity was also observed in several tobacco transformants cultured on fatty acid containing media. Some tobacco transformants carrying Gus-coding regions driven by either 35S or 1'2' promoters responded with a significant reduction in GUS activity. This study suggests that, rather than exerting a general response on all chromatin regions, fatty acids appear to affect genes in a labile epigenetic surrounding or all genes in a susceptible chromatin configuration. Thus, application of these agents may be useful to screen and monitor transgenes prone to epigenetic instabilities.

Acetylation↗
PubMed1995

Local action of the renin angiotensin system in the porcine ophthalmic circulation: effects of ACE-inhibitors and angiotensin receptor antagonists.

PURPOSE: The renin angiotensin system and endothelium-derived substances are important regulators of the microcirculation. The authors studied the roles of angiotensins (Ang), angiotensin converting enzyme (ACE)-inhibitors, and Ang II-receptor antagonists in the porcine ophthalmic circulation. METHODS: Isolated porcine ciliary arteries were studied in myographs and the intact porcine eye in a perfusion system at 80 cm H2O perfusion pressure with Krebs-ringer bicarbonate solution (37 degrees C, 95% O2, 5% CO2). RESULTS: ACE-inhibitors enalaprilat and benazepril (both 10(-5) M) did not change ciliary vascular tone nor flow of perfused porcine eyes. However, enalaprilat or benazepril enhanced the relaxation of ciliary arteries to bradykinin (P < 0.02). In the perfused porcine eye, enalaprilat (10(-5) M) augmented vasodilation to bradykinin (P < 0.02). The bradykinin antagonist Hoe 140 (3 x 10(-7) M) prevented the relaxation of ciliary arteries to bradykinin (P < 0.001), but not to acetylcholine. In perfused eyes, Hoe 140 reduced the vasodilation to bradykinin (P < 0.01). Ang II (10(-8) to 10(-6) M) evoked a contraction of ciliary arteries and was more potent than Ang I. Enalaprilat abolished the effect of Ang I. The AT1-receptor antagonist, valsartan (10(-9) to 10(-5) M; 30 minutes) inhibited the response of ciliary arteries to Ang II, whereas the AT2-receptor ligand CGP 42112 B (10(-7) to 10(-8) M) was ineffective. In the perfused porcine eye, valsartan restored the decrease in flow to Ang II. CONCLUSIONS: Angiotensins play an important regulatory role in the porcine ophthalmic microcirculation through AT1-receptors. ACE-inhibitors prevents the effects of Ang 1 and augment endothelium-dependent relaxation to bradykinin, which releases nitric oxide through B2 receptors.

Angiotensin I↗
PubMed1994

Epigenetic variants of a transgenic petunia line show hypermethylation in transgene DNA: an indication for specific recognition of foreign DNA in transgenic plants.

We analysed de novo DNA methylation occurring in plants obtained from the transgenic petunia line R101-17. This line contains one copy of the maize A1 gene that leads to the production of brick-red pelargonidin pigment in the flowers. Due to its integration into an unmethylated genomic region the A1 transgene is hypomethylated and transcriptionally active. Several epigenetic variants of line 17 were selected that exhibit characteristic and somatically stable pigmentation patterns, displaying fully coloured, marbled or colourless flowers. Analysis of the DNA methylation patterns revealed that the decrease in pigmentation among the epigenetic variants was correlated with an increase in methylation, specifically of the transgene DNA. No change in methylation of the hypomethylated integration region could be detected. A similar increase in methylation, specifically in the transgene region, was also observed among progeny of R101-17del, a deletion derivative of R101-17 that no longer produces pelargonidin pigments due to a deletion in the A1 coding region. Again de novo methylation is specifically directed to the transgene, while the hypomethylated character of neighbouring regions is not affected. Possible mechanisms for transgene-specific methylation and its consequences for long-term use of transgenic material are discussed.

Chromatin↗
PubMed1994

Pulmonary infiltrations in febrile patients with neutropenia. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter study.

BACKGROUND: Different empirical approaches to antimicrobial treatment of lung infiltrates in patients with neutropenia were studied within a prospective, randomized multicenter trial. METHODS: Patients with neutropenia with hematologic malignancies and fever of 38.5 degrees C or higher associated with newly diagnosed lung infiltrates were randomized for an initial therapy with acylaminopenicillin plus aminoglycoside (Group A), third-generation cephalosporin plus aminoglycoside (Group B), or the double beta-lactam combination (Group C), each in combination with rifampin. Nonresponders were given empirical amphotericin B plus 5-fluorocytosine beginning on day 4, day 5, or day 6 under study. RESULTS: Of 295 patients entered, 91.2% were evaluable. Complete response was obtained in 61.3% with no significant difference between treatment groups. The addition of rifampin did not improve treatment results. Only 27.1% of patients achieved a complete response by antibiotic therapy without additional antifungal therapy. Fungi dominated in cases of microbiologically documented infections and were associated with a poorer outcome compared with bacterial pneumonias. The trend of leukocyte counts under study had a highly significant effect on the outcome of infection. CONCLUSIONS: Lung infiltrates in febrile patients with neutropenia represent a high risk of treatment failure. Persistent neutropenia has a significantly adverse effect on the outcome of infection. Incorporation of systemic antifungal agents into first-line therapy, particularly in selected high-risk subgroups, might improve future treatment results. The quality of diagnostic techniques to establish the etiology of pulmonary infiltrates needs to be improved.

Adolescent↗
PubMed1994

Evidence for cytosine methylation of non-symmetrical sequences in transgenic Petunia hybrida.

A considerable proportion of cytosine residues in plants are methylated at carbon 5. According to a well-accepted rule, cytosine methylation is confined to symmetrical sequences such as CpG and CpNpG, which provide the signal for faithful transmission of symmetrical methylation patterns by maintenance methylase. Using a genomic sequencing technique, we have analysed cytosine methylation patterns within a hypermethylated and a hypomethylated state of a transgene in Petunia hybrida. Examination of a part of the transgene promoter revealed that in both states m5C residues located within non-symmetrical sequences could be detected. Non-symmetrical C residues in the two states were methylated at frequencies of 5.9 and 31.9%, respectively. Methylation appeared to be distributed heterogeneously, but some DNA regions were more intensively methylated than others. Our results show that at least in a transgene, a heterogeneous methylation pattern, which does not depend on symmetry of target sequences, can be established and conserved.

Base Sequence↗
PubMed1994

[Empirical antimicrobial therapy in neutropenic patients. Results of a multicenter study by the Infections in Hematology Study Group of the Paul Ehrlich Society].

BACKGROUND: Severe infections are the predominant cause of treatment failure in patients with high grade malignant hematological disorders undergoing intensive chemotherapy. PATIENTS AND METHODS: In a multicenter trial of the Paul Ehrlich Society (PEG) study group, febrile neutropenic patients with acute leukemias or other high grade hematological malignancies were randomized for a three phase sequential antimicrobial intervention comparing different widely applied regimes for empirical therapy. Patients with clinically documented infections were treated according to a modification depending on the respective source of infection, whereas in patients with microbiologically documented infections, treatment could be adapted to the sesceptibility patterns of detected pathogens. Criteria for evaluation as well as time points for response assessment and treatment escalation were strictly prescribed by the study protocol. RESULTS: Of 1573 evaluable patients, 50.9% had fever of unknown origin (FUO) throughout the study period, 17.1% had lung infiltrates, 14.1% primary bacteremia or fungemia (B/F), 12.6% other clinically documented (CDI) and 5.3% other clinically as well as microbiologically documented infections (CMDI). Cumulative response rate (CR) in patients with FUO was 91.3%, a significant difference between various regimens could not be detected in either of the three treatment phases. Patients with lung infiltrates had a significantly worse treatment outcome as compared to patients with other documented infections or with FUO (61.3% vs 82.9% vs 91.3%). Gram-positive pathogens dominated in case of microbiologically documented infections (MDI), whereas the proportion of fungal infections increased dramatically in MDI with pathogens detected only after more than six days under study. Of numerous prognostic factors analyzed, only the trend in white blood cell counts had a significant impact on treatment outcome. CONCLUSION: Infection-related mortality in neutropenic patients with high grade hematological malignancies can be markedly reduced by a systematically escalating interventional antimicrobial therapy. Early systemic antifungal treatment, especially in patients with lung infiltrates, might further improve treatment results.

Adolescent↗
PubMed1994

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites.

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2-2.5-times higher in patients with severe renal impairment (CLCR < 10 ml.min-1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR > 30 ml.min-1) should not be changed. In patients with moderate renal impairment (CLCR 10-30 ml.min-1) it should be reduced by 50%. In patients with severe renal impairment (CLCR < 10 ml.min-1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.

Adult↗
PubMed1994

Interventional antimicrobial therapy in febrile neutropenic patients. Study Group of the Paul Ehrlich Society for Chemotherapy.

In this prospective multicenter trial, treatment strategies for 1573 patients with neutropenia < 1000/microliters and fever > or = 38.5 degrees C after cytotoxic chemotherapy were compared. Patients with unexplained fever were randomized to a three-phase sequential study for different established drug regimens. If an infection could be defined microbiologically or clinically, treatment modifications were determined. In phase I, treatment for all patients consisted of acylaminopenicillin (PEN) plus aminoglycoside (AMG); or third-generation cephalosporin (CEPH) plus AMG; or PEN plus CEPH. In 800 patients with unexplained fever the response rates were: PEN/AMG (n = 258): 74.4%, CEPH/AMG (n = 252): 73.4%; PEN/CEPH (n = 290): 70.0%. Total response rate was 72.5%. In phase II, patients not responding after 3 days received PEN/CEPH/vancomycin (n = 70) or PEN/CEPH/AMG (n = 74). The respective response rates were 52.9% and 55.4%, total 54.2%. If fever did not resolve, the patients received either PEN/CEPH (n = 40) or imipenem/cilastatin (n = 59) both in combination with amphotericin-B/5-flucytosin/rifampin. The response rates were 62.5% and 79.7%, respectively (p = 0.07), total 72.7%. No significant differences between the treatment modalities compared were found. Analyzing all three phases together, 91.3% of patients with unexplained fever were cured. The response rate was also analyzed according to patients with gram-positive bacteremia (n = 183), response rate = 82.5%; gram-negative organisms (n = 145) 78.6%; fungemia (n = 51) 43.1% (p < 0.001); lung infiltrates (n = 269) 61.3% (p < 0.001); clinically documented infections (n = 198) 84.4%; and clinically and microbiologically documented infections (n = 84) 82.1%. If infections were diagnosed after at least 5 febrile days, more lung infiltrates and fungal infections occurred (p < 0.001). Leukocytes rising above 500/mu during the infection predicted better response rates (p < 0.001): in unexplained fever 97.8% vs 86.5% and lower death rates 1.5% vs 8.5%. In documented infections the response rates were then 89.9% vs 62.3% and the death rates 7.0% vs 20.5%. Therapy of neutropenic fever and infections must be adapted according to risk factors and should include early empiric antifungal therapy. The therapeutic and prophylactic use of hematopoietic growth factors to overcome neutropenia should be evaluated.

Adolescent↗
PubMed1994

[Central pontine myelinolysis: apropos of an oligosymptomatic form].

The authors report a case of paucisymptomatic central pontine myelinolysis (CMP). A 66 years old female had severe hypochloronatremia and hypokaliemia due to diuretic. Despite a slow hydroelectrolytic correction, she presented with dumbness and seizure. CT scan showed hypodensity of protuberance and magnetic resonance imaging (MRI) shown hypersignal of protuberance and undercortex, compatible with central and extra pontine myelinolysis. The long term clinical outcome was good, as MRI's data. Rapid and important correction of severe hyponatremia should be the most important factors of demyelination, secondary to interference with cerebral adaptation mechanisms to hypoosmolality. These factors were not present in this case.

Aged↗