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Biomedical subjects

F Weber

Publications and source records attributed to F Weber.

At least 109 records · Page 6Linked to original sources
PubMed1999

PB2 polymerase subunit of Thogoto virus (Orthomyxoviridae family).

Thogoto virus (THOV) represents a new genus in the family Orthomyxoviridae. The three polymerase subunits PB1, PB2, and PA initiate transcription by a unique cap-stealing mechanism that involves the cleavage of only the m(7)GpppAm structure from cellular hnRNAs. Here, we report the cloning of the longest genomic segment of THOV coding for PB2. It comprises 2,375 nucleotides encoding a single large open reading frame flanked by the conserved terminal regions typical for orthomyxoviruses. The deduced amino acid sequence corresponds to a protein of 769 amino acids, with an estimated Mr of 88,042. Expression of the PB2 cDNA in mammalian cells revealed nuclear accumulation of the recombinant protein, consistent with the replication of THOV in the cell nucleus.

Amino Acid Sequence↗
PubMed1999

Brain metastases in breast cancer: prognostic factors and management.

In this retrospective study, 162 breast cancer patients were analysed in whom brain metastases had been diagnosed clinically between 1969 and 1995 at a single institution. 145 patients were treated with megavoltage irradiation (60 cobalt or 6MV) of the whole brain using opposed fields. The most common applied schedule consisted of 30 Gy in 15 daily fractions over 3 weeks. 10 patients underwent surgery and 17 patients received symptomatic treatment only. The median age was 50 years (range 30-78 years). 81 of 162 patients (50%) were premenopausal. Women younger than 40 years of age had a shorter survival (median 12 weeks) than those of all other groups (median 29 weeks). Median survival was 82 weeks for the 10 surgical patients, 26 weeks for the 145 patients treated with radiotherapy and 5 weeks for the patients who received symptomatic (corticosteroid) therapy only. Patients with solitary metastases treated with radiation alone (45 patients) had a survival of 44 weeks versus 23 weeks in patients with multiple brain metastases. Multivariate stepwise regression analyses revealed Karnofsky Index, dose of radiation (P < 0.001), solitary metastases (P < 0.04) and primary tumour size (P < 0.04) as significant prognostic factors for survival.

Adult↗
PubMed1999

Methodological developments and strategies for a fast flexible superposition of drug-size molecules.

An alternative to experimental high through-put screening is the virtual screening of compound libraries on the computer. In absence of a detailed structure of the receptor protein, candidate molecules are compared with a known reference by mutually superimposing their skeletons and scoring their similarity. Since molecular shape highly depends on the adopted conformation, an efficient conformational screening is performed using a knowledge-based approach. A comprehensive torsion library has been compiled from crystal data stored in the Cambridge Structural Database. For molecular comparison a strategy is followed considering shape associated physicochemical properties in space such as steric occupancy, electrostatics, lipophilicity and potential hydrogen-bonding. Molecular shape is approximated by a set of Gaussian functions not necessarily located at the atomic positions. The superposition is performed in two steps: first by a global alignment search operating on multiple rigid conformations and then by conformationally relaxing the best scored hits of the global search. A normalized similarity scoring is used to allow for a comparison of molecules with rather different shape and size. The approach has been implemented on a cluster of parallel processors. As a case study, the search for ligands binding to the dopamine receptor is given.

Algorithms↗
PubMed1999

Differences in blood pressure values by simultaneous auscultation of Korotkoff sounds inside the cuff and in the antecubital fossa.

To elucidate whether auscultation of the Korotkoff sounds inside the cuff and in the antecubital fossa leads to different blood pressure (BP) values we measured BP at both sites simultaneously with identical flat stethoscopes in a same-arm test design (part A) in 64 normotensive (N: 32 men, 32 women; mean age: 38.7 +/- 15.1 years) and 67 hypertensive subjects (H: 36 men, 31 women; mean age: 44.6 +/- 12.9 years), and additionally in a same- and opposite-arm test design (part B) in 20 normotensive young women. While in part A systolic BP measured inside the cuff was only slightly higher (N: +1. 6 +/- 3.2 mm Hg; H: +1.0 +/- 1.4 mm Hg), diastolic BP was considerably lower (N: -10.6 +/- 5.6 mm Hg; H: -8.4 +/- 4.9 mm Hg). This result was corroborated by part B with differences in systolic/diastolic BP of +0.8 +/- 1.0/-8.5 +/- 2.2 mm Hg in the same-arm test and +0.4 +/- 4.8/-10.6 +/- 5.2 mm Hg in the opposite-arm test. Subject's age was the main variable determining differences in diastolic BP with significantly higher differences in younger than in older subjects, indicating that the elastic properties of arteries may be responsible for these differences. Our results demonstrate that a modification in the auscultatory technique of BP measurement produces significantly different diastolic BP values, the magnitude of which is important for our conceptions of threshold and target values in diagnosing and treating hypertension.

Adolescent↗
PubMed1999

High prevalence of a variety of epidermodysplasia verruciformis-associated human papillomaviruses in psoriatic skin of patients treated or not treated with PUVA.

Epidermodysplasia verruciformis-associated human papillomaviruses and in particular human papillomavirus type 5 were recently shown to be highly prevalent in psoriatic skin. We have analyzed lesional skin from 54 psoriasis patients for infections with genital-specific and epidermodysplasia verruciformis-specific human papillomaviruses to define the spectrum of involved human papillomavirus types and to test if it is influenced by psoralen ultraviolet A therapy. Using polymerase chain reaction analysis we could detect human papillomavirus sequences in skin lesions of 83% of the tested patients. In contrast, human papillomavirus-DNA was only demonstrated in 19% of skin samples from 42 dermatologically healthy, immunocompetent individuals. Sequence analysis of the polymerase chain reaction amplimers revealed 14 human papillomavirus types, all belonging to the epidermodysplasia verruciformis or epidermodysplasia verruciformis-related papillomaviruses. Only in one case we identified sequences related to those of genital viruses, which, however, represented a putatively new human papillomavirus type. The most prevalent human papillomavirus type in our patient series was human papillomavirus type 36, found in 62% of the patients positive for human papillomavirus-DNA, followed by human papillomavirus type 5 (38%) and human papillomavirus type 38 (24%). Multiple infections with two to five different human papillomavirus types could be detected in skin samples of 63% of the analyzed patients. The overall human papillomavirus detection rate did not differ significantly between patients which have been subjected to psoralen ultraviolet A photochemotherapy or solely treated with topical preparations (77 vs 89%). Human papillomavirus type 5, however, could be detected significantly more frequent in lesions of psoralen ultraviolet A-treated patients (p < 0.001). Our data strongly argue for infections with epidermodysplasia verruciformis-specific papillomaviruses being an almost consistent feature of the lesional psoriatic skin and substantiate the importance of further studies to elucidate a possible involvement of human papillomaviruses in psoriasis pathology.

Adolescent↗
PubMed1999

Heart rate variability and ischaemia in patients with coronary heart disease and stable angina pectoris; influence of drug therapy and prognostic value. TIBBS Investigators Group. Total Ischemic Burden Bisoprolol Study.

AIMS: Determination of the influence of therapy with bisoprolol and nifedipine on the heart rate variability of patients from the Total Ischemic Burden Bisoprolol Study and examination of the prognostic value. METHODS AND RESULTS: Four hundred and twenty-two patients with stable angina were included. The heart rate variability was determined over a period of 24 h. Parameters determined: standard deviation of the mean of all corrected RR intervals, standard deviation of all 5 min mean cycle lengths, square root of the mean of the squared differences of successive corrected RR intervals. Nifedipine reduced the mean values of all heart rate variability parameters tested. Square root of the mean of the square differences of successive corrected RR intervals increased under bisoprolol. Standard deviation of the mean of all corrected RR intervals and standard deviation of all 5 min mean cycle lengths increased from low baseline values and declined from higher baseline values. The increase in heart rate variability under therapy was accompanied by a tendency towards a better prognosis. Patients with an increase in heart rate variability and simultaneous complete suppression of ischaemia under therapy displayed no serious events in the course of one year. CONCLUSIONS: The increase in the heart rate variability, which can be regarded as prognostically favourable, was predominantly observed under bisoprolol. The parameter constellation of an increase in heart rate variability and complete ischaemia suppression on the 48-h Holter ECG was associated with the greatest benefit.

Adrenergic beta-Antagonists↗
PubMed1999

The impact of television on attitudes towards organ donation--a survey in a German urban population sample.

BACKGROUND: The stagnation or decrease in organ donation rates since 1992 in Germany has partly been attributed to the negative impact of reports about organ donation periodically presented by German television between 1992 and 1997. This study was performed to elucidate the impact of the media on the public's attitudes towards organ donation. METHODS: A questionnaire concerning different aspects of organ donation was sent to the parents of pupils of a high school in a German city in 1994 and 1998. RESULTS: In 1994, 940 adults could be identified who had (TV+, n = 546) or had not (TV-, n = 394) followed at least one television discussion about the topic. In 1998, the group consisted of 756 (TV+, n = 443 and TV-, n = 313) adults. The discriminating question was of sufficient strength to reveal significant differences between TV(+) and TV(-) respondents. Contrary to an assumed negative impact of TV, differences between the groups were detectable mainly in questions regarding information, but not in those which dealt with personal fears and concerns. The main results obtained in both surveys were identical. Furthermore, from 1994 to 1998 there was a trend in favour of information and organ donation for TV(+) but not for TV(-) respondents. CONCLUSION: The assumption that TV has had a negative impact on donation rates must be rejected. Therefore, the stagnation/decline in donation rates must be attributed to other factors.

Attitude↗
PubMed1999

Immediate and late effects of coronary angiography on soluble endothelial cell markers and P-selectin in patients with and without coronary artery disease.

Endothelial cell injury and platelet activation are considered primary events in the pathogenesis of coronary artery disease (CAD) and are marked by plasma concentrations of von Willebrand factor (vWF) and soluble thrombomodulin, and by soluble P-selectin, respectively. Because both endothelial cells and platelets interact with contrast media, we aimed to detect immediate and 24-h changes in these markers following coronary angiography in patients with and without CAD. Sixteen patients with angiographically proven CAD and 14 patients without significant coronary stenosis were investigated. Blood samples were obtained from an antecubital vein before and 24 h after cardiac catheterization, and from the coronary sinus before and immediately after angiography. Concentrations of the markers were determined using enzyme-linked immunosorbent assays. In the coronary sinus samples, the only significant finding was an increase in levels of soluble P-selectin in the patients with CAD (P < 0.038). In the post-catheterization peripheral blood samples, concentrations of soluble P-selectin (P = 0.004), vWF (P = 0.0007) and soluble thrombomodulin (P = 0.0013) were all increased in patients with CAD. In contrast, patients without CAD demonstrated increased levels of vWF only (P = 0.0015) in peripheral blood samples obtained 24 h after angiography. We conclude that both immediate and 24-h changes take place in endothelial cells and platelet markers in response to cardiac catheterization, and that these changes are different in patients with angiographically proven CAD and in patients free of disease. These differences may reflect alterations in endothelial cell or platelet reactivity in patients with CAD.

Aged↗
PubMed1999

Molecular cloning and expression of major structural protein VP1 of the human polyomavirus JC virus: formation of virus-like particles useful for immunological and therapeutic studies.

The major structural viral protein, VP1, of the human polyomavirus JC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy (PML), was expressed by using recombinant baculoviruses. Recombinant VP1 formed virus-like particles (VLP) with the typical morphology of empty JCV capsids. Purified VP1 VLP bind to SVG, B, and T cells, as well as to monkey kidney cells. After binding, VP1 VLP were also internalized with high efficiency and transported to the nucleus. Immunization studies revealed these particles as highly immunogenic when administered with adjuvant, while immunization without adjuvant induced no immune response. VP1 VLP hyperimmune serum inhibits binding to SVG cells and neutralizes natural JCV. Furthermore, the potential of VP1 VLP as an efficient transporter system for gene therapy was demonstrated. Exogenous DNA could be efficiently packaged into VP1 VLP, and the packaged DNA was transferred into COS-7 cells as shown by the expression of a marker gene. Thus, VP1 VLP are useful for PML vaccine development and represent a potential new transporter system for human gene therapy.

Animals↗
PubMed1999

Wrist measurement of blood pressure: some critical remarks to oscillometry.

UNLABELLED: Oscillometric blood pressure measuring devices worn at the wrist are preferred by a growing part of hypertensive patients for self-measurement because of their compactness and ease of use. However, little is known about the accuracy of such instruments. The accuracy of such devices was evaluated by measuring the blood pressure at the end of a coronary angiography procedure in 27 subjects nearly simultaneously in the aortic arch, using a Statham P23 transducer, and at the wrist, using the blood pressure watch (BPW) by NAIS-Matsushita. Four replicate comparative measurements were performed in each subject. On average, the blood pressure measured by the BPW was found to be higher: systolic +1.2+/-(SD)10.2 mm Hg, diastolic +4.1+/-7.2 mm Hg. The correlation coefficient between the two methods was 0.85 for the systolic and 0.84 for the diastolic pressure, but 39% of the systolic and 22% of the diastolic differences were outside the range of +/-1 SD. There was no correlation between systolic differences and blood pressure or patients' variables, but multiple regression analysis revealed that the diastolic blood pressure differences were negatively correlated with the aortic diastolic pressure (r = 0.89, p<0.001), indicating that the BPW is less accurate to detect lower values. CONCLUSIONS: (1) Though the average systolic and diastolic deviations between both methods and the relative correlation coefficients suggest that the BPW is to be used carefully for monitoring blood pressure, the great variability of differences and the inability of the BPW to detect lower diastolic blood pressure calls for a mandatory validation test by an approved protocol before this new device can be recommended for general use. (2) On the basis of our results for wrist oscillometry with the BPW and data reported in the literature for upper-arm oscillometric devices, we recommend to use oscillometric devices only when they were validated properly. In particular, the oscillometric measurement should be employed with caution for epidemiological studies or for investigation of population groups (e.g., children or pregnant women) that are expected to display lower diastolic pressures.

Adult↗
PubMed1999

Indirect and direct simultaneous, comparative blood pressure measurements with the Bosotron 2 device.

Testing the accuracy of the automatic blood pressure measuring device Bosotron 2, we performed simultaneous, same-arm, comparative blood pressure measurements with three instruments (A, B, and C) of the device and by auscultation in the antecubital fossa by a trained observer in 24 volunteers each. The volunteers were evenly matched for age, sex, and blood pressure level. The mean systolic differences and their standard deviations (24 subjects each, n = 288 single measurements) were -1.32+/-3.8 mm Hg for instrument A, -0.99+/-3.9 mm Hg for instrument B, and -1.12+/-5.0 mm Hg for instrument C. The corresponding values for the diastolic differences were -2.71+/-4.4, -3.46+/-4.3, and -2.72+/-3.9 mm Hg, respectively. Combining the results for the three instruments, the comparison yielded a good accuracy (mean difference) and sufficient repeatability of the differences (standard deviation) for the systolic and diastolic blood pressures (systolic -1.14+/-4.3 mm Hg; diastolic -2.96+/-4.2 mm Hg). In addition to the British Hypertension Society protocol, in 33 patients with coronary artery disease the measurements using the three Bosotron 2 devices were compared with measurements within the aortic arch. The mean systolic/diastolic differences (+/-SD) were +1.45+/-4.3 and +7. 27+/-4.7 mm Hg for instrument A, +4.70+/-12.8 and +1.73+/-7.4 mm Hg for instrument B, and -3.74+/-8.0 and +5.61+/-2.6 mm Hg for instrument C. Combining the results of the three instruments, the blood pressure was determined to be only slightly higher (systolic +1.74+/-9.6 mm Hg; diastolic +4.87+/-5.6 mm Hg) by the Bosotron 2 R device as compared with the aortic arch pressure. The Bosotron 2 R device seems to be suitable for clinical use and for monitoring blood pressure during clinical-pharmacological studies.

Adolescent↗
PubMed1998

Experimental pneumococcal meningitis in rabbits: the increase of matrix metalloproteinase-9 in cerebrospinal fluid correlates with leucocyte invasion.

Gelatinolytic activity of matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-2, was studied by quantitative zymography in a rabbit model of bacterial meningitis during 24 h after inoculation with Streptococcus pneumoniae. In cerebrospinal fluid (CSF), MMP-2 was constitutively present and its level did not change during the experiment. In contrast, MMP-9, hardly detectable in CSF of healthy animals, increased dramatically. The increase of MMP-9 was correlated with both, an increase of CSF cell count and of total protein concentration. Intrathecal production of MMP-9 and MMP-2 was demonstrated by zymography of equal amounts of total protein from CSF and serum. Homogenates, prepared from various cortical regions of infected rabbits did not show increase of MMP activities. On the other hand, leucocytes isolated from CSF expressed high levels of MMP-9 suggesting a significant contribution of these cells to the elevation of MMP-9 activity in this body fluid.

Animals↗
PubMed1998

A classical bipartite nuclear localization signal on Thogoto and influenza A virus nucleoproteins.

We have previously shown that the nucleoprotein (NP) of Thogoto virus (THOV), a tick-borne member of the Orthomyxoviridae family, accumulates in the cell nucleus. Here we demonstrate that THOV NP contains a motif (KRxxxxxxxxxKTKK) at amino acid positions 179-193 that represents a classical bipartite nuclear localization signal (NLS). This sequence motif (named cNLS) was able to translocate a cytoplasmic 80-kDa reporter protein into the nucleus. Targeted mutations substituting lysines for alanines in the downstream cluster of the bipartite motif abolished the capacity of cNLS to mediate nuclear import. In contrast, identical mutations had no effect on nuclear localization when introduced into THOV NP, indicating that additional transport signals are present in NP. Amino-acid sequence comparisons revealed that THOV NP lacks the N-terminal nonconvential NLS (named here nNLS), which has been implicated in nuclear import of influenza A virus NP. Accordingly, THOV NP failed to interact in coprecipitation assays with the cellular NPI-1/3 transport factors of the karyopherin alpha family. A highly conserved motif identified in THOV NP was the so-called nuclear accumulation sequence (NAS). Mutating NAS alone, or in combination with cNLS, had no gross effect on the intracellular distribution of the protein, indicating that a functional NAS is not required for nuclear accumulation of THOV NP in mammalian cells. We also studied nuclear transport of influenza A/PR/8/34 virus NP. Interestingly, we found a cNLS motif at amino acid positions 198-216 in addition to the previously described nonconventional nNLS. To further assess the functional role of cNLS, nNLS, and NAS, we analyzed single, double, and triple mutants of influenza A virus NP. When nNLS was destroyed, the protein stayed in the cytoplasm as expected. When NAS was disrupted in addition to nNLS, the double mutant accumulated in the nucleus, suggesting that cNLS was active. Indeed, when cNLS was also inactivated, the triple mutant protein localized again predominantly to the cytoplasm. These findings suggest that NP of orthomyxoviruses have two independent NLSs, namely cNLS and nNLS. They further suggest that NAS and NLSs may assume opposing roles in nucleocytoplasmic transport of NP.

Amino Acid Sequence↗
PubMed1998

Human myelin basic protein specific T cell lines display differential cytotoxicity against astrocytes, but are consistently cytotoxic against monocytes.

In experimental allergic encephalomyelitis (EAE) myelin basic protein (MBP) specific T cells differ in their encephalitogenic potential. To investigate the functional diversity of human MBP specific T cell lines, we analysed their cytotoxic activity against human astrocytes and monocytes. Five out of 14 MBP specific T cell lines killed astrocytes in the presence of MBP. Nevertheless, all lines lysed blood derived monocytes. T cell lines that lysed astrocytes efficiently in the presence of MBP, recognized peptide aa 80-99/86-105 in context with HLA-DRB5 * 0101, peptide aa 50-69/61-83 in context with HLA-DRB1 * 1501 and peptides aa 139-153, and aa 148-162 in context with HLA-DRB1 * 0101. There was no correlation of MBP-mediated lysis of astrocytes with TCR-Vbeta usage, HLA-restriction and the production of tumor-necrosis-factor-alpha (TNF-alpha), lymphotoxin (LT) and interferon-gamma (IFN-gamma). Different lysis of astrocytes, however, revealed a functional heterogeneity of MBP specific T cells, which was not observed by using monocytes as targets.

Astrocytes↗