Biomedical subjects

M Brunner

Publications and source records attributed to M Brunner.

At least 73 records · Page 4Linked to original sources

PubMed1999

[Test construction, analysis and trial of the Heidelberg Sound Discrimination Test for measuring auditory-kinesthetic perceptual discrimination acuity].

The provisional trial was carried out in a sample of 133 second- and 139 fourth-graders from the Heidelberg area. The HD-LT was subjected to an item selection, test criteria were ascertained and temporary percentile norms for the second and fourth grades were established. High item difficulty resulted for both grades, i.e. the test was relatively easy. Test criteria were generally satisfactory. Significant correlations were found in both grades between the HD-LT and the children's spelling ability. The HD-LT accounted for 30% of the spelling variance among second-graders as compared to 10% of that among fourth-graders. This reflects the specific significance of phonetic discrimination ability in the first years of elementary school. Children with spelling difficulties were compared to those with good spelling abilities in respect to their ability to discriminate sound. Spelling-impaired children in both grades exhibited a significantly lower overall HD-LT score. No significant sex differences were found with regard to the auditory and kinesthetic phonetic discrimination ability. Since the HD-LT turns out to be well-suited to indicate a phonetic discrimination disability during the initial phases of acquisition of written language, its further development and extension of its application to the pre-school level are recommended.

Child↗

PubMed1999

Urea induces macrophage proliferation by inhibition of inducible nitric oxide synthesis.

BACKGROUND: Atherosclerosis is a major cause of morbidity and mortality in chronic renal failure and is associated with the proliferation of macrophages within atherosclerotic lesions. METHODS: Because the progression of atherosclerosis as a consequence of decreased nitric oxide synthesis has been described, we investigated the correlation between the inhibition of inducible nitric oxide synthase (iNOS) by urea, macrophage proliferation as assayed by cell counting, tritiated thymidine incorporation and measurement of cell protein, and macrophage apoptosis. RESULTS: Urea induces a dose-dependent inhibition of inducible nitric oxide synthesis in lipopolysaccharide-stimulated mouse macrophages (RAW 264.7) with concomitant macrophage proliferation. Macrophage proliferation, as determined by cell counting, became statistically significant at 60 mM urea, corresponding to a blood urea nitrogen level of 180 mg/100 ml, concentrations seen in uremic patients. iNOS protein expression showed a dose-dependent reduction, as revealed by immunoblotting when cells were incubated with increasing amounts of urea. The decrease of cytosolic DNA fragments in stimulated macrophages incubated with urea shows that the proliferative actions of urea are associated with a decrease of NO-induced apoptosis. CONCLUSIONS: Our data demonstrate that the inhibition of iNOS-dependent NO production caused by urea enhances macrophage proliferation as a consequence of diminished NO-mediated apoptosis.

Animals↗

PubMed1999

The migration from the internal coatings of food cans; summary of the findings and call for more effective regulation of polymers in contact with foods: a review.

The analysis of migrates from the internal coatings of food cans showed that the present regulation is not sufficient to ensure safety of food contact polymers. The migrates often consist of complex mixtures of reaction products and impurities, and their harmlessness cannot be deduced from the use of non-toxic starting substances compiled in positive lists. The regulation proposed herein asks producers to analyse the composition of the migrates. It includes an upper limit for the molecular weight (e.g. 1000 Da) and thresholds defining concentrations in the foods down to which components must be identified and evaluated. Primarily considering feasibility at reasonable costs, thresholds of 30 micrograms/kg for individual components and 300 micrograms/kg for the sum of the unidentified materials are proposed. Producers must be able to demonstrate that the individual components or mixtures exceeding this limit, including reaction products with food components, have no toxic effect.

Epoxy Resins↗

PubMed1999

The dose-response of caudal ropivacaine in children.

BACKGROUND: Ropivacaine, a new local anesthetic, is less cardiotoxic in adults and is less likely to cause motor blockade than is bupivacaine. The authors evaluated the clinical effectiveness and hemodynamic effects of ropivacaine compared with bupivacaine and the pharmacokinetics of ropivacaine when given for caudal blocks in 56 children 4.1 +/- 1.2 yr old (mean +/- SD). METHODS: Patients scheduled for inguinal hernia repair were randomly given a caudal injection (0.75 ml/kg) of ropivacaine, 0.25% (R0.25 group); ropivacaine, 0.5% (R0.5 group); or bupivacaine, 0.25% (B0.25 group). Postoperative measurements included the duration of analgesia, which was our primary outcome variable, and hemodynamic and respiratory monitoring for 4 h in the recovery room. Thereafter, analgesic requirements for the following 24 h were assessed by an independent observer on the ward using an observational pain-discomfort scale, which gives a cumulative score from 5 to 15 to estimate the quality of analgesia by assessment of behavioral objective parameters. Plasma levels of ropivacaine were measured before the procedure was started and 5, 10, 15, 20, 25, 30, and 45 min and 1, 2, 4, 6, 8, and 24 h after caudal block. RESULTS: A significantly longer (P < 0.0001) duration of analgesia (median [range]) was observed in the R0.5 group (1,440 [335-1,440] min), whereas the R0.25 group (208 [175-340] min) and the B0.25 group (220 [100-390] min) were comparable. All groups showed a significant decrease in mean arterial blood pressure and heart rate from baseline values, but differences between groups were not observed. CONCLUSION: Ropivacaine is well tolerated and provides effective analgesia when given for caudal blockade in small children for inguinal hernia repair.

Amides↗

PubMed1999

Penetration of moxifloxacin into peripheral compartments in humans.

To characterize the penetration of moxifloxacin (BAY 12-8039) into peripheral target sites, the present study aimed at measuring unbound moxifloxacin concentrations in the interstitial space fluid by means of microdialysis, an innovative clinical sampling technique. In addition, moxifloxacin concentrations were measured in cantharides-induced skin blisters, saliva, and capillary plasma and compared to total- and free-drug concentrations in venous plasma. For this purpose, 12 healthy volunteers received moxifloxacin in an open randomized crossover fashion either as a single oral dose of 400 mg or as a single intravenous infusion of 400 mg over 60 min. An almost-complete equilibration of the free unbound plasma fraction of moxifloxacin with the interstitial space fluid was observed, with mean area under the concentration-time curve (AUC)(interstitial fluid)/AUC(total-plasma) ratios ranging from 0.38 to 0.55 and mean AUC(interstitial fluid)/AUC(free-plasma) ratios ranging from 0.81 to 0.86. The skin blister concentration/plasma concentration ratio reached values above 1.5 after 24 h, indicating a preferential penetration of moxifloxacin into inflamed lesions. The moxifloxacin concentrations in saliva and capillary blood were similar to the corresponding levels in plasma. Our data show that moxifloxacin concentrations attained in the interstitial space fluid in humans and in skin blister fluid following single doses of 400 mg exceed the values for the MIC at which 90% of isolates are inhibited for most clinically relevant bacterial strains, notably including penicillin-resistant Streptococcus pneumoniae. These findings support the use of moxifloxacin for the treatment of soft tissue and respiratory tract infections in humans.

4-Quinolones↗

PubMed1999

Distribution and antimicrobial activity of ciprofloxacin in human soft tissues.

Interstitial ciprofloxacin concentrations in soft tissues were measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum drug concentrations; the interstitium-to-serum concentration ratios ranged from 0.55 to 0.73. An in vitro simulation based on interstitial pharmacokinetics showed a substantially lower antimicrobial activity than did the simulation based on serum pharmacokinetics. Thus, ciprofloxacin concentrations at the site of effect may be subinhibitory although effective concentrations are attained in serum.

Adult↗

PubMed1999

Penetration of ciprofloxacin into the interstitial space of inflamed foot lesions in non-insulin-dependent diabetes mellitus patients.

Interstitial ciprofloxacin concentrations were measured by microdialysis in inflamed foot lesions of non-insulin-dependent diabetes mellitus patients following intravenous administration of 0. 2 g of ciprofloxacin. Interstitial ciprofloxacin concentrations were significantly lower than corresponding serum concentrations. There was no significant difference in the penetration of ciprofloxacin into inflamed and unaffected tissue (area under the concentration-time curve(infection)/area under the concentration-time curve(unaffected tissue) = 0.99 +/- 0.15 [mean +/- standard error], n = 6). Thus, inflammation appears to have little or no effect on the penetration of ciprofloxacin into tissue.

Aged↗

PubMed1998

Unfolding of preproteins upon import into mitochondria.

Unfolding of preproteins and translocation across the mitochondrial membranes requires their interaction with mt-Hsp70 and Tim44 at the inner face of the inner membrane and ATP as an energy source. We measured the temperature dependence of the rates of unfolding and import into the matrix of two folded passenger domains, the tightly folded heme-binding domain (HBD) of cytochrome b2 and the loosely folded mouse dihydrofolate reductase (DHFR). Despite the stability of the HBD, its rates of thermal breathing were fast and the preprotein was imported rapidly at all temperatures. In contrast, rates of unfolding and import of DHFR were strongly temperature dependent and import was significantly slower than unfolding. In addition, import rates of DHFR were strongly dependent on the length of the presequence. We propose that the mitochondrial import motor does not exert a constant pulling force. Rather, mt-Hsp70 appears to release a translocating polypeptide chain such that the precursor can then slide back and refold on the surface of the mitochondria. Refolding competes with translocation, and passengers may undergo several rounds of unfolding and refolding prior to their import.

Adenosine Triphosphate↗

PubMed1998

C- to N-terminal translocation of preproteins into mitochondria.

Nuclear-encoded mitochondrial matrix proteins in most cases contain N-terminal targeting signals and are imported in a linear N- to C-terminal (N-->C) fashion. We asked whether import can also occur in a C- to N-terminal direction (C-->N). We placed targeting signals at the C-terminus of passenger proteins. Import did occur in this 'backwards' fashion. It paralleled that of the 'normal' N-->C mechanism in terms of efficiency, rate, energetic requirements and ability to mediate unfolding and refolding during and following import of protein containing a folded domain. Furthermore, this reaction was mediated by the TIM17-23 machinery. The import pathway taken by certain inner-membrane proteins contains elements of such a C-->N translocation pathway, as they are targeted to mitochondria by internal targeting signals. These internal targeting signals appear to form loop structures together with neighbouring transmembrane segments, and penetrate the inner membrane in a membrane-potential-dependent manner. The dimeric TIM17-23 complex, together with mt-Hsp70, acts on both sides of the loop structure to facilitate their translocation into the matrix. On one side of the loop import occurs in the common N-->C direction, whereas the translocation of the other side involves the novel C-->N import direction. We conclude therefore that the mitochondrial import machinery displays no preference for the directionality of the import process.

Base Sequence↗

PubMed1998

Fzo1p is a mitochondrial outer membrane protein essential for the biogenesis of functional mitochondria in Saccharomyces cerevisiae.

Fzo1p is a novel component required for the biogenesis of functional mitochondria in the yeast Saccharomyces cerevisiae. The protein is homologous to Drosophila Fzo, the first known protein mediator of mitochondrial fusion. Deletion of the FZO1 gene results in a petite phenotype, loss of mitochondrial DNA, and a fragmented mitochondrial morphology. Fzo1p is an integral protein of the mitochondrial outer membrane exposing its major part to the cytosol. It is imported into the outer membrane in a receptor-dependent manner. Fzo1p is part of a larger protein complex of 800 kDa, and presumably is the first identified component of the yeast mitochondrial fusion machinery.

Fungal Proteins↗

PubMed1998

Interstitial methotrexate kinetics in primary breast cancer lesions.

The transfer of cytotoxic agents across the tumor endothelium into the interstitial tumor space is considered a critical step in clinical resistance of solid tumors to antineoplastic chemotherapy. However, experimental data on drug transfer from the blood into the interstitium of solid tumors are scarce. Therefore, in this study, we used an innovative technique, in vivo microdialysis, for measuring interstitial tumor pharmacokinetics and plasma-to-tumor transfer rates of methotrexate (MTX) in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of nine previously chemotherapy-naive breast cancer patients to monitor interstitial concentrations following i.v. administration of MTX (40 mg/m2) during a three-drug treatment regimen. Mean interstitial MTX load in breast tumors, expressed as area under curve (AUC), was 60 +/- 20% (mean +/- SE; coefficient of variation = 100%) of mean plasma MTX load. There was no correlation between plasma AUC and the AUC in the interstitial space of tumor tissue (P = 0.93). Not one of the parameters plasma, interstitial tumor load, and transfer rate of MTX to the interstitial space was associated with favorable clinical response. In conclusion, plasma levels of MTX are not predictive of intratumor levels. There is a high interindividual variability in transendothelial MTX transfer. Under the present conditions, access of MTX to the interstitial space is not a rate-limiting step for clinical response to chemotherapy.

Antimetabolites, Antineoplastic↗

PubMed1998

Biogenesis of Tim23 and Tim17, integral components of the TIM machinery for matrix-targeted preproteins.

We analysed the import pathway of Tim23 and of Tim17, components of the mitochondrial import machinery for matrix-targeted preproteins. Tim23 contains two independent import signals. One is located within the first 62 amino acid residues of the hydrophilic domain that, in the assembled protein, is exposed to the intermembrane space. This signal mediates translocation of Tim23 across the outer membrane independently of the membrane potential, DeltaPsi. A second import signal is located in the C-terminal membrane-integrated portion of Tim23. It mediates translocation across the outer membrane and insertion into the inner membrane in a strictly DeltaPsi-dependent fashion. Structurally, Tim17 is related to Tim23 but lacks a hydrophilic domain. It contains an import signal in the C-terminal half and its import requires DeltaPsi. The DeltaPsi-dependent import signals of Tim23 and Tim17 are located at corresponding sites in these two homologous proteins. They exhibit features reminiscent of the positively charged N-terminal presequences of matrix-targeted precursors. Import of Tim23 and its insertion into the inner membrane requires Tim22 but not functional Tim23. Thus, biogenesis of the Tim23.17 complex depends on the Tim22 complex, which is the translocase identified as mediating the import of carrier proteins.

Amino Acid Sequence↗

PubMed1998

Carrier protein import into mitochondria mediated by the intermembrane proteins Tim10/Mrs11 and Tim12/Mrs5.

Import of nuclear-encoded precursor proteins into mitochondria and their subsequent sorting into mitochondrial subcompartments is mediated by translocase enzymes in the mitochondrial outer and inner membranes. Precursor proteins carrying amino-terminal targeting signals are translocated into the matrix by the integral inner membrane proteins Tim23 and Tim17 in cooperation with Tim44 and mitochondrial Hsp70. We describe here the discovery of a new pathway for the transport of members of the mitochondrial carrier family and other inner membrane proteins that contain internal targeting signals. Two related proteins in the intermembrane space, Tim10/Mrs11 and Tim12/Mrs5, interact sequentially with these precursors and facilitate their translocation across the outer membrane, irrespective of the membrane potential. Tim10 and Tim12 are found in a complex with Tim22, which takes over the precursor and mediates its membrane-potential-dependent insertion into the inner membrane. This interaction of Tim10 and Tim12 with the precursors depends on the presence of divalent metal ions. Both proteins contain a zinc-finger-like motif with four cysteines and bind equimolar amounts of zinc ions.

Amino Acid Sequence↗

PubMed1998

A role for CTLA-4-mediated inhibitory signals in peripheral T cell tolerance?

Occupancy of the antigen receptor is not sufficient for activation of naïve T cells--additional co-stimulatory signals are required that can be provided only by 'professional' antigen-presenting cells. This two-signal model for T cell activation has been thought to provide a mechanism for the induction and maintenance of peripheral tolerance. Work over the past six years has demonstrated that the relevant co-stimulatory receptor on T cells is the molecule CD28. Recent data shows that the CD28 homologue CTLA-4 plays a role in negative regulation of T cell responses. Here we suggest that CTLA-4 may also serve as an attenuator of T cell-activating signals, raising the threshold of stimulation required to obtain full activation. The inhibitory signals mediated by CTLA-4 may provide an additional mechanism for the maintenance of peripheral tolerance.

Abatacept↗

PubMed1998

Analysis of microdialysates from cancer patients by capillary electrophoresis.

Microdialysis (MD) is an innovative clinical technique for measuring interstitial tissue pharmacokinetics and plasma-to-tissue transfer rates of drugs in humans. However, microdialysis requires the availability of specialized analytical techniques. Capillary electrophoresis (CE), which enables concentration measurements of small volume samples, theoretically constitutes an ideal analytical technique for measuring drug concentrations in microdialysates. In the present experiments, we aimed at assessing the potential utility and limitations of CE for analysis of microdialysates in a clinical situation. Microdialysates were obtained from primary breast cancer patients who received chemotherapy including 5-fluorouracil (5-FU; 600 mg/m2). Subsequently, 5-FU concentrations were measured in tumor - and subcutaneous adipose tissue - microdialysates by CE. By combining MD and CE, complete time versus concentrations profiles could be obtained for 5-FU in the interstitial tumor space and important clinical questions could be addressed. We conclude that the combination of MD and CE leads to important and previously inaccessible information about the drug distribution process in a clinical setting.

Antimetabolites, Antineoplastic↗

PubMed1998

Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in long-circulating, pegylated liposomes in cynomolgus monkeys.

The toxicity of cisplatin encapsulated in pegylated, long-circulating liposomes (SPI-077) was compared with nonliposomal cisplatin in male and female cynomolgus monkeys (n = 2-4 per sex per group) treated with intravenous infusions of 2.5 or 25 mg/kg SPI-077, 2.5 mg/kg cisplatin, placebo liposomes, or saline once every 3 weeks for total of five treatments. All animals survived until scheduled necropsy at 3 days after the final treatment or after a treatment-free 4-week recovery period. Emesis occurred after each treatment in all cisplatin-treated monkeys, but only once in one monkey treated with high-dose SPI-077. Dose-related mild decreases in red blood cell (RBC) count, hemoglobin, and hematocrit to or slightly below low normal range occurred in the high-dose SPI-077 and placebo liposome treatment groups after each treatment, with partial to complete recovery between treatments and no signs of correlating bone marrow toxicity. Decreases were similar in cisplatin-treated monkeys, but resolved only slightly between treatments and after the end of treatment (continuing to decrease in females) and were accompanied by bone marrow hypocellularity. Indirect, but not direct, bilirubin levels were cyclically elevated in the high-dose SPI-077 and placebo-treated animals, but not in the other treatment groups. Levels had either fully resolved or were near baseline and/or saline group values prior to the next treatment. Serum cholesterol levels were cyclically increased in SPI-077- and placebo liposome-treated animals, and minimally increased numbers of foam cells were seen in the liver, spleen, kidney, and other organs; both were considered related to the lipid dose administered. Cisplatin-treated monkeys exhibited sensory polyneuropathy and moderate irreversible toxic tubular nephrosis, but no neuropathy or nephrotoxicity was seen in either SPI-077 treatment group. Microscopically, treatment-related cell death was seen in dorsal root ganglia (DRG), affecting 15% of the cells in cisplatin-treated animals, compared to 8 and 12% in the low- and high-dose SPI-077 treatment groups. Neither drug was ototoxic. In summary, repeated administration of SPI-077 produced minimal, reversible effects related to the lipid dose administered, mostly limited to the 25 mg/kg dose group. The most notable effects in this group were cyclical decreases in hematology parameters thought to be related to increased recycling of a small fraction of RBCs and limited cell death in the DRG in the absence of any neurophysiological changes. Animals treated with a 10-fold lower dose of cisplatin (2.5 mg/kg), in contrast, exhibited myelo-, nephro-, and neurotoxicity, including sensory neuropathy, and were emetic after every dose. The SPI-077 liposomal formulation of cisplatin may provide a less toxic alternative to standard cisplatin solution.

Animals↗

PubMed1998

[Treatment strategies in therapy refractory angina pectoris: transmyocardial laser revascularization].

BACKGROUND: Does transmyocardial laser revascularization (TMLR) as a new surgical technique for treating patients with otherwise intractable angina pectoris improve myocardial perfusion or contractility? METHODS: Sixty-seven patients transferred for TMLR were evaluated by clinical evaluation, treadmill stress testing, echocardiography, ventriculography, and hybrid positron emission tomography preoperatively and in patients treated with TMLR at 6 and 12 month follow up. Hemodynamic assessment and clinical evaluation were performed perioperatively. RESULTS: In 28/67 cases (42%) CABG, in 9/67 patients (13%) CABG in combination with TMLR (combined group), and in 30/67 patients (45%) only TMLR (sole group) were performed. Perioperative mortality in the sole group was 13%, in the combined group zero, and in the CABG group 11%. In all groups a significantly improved clinical status (p < or = 0.01) 1 week postoperatively and in TMLR groups also at 6 and 12 months was observed. In the TMLR groups treadmill tolerance (p < 0.05) improved, although function, perfusion, and metabolism did not change significantly at the 6 and 12 month follow up. CONCLUSION: TMLR significantly improves clinical status and treadmill stress tolerance, but does not change function, perfusion, and metabolism.

Aged↗

PubMed1998

Comparison of three different experimental methods for the assessment of peripheral compartment pharmacokinetics in humans.

In many cases the concentration reached in a peripheral effect compartment rather than in plasma determines the clinical outcome of therapy. Therefore, several experimental approaches have been developed for direct assessment of drug kinetics in peripheral compartments. Particularly saliva sampling, skin blister fluid sampling, and in vivo microdialysis are frequently employed for measuring peripheral drug concentrations. However, data derived from these techniques have never been directly compared. In the present study, the tissue kinetics of theophylline were measured following single dose administration simultaneously in cantharides induced skin blisters, saliva and microdialysates of subcutaneous- and skeletal muscle- tissue and compared to plasma concentrations. Theophylline was administered to 9 healthy volunteers as an i.v. infusion of 240 mg. Mean ratio (AUCsaliva/AUCplasma) was 0.63 +/- 0.05, mean ratio (AUCblister/AUCplasma) was 0.69 +/- 0.12, mean ratio (AUCmuscle/AUCplasma) was 0.41 +/- 0.10, mean ratio (AUCsubcutaneous/AUCplasma) was 0.34 +/- 0.07. The time course of the concentration(peripheral)/concentration(plasma)-ratios showed that tissue concentrations obtained by microdialysis were closely correlated to free plasma levels, whereas saliva- and cantharides blister data overestimated the corresponding free plasma concentrations. It is concluded that microdialysis represents a reliable technique for the measurement of unbound peripheral compartment concentrations and is superior to saliva- and skin blister concentration measurements.

Adult↗