Biomedical subjects

G Fischer

Publications and source records attributed to G Fischer.

At least 19 recordsLinked to original sources

PubMed2025

Magnesium protects against anaphylactic shock and cardiac myolysis in guinea-pigs.

The pathophysiological responses to immune stress (IS) include activation of several processes which are dependent on cytosolic Ca2+ elevation. Magnesium frequently acts as a natural Ca2+ antagonist. In this study we have observed that Mg2+ can protect guinea-pigs against IS. Antigen-sensitized guinea-pigs, which had been fed a magnesium-deficient diet, were given a single dose (15 mg) of MgCl2 intraperitoneally 1 h before antigen challenge. The development of anaphylactic shock (AS) was observed during the next 2 h, and the hearts were subsequently examined histologically for signs of cardiac myolysis (CM). Magnesium (i) reduced the incidence of CM from 40% to 10% (p < 0.05); (ii) reduced the incidence of AS from 61% to 35% (p < 0.05); (iii) attenuated the severity of the AS; and (iv) lowered mortality from 39% in the control to 19% in the Mg(2+)-treated group (p = 0.1). Serum and tissue total [Mg2+] were not affected by the administration of MgCl2. Also, the serum and heart Mg2+ levels were the same whether or not the guinea-pigs developed AS or CM. In cell culture we demonstrated that by elevating the [Mg2+] in the medium bathing sensitized rat basophilic leukemia (RBL) cells, the increase in cytosolic [Ca2+] subsequent to antigen challenge was reduced from 174 +/- 23.28% (1 mM) to 82.74 +/- 13.22% (3 mM). We conclude that a single treatment with Mg2+ can considerably diminish damage induced by immune stress, probably by its altering the Ca2+: Mg2+ ratio. Since the physiological reaction to different types of stress is similar, Mg2+ could prove beneficial in preventing stress-induced shock in general. Studies examining the mechanisms by which Mg2+ exerts its effects thus provide a scientific basis for the current clinical use of Mg2+ in acute myocardial infarction (AMI) and asthma.

Anaphylaxis↗

PubMed1999

Synthesis and cytotoxic evaluation of cycloheximide derivatives as potential inhibitors of FKBP12 with neuroregenerative properties.

On the basis of the new finding that the protein synthesis inhibitor cycloheximide (1, 4-[2-(3, 5-dimethyl-2-oxocyclohexyl)-2-hydroxyethyl]-2,6-piperidinedione) is able to competitively inhibit hFKBP12 (K(i) = 3.4 microM) and homologous enzymes, a series of derivatives has been synthesized. The effect of the compounds on the activity of hFKBP12 and their cytotoxicity against eukaryotic cell lines (mouse L-929 fibroblasts, K-562 leukemic cells) were determined. As a result, several less toxic or nontoxic cycloheximide derivatives were identified by N-substitution of the glutarimide moiety and exhibit IC(50) values in the range of 22.0-4.4 microM for inhibition of hFKBP12. Among these compounds cycloheximide-N-(ethyl ethanoate) (10, K(i) = 4.1 microM), which exerted FKBP12 inhibition to an extent comparable to that of cycloheximide (1), was found to cause an approximately 1000-fold weaker inhibitory effect on eukaryotic protein synthesis (IC(50) = 115 microM). Cycloheximide-N-(ethyl ethanoate) (10) was able to significantly speed nerve regeneration in a rat sciatic nerve neurotomy model at dosages of 30 mg/kg.

Animals↗

PubMed1999

Polypeptide flux through bacterial Hsp70: DnaK cooperates with trigger factor in chaperoning nascent chains.

A role for DnaK, the major E. coli Hsp70, in chaperoning de novo protein folding has remained elusive. Here we show that under nonstress conditions DnaK transiently associates with a wide variety of nascent and newly synthesized polypeptides, with a preference for chains larger than 30 kDa. Deletion of the nonessential gene encoding trigger factor, a ribosome-associated chaperone, results in a doubling of the fraction of nascent polypeptides interacting with DnaK. Combined deletion of the trigger factor and DnaK genes is lethal under normal growth conditions. These findings indicate important, partially overlapping functions of DnaK and trigger factor in de novo protein folding and explain why the loss of either chaperone can be tolerated by E. coli.

Bacterial Proteins↗

PubMed1999

A genome-wide search for linkage to asthma. German Asthma Genetics Group.

Asthma is among the most frequent chronic diseases in childhood. Although numerous environmental risk factors have already been identified, the basis for familial occurrence of asthma remains unclear. Previous genome screens for atopy in British/Australian families and for asthma in different American populations showed inconsistent results. We report a sib pair study of a sample of 97 families, including 415 persons and 156 sib pairs. Following an extensive clinical evaluation, all participants were genotyped for 351 polymorphic dinucleotide markers. Linkage analysis for asthma identified four chromosomal regions that could to be linked to asthma: chromosome 2 (at marker D2S2298, P = 0.007), chromosome 6 (around D6S291, lowest P = 0.008), chromosome 9 (proximal to D9S1784, P = 0.007), and chromosome 12 (D12S351, P = 0.010). These linkage regions could be reproduced for all loci by analysis of total or specific immunoglobulin E (minimum P values at these regions were 0. 003, 0.001, 0.010, and 0.015, respectively).

Asthma↗

PubMed1999

Identification and characterization of a 14 kDa human protein as a novel parvulin-like peptidyl prolyl cis/trans isomerase.

A second member of the parvulin family of peptidyl-prolyl cis/trans isomerases was identified in a human lung cDNA library. The gene encoded a protein named hPar14 that has 131 amino acid residues and a molecular mass of 13676 Da. Sequence comparison showed 34.5% identity to E. coli Par10 and 34% identity to human Pin1 (hPar18) within a C-terminal region of 87 or 120 amino acid residues, respectively. In comparison to the E. coli Par10, hPar14 possesses a N-terminal extension of 41 amino acid residues. This extension does not contain a polyproline II helix-binding motif typical of the known eukaryotic parvulins. The hPar14 does not accelerate the cis to trans interconversion of oligopeptides with side chain-phosphorylated Ser(Thr)-Pro moieties as hPin1 did. In contrast, it showed preference of an arginine residue adjacent N-terminal to proline. Northern blot analysis revealed expression of the gene within various human tissues like heart, placenta, liver, kidney and pancreas.

Amino Acid Sequence↗

PubMed1999

A selective imaging of tinnitus.

We selectively imaged the neural correlates of tinnitus, by contrasting a condition with no phantom auditory sensation with a condition during which tinnitus is present, using a rare form of tinnitus elicited by eye movements. Using positron emission tomography (PET), we demonstrate that phantom auditory sensation increases regional cerebral blood flow bilaterally in temporo-parietal association auditory areas but not in the primary auditory cortex. These results confirm that conscious perception does not necessarily require activation in primary areas and suggest that the perceptual qualities of tinnitus, e.g. intensity, frequency and spatial localization, are represented in temporo-parietal regions. Activation in these regions is compatible with cortical processing of ascending auditory messages generated at subcortical levels.

Adult↗

PubMed1999

Mutations in a peptidylprolyl-cis/trans-isomerase gene lead to a defect in 3'-end formation of a pre-mRNA in Saccharomyces cerevisiae.

In a genetic screen aimed at the identification of trans-acting factors involved in mRNA 3'-end processing of budding yeast, we have previously isolated two temperature-sensitive mutants with an apparent defect in the 3'-end formation of a plasmid-derived pre-mRNA. Surprisingly, both mutants were rescued by the essential gene ESS1/PTF1 that encoded a putative peptidylprolyl-cis/trans-isomerase (PPIase) (Hani, J., Stumpf, G., and Domdey, H. (1995) FEBS Lett. 365, 198-202). Such enzymes, which catalyze the cis/trans-interconversion of peptide bonds N-terminal of prolines, are suggested to play a role in protein folding or trafficking. Here we report that Ptf1p shows PPIase activity in vitro, displaying an unusual substrate specificity for peptides with phosphorylated serine and threonine residues preceding proline. Both mutations were found to result in amino acid substitutions of highly conserved residues within the PPIase domain, causing a marked decrease in PPIase activity of the mutant enzymes. Our results are suggestive of a so far unknown involvement of a PPIase in mRNA 3'-end formation in Saccharomyces cerevisiae.

Amino Acid Isomerases↗

PubMed1999

[Buprenorphine vs. methadone as maintenance treatment for opioid dependence].

The efficacy of buprenorphine in opioid dependent patients (n = 20) was compared to methadone maintained subjects (n = 20) in a randomized comparison trial. Sublingual application of buprenorphine as an alternative synthetical opioid is being compared to methadone during a 24 week study period. A trend (p = 0.06) could be found in the retention rate of investigated patients being maintained on a mean dosage of 63 mg oral applicable methadone (racemat of L- and D-methadone) in comparison to the group on a mean dosage of 7.3 mg buprenorphine (sublingual tablets). The dropout-rate of 11 subjects at the end of the study in the buprenorphine group was higher when compared to the dropout-rate of 5 in the methadone group. There was no significant difference between the two groups over the treatment period in respect to additional consumption of opiates, benzodiazepines and cocaine as evaluated through urine toxicology. The result in regard to compliance over the study period demonstrates that methadone appears to be the more successful oral opioid (p = 0.04). Nevertheless, efficacy of buprenorphine in maintenance could be demonstrated in the remaining subjects, and further studies with higher daily doses and a higher number of subjects have to be performed.

Administration, Sublingual↗

PubMed1999

Characterization of the MICA polymorphism by sequence-specific oligonucleotide probing.

A large number of diseases occur in association with specific HLA-B or -C alleles. Recently a new gene, termed major histocompatibility complex class I chain-related gene A (MICA), has been identified in close proximity to HLA-B. The function of this gene is still unknown, but, it is structurally related to HLA class I genes, is polymorphic, and is potentially associated with several diseases. Some DNA-based techniques have previously been described to type for MICA including sequencing and single-strand conformational polymorphism. In this paper we describe the application of sequence-specific oligonucleotide probe based typing for the analysis of the MICA gene. We used a set of 30 oligonucleotide probes to screen for the polymorphisms in exons 2, 3, and 4, which account for the 16 known alleles. We report here the typing results of MICA for 103 B-cell lines that have been well characterized for HLA and describe the linkage disequilibrium between MICA and HLA-B. Unequivocal MICA typing was achieved for 85 of the 103 cells tested, 6 cells gave ambiguous MICA types, and a further 12 cells showed patterns consistent with them expressing at least one new MICA allele.

Alleles↗

PubMed1999

Stress-induced expression of cyclophilins in proembryonic masses of Digitalis lanata does not protect against freezing/thawing stress.

Using proembryonic masses (PEMs) of Digitalis lanata Erh., it was demonstrated that cold, hormonal or osmotic stress, which increased freezing tolerance during cryopreservation, induced an increasing level of two peptidyl-prolyl-cis/transisomerases (PPIases). The difference in pI (9.2 +/- 0.2 and 9.5 +/- 0.2, +/- SD; n = 3) allowed the separation of the two enzymes by free-flow isoelectrophoresis. Both were inhibited by cyclosporin A and thus belong to the cyclophilin family of PPIases. The enzymes differed slightly in their substrate specificity and their relative molecular masses of 18038 +/- 4 Da (D. lanataCyp18.0) and 18132 +/- 3 Da (D. lanataCyp18.1). Both cyclophilins were blocked N-terminally. Partial internal amino acid sequences from the two cyclophilins, with a length of 34 amino acids, displayed 82% sequence identity to each other. Pretreatment of PEMs with abscisic acid, sorbitol or a combination of both substances led to a 270 +/- 30% elevation of the total cytosolic cyclophilin concentration determined with a cyclophylin affinity sensor. During the first 4 d of pretreatment, the total PPIase activity was enhanced up to 230 +/- SD% compared with the control culture. The lag phase between maximal PPIase concentration after 4 d of pretreatment and maximal effect of freezing tolerance after 10 d of pretreatment indicated that increasing levels of cytosolic PPIases may be necessary to overcome the stress induced by hormones and osmotica during pretreatment but not to protect against freezing/thawing stress.

Adaptation, Physiological↗

PubMed1999

Mycotoxins of Aspergillus fumigatus in pure culture and in native bioaerosols from compost facilities.

Exposure to secondary metabolites of airborne fungi in waste handling facilities is discussed in regard to potential toxic impacts on human health. The relevance of mycotoxins has been intensely studied in connection with contamination of food and feed. Toxic secondary metabolites are expected to be present in airborne spores, but exposure to mycotoxins in bioaerosols has not been studied sufficiently. Aspergillus fumigatus is one of the most frequent species in the air of compost plants. A wide range of secondary metabolites was found in pure cultures of freshly isolated strains of A. fumigatus. Tryptoquivaline, a compound with tremorgenic properties, and trypacidin, for which no toxic properties are described, were found in native bioaerosols in a compost facility. The highly toxic metabolites gliotoxin and verruculogen were not found in the bioaerosols.

Aerosols↗

PubMed1999

Species-specific production of microbial volatile organic compounds (MVOC) by airborne fungi from a compost facility.

Thirteen airborne fungal species frequently isolated in composting plants were screened for microbial volatile organic compounds (MVOC), i.e., Aspergillus candidus, A. fumigatus, A. versicolor, Emericella nidulans, Paecilomyces variotii, Penicillium brevicompactum, Penicillium clavigerum, Penicillium crustosum, Penicillium cyclopium, Penicillium expansum, Penicillium glabrum, Penicillium verruculosum, and Tritirachium oryzae. Air samples from pure cultures were sorbed on Tenax GR and analyzed by thermal desorption in combination with GC/MS. Various hydrocarbons of different chemical groups and a large number of terpenes were identified. Some compounds such as 3-methyl-1-butanol and 1-octen-3-ol were produced by a number of species, whereas some volatiles were specific for single species. An inventory of microbial metabolites will allow identification of potential health hazards due to an exposure to fungal propagules and metabolites in the workplace. Moreover, species-specific volatiles may serve as marker compounds for the selective detection of fungal species in indoor domestic and working environments.

Air Microbiology↗

PubMed1999

Application of high-order boundary elements to the electrocardiographic inverse problem.

Eight-noded quadrilateral boundary elements are applied to the electrocardiographic inverse problem as an example for high-order boundary elements. It is shown that the choice of the shape functions used for approximation of the potentials has a remarkable influence on the solution obtained if the number of electrodes is smaller than the number of primary source points (under-determined equation system). Three different formulations are investigated considering a concentric spheres problem where an analytic solution is available: (a) the isoparametric formulation; (b) the quasi-first-order formulation; and (c) the pseudo-subparametric formulation as a new method. In a second step the pseudo-subparametric formulation (which provided the best results in the test problem) is applied to real word data. The transmembrane potential pattern of a 40 years old female suffering from severe heart failure and ventricular tachycardia after large anterior wall myocardial infarction is reconstructed for one time instant. Furthermore, an algorithm for the calculation of the transfer matrix is presented which avoids restrictions to the boundary element mesh caused by the placement of the electrodes.

Adult↗

PubMed1999

Limitations of the evaluation of adnexal masses by its macroscopic aspects, cytology and biopsy.

To investigate the relevance of intraoperative macroscopic evaluation of adnexal masses a prospective study was conducted from June 1st, 1993 to May 31st, 1994, which included 57 premenopausal and 60 postmenopausal women, who underwent laparotomy because of a cystic adnexal mass. The surgeons were asked to classify the tumor intraoperatively as benign or malignant and to assign to histologic groups. In addition cytology of the cyst fluid and a biopsy from the cystic wall were evaluated. Comparison of these items with the results of permanent section diagnosis revealed the tendency of the surgeons to underestimate adnexal masses depending on patients' age and the complexity of the tumor, despite of the knowledge of preoperative ultrasonographic findings. Sufficient cytolologic examination was possible in only one third of aspirates and only 21% of the examined postmenopausal malignant neoplasms have correctly been diagnosed by cytology. Evaluation of the biopsy specimens demonstrates a marked percentage of false negatives with respect to benign tumors (30% of non-functional benign neoplasms in the premenopause were assessed as functional cysts) as well as malignant neoplasms (only 72% were diagnosed correctly in the postmenopause group). In conclusion intraoperative subjective assessment, cytology and representative biopsies do not necessarily concur with the definitive histological diagnosis.

Biopsy↗

PubMed1999

Low transplant-related mortality in patients receiving unrelated donor marrow grafts for leukemia.

Transplantation with unrelated donor (UD) marrow has been shown to potentially cure patients with leukemia. Between January 1991 and April 1998, 54 patients with leukemia have received an UD BMT at our institution. Five patients received their UD BMT as a second transplant after a preceding autologous or syngeneic BMT and were excluded from further analysis. Forty-nine patients with leukemia (acute leukemia n = 26; CML n = 23) and a median age of 36 years (range 19-51) were analyzed. For conditioning, all patients received a combination of fractionated TBI and CY. GVHD prophylaxis consisted of MTX and CsA in all patients. As of 30 April 1998, 27 of 49 (55%) patients survive after a median observation time of 18 months. The probability of overall survival for standard risk and high risk patients is 54% and 31% (P = 0.05). Probability of transplant-related mortality (TRM) is 27%, 24% in standard risk and 31% in high risk patients (P = 0.44). Patients younger than 40 years (n = 33) had a similar TRM as patients 40 years and older (n = 16). The probability of relapse is 41% for the whole group, 29% for standard risk and 55% for high risk pts (P<0.05). Our data confirm that UD BMT is an effective treatment for patients with leukemia. TRM is almost similar to related sibling BMT, most probably due to improvements in HLA typing technology, conditioning regimen and supportive patient care.

Adult↗

PubMed1999

Comparison of methadone and slow-release morphine maintenance in pregnant addicts.

AIMS: To investigate whether the neonatal abstinence syndrome (NAS) is different in children born to women maintained on slow-release morphine, compared with those maintained on methadone, and to compare additional drug consumption in these groups of women. DESIGN, SETTING AND PARTICIPANTS: An open, randomized trial was conducted in an established clinic. Forty-eight pregnant women who presented to the clinic as opiate or polysubstance abusers were enrolled and maintained on either methadone (24 women) or slow-release morphine (24 women) up to and following delivery. The programme included psychosocial therapy and support for their opiate-addicted partners. MEASUREMENTS: Standard urinalysis methods were used to measure consumption of cocaine and benzodiazepines during pregnancy. Injection sites were monitored to indicate additional opiate use. NAS was measured according to Finnegan score and the amount of phenobarbiturates prescribed to alleviate the symptoms. FINDINGS: No difference was found in the number of days that NAS was experienced by neonates born to methadone or morphine maintained mothers (mean = 16 and 21 days, respectively). All children were born healthy and no serious complications arose. Fewer benzodiazepines (p < 0.05) and fewer additional opiates (p < 0.05) were consumed by the morphine-maintained women compared with those who took methadone, but no difference was seen in cocaine consumption. Nicotine consumption was reduced significantly in both groups during pregnancy (p < 0.02). CONCLUSIONS: Both methadone and morphine are suitable maintenance agents for pregnant opiate addicts. Maintenance agents that result in a less prolonged NAS should be studied in further trials.

Adolescent↗

PubMed1999

Effect of MTHFR 677C>T on plasma total homocysteine levels in renal graft recipients.

BACKGROUND: Hyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T has been shown to result in increased total homocysteine concentrations on the basis of low folate levels caused by a decreased enzyme activity. The effect of this polymorphism on total homocysteine and folate plasma levels in renal transplant patients is unknown. METHODS: We screened 636 kidney graft recipients for the presence of the MTHFR C677T gene polymorphism. The major determinants of total homocysteine and folate plasma concentrations of 63 patients, who were identified to be homozygous for this gene polymorphism compared with heterozygotes (N = 63), and patients with wild-type alleles (N = 63), who were matched for sex, age, glomerular filtration rate (GFR), and body mass index, were identified by analysis of covariance. The variables included sex, age, GFR, body mass index, time since transplantation, folate and vitamin B12 levels, the use of azathioprine, and the MTHFR genotype. To investigate the impact of the kidney donor MTHFR genotype on total homocysteine and folate plasma concentrations, a similar model was applied in 111 kidney graft recipients with stable graft function, in whom the kidney donor C677T MTHFR gene polymorphism was determined. RESULTS: The allele frequency of the C677T polymorphism in the MTHFR gene was 0.313 in the whole study population [wild-type (CC), 301; heterozygous (CT), 272; and homozygous mutant (TT), 63 patients, respectively] and showed no difference in the patient subgroups with various renal diseases. The MTHFR C677T gene polymorphism significantly influenced total homocysteine and folate plasma concentrations in renal transplant recipients (P = 0.0009 and P = 0.0002, respectively). Furthermore, a significant influence of the GFR (P = 0.0001), folate levels (P = 0.0001), age (P = 0.0001), body mass index (P = 0.0001), gender (P = 0.0005), and vitamin B12 levels (P = 0.004) on total homocysteine concentrations was observed. The donor MTHFR gene polymorphism had no influence on total homocysteine and folate levels. Geometric mean total homocysteine levels in patients homozygous for the mutant MTHFR allele were 18.6 micromol/liter compared with 14.6 micromol/liter and 14.9 micromol/liter in patients heterozygous for the MTHFR gene polymorphism and those with wild-type alleles (P < 0.05 for TT vs. CT and CC). Geometric mean folate levels were lower in CT and TT patients (11.2 and 10.2 nmol/liter) compared with CC patients (13.6 nmol/liter, P < 0.05 vs. CT and TT). CONCLUSIONS: This study demonstrates that homozygosity for the C677T polymorphism in the MTHFR gene significantly increases total homocysteine concentrations and lowers folate levels in kidney graft recipients, even in patients with excellent renal function (GFR more than median). These findings have important implications for risk evaluation and vitamin intervention therapy in these patients who carry an increased risk for the development of cardiovascular disease.

Adult↗

PubMed1999

Transcatheter closure of secundum atrial septal defects with the new self-centering Amplatzer Septal Occluder.

AIMS: The study was set up to find out whether a new self-centering prosthesis for transcatheter closure of secundum atrial septal defects could overcome the disadvantages of previously described devices. METHODS AND RESULTS: Fifty-two consecutive patients with a significant atrial septal defect were considered for transcatheter closure with the Amplatzer Septal Occluder. The device, made of a Nitinol and polyester fabric mesh, provides a different approach to defect occlusion by stenting the atrial septal defect up to a stretched diameter of 26 mm. Three infants whose large defects were demonstrated on a transthoracic echocardiogram were excluded from transcatheter treatment. On transoesophageal echocardiography, 49 defects ranged from 6-26 mm, in one adult the defect measured 28 mm and this patient was excluded from attempted transcatheter closure. At cardiac catheterization in five further patients, devices were not implanted, in two because the stretched diameter exceeded 26 mm and in three the device was withdrawn because it was unstable or compromised the mitral valve. Thus, device closure was performed in 43 patients. At follow-up after 3 months the complete closure rate was 97%. CONCLUSION: The self-centering Amplatzer Septal Occluder is very efficient and user-friendly and offers interventional closure in 83% of an unselected group of patients presented with an atrial septal defect.

Adolescent↗