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Biomedical subjects

A Hoffmann

Publications and source records attributed to A Hoffmann.

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

Induction of the PAC1-R (PACAP-type I receptor) gene by p53 and Zac.

Pituitary adenylate cyclase-activating polypeptides and PAC1-R are expressed during early embryogenesis and PACAP's neurotrophic action supports a role in neuronal development. In the adult brain PACAP functions as a neuroprotective factor that attenuates the neuronal damage resulting from various insults. The tumor suppressor gene p53 and the new zinc finger protein Zac regulate apoptosis and cell cycle arrest through unrelated pathways and both genes are up-regulated under cerebral ischemia. We report here that p53 and Zac induce expression of the PAC1-R gene. By this mechanism p53 and Zac could fine-tune the balance between death promoting and protective signals and may thus fulfil a dual role in ischemia.

Animals↗
PubMed1999

[Quality of care of patients with diabetes mellitus living in a rural area of Germany].

PATIENTS AND METHOD: In a population based study the quality of diabetes care of insulin-treated diabetic patients aged 16 to 60 years and living in a rural area was studied. The parameters of metabolic control as well as the incidence of acute complications (severe hypoglycemia with the need of glucose or glucagon injection, ketoacidosis with hospital admission) were assessed by examination and with a standardized questionnaire in 81% of the target population (type-1/type-2-diabetic patients: n = 25/33). Also, in all the patients diabetic long-term complications (retinopathy, nephropathy, amputations of the lower extremities) were examined. 76% of the patients with type-1-diabetes and 91% of the patients with type-2-diabetes mellitus completed standardized questionnaires to assess quality of life and treatment satisfaction. RESULTS: In type-1-diabetic patients HbA1c was 9.38 +/- 1.6%. In type-2-diabetic patients it was 9.53 +/- 1.91%. None of the patients examined was regularly treated by a specialized physician/diabetologist. The goal of metabolic control, a HbA1c value below 7.2%, was reached only by 4% of the patients with type-1-and 12% of the patients with type-2-diabetes mellitus. In multivariate analysis the most important factor associated with HbA1c was in type-1-diabetic patients female sex (R-squared = 0.17, c = 0.38, p = 0.059); in patients with type-2-diabetes mellitus it was the number of insulin injections per day (R-squared = 0.37, c = 0.19, p = 0.0096). All other factors investigated in the model (diabetes duration, insulin dosage/kg body weight, frequency of blood- or urine-glucose self-monitoring/week, body mass index, educational level) showed no significant associations. Quality of life and treatment satisfaction of the patients were good and comparable to other trials. CONCLUSION: Out of other studies there is evidence for better metabolic control in patients regularly treated by specialized physicians/diabetologists and in patients who participated in structured treatment and teaching programs. These features must be the main goals of treatment for all patients with diabetes mellitus.

Adolescent↗
PubMed1999

Reciprocal connections between the preglomerular complex and the dorsolateral telencephalon in the weakly electric fish, Gymnotus carapo.

The diencephalic preglomerular complex of gymnotiform fish receives inputs from several sensory areas. By employing anterograde and retrograde tracing techniques, we studied the afferent and efferent connections of the dorsolateral area (dorsal subdivision) of the telencephalon with the preglomerular nuclei in the weakly electric fish, Gymnotus carapo. Neurons of the medial preglomerular nucleus project to intermediate and deep portions of the middle (commissural) level of the dorsolateral telencephalon, and neurons located in the lateral preglomerular nucleus project to superficial portions of the middle levels of the dorsolateral telencephalon. Therefore, we observed a spatial distribution pattern of connectivity between dorsolateral telencephalon and preglomerular complex.

Animals↗
PubMed1999

Pollen-related food allergy: cloning and immunological analysis of isoforms and mutants of Mal d 1, the major apple allergen, and Bet v 1, the major birch pollen allergen.

BACKGROUND: Mal d 1, the major apple allergen, cross-reacts with IgE specific for the major birch pollen allergen, Bet v 1, and is responsible for birch pollen related food allergy to apple. Isoforms of Bet v 1 showing minor sequence variations display different binding capacity for specific IgE antibodies from allergic patients. Moreover, strain-dependent variation of allergenicity has been reported for apples. OBJECTIVE: To investigate the occurrence of strain-dependent isoforms of Mal d 1 which may differ in their allergenic potential, to obtain data on structures essential for binding of Mal d 1 to the antibody, and to gain insights into the structures responsible for its IgE cross-reactivity to Bet v 1. METHODS: The cDNA of Mal d 1 from various apple strains was amplified by a PCR strategy based on conserved regions of known Mal d 1-sequences, and sequenced. Two major isoforms of Mal d 1 were expressed as recombinant proteins and purified, as were different variants of the major birch pollen allergen, Bet v 1. Together with already existing recombinant birch pollen and apple allergens, these were subjected to allergenicity testing by IgE-immunoblotting, enzyme allergo sorbent test and dose related mediator release. "Hot-spots" for IgE-reactivity were identified by site-directed mutagenesis. RESULTS: Twelve Mal d 1-clones were sequenced from 7 apple varieties and compared to 3 known Mal d 1 sequences. The clones were clustered into two groups, each showing a high degree of sequence identity to one of the known sequences and specific differences to the third sequence. No strain-specific sequences were identified. In contrast, apple strains with reported differences in allergenicity showed different expression levels of the major allergen. Immunologic testing of recombinant allergens revealed high IgE binding capacity of 2 major isoforms, named GD26 and GS29, with a slightly higher IgE binding capacity of GD26. Moreover, the allergenicity was similar to another r Mal d 1 reported in the literature, representing the isoform divergent from our clones. Mutational analysis of our Mal d 1 allergens identified serine in position 111 as essential for IgE binding. Allergenicity was almost depleted by changing this residue into a proline. Moreover, the corresponding serine residue, present in position 112 of Bet v 1, was in a similar manner crucial for the allergenicity of the birch pollen allergen. CONCLUSION: We conclude that divergent allergenicity of apple strains mainly depends on different expression levels of the major allergen. Introduction of a proline residue in position 111 of Mal d 1 and in position 112 of Bet v 1 led to a drastic reduction of allergenicity of both the pollen and the food allergen, obviously also removing the cross-reactive epitope. Mutants with reduced IgE-reactivity but maintained T-cell reactivity may represent new candidates for a safer specific immunotherapy with reduced side-effects.

Allergens↗
PubMed1999

Molecular cloning and characterization of a birch pollen minor allergen, Bet v 5, belonging to a family of isoflavone reductase-related proteins.

BACKGROUND: Birch pollen is a major cause of pollinosis and is responsible for cross-reactive oral allergies to fruits, nuts, and vegetables. The major allergen, Bet v 1, has been extensively characterized, and 3 minor allergens, Bet v 2, Bet v 3, and Bet v 4, have been cloned and sequenced. Recently, another birch pollen protein with an apparent mass of 35 kd was described as a new IgE-binding protein in birch pollen with cross-reacting homologues in plant foods. OBJECTIVE: The aim of this study was to determine the primary structure of the 35-kd birch pollen allergen and to investigate its immunologic properties. METHODS: On the basis of a known complementary DNA fragment, a PCR strategy was applied to obtain the full-length nucleotide sequence of the coding region. The protein was expressed as His-Tag fusion protein in Escherichia coli and purified by Ni-chelate affinity chromatography. Nonfusion protein was obtained by cyanogen bromide treatment of the fusion protein. IgE-binding characteristics and potential allergenicity were investigated by immunoblot, immunoblot inhibition analysis, rat basophil leukemia-cell mediator release assay, and basophil histamine release and compared with those of natural (n) Bet v 5, recombinant (r)Bet v 1, and rBet v 2. RESULTS: Recombinant Bet v 5 has a mass of 33 kd, an isoelectric point of 9.0, and sequence identity of 60% to 80% to isoflavone reductase homologue proteins from various plants. On immunoblots the recombinant Bet v 5 bound IgE from 9 (32%) of 28 sera from patients allergic to birch pollen with a CAP class of at least 3; Bet v 1 was detected by 89% of these patients. IgE immunoblot and inhibition experiments showed that nBet v 5 and rBet v 5 shared identical epitopes. A rabbit antiserum raised against pea isoflavone reductase and patients' IgE reacted with Bet v 5 and proteins of similar size in several vegetable foods, including exotic fruits. A similar reaction pattern was obtained with 2 Bet v 5-specific mAbs. Furthermore, Bet v 5 triggered a dose-dependent mediator release from rat basophil leukemia 2H3 cells passively sensitized with murine anti-birch pollen IgE and from basophils of a Bet v 5-reactive subject with birch pollen allergy. In contrast, no mediator release could be induced from basophils of a subject who was monosensitized to Bet v 1. CONCLUSIONS: This 33-kd protein, designated as Bet v 5, is a new minor allergen in birch pollen and may be responsible for pollen-related oral allergy to specific foods in a minority of patients with birch pollen allergy. Amino acid sequence comparison and immunoreactivity to anti-isoflavone reductase serum indicate that Bet v 5 is related to isoflavone reductase, a protein family that is involved in plant defense reactions.

Allergens↗
PubMed1999

Cross-reactivity and epitope analysis of Pru a 1, the major cherry allergen.

A high percentage of birch pollen allergic patients experiences food hypersensivity after ingestion of fresh fruits and vegetables. The cross-reactivity of the major allergens of sweet cherry (Pru a 1), apple (Mal d 1), pear (Pyr c 1), celery tuber (Api g 1) and carrot (Dau c 1) is due to structural similarities which are reflected by high amino acid sequence identities with Bet v 1a, the major birch pollen allergen. Apart from a strong cross-reactivity to Bet v 1a, IgE inhibition experiments with Mal d 1, Pru a 1 and Api g 1 demonstrated the presence of common and different epitopes among the tested food allergens. Secondary structure prediction of all investigated allergens indicated the presence of almost identical structural elements. In particular, the 'P-loop' region is a common domain of the pollen related food allergens and of pathogenesis related proteins. To identify the IgE binding epitopes, five overlapping recombinant Pru a 1 fragments representing the entire amino acid sequence with lengths of approximately 60-120 residues were investigated. Weak IgE binding capacity was measured exclusively with Pru a IF4 (1-120) by immunoblotting, whereas none of the fragments showed allergenicity in the rat basophil leukaemia cell mediator release assay. Site-directed mutagenesis experiments with Pru a 1 revealed that amino acid S112 is critical for IgE binding of almost all patients sera tested. This reduced IgE binding was also observed with a single point mutant of Bet v 1a (S112P) and thus indicated serine 112 as an essential residue for preserving the structure of a cross-reactive IgE epitope. Moreover, two Pru a 1 mutants with an altered 'P-loop' region, showed a lowered IgE binding capacity for IgE from a subgroup of allergic patients. The investigation of essential features for preserving cross-reactive IgE-epitopes provides the structural basis for understanding the clinically observed cross-allergenicity between pollen and fruits. Moreover, non-anaphylactic allergen fragments or variants derived from the IgE-inducing pollen allergens may serve as useful tools for a new strategy of specific immunotherapy.

Allergens↗
PubMed1999

Recombinant GM2-activator protein stimulates in vivo degradation of GA2 in GM2 gangliosidosis AB variant fibroblasts but exhibits no detectable binding of GA2 in an in vitro assay.

The interaction between glycosphingolipids and recombinant human GM2-activator was studied in a microwell binding assay. A-series gangliosides like GM3, GM2 and GM1 were strongly bound by the recombinant human GM2 activator. A weak binding was observed to GD1b and sulfatide, while neutral glycolipids were not bound. Optimal binding occurred at pH 4.2 and was inhibited by increasing concentrations of citrate buffer and NaCl. In contrast with these in vitro results the recombinant human GM2-activator is able to restore the degradation of GA2 in fibroblasts from patients with the AB variant of GM2 gangliosidosis in vivo.

Biotin↗
PubMed1999

Determination of the allergenic activity of birch pollen and apple prick test solutions by measurement of beta-hexosaminidase release from RBL-2H3 cells. Comparison with classical methods in allergen standardization.

BACKGROUND: A murine in vitro model of the allergic type I reaction was set up to determine the biologic activity of extracts without involvement of human beings. It is based on beta-hexosaminidase release from passively sensitized RBL cells after allergen challenge. The intended application of this RBL cell assay in the field of quality control of allergenic extracts requires its comparison with established methods. METHODS: The activity of five standardized birch-pollen prick test solutions was determined in parallel by RBL assay, direct IgE binding, IgE-binding inhibition, major allergen content, histamine-release assay, and skin testing. RESULTS: The RBL cell-release assay corresponded well to other methods if a reagin raised against natural birch-pollen extract was used for passive sensitization. However, in the case of a reagin against recombinant Bet v 1, only a decreased activity was observed, presumably because a reduced number of epitopes were recognized by the monospecific reagin. In contrast to standardized birch-pollen extracts, nonstandardized apple extracts showed poor activity in all assays. CONCLUSIONS: This murine model might be a useful tool in the quality control of allergenic extracts. It combines properties of assays based on standardized antisera and of assays that consider IgE cross-linking properties.

Allergens↗
PubMed1999

[Serum level-adjusted dosage of once-daily aminoglycoside therapy in critical illness: results of a prospective study].

OBJECTIVE: In critically ill patients, the adjustment of target peak and trough levels of tobramycin was investigated because aminoglycoside pharmacokinetics can be changed by multiple influences. Sufficient but not too high peak serum concentrations and low trough levels, however, should be achieved to ensure a therapeutic effect and to minimize toxicity. METHODS: 70 critically ill patients of 51 +/- 18 years were monitored daily during their aminoglycoside treatment on the intensive care unit targeting a peak of about 12 micrograms/ml 30 minutes after infusion and a trough level below 1 to 2 micrograms/ml. Dose recommendations were given daily, taking into consideration serum levels, dose predictions (Bayesian method, ABBOTTBASE), creatinine clearance and clinical findings. Creatinine clearance was estimated according to the Cockcroft-Gault-formula as well as directly by the urine collection method. RESULTS: The standardized initial dose of 400 mg tobramycin led to average peak serum levels of 14.2 +/- 3.9 micrograms/ml in the patients with an apparent distribution volume of 0.345 +/- 0.074 L/kg. In 95% of the patients, the initial peak was higher than 8.5 micrograms/ml; levels higher than 20 micrograms/ml were observed in 7%, extremely low concentrations (below 5 micrograms/ml) in 2%. With individually adjusted doses between 160 and 560 mg, a mean peak of 11.5 +/- 2.7 micrograms/ml was measured subsequently. The levels amounted to 96 +/- 23% of the predicted values, deviations greater than 50% occurred in 5%. The target trough level was achieved in 99%, in less than 3% the dosing interval was extended up to 72 hours. A tobramycin clearance below 80 ml/min/1.73 m2 was associated with average 80% and 33% higher creatinine clearance values according to the Cockcroft-method and the direct method, respectively. CONCLUSION: Target peak and trough aminoglycoside levels are adjustable even in critically ill patients. Reduced tobramycin clearance can be associated with normal creatinine clearance. Assuming an exact methodology, a reduced "direct" creatinine clearance, however, indicates a reduced drug clearance.

Anti-Bacterial Agents↗
PubMed1999

Volatile anaesthetics and the atmosphere: atmospheric lifetimes and atmospheric effects of halothane, enflurane, isoflurane, desflurane and sevoflurane.

The atmospheric lifetimes of the halogenated anaesthetics halothane, enflurane, isoflurane, desflurane and sevoflurane with respect to reaction with the hydroxyl radical (OH.) and UV photolysis have been determined from observations of OH. reaction kinetics and UV absorption spectra. Rate coefficients for the reaction with OH radicals for all halogenated anaesthetics investigated ranged from 0.44 to 2.7 x 10(-14) cm3 molec-1 s-1. Halothane, enflurane and isoflurane showed distinct UV absorption in the range 200-350 nm. In contrast, no absorption in this wavelength range was detected for desflurane or sevoflurane. The total atmospheric lifetimes, as derived from both OH. reactivity and photolysis, were 4.0-21.4 yr. It has been calculated that up to 20% of anaesthetics enter the stratosphere. As a result of chlorine and bromine content, the ozone depletion potential (ODP) relative to chlorofluorocarbon CFC-11 varies between 0 and 1.56, leading to a contribution to the total ozone depletion in the stratosphere of approximately 1% for halothane and 0.02% for enflurane and isoflurane. Estimates of the greenhouse warming potential (GWP) relative to CFC-12 yield values of 0.02-0.14, resulting in a relative contribution to global warming of all volatile anaesthetics of approximately 0.03%. The stratospheric impact of halothane, isoflurane and enflurane and their influence on ozone depletion is of increasing importance because of decreasing chlorofluorocarbons globally. However, the influence of volatile anaesthetics on greenhouse warming is small.

Air Pollutants↗
PubMed1999

[Recurrent ventricular fibrillation in a patient with Prinzmetal angina pectoris--case report].

The description of the case of 35 years old patient with paroxysmal ventricular fibrillation in a course of Prinzmetal angina pectoris treated unsuccessfully with antiarrhythmic drugs who required implantation of cardioverter/defibrillator. The via-venous cardioverter/defibrillator was implanted (ICD). During 6 months observation ventricular tachycardia and ventricular fibrillation occurred four times and was effectively interrupted by the cardioverter/defibrillator.

Adult↗
PubMed1999

[Success and complication rates of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography--a prospective study].

The aim of the prospective study was to evaluated the efficacy and the complications of 2,820 ERCP-examinations in 1,717 consecutive patients (performed over a three-year period). The rate of success was 82.8% for diagnostic ERCP, 96.6% for endoscopic sphincterotomy, 76.8% for the extraction of stones on common bile tract, 87.5% for drainage in bile tract obstruction, respectively. The rate of all complications amounted to 7.9% (4.9% diagnostic ERCP, 9.2% therapeutic ERCP, in detail: 3.8% acute pancreatitis, 2.1% cholangitis, 1.3% bleeding, 0.2% perforation, 0.5% other respectively). The total mortality was 0.1% (three cases of death). The frequency of complications increased with the number of procedure at the papilla Vateri in patients, who underwent needle knife papillotomy in combination with standard papillotomy.

Adolescent↗
PubMed1999

[Therapy of osteoporosis: strategies for individualized treatment].

Pharmacological and non-pharmacological interventions are available and useful for effective treatment of osteoporosis. Drugs act by stimulation of bone formation (fluoride) or inhibition of bone resorption (calcium, vitamin D compounds, bisphosphonates, hormone replacement therapy, calcitonin). Published data for effectiveness on bone mineral density and/or fracture rates vary considerably. Non-pharmacological interventions to prevent falls or the impact of falls (hip protectors) must be part of a sufficient treatment strategy. Costs of treatment have to be considered in comparison to costs of fracture repair and rehabilitation.

Accidental Falls↗
PubMed1998

LBP-p40 binds DNA tightly through associations with histones H2A, H2B, and H4.

Laminin binding protein precursor p40 (LBP-p40) was long believed to be located exclusively in the cytoplasm. We recently reported localization of epitope-tagged LBP-p40 to the nucleus tightly associated with nuclear structure as well as on ribosomes. In this paper, we analyze the interaction of LBP-p40 with DNA and nuclear proteins in vitro. LBP-p40 was found to bind to a double-stranded DNA cellulose column at moderate salt. However, when mixed with a high salt nuclear extract, LBP-p40 was eluted from the DNA cellulose column only at higher salt. An LBP-p40 affinity column indicated that both histone H1 and in particular the core histones associate with LBP-p40. Using recombinant core histone molecules fused with glutathione S-transferase (GST), we demonstrate that histones H2A, H2B, and H4 are capable of interacting with LBP-p40, whereas H3 is not. These results suggest that association of LBP-p40 with histones H2A, H2B, and H4 confers tight binding of LBP-p40 to chromatin DNA in the nucleus.

Animals↗
PubMed1998

Induction of type I PACAP receptor expression by the new zinc finger protein Zac1 and p53.

We reported recently the cloning of the type I PACAP receptor by a functional expression cloning technique. Unexpectedly, we observed additional PACAP-positive pools that turned out to encode the wild-type form of the tumor suppressor gene p53 and the novel zinc finger protein Zac1, which regulates apoptosis and cell cycle arrest. Both Zac1 and p53 caused, under transient or stably regulated expression, induction of the type I PACAP receptor by transcriptional mechanisms. Transactivation of the type I PACAP receptor gene by Zac1 and p53 points to a subtle balance between death promoting and protective mechanisms. The control of these processes is central to various physiological conditions ranging from development to senescence, whereas dysregulation may lead to overt pathological outcomes, notably cancer, immune deficiency syndromes, and neurodegenerative disorders.

Animals↗