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Biomedical subjects

A Hoffmann

Publications and source records attributed to A Hoffmann.

At least 73 records · Page 4Linked to original sources

Local proliferation contributes to lymphocyte numbers in normal lungs.

Lymphocytes in the bronchoalveolar lavage fluid (BAL) are increased in many lung diseases, which might be an indicator for protective reactions or pathology. Higher lymphocyte numbers at distinct organ sites may be due to a number of reasons such as increased entry, increased proliferation, reduced apoptosis or reduced exit. It is not known whether lymphocyte numbers are influenced by local proliferation in the healthy lung. Therefore, the proliferation of lymphocytes was studied in vivo in different lung compartments of healthy rats: the marginal vascular pool, the interstitial pool and the bronchoalveolar pool. Bromodeoxyuridine (BrdU) was used as an S-phase proliferation marker. The cells were obtained 1 h and 24 h after i.v. injection of BrdU. The labeled cells and their phenotypes were determined by immunocytochemistry, since it was not possible to use flow cytometry because of the low numbers. In the lung compartments 0.7-1.5% of all nucleated cells were found to be BrdU+, whereas 24 h later this increased to 3.2-5.7%. The frequency of BrdU+ T cells was significantly higher in the lung compartments compared to the blood, with the maximum in the marginal vascular pool. Local proliferation of lymphocytes involved mainly CD8+ T cells. Thus, local proliferation plays a role in the number and composition of lymphocytes in the healthy normal lung.

Animals↗

Nonclinality of molecular variation implicates selection in maintaining a morphological cline of Drosophila melanogaster.

One general approach for assessing whether phenotypic variation is due to selection is to test its correlation with presumably neutral molecular variation. Neutral variation is determined by population history, the most likely alternative explanation of spatial genetic structure, whereas phenotypic variation may be influenced by the spatial pattern of selection pressure. Several methods for comparing the spatial apportionment of molecular and morphological variation have been used. Here, we present an analysis of variance framework that compares the magnitudes of latitudinal effects for molecular and morphological variation along a body size cline in Australian Drosophila populations. Explicit incorporation of the relevant environmental gradient can result in a simple and powerful test of selection. For the Australian cline, our analysis provides strong internal evidence that the cline is due to selection.

Animals↗

Hepatitis B virus nucleic acids circulating in the blood: distinct patterns in HBs carriers with hepatocellular carcinoma.

Circulating nucleic acids in serum and plasma are common in a variety of disease conditions. Here, we focus (i) on our approach for the detection of various hepatitis B virus (HBV)-related nucleic acids in liver tissue and in serum, (ii) on the progression of the chronic HBV infection, (iii) on the relation of HBV-specific nucleic acids circulating in the blood of patients with hepatocellular carcinoma, and in general (iv) on the diagnostic potential of circulating HBV nucleic acids.

Amino Acid Sequence↗

Subcytocidal attack by staphylococcal alpha-toxin activates NF-kappaB and induces interleukin-8 production.

Formation of transmembrane pores by staphylococcal alpha-toxin can provoke a spectrum of events depending on target cell species and toxin dose, and in certain cases, repair of the lesions has been observed. Here, we report that transcriptional processes are activated as a response of cells to low toxin doses. Exposure of monocytic (THP-1) or epithelial (ECV304) cells to 40 to 160 ng/ml alpha-toxin provoked a drop in cellular ATP level that was followed by secretion of substantial amounts of interleukin-8 (IL-8). Cells transfected with constructs comprising the proximal IL-8 promoter fused to luciferase or to green fluorescent protein cDNA exhibited enhanced reporter gene expression following toxin treatment. Electrophoretic mobility shift and immunofluorescence assays demonstrated that IL-8 secretion was preceded by activation of NF-kappaB. Transfection experiments conducted with p65/p50 double-deficient cells showed that activation of the IL-8 promoter/reporter by toxin was absolutely dependent on NF-kappaB. In contrast, this transcription factor was not required for lesion repair. Attack of cells by low doses of a pore-forming toxin can lead to transcriptional gene activation, which is followed by production of mediators that may contribute to the initiation and propagation of inflammatory lesions.

Adenosine Triphosphate↗

Polymorphism and polytypy for pericentric inversions in 38-chromosome Mastomys (Rodentia, Murinae) and possible taxonomic implications.

Chromosome banding analysis (R- and C-bands) of two 38-chromosome Mastomys specimens originating from the Ivory Coast and Uganda revealed different numbers of autosome arms (NFa), equal to 51 and 60, respectively. Comparison of their chromosome banding patterns with those of Mastomys specimens from the Sudan (NFa = 41) and Senegal (NFa = 51-54), studied previously, showed that variation of the NFa from 40 to 60 throughout the species distribution is the result of a pericentric inversion polymorphism involving 3-12 chromosome pairs. At the population level, this variation is much narrower and never results from more than two chromosome pairs involved in inversion polymorphism. Taking into account that the NFa values recorded to date form a well-defined discontinuous row, we presume that introgressive hybridization between populations differing from each other by 3-5 to 11-12 pericentric inversions is interrupted. From there, the hypothesis of the existence of at least three cryptic species (designated provisionally as MER-1, MER-2, and MER-3) within 38-chromosome Mastomys populations previously assigned to M. erythroleucus can be made. It looks likely that one of them, possessing a karyotype with an NFa = 50-56, is widely distributed throughout sub-Saharan Africa and includes karyotyped populations from Senegal, the Ivory Coast, Mali, Benin, Cameroon, Zaire, and the Sudan. The second species (MER-2) includes the specimens karyotyped (NFa = 40-41) from Chad and the Sudan. Finally, a third tentative species (MER-3) corresponds to specimens with NFa = 59-60 found in East Zaire and Uganda, as well as possibly Mali and Chad.

Animals↗

Adverse drug reaction monitoring--digitoxin overdosage in the elderly.

Drug-related illness is an everlasting universal problem and also an important cause of admissions to hospitals. Adverse reactions are still grossly underreported by medical professions. Little information is available regarding the frequency or type of ADRs managed in hospitals. Since January 1997, we have taken part in a study, supported by the German Federal Institute for Drugs and Medical Device to improve the spontaneous drug information reporting system in Germany. Three German regionalized Departments of Clinical Pharmacology--Jena, Dresden, Rostock--serve as Pharmacovigilance Centers in collaboration with the Pharmacoepidemiology Research Group of the University of Munich. Since January 1997, the regional group in Jena has been monitoring the University Clinic of Internal Medicine for admissions caused by adverse drug reactions. All emergency cases and patients on intensive care units were checked for adverse drug reactions. We present our results, including clinical and demographic data, concerning intoxications and especially those involving digitoxin in 210 patients with ADR. Forty patients with digitoxin toxicity had an average age of 81 years (81.1+/-6.3), a low body weight (59.7+/-12.7 kg) and 3 out of 4 were women. 75% of all patients with digitoxin side effects had elevated serum digitoxin levels with concentrations higher than 25 microg/ml. The relatively high frequency of digitoxin intoxications in our hospital may reflect the advanced age and low body weight of patients. Patients received digitoxin regardless of age, weight and, sometimes, clinical indication. Physicians should be aware of drugs having a high risk when used in elderly patients. The use of digitoxin assays and keeping serum levels within or near the therapeutic range will diminish the incidence of overdoses.

Adverse Drug Reaction Reporting Systems↗

[Mediator release assay of rat basophil leukemia cells as alternative for passive cutaneous anaphylaxis testing (PCA) in laboratory animals].

Passive cutaneous anaphylaxis (PCA) is an animal model for inflammatory reactions in Type I allergy. An in vitro assay based on IgE dependent and allergen-induced mediator release of RBL-2H3 cells is presented as an alternative for PCA. The assay has been adopted to the special needs of examining allergen extracts and has been proven to be practicable and reliable. A high number of samples can be processed quickly in one assay, with intra-assay variations below 10%. The first successful applications are the measurement of biologic potencies in allergenic extracts and the determination of murine serum IgE antibodies. Further studies will show whether this assay is suited to evaluate the efficiency of anti-inflammatory and anti-allergic drugs.

Allergens↗

BMP signaling pathways in cartilage and bone formation.

This review focuses on the molecular aspects of osteogenesis and chondrogenesis as they relate to cellular and developmental levels. We discuss BMP (bone morphogenetic protein)-mediated signaling pathways for the patterning of skeletal elements and mechanisms for the induction of cartilage and bone formation. We emphasize BMP-mediated initiation of chondrogenesis and osteogenesis and consider BMP-dependent signaling cascades in mesenchymal progenitor cells during the development of the axial and appendicular skeleton and during growth plate and joint formation. In particular, we discuss BMP-signaling mediators of the Smad and TAK family and the modulation of these signals by cross-talk and integration with other signaling pathways.

Alkaline Phosphatase↗

Pattern of outpatient drug therapy in diabetics admitted to hospital--preliminary results.

UNLABELLED: The prevalence of outpatient treatment with various drug groups is significantly higher in diabetics than in non-diabetic control patients. In addition to the specific diabetes-related prescriptions, diabetics were more frequently treated with drugs acting on the alimentary tract or used in metabolic disorders (ATC code A), drugs used in disorders of the blood and blood-forming organs (ATC B), cardiovascular system (ATC C), musculo-skeletal system (ATC M) and nervous system (ATC N)-- resulting in markedly higher outpatient costs in this patient group. Objective of this investigation was to analyze the pre-hospital prescription pattern of diabetics and non-diabetic controls at the time of admission to hospital. METHOD: A sample survey of a total of 189 general medical and 68 surgical admissions involving diabetics and 676 and 143 non-diabetic control patients corresponding in age, sex and main diagnosis--were analyzed with regard to selected medical and demographic characteristics and pharmacotherapy. RESULTS AND DISCUSSION: The prevalence of non-diabetic drug treatment in diabetics was highest for ATC C (87.8% and 69.1%), ATC A (40.7% and 27.9%; without A10) and ATC B (39.2% and 29.4%) in internal and surgical admissions, respectively. A substantially higher prevalence was found for ATC groups B and C in diabetics and controls admitted to medical wards than in epidemiological prescription analyses. CONCLUSION: Data indicate that the need for treatment with cardiovascular drugs and drugs used to treat disorders of the blood and blood-forming organs may be associated with a higher risk of hospitalization in general medical wards.

Aged↗

Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun.

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) produce IL-6 and IL-8, which contribute to inflammation and joint damage. The promoters of both cytokines possess binding sites for NF-kappaB, C/EBPbeta, and c-Jun, but the contribution of each to the regulation of IL-6 and IL-8 in RA FLS is unknown. We employed adenoviral-mediated gene delivery of a nondegradable IkappaBalpha, or dominant-negative versions of C/EBPbeta or c-Jun, to determine the contribution of each transcription factor to IL-6 and IL-8 expression. Inhibition of NF-kappaB activation significantly reduced the spontaneous and IL-1beta-induced secretion of IL-6 and IL-8 by RA FLS and the IL-1ss-induced production of IL-6 and IL-8 by human dermal fibroblasts. Inhibition of C/EBPbeta modestly reduced constitutive and IL-1beta-induced IL-6 by RA FLS, but not by human dermal fibroblasts, and had no effect on IL-8. Inhibition of c-Jun/AP-1 had no effect on the production of either IL-6 or IL-8. Employing gel shift assays, NF-kappaB, C/EBPbeta, and c-Jun were constitutively activated in RA FLS, but only NF-kappaB and c-Jun activity increased after IL-1beta. The reduction of cytokines by IkappaBalpha was mediated through inhibition of NF-kappaB activation, which resulted in decreased IL-6 and IL-8 mRNA. NF-kappaB was essential for IL-6 expression, because fibroblasts in which both NF-kappaB p50/p65 genes were deleted failed to express IL-6 in response to IL-1. These findings document the importance of NF-kappaB for the regulation of the constitutive and IL-1beta-stimulated expression of IL-6 and IL-8 by RA FLS and support the role of inhibition of NF-kappaB as a therapeutic goal in RA.

Adenoviruses, Human↗

Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages.

A major challenge in the study of gene regulation by NF-kappaB/Rel transcription factors is to understand, at the biological and mechanistic levels, the selective functions of individual Rel family members. To study selectivity, we have examined the NF-kappaB/Rel protein binding site (Rel site) within the IL-12 p40 promoter. IL-12 is a proinflammatory cytokine expressed by activated macrophages that serves as an essential inducer of T helper 1 cell development. In nuclear extracts from lipopolysaccharideactivated macrophages, the predominant Rel dimers capable of binding the IL-12 p40 Rel site were the p50/p65 and p50/c-Rel heterodimers and p50/p50 homodimer. The two heterodimers bound the site with comparable affinities and exhibited comparable transactivation activities. In striking contrast, p40 mRNA and protein concentrations were reduced dramatically in c-Rel(-/-) macrophages and only modestly in p65(-/-) macrophages. Other proinflammatory cytokine mRNAs and proteins were not significantly reduced in c-Rel(-/-) macrophages. These results reveal that a c-Rel-containing complex is an essential and selective activator of p40 transcription, which may reflect unique regulatory mechanisms or biological functions of IL-12. Furthermore, because selectivity was not observed in vitro or in transient transactivation experiments, these findings suggest that an understanding of the selectivity mechanism may require an analysis of the endogenous p40 locus.

Animals↗

Effect of the dry-cold season dormancy on the tonic and phasic neural control of heart rate in the toad, Bufo paracnemis.

This work examined basal heart rate and autonomic cardiac tone as well as sympathetic cardiac reactivity to hypotension induced by systemic nitroprusside injection in dormant toads (dry-cold season), Bufo paracnemis, comparing the values with those of toads collected during the active months (hot-rainy season). Autonomic tone was calculated according to the method of Lin and Horwath ('72), which allows its evaluation as a percentage of intrinsic heart rate. Specimens were maintained in an outdoors terrarium except for the week preceding surgery, when they were transferred to indoor nonclimatized tanks. The heart rate of dormant toads (27.8 +/- 2.7 beats/min) was lower than that of active toads at rest (38.6 +/- 2. 3). Cholinergic tone was higher than adrenergic tone both in active (26.2% and 7.8%, respectively) and aestivated (19.5% and 4.8%, respectively) animals. Thus, cholinergic tone and adrenergic tone were both lower in dormant animals. The reflex tachycardia elicited by nitroprusside-induced hypotension was lower in aestivated toads (9.3 +/- 0.9 beats/min) when compared to active toads (19.9 +/- 1.0), indicating a reduced sympathetic reactivity. Nitroprusside-induced hypotensions were not different in the two groups. We conclude that at rest Bufo paracnemis heart is under the influence of a double cholinergic and adrenergic tone, and that both influences, as well as the reflex adrenergic reactivity to the unloading produced by nitroprusside-induced hypotension, are reduced in aestivated toads.

Adrenergic Fibers↗

Baroreceptor control of heart rate in the awake toad: peripheral autonomic effectors and arterial baroreceptor areas.

Systemic injection of sodium nitroprusside (30 microg/kg, i.v.) in the awake Bufo paracnemis toad induced a fall in arterial blood pressure and tachycardia. This tachycardia, but not the hypotension, was significantly reduced in toads with bilateral electrolytic lesion of the caudal and commissural regions of the solitary tract nucleus and in animals with transection of the spinal cord, 2 mm below the obex. This indicates that the tachycardia is reflex, depends on the integrity of the solitary tract nucleus and is due to descending spinal autonomic activation. Pretreatment with propranolol (4 mg/kg, i.v.) significantly reduced the tachycardia but did not block it completely, showing the importance of beta-adrenoceptors in its genesis. The reflex increase in heart rate induced by nitroprusside was not statistically significant in animals with bilateral section of the laryngeal nerve, whose baroreceptor fibers originate from the pulmocutaneous artery or in animals in which the bilateral section of the laryngeal nerve was performed together with section of the glossopharyngeal nerves, which incorporate fibers originating from the carotid labyrinth. The reduction of the reflex tachycardia was significant in toads with aortic arch denervation alone or combined with section of the laryngeal nerves or in animals with complete denervation of the three baroreceptors areas. These results suggest that the region of the aortic arch, when submitted to unloading, is the most important baroreceptor zone for cardiac compensation in toads.

Animals↗

Cardiac allograft vascular disease after orthotopic heart transplantation: methylenetetrahydrofolate reductase gene polymorphism C677T does not account for rapidly progressive forms.

BACKGROUND: Recently, homocysteine (HCY) levels have been suggested to be a risk factor in cardiac allograft vascular disease (CAVD). As plasma levels are partially under genetic control, we investigated the influence of the methylenetetrahydrofolate reductase (MTHFR) polymorphism on HCY levels and development of CAVD in heart transplant (HTX) recipients. METHODS: Genotyping and assessment of fasting HCY levels were performed in a cohort of 146 HTX recipients and correlated to the onset and progression of CAVD, assessed by serial angiography. RESULTS: Actuarial freedom from CAVD did not differ significantly between the genotypes. However, patients positive for CAVD presented with higher HCY levels than CAVD-negative individuals (21.0+/-9.4 vs. 18.2+/-6.6 micromol/L, P=0.046). CONCLUSIONS: There is some evidence that plasma HCY might be involved in development of CAVD. However, polymorphism of the MTHFR gene could not be shown to be related to severity of allograft vascular disease.

Adult↗

Electromyography in MRI--first recordings of peripheral nerve activation caused by fast magnetic field gradients.

Prior studies on the evaluation of stimulation by MRI were based on the subjective feeling of the volunteers. A wide variety of stimulation thresholds between the subjects was observed. In order to exclude subjective perception levels as a cause of this variation, we developed a method to investigate the activation of peripheral nerves after gradient switching by electromyography (EMG) within the MR-imager. Five healthy volunteers were positioned in the MR-scanner with the bridge of the nose at isocenter. The amplitude of sinusoidal pulse trains of the anterior-posterior gradient (rise-times: 200 or 300 micros, various numbers of oscillations) was increased stepwise. Four surface electrodes were placed on the region where a muscle-twitch was reported. Electric activity of the muscle during stimulation experiments was recorded with an MR-compatible electro-physiologic amplifier. Stimulation thresholds were defined by the appearance of an EMG-signal. Thresholds were sharp and consistent with the report of the subjects.

Adult↗

Electroencephalography during functional echo-planar imaging: detection of epileptic spikes using post-processing methods.

EEG has been used to trigger functional MRI of patients with focal epilepsy, but EEG can be obscured by artifacts during MR data acquisition, and no continuous correlation of EEG and MRI has been possible without limiting the image time. Artifacts caused by an MRI sequence were investigated in five healthy subjects, and an EEG of five patients with epileptic discharges was recorded during echo-planar imaging. All interfering frequencies in the EEG were discrete and defined by loop structures in the MRI sequence. In post-processing of the EEG interfering frequencies were automatically detected by comparing the frequency spectra of the EEG recorded before and during imaging. After elimination of interfering frequencies by filters in the time domain or by Fourier transform, reliable spike detection in the EEG recorded during MR data acquisition became feasible, without loss of EEG quality.

Algorithms↗