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Biomedical subjects

B Hartmann

Publications and source records attributed to B Hartmann.

At least 55 records · Page 3Linked to original sources
PubMed1994

Fusidic acid suppresses nitric oxide toxicity in pancreatic islet cells.

Earlier preclinical and clinical trials indicate that fusidic acid, a triterpenoid compound originally described as an antimicrobial drug may protect islet beta cells from destruction in type I (insulin-dependent) diabetes mellitus. Since nitric oxide appears to be an important mediator of inflammatory islet cell death we analyzed whether fusidic acid interferes with nitric oxide production or action. We report here that fusidic acid dose-dependently inhibits lysis of isolated islet cells by activated macrophages, a process mediated by nitric oxide. In the presence of 100 microM fusidic acid macrophage-mediated islet cell lysis was reduced from 52.5 to 1.7% (P < 0.001). Fusidic acid only slightly affected macrophage function and did not inhibit the release of nitric oxide. We therefore tested whether fusidic acid suppresses nitric oxide toxicity in target cells. Isolated islet cells were exposed to the nitric oxide donor nitroprusside which led to DNA strand breaks and plasma membrane lysis. DNA strand breaks were reduced from 54.6 to 34.9% (P < 0.001) in the presence of 100 microM fusidic acid and cell lysis was reduced from 60.1 to 27.5% with 100 microM (P < 0.001). In the presence of 500 microM fusidic acid DNA strand breaks and cell lysis were reduced further to 27.1 and 10.7%, respectively (P < 0.001). No protection by fusidic acid was observed when cells were exposed to oxygen radicals or the alkylating beta cell toxin streptozotocin. The suppression of nitric oxide toxicity by fusidic acid was not due to its known inhibitory action on protein biosynthesis and thus represents a hitherto unknown activity of this drug.

Animals↗
PubMed1994

Proglucagon processing in porcine and human pancreas.

In the pancreas proglucagon (PG), a peptide precursor of 160 amino acids is cleaved to produce glucagon and a 30-amino acid N-terminal flanking peptide, but the fate of the C-terminal flanking peptide (99 amino acids) is incompletely known. We subjected acid ethanol extracts of human and porcine pancreases to gel filtration and analyzed the fractions with specific radioimmunoassays for the following regions of proglucagon: PG 62-69, PG 72-81, PG 78-87, PG 98-107 amide, PG 126-134, and PG 149-158. Based on these assays and successive purifications by high performance liquid chromatography we isolated and purified to homogeneity three porcine peptides which were subjected to mass spectrometry and sequencing. One peptide was PG 64-69. The second was PG 72-108, as determined by mass spectrometry, N-terminal amino acid sequencing, and specific radioimmunoassays. The third had a molecular size of approximately 10,000, an N-terminal sequence corresponding to PG 72-81, and a C-terminal sequence terminating at PG 158 (specific radioimmunoassay). A similar peptide with an identical N-terminal sequence, a C-terminal sequence corresponding to PG 146-158, and a molecular mass of 9969 (theoretical mass for human PG 72-158 = 9971) was isolated from human pancreas together with small amounts of a peptide corresponding to PG 72-107 amide. Thus, the pancreatic processing of the C-terminal flanking peptide in proglucagon includes the formation of equimolar (to glucagon) amounts of PG 64-69 and PG 72-158 (major proglucagon fragment) and smaller amounts of N-terminally extended glucagon-like peptide-1 (GLP-1) (PG 72-108 in pigs and PG 72-107 amide in humans).

Amino Acid Sequence↗
PubMed1994

Nitric oxide toxicity in islet cells involves poly(ADP-ribose) polymerase activation and concomitant NAD+ depletion.

Previous studies have shown that DNA strand breaks are an early consequence of nitric oxide toxicity in pancreatic islet cells. We show here that exposure of islet cells to chemical NO donors causes the formation of ADP-ribose polymers in cell nuclei, with concomitant depletion of intracellular NAD+. Islet cell lysis was largely prevented by the ADP-ribosylation inhibitors nicotinamide, 3-aminobenzamide, and 4-amino-1,8-naphthalimide, the latter being a potent new-generation compound with high selectivity for poly(ADP-ribosyl)-ation. These findings indicate a key role of poly(ADP-ribose) polymerase activation in NO toxicity in islet cells.

1-Naphthylamine↗
PubMed1994

Depletion of total cysteine, glutathione, and homocysteine in plasma by ifosfamide/mesna therapy.

The sulfhydryl status of cells, particularly the intracellular concentration of glutathione, is a critical determinant of the response of tumor and normal cells to cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate (mesna), which is often combined with ifosfamide, markedly decreases the circulating concentration of total cysteine and could thereby influence the response of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced sarcoma for 5 days at a dose of 2.4-3.2 g/m2 per day together with mesna. The plasma concentrations of total mesna, cysteine, glutathione, and homocysteine were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy and prior to the next course of chemotherapy, and the urinary excretion of cysteine and mesna was monitored daily using a high-performance liquid chromatography (HPLC) method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine, i.e., cysteine, cystine, and cysteine mixed disulfides [from 245 +/- 36 to 50 +/- 14 nmol/ml (mean +/- 95% CI) on day 6], total glutathione (from 6.9 +/- 1.1 to 2.5 +/- 1.1 nmol/ml), and total homocysteine (from 12.3 +/- 2.1 to 1.4 +/- 1.1 nmol/ml). The values returned to baseline levels prior to the next course of chemotherapy. The urinary excretion of cysteine increased significantly from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An average of 62% +/- 6% of the delivered dose of mesna was recovered in urine. The combination of ifosfamide/mesna results in depletion of circulating total cysteine, glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.

Adult↗
PubMed1994

Modelling DNA conformational mechanics.

Using a modelling technique specifically adapted to DNA helices, we have systematically studied the impact of base sequence on the geometry of the double helix. The results obtained show that each repetitive base sequence leads to several stable conformations belonging to the B-DNA family. These conformational sub-states generally have similar stabilities, but often differ considerably in terms of their helical and backbone parameters. Each sub-state can be characterised by the puckering of its sugar rings. Surface energy mapping and combinatorial search techniques are used to further understand the DNA conformational hypersurface and to extend our study from dinucleotide repeats to tetranucleotide sequences. The resulting structural database should be useful for predicting the properties of longer and more irregular base sequences and thus should contribute to understanding how DNA target sites are recognised.

Base Sequence↗
PubMed1994

The role of prolactin in the menopause.

Within a study on menopausal discomforts, 2322 women were seen for the first time at the Outpatients Department for Climacteric Disturbances and Prophylaxis of Osteoporosis at our clinic. Amongst routine hormonal examination we measured prolactin levels. We found hyperprolactinemia in 23 women. Furthermore, in 224 women who initially had normal hPRL values, an estrogen-gestagen replacement therapy was administered and within this we found a significant increase of the prolactin levels (P < 0.005). The role of prolactin in the climacteric period as well as the mechanism of the estrogen effect upon prolactin secretion are subjects of discussion.

Climacteric↗
PubMed1994

[Drug information in hormone substitution drugs].

The package leaflets of hormone preparations used for Hormone Replacement Therapy (HRT) in hypoestrogenaemic women contain contraindications, which are taken from the package insert of oral contraceptives: Clots in the blood vessels (thrombotic disorders), high blood fats, severe diabetes, abnormal red blood cells, deterioration of inherited deafness and jaundice not explained by infections, disturbances of the liver function and of existing or treated hormone-dependent tumours of the breast or of the lining of the womb. Numerous epidemiologic, animal-experimental and also clinical studies proved that the cardiovascular risk, hepatic discomfort and the influence on the blood system of oestradiol 17-beta have to be evaluated completely differently compared to the ethinyloestradiol used in oral contraceptives; therefore, many of the listed contraindications must be reconsidered. In our review we try to emphasise this postulation by scrutinizing recent publications.

Adult↗
PubMed1994

[Flap resection and split-thickness skin transplantation as a method of flap correction of the hand].

Hand injuries involving extensive skin loss and soft-tissue destruction in depth will require flap coverage. Once successful grafting has taken place, however, the thickness of the flap often necessitates further surgical intervention for reasons of good function and cosmesis. A surgical regime is described in which the healed flap is partially removed, leaving a healthy surface upon which split-thickness grafts are applied. During the years 1991 and 1992, 21 patients have been treated according to this method in our department. The technique and results of 16 of these 21 cases are described.

Adult↗
PubMed1993

BI-BII transitions in B-DNA.

Molecular modelling is used to study the conformational and energetic aspects of BI-BII transitions within the backbone of a B-DNA dodecamer d(CATGACGTCATG) whose fine structure has previously been determined by molecular modelling combined with NMR spectroscopy. It is shown that while the dodecamer under investigation does not contain any BII junctions, the central CpG step can most easily undergo the transition. More generally, it is also found that the base sequence and hence the backbone geometry of a DNA segment, strongly influences both the conformational impact of the transition, the associated energy barrier and the stability of the resulting BII state.

Base Sequence↗
PubMed1993

Islet cell DNA is a target of inflammatory attack by nitric oxide.

NO has been identified recently as the prime islet-toxic product of inflammatory macrophages. The adverse effects of IL-1 on isolated islets also have been reported to involve NO. We now show that exposure of an islet cell suspension to the NO donor nitroprusside or to activated macrophages leads to DNA strand breaks. Macrophages did not induce DNA damage in the presence of the NO synthase inhibitor NG-methyl-L-arginine. DNA strand breaks were demonstrated at the level of single cells by a modified nick-translation procedure and confirmed by analysis of DNA fragmentation by gel electrophoresis. DNA strand breaks occurred within 1 h and preceded islet cell lysis. DNA damage could not be prevented by inhibitors of endogenous endonucleases. We conclude that islet cell DNA is an early target of NO action.

Animals↗
PubMed1992

The fine structure of two DNA dodecamers containing the cAMP responsive element sequence and its inverse. Nuclear magnetic resonance and molecular simulation studies.

1H and 31P n.m.r. (nuclear magnetic resonance) spectroscopy have been used in conjunction with molecular simulation to determine the structure of two DNA dodecamers. The first of these, CATGACGTCATG, contains the octameric sequence CRE (cAMP responsive element), while the second is the reversed sequence, GTACTGCAGTAC. Structure determination was based on both NOESY (nuclear Overhauser spectroscopy) derived distances and COSY (correlated spectroscopy) dihedral angle data. Access to the 31P spectra also allowed the epsilon backbone angles to be determined. Considerable care was taken in deriving structural parameters from the n.m.r. data and an excellent level of agreement is obtained with the simulated conformations. Both dodecamers are found to belong to the B-DNA family; however, there is a striking difference between the CRE sequence and its inverse, the former conformation alone showing a strong structural heterogeneity.

Base Sequence↗
PubMed1992

Conformational sub-states in B-DNA.

Theoretical studies of the sequence-dependent conformation of B-DNA have been carried out using Jumna, a helicoidal co-ordinate minimization algorithm. The results obtained for a series of six oligomers with repetitive sequences show that, with the exception of the homopolymers (dA)n.(dT)n and (dG)n.(dC)n, all sequences can adopt a variety of conformations characterized by considerable changes in helicoidal parameters and also in sugar puckers which adopt C(2')-endo (falling into 2 classes) or, in the case of pyrimidine nucleotides, O(1')-endo forms. These studies lead to an improved understanding of the role of base sequence on DNA conformation and point to a number of interesting correlations between the various structural parameters describing the double helix.

Algorithms↗
PubMed1992

[Colposcopy in gynecologic cancers. Retrospective study of 192 examinations].

One hundred and ninety two colposcopic examinations carried out on 183 patients of whom 140 had carcinoma of the cervix, 26 carcinoma of the endometrium and 17 carcinoma of the ovaries were analysed in order to assess the value of colposcopy in patients with gynaecological cancer. The mean distance from the edge of the anus that was looked at was 45 cms--the range being from--130. Out of all the systematic examinations that were carried out before any treatment was started, 103 were for cervical cancer and among these invasion of the rectal mucosa was found in two cases (1.9%). Twelve cases of external pressure on the rectum and 9 cases of recto-colic polyadenomata (8.7%) of which one was malignant. Out of the 14 colposcopies that were carried out for carcinoma of the endometrium one case of rectal invasion was found and one case of external compression. In the 12 cases of cancer of the ovary 2 were found to have recto-colic spread, 1 external compression and 1 malignant polyadenoma. All these cases of spread to the rectum and colon were diagnosed in advanced cases (stage III or IV). In the 63 examinations carried out on follow-up the most common warning sign was a rectal discharge and the most commonly found lesion in the rectum was actinomycotic inflammation of the rectum. The 5 cases of recurrence in the rectum expressed themselves most often by the rectal syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[Bioequivalence and bioavailability after single administration of effervescent ranitidine tablets].

An open two-way cross-over study in 12 healthy male volunteers was performed in order to determine the relative bioavailability of a 150 mg ranitidine (Zantic, CAS 66357-35-5) effervescent tablet sweetened with saccharine in comparison to the 150 mg standard ranitidine dispersible tablet (Trinkette). On two occasions separated by a wash-out period of 1 week volunteers received a single oral dose of both formulations. On each administration day blood samples were collected at predetermined time points in order to investigate the pharmacokinetic parameters. Single oral doses of ranitidine were very well tolerated by healthy male volunteers. The non-parametric 95% confidence intervals for AUC and Cmax were 87 to 116% and 84 to 107%, respectively. The relative bioavailability of the ranitidine effervescent tablet was 99% compared to the dispersible tablet. The mean of the Cmax ratio was 95%. The ranitidine effervescent tablet could thus be claimed to be bioequivalent to the dispersible tablet.

Adult↗
PubMed1991

[CO2-induced acral blood flow and the oxygen partial pressure in arterial occlusive disease].

The effect of CO2-containing water on foot skin blood flow (laser-Doppler flux) and transcutaneous oxygen partial pressure (tcpO2) was measured in 16 patients (15 men and 1 woman; mean age 58 [49-71] years) with peripheral arterial occlusive disease (stage II of Fontaine: bilateral occlusions of the superficial femoral arteries). After 30 minutes lying down and 10 minutes sitting up, one lower leg was immersed in fresh water, the other in CO2-containing water (1400 mg CO2/kg H2O), both at 34 degrees C for 20 minutes. On the next day the measurements were repeated changing sides. Skin blood flow of the dorsum of the foot and rhythmic flow oscillations (flux motion) increased threefold in the CO2 water-bath, after a latency period averaging 2 minutes, within 3 minutes from 1.1 to 3.9 relative units (P less than 0.005). Average tcpO2 increased during the bath in CO2 water by 9 mm Hg (P less than 0.005). There was no change in fresh water. The increase in cutaneous blood flow and oxygen partial pressure, which persisted throughout the period in CO2 water, is interpreted as an increase in microcirculation and can explain part of the effectiveness of this largely empirical treatment.

Aged↗