Biomedical subjects
Publications and source records attributed to R Müller.
Adverse drug side effects of the antihypertensive substance dihydralazine have been increasingly observed in recent years. Damage is concentrated on the liver and is characterized by drug-induced hepatitis with confluent necrosis. Three cases (60 year old woman, 79 year old woman, 61 year old man) with lethal course after antihypertensive treatment, using dihydralazine are reported in this paper.
The bilin binding protein (BBP) from the insect Pieris brassicae has been analysed for amino acid sequence, spectral properties and three-dimensional structure. The crystal structure that had been determined by isomorphous replacement has been refined at 2.0 A (1 A = 0.1 nm) resolution to an R-value of 0.20. The asymmetric unit contains four independent subunits of BBP. The co-ordinate differences are 0.25 A, in accord with the estimated error in co-ordinates. The polypeptide chain fold is characterized by an eight-stranded barrel. The connecting loops splay out at the upper end of the barrel and open it, whilst the lower end is closed. The overall shape resembles a calyx. The biliverdin IX gamma chromophore is located in a central cleft at the upper end of the barrel. The bilatriene moiety is in cyclic helical geometry with configuration Z,Z,Z and conformation syn,syn,syn. The geometry is in accord with the spectral properties and permits a correlation between sign of the circular dichroism bands and sense of the bilatriene helices. The fold of BBP is related to retinol binding protein (RBP), as had been recognized in the preliminary analysis, although the amino acid sequences of RBP and BBP show only 10% homology. There are large differences in the loops at the upper end of the barrel, whilst the segments of the centre and the lower end of the barrel superimpose closely. The ligands of BBP and RBP, biliverdin and retinol, respectively, are also similarly located.
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We have undertaken a detailed structure-function analysis of v-fos protein, taking the ability to induce transformation and immortalization as criteria of biological activity. Our results demonstrate that the evolutionarily conserved center region of fos, comprising ca. 28% of the protein, is indispensable for its function. A single amino acid change (Glu 138----Val 138) in this region activates the immortalizing potential of v-fos without affecting its transforming capacity. The presence of additional either N- or C-terminal amino acids, however, is required for efficient expression of a stable protein, and significantly increases its biological activity. In contrast, sequences in the C-terminal half (between positions 228 and 267) strongly downmodulate the transforming activity of v-fos protein without decreasing its immortalizing potential.
The c-fos proto-oncogene is rapidly and transiently induced by PDGF in fibroblast and by CSF-1 in macrophages. In both cells, the breakdown of phospholipids with the ensuing activation of protein kinase C (PKC) and intracellular release of Ca2+ seems to play a role in the induction of c-fos. The transient induction of c-fos mRNA and protein by PDGF is both increased and prolonged by inhibitors of calmodulin, apparently by inhibiting the degradation of c-fos mRNA. While no response to cyclic nucleotides is observed in fibroblasts, cAMP is a strong inducer of c-fos in macrophages. In contrast to the transient induction by PKC/Ca2+, cAMP induces stable transcription of the c-fos gene for many hours, suggesting the existence of different mechanisms regulating c-fos transcription in the same cell.
As a first step in the analysis of the molecular function of the nuclear c-fos proto-oncogene product we have studied its subnuclear localization in serum-stimulated mouse fibroblasts where it forms a non-covalent, apparently monodisperse complex with another nuclear protein, p39. The c-fos/p39 complex is almost quantitatively released from intact nuclei by DNasel or micrococcus nuclease treatment under conditions where only a minor fraction of DNA and nuclear proteins is released. In gel filtration experiments, c-fos/p39 comigrates with chromatin and seems to be associated with regions of increased DNasel accessibility. c-fos/p39 is bound to chromatin by electrostatic forces of moderate strength since greater than 90% of the complex can be eluted from nuclei at 0.4 M NaCl. In vitro, the c-fos/p39 complex in nuclear extracts binds to double- and single-stranded calf thymus DNA, suggesting that the association of c-fos/p39 with chromatin is at least in part due to its interaction with DNA. In agreement with this conclusion, c-fos/p39 is released from nuclei by incubation with tRNA, presumably due to competition for binding sites. Our observations are compatible with the hypothesis that c-fos may play a role in the regulation of gene expression.
We have cloned 215-kb DNA containing the maternal effect region (ME) of the Shaker gene complex (shC) at 16F of the Drosophila X chromosome. Five translocation and deletion breakpoints have been mapped on the cloned DNA allowing a correlation of the genetic map to transcription units. The ME region spans 100 kb. The genetic behavior of this region correlates with the occurrence of maternal RNAs in this part of the ShC. Two transcripts have been identified in the vicinity of chromosomal rearrangements which cause a Sh phenotype. These are a 4.5-kb transcript interrupted by T(x;2)B27 and a 2-kb transcript interrupted by T(X;3)Sh and T(X;Y)W32. The latter transcript is derived from a primary transcript which spans >65 kb genomic DNA. The cDNA-sequencing data show that this Shaker (I(A)channel) gene can encode a protein of 35 kd with three alpha-helical membrane-spanning sequences near its carboxyl terminus. These have a striking homology with membrane-spanning sequences of the vertabrate Na channel.
The elimination of the low molecular weight proteinase inhibitor camostate (FOY 305) was studied in rats after oral administration and in the the situ perfused rat liver. After feeding of camostate (400 mg/kg b.w.) only the metabolites (FOY 251, GBA) were detected in blood samples withdrawn from the portal and hepatic vein. This indicated a rapid degradation of FOY 305 after absorption from the gut lumen. The hepatic extraction of the anti-proteolytic active metabolite FOY 251 during a single liver passage was 23%. It remained almost constant over the period of 120 min. In the perfused rat liver, FOY 305 was given in concentrations comparable to the in vivo studies. It was eliminated by 20%. In these experiments, the compound was metabolized to FOY 251 and in minor amounts to guanidino-benzoate (GBA), the latter being an anti-proteolytic ineffective degradation product. In conclusion, a low hepatic extraction of FOY 305 led to pharmacologically effective concentrations of the active metabolite FOY 251 in the circulation after oral ingestion of the proteinase inhibitor.
We have studied the effect of the potent mitogen bombesin on the expression of c-fos and c-myc genes in quiescent mouse fibroblasts. We have demonstrated that bombesin rapidly induces a transient expression of c-fos mRNA followed by a more protracted elevation in c-myc mRNA levels. The intensity of the induction of expression of both proto-oncogenes depended on the dose of bombesin used. Prolonged treatment of the cells with TPA, which causes a selective decrease in protein kinase C activity, partially inhibited the induction of c-fos and c-myc gene expression by bombesin, similar to what has been observed with PDGF. However, a dramatic inhibition of the mitogenic response to bombesin--but not to PDGF--was found in TPA-treated cells. In contrast, TPA-treated cells showed an increased response to EGF with regard to proto-oncogene expression. The role of protein kinase C and Ca2+-dependent pathways in proto-oncogene induction by bombesin is discussed.
Therapeutical efforts in epilepsies with infantile spasms (IS) often show unsatisfying results, especially if neurological impairments are found. In a clearly negatively selected group of 24 children with IS and 10 patients with symptomatic myoclonic-astatic epilepsies--pretreated without success with ACTH and/or benzodiazepines (BDZ) alone or combined with other anticonvulsants--we tried a two-drug therapy of BDZ with carbamazepine (CBZ). Dosage of both drugs was within the usual range. In a follow-up period of 1-5 years, 8 of the IS patients and 4 of those with myoclonic-astatic seizures became seizure-free; furthermore, 6 children showed a marked reduction in their seizure frequency: 3 more than 80%, 3 more than 50%. Besides the fact that the patients did not develop a so-called escape-phenomenon--as often seen in therapy with benzodiazepines--they also showed fewer and less intensive side-effects. Without optioning for antiepileptic polytherapy in general, we conclude that in cases of "intractable" IS the combination of BDZ with CBZ might be more successful than the single drug. To confirm these preliminary findings further controlled studies have to be carried out.
The aim of this study was to establish the risk of acquiring common respiratory and gastrointestinal illness for paediatric nurses. Using self-administered questionnaires, student nurses at two children's hospitals and students at one school of medical technology reported biweekly the number of minor illnesses, symptoms, and indicators of severity of infection over a 3-year period (1975-8). Although a systematic bias was evident with some symptoms, others appeared to be quite reliable. The following four syndromes were defined to estimate the risk: upper respiratory syndrome (URS), lower respiratory syndrome (LRS), respiratory and gastrointestinal syndrome (RGS), and gastrointestinal syndrome (GS). Surveillance days were allocated to groups with high- or low-intensity contact with children. The incidence of all illnesses was 2.9 per person-year in the low-intensity contact group and 4.4 per person-year in the high-intensity contact group. The reported incidence of LRS and RGS in the high-intensity contact group was 1.55 times higher than in the low-intensity group (P less than 0.001). LRS and RGS incidence was similar in nurses at both schools. During low contact periods it corresponded to that of the medical technologists.
The occupational risk of acquiring minor respiratory infections for paediatric student nurses was estimated by performing serological examinations with influenza A, B, C, parainfluenza, mumps, respiratory syncytial virus, adenovirus and Mycoplasma pneumoniae at 6-month intervals over a period of 4 years in paediatric student nurses at two schools of nursing and students at one school of medical technology. Titre increases against all tested agents occurred 1.86 times more often in the student nurses than in the medical technology students, the most frequent agents in both groups being influenza A and B. No difference in the relative distribution of the agents could be verified in the two occupational groups. Data on the protective value of pre-infectious antibody levels for influenza A, B, and coronavirus OC43 and on the importance of the spread of single agents among classmates are presented.
Standard retinoids (e.g. etretinate, isotretinoin) are successful in the treatment of a variety of dermatological disorders. However, they are handicapped by an unfavorable ratio between activity and toxicity. In order to find more successful substances new promising compounds were recently synthesized. The aim of this study was to screen new monoaromates (etretin (Ro 10-1670) ), demethyletretin (Ro 12-7310), 13-cis-etretin (Ro 13-7652) and the polyaromates arotinoid (Ro 15-0778), arotinoid acid (Ro 13-7410) and arotinoid ethyl sulfone (Ro 15-1570) for their effect on keratinocyte differentiation in vitro and to compare these results with differentiation data of retinoids currently used clinically. It was found that the second generation of retinoids had a lower antikeratinizing potential than the third generation of retinoids. They markedly inhibited crosslinked keratins and envelope proteins. Arotinoid acid was found to be the most potent derivative. In contrast to this, differences with regard to the synthesis of keratohyalingranule macroaggregates were detected between the retinoid derivatives. Arotinoid acid and arotinoid sulfone stimulated this protein fraction, whereas arotinoid left this fraction uninfluenced. If the data obtained were considered the selection criterion for the future therapeutic application of the new arotinoids in psoriasis therapy, it should be more useful to employ arotinoid acid or arotinoid sulfone rather than arotinoid in clinical psoriasis studies.
The rheological behavior of blood and its components under physiologic and pathophysiologic conditions is reviewed, with a focus on the type and extent of pathohemorheological changes in surgical patients during hospitalization and thereafter, as well as their clinical consequences with regard to thromboembolic complications. During the operation and the postoperative period various hemorheological and hemostasiological alterations acquire clinical significance: 1. hyperreagibility of platelets with increased aggregation and adhesion tendency 2. changes in fibrinogen, albumin, and globulin concentrations, which affect viscosity and red cell aggregation 3. impairment of red cell deformability 4. increase in clotting factors 5. disturbance of fibrinolysis characterized by diminution of plasmatic plasmin and increase in antiplasmin activity In addition, anesthetic techniques have also been shown to affect hemorheological and hemostasiological parameters. The complex pattern of pathohemorheological and hemostasiological changes shows that thromboembolism in the course of surgical interventions is provoked by multifactorial disorders. Thrombosis prevention should, therefore, counteract both hemorheological and hemostasiological disturbances. Since pathohemorheological and pathohemostasiological changes are already detectable before, and increase during operation, preventive measures should start before the surgical intervention to obtain maximum benefit. Therapeutic possibilities for the avoidance of these multifactorial disturbances are discussed with particular reference to pentoxifylline, which satisfies the complex requirements of a hemorheologically and hemostasiologically active therapeutic agent.
Blood flow velocity waveforms were recorded by pulsed Doppler examination from fetal intracranial arteries in 83 normal and 84 high-risk pregnancies. The normal cases showed a decreasing resistance index of the waveform toward the end of pregnancy, and a continuous forward flow that was always present in these arteries. A low resistance index predicted the birth of a small-for-dates newborn and/or the appearance of subsequent cardiotocographic abnormality, with 57% sensitivity and 94% specificity. Two hydrocephalic fetuses had abnormally high resistance index values. An abnormal fetal intracranial arterial velocity waveform can be seen as a sign of increased perinatal risk.
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