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Biomedical subjects

E Fuchs

Publications and source records attributed to E Fuchs.

At least 55 records · Page 3Linked to original sources
PubMed1990

A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.

BACKGROUND: The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. METHODS: To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). RESULTS: The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the standard-treatment group and 34 percent for the low-dose group (P = 0.033). In both groups, 82 percent of the subjects had another opportunistic infection, and the length of time to that infection was similar in the two groups (P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved transiently in both groups, and serum levels of HIV antigen decreased in the subjects with antigenemia. The hemoglobin level declined to less than 5 mmol per liter (80 g per liter) in 101 subjects in the standard-treatment group and in 77 in the low-dose group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The neutrophil count declined to less than 0.750 x 10(9) per liter in 134 subjects in the standard-treatment group and in 96 in the low-dose group (51 vs. 37 percent, P = 0.0001). CONCLUSIONS: The reduced daily dose of zidovudine used in this study was at least as effective as the standard dose and was less toxic; however, with the use of a four-week induction period with a high dose followed by low-dose treatment, severe anemia and neutropenia were common complications of treatment with zidovudine.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Localization and quantification of [125I]-endothelin binding sites in human fetal and adult kidneys--relevance to renal ontogeny and pathophysiology.

Endothelins, 21 amino acid peptides, produced by endothelial cells are potent vasoconstrictors and mitogens. According to experimental studies in animals, endothelins seem to be involved in the regulation of renal hemodynamics. In order to gain insight into its potential effects in man, a quantitative analysis of its binding sites was performed in human kidneys. Because of the proliferative action of endothelin in cell culture we also compared binding sites in fetal and adult kidneys. Binding sites for [125I]-endothelin-1,2,3 were visualized by in-vitro autoradiography and quantified by densitometry. In both adult and fetal tissue, specific binding sites occurred in the cortex, medulla, and renal vessels. Unlabeled endothelins and sarafotoxin, a peptide with a high sequence homology to endothelins, inhibited [125I]-endothelin-1 binding with IC50 in the 9.8 to 0.023 nM range, whereas unrelated peptides (angiotensin II, atrial natriuretic peptide) and the calcium antagonist nitrendipine failed to compete for [125I]-endothelin-1 binding sites. Linear Scatchard analysis revealed that the number of binding sites (expressed per tissue equivalent: TE) were consistently higher in fetal than in adult kidneys, while affinities did not differ significantly in cortex, medulla, and vessels (fetal/adult: cortex KD 43.4 +/- 19.6/55.9 +/- 16.7 nM; BMax 13.5 +/- 7.8/2.7 +/- 1.3 fmol/mg TE; medulla KD 26.3 +/- 10.9/34.6 +/- 7.4 nM; BMax 10.1 +/- 0.9/3.7 +/- 1.1 fmol/mg TE; vessels KD 41.1 +/- 22.9/23.7 +/- 8.1 nM; BMax 12.9 +/- 3.9/4.1 +/- 1.2 fmol/mg TE). Medullary capillaries and veins showed strong binding in human and rat kidneys which may be important for the pathophysiology of acute renal failure. Human adult and fetal glomeruli had only a few binding sites. This contrasts to findings in the rat kidney in which glomeruli have a high concentration of endothelin binding sites; although this does not role out an influence per se, it does point out the need to subject the assumption of a relevant glomerular effect of endothelin in man to closer scrutiny. The diffuse and strong binding in fetal kidney may indicate a role for endothelin in the process of renal maturation.

Adult↗
PubMed1990

Alpha 2-adrenergic binding sites in the medulla oblongata of tree shrews demonstrated by in vitro autoradiography: species related differences in comparison to the rat.

Alpha 2-adrenergic binding sites in the medulla oblongata of tree shrews and rats were detected and quantified by in vitro-autoradiography with the alpha 2-antagonist 3H-rauwolscine (3H-RAUW). The autoradiographic pattern of the radioligand binding in the tree shrew medulla oblongata resembles that which has been described by others for the human myelencephalon. This pattern coincides well with the occurrence of catecholaminergic structures detected by immunocytochemistry with antibodies against phenylethanolamine-N-methyltransferase and tyrosine hydroxylase. In contrast to the rat, where only the nucleus tractus solitarii and the nucleus dorsalis nervi vagi were labeled, five discrete nuclei specifically bound 3H-RAUW in tree shrews. The highest number of binding sites was detected in the nucleus dorsalis nervi vagi (nX; Bmax: 333 fmoles/mg) and the nucleus tractus solitarii (NTS; 311 fmoles/mg), followed by the nucleus nervi hypoglossi (nXII; 297 fmoles/mg), the nucleus reticularis parvocellularis (FRS; 230 fmoles/mg), and the area of the catecholamine cell groups A1 and C1 (area C1; 202 fmoles/mg). Maximal binding in the two labeled nuclei of the rat was 158 fmoles/mg. The discrete nuclei of the two species also showed different affinities for 3H-RAUW with Kd ranging from 0.17 to 0.83 nM in tree shrews and 1.80 to 1.95 nM in rats. Competition experiments revealed that the radioligand bound specifically to alpha 2-binding sites. In the tree shrew, nX, nXII and the area C1, also have a relatively high affinity for the alpha 1-antagonist prazosin which is a quality of the adrenoceptor subtype alpha 2B. Furthermore, in the area C1, 3H-RAUW binding was inhibited by the dopamine antagonist haloperidol. There are thus species related as well as regional differences with respect to the number, the affinity, and the pharmacological properties of alpha 2-binding sites in the medulla oblongata. In tree shrews, alpha 2-adrenoceptors can be autoradiographically quantified in regions which are not labeled in the rat, although former data predicted the existence of such receptors, e.g., in the area of the adrenaline cell group C1.

Animals↗
PubMed1990

The initiation of translation in E. coli: apparent base pairing between the 16srRNA and downstream sequences of the mRNA.

Bacteriophage T7's gene 0.3, coding for an antirestriction protein, possesses one of the strongest translation initiation regions (TIR) in E. coli. It was isolated on DNA fragments of differing length and cloned upstream of the mouse dihydrofolate reductase gene in an expression vector to control the translation of this gene's sequence. The TIR's efficiency was highly dependent on nucleotides +15 to +26 downstream of the gene's AUG. This sequence is complementary to nucleotides 1471-1482 of the 16srRNA. Similar sequences complementary to this rRNA region are present in other efficient TIRs of the E. coli genome and those of its bacteriophages. There seems to be a correlation between this sequence homology and the efficiency of the initiation signals. We propose that this region specifies a stimulatory interaction between the mRNA and 16srRNA besides the Shine-Dalgarno interaction during the translation initiation step.

Bacterial Proteins↗
PubMed1990

Occupational performance of a paced secondary task under conditions of sensory deprivation. I. Heart rate changes in train drivers as a result of monotony.

Twelve experienced train drivers were asked to operate the train function safety circuit (SIFA)--a paced secondary motor task which is expected to guarantee the driver's fitness for service on engines of the German Federal Railway--under laboratory conditions of extreme monotony. In spite of massive decreases in vigilance as shown by theta-activity in the EEG, all subjects were able to operate the device without major errors. A prerequisite for adequate performance is an EEG-defined arousal reaction, which is synchronized with the SIFA cycles. For 7 subjects the time-related cross-correlation coefficients between SIFA operation, alpha-activity (indicative of alertness), theta-activity (indicative of reduced vigilance), and heart rate were calculated. The central-nervous arousal found in the EEG corresponded to distinct increases in heart rate. The moments of SIFA operation after phases of light sleep correlated significantly and positively with increases in heart rate. These increases constituted a physiological overcompensation as far as the physical readiness was concerned which reached its peak after the task had been performed satisfactorily, constituting additional and superfluous occupational stress. The results of this study indicate clearly that monotony stress is not a result of occupational monotony itself, but the result of the physiological effort which is required in order to regain a level of alterness which allows adequate performance under monotonous conditions.

Electroencephalography↗
PubMed1990

Occupational performance of a paced secondary task under conditions of sensory deprivation. II. The influence of professional training.

Twelve truck drivers operated the train function safety circuit (SIFA), a paced secondary task used as a job monitor on German railways engines, under laboratory conditions of extreme monotony, in a comparison with 12 train drivers who were well acquainted with SIFA. Alertness was determined by means of EEG evaluations. Heart rate was monitored as the parameter for physical load, and the precoded SIFA tasks as the active response parameter. In spite of significantly more frequent and more distinct decreases in alterness, the SIFA-trained subjects (TS) performed better. Nine out of 12 TS reached the stage of light sleep at least once during the experimental run, as compared to 4 out of 12 untrained subjects (US). Nevertheless, the ratio acoustic warnings/occurrence of light sleep was significantly lower in TS (P less than 0.01), and there were three operational errors (equivalent to emergency braking) in US. Whereas US received fewer acoustic warnings in the stages of slightly reduced altertness, this trend was reversed as soon as low frequency theta-activity appeared in the EEG. A time-related calculation of the cross-correlation coefficients between SIFA operation, alpha-activity, theta-EEG-activity, and heart rate showed that timing of SIFA operation interrupting phases of light sleep correlated significantly and positively with increases in heart rate. The results suggest that a mechanism of rhythmic central nervous arousal interrupting phases of decreased alertness/drowsiness can be learned, whereas the physiological consequences of the effort to prevent the deterioration of performance under conditions of monotony are not reduced by professional adaptation.

Automobile Driving↗
PubMed1990

Psychosocial stress affects pineal function in the tree shrew (Tupaia belangeri).

Using a recently developed commercially available radioimmunoassay the concentration of the principal melatonin metabolite 6-sulfatoxymelatonin (aMT6s) in the morning urine of male tree shrews was determined. Chronic social confrontation elicited a drastic increase of aMT6s excretion in subordinate tree shrews, whereas there was a tendency to reduced excretion of the melatonin metabolite in dominant animals. These results substantiate the function of the pineal gland in transforming stimuli from the social environment to endocrine information and, therefore, are indicative for the relevant role the gland may play in the physiological reactions to chronic psychosocial stress.

Agonistic Behavior↗
PubMed1990

Dialysis acne.

Explore the source record for details and available documents.

Acne Vulgaris↗
PubMed1990

Elucidating the early stages of keratin filament assembly.

Because of extraordinarily tight coiled-coil associations of type I and type II keratins, the composition and structure of keratin subunits has been difficult to determine. We report here the use of novel genetic and biochemical methods to explore the early stages of keratin filament assembly. Using bacterially expressed humans K5 and K14, we show that remarkably, these keratins behave as 1:1 complexes even in 9 M urea and in the presence of a reducing agent. Gel filtration chromatography and chemical cross-linking were used to identify heterodimers and heterotetramers as the most stable building blocks of keratin filament assembly. EM suggested that the dimer consists of a coiled-coil of K5 and K14 aligned in register and in parallel fashion, and the tetramer consists of two dimers in antiparallel fashion, without polarity. In 4 M urea, both end-to-end and lateral packing of tetramers occurred, leading to a variety of larger heteromeric complexes. The coexistence of multiple, higher-ordered associations under strongly denaturing conditions suggests that there may not be a serial sequence of events leading to the assembly of keratin intermediate filaments, but rather a number of associations may take place in parallel.

Chromatography, Gel↗
PubMed1990

Deletions in epidermal keratins leading to alterations in filament organization in vivo and in intermediate filament assembly in vitro.

To investigate the sequences important for assembly of keratins into 10-nm filaments, we used a combined approach of (a) transfection of mutant keratin cDNAs into epithelial cells in vivo, and (b) in vitro assembly of mutant and wild-type keratins. Keratin K14 mutants missing the nonhelical carboxy- and amino-terminal domains not only integrated without perturbation into endogenous keratin filament networks in vivo, but they also formed 10-nm filaments with K5 in vitro. Surprisingly, keratin mutants missing the highly conserved L L E G E sequence, common to all intermediate filament proteins and found at the carboxy end of the alpha-helical rod domain, also assembled into filaments with only a somewhat reduced efficiency. Even a carboxy K14 mutant missing approximately 10% of the rod assembled into filaments, although in this case filaments aggregated significantly. Despite the ability of these mutants to form filaments in vitro, they often perturbed keratin filament organization in vivo. In contrast, small truncations in the amino-terminal end of the rod domain more severely disrupted the filament assembly process in vitro as well as in vivo, and in particular restricted elongation. For both carboxy and amino rod deletions, the more extensive the deletion, the more severe the phenotype. Surprisingly, while elongation could be almost quantitatively blocked with large mutations, tetramer formation and higher ordered lateral interactions still occurred. Collectively, our in vitro data (a) provide a molecular basis for the dominance of our mutants in vivo, (b) offer new insights as to why different mutants may generate different phenotypes in vivo, and (c) delineate the limit sequences necessary for K14 to both incorporate properly into a preexisting keratin filament network in vivo and assemble efficiently into 10-nm keratin filaments in vitro.

Amino Acid Sequence↗
PubMed1990

TGF-beta and retinoic acid: regulators of growth and modifiers of differentiation in human epidermal cells.

In the epidermis of skin, a fine balance exists between proliferating progenitor cells and terminally differentiating cells. We examined the effects of TGF-beta s and retinoic acid (RA) on controlling this balance in normal and malignant human epidermal keratinocytes cultured under conditions where most morphological and biochemical features of epidermis in vivo are retained. Our results revealed marked and pleiotropic effects of both TGF-beta and RA on keratinocytes. In contrast to retinoids, TGF-beta s acted on mitotically active basal cells to retard cell proliferation. Although withdrawal from the cell cycle is a necessary prerequisite for commitment to terminal differentiation, TGF-beta s inhibited normal keratinization in suprabasal cells and promoted the type of differentiation commonly associated with wound-healing and epidermal hyperproliferation. The actions of TGF-beta s and RA on normal keratinization were synergistic, whereas those on abnormal differentiation associated with hyperproliferation were antagonistic. These observations underscore the notion that environmental changes can act separately on proliferating and differentiating cells within the population. Under the conditions used here, the action of TGF-beta s on human keratinocytes was dominant over RA, and TGF-beta s did not seem to be induced as a consequence of RA treatment. This finding is consistent with the fact that RA accelerated, rather than inhibited, proliferation in raft cultures. Collectively, our data suggest that the effects of both factors on epidermal growth and differentiation are multifaceted and the extent to which their action is coupled in keratinocytes may vary under different conditions and/or in different species.

Carcinoma, Squamous Cell↗
PubMed1990

Regulation of a human epidermal keratin gene: sequences and nuclear factors involved in keratinocyte-specific transcription.

The keratinocyte is a major cell type of the body, and in epidermis, keratinocytes have potential for future gene targeting and drug therapy. Despite the importance of keratinocytes in cell biology and medicine, little is known about the molecular mechanisms underlying keratinocyte-specific gene expression. Here, we report the first detailed characterization of the sequences and factors controlling expression of a human gene expressed specifically in keratinocytes. Using 5' upstream sequence of the human K14 keratin gene coupled to one of two reporter genes, we examined sequences necessary and sufficient for expression of K14 in both cultured human keratinocytes and in mitotically active basal keratinocytes of transgenic mouse epidermis. We demonstrated the existence of distal and proximal elements located 5' from the transcription initiation site of the hK14 gene, which when combined with a TATA box element, appear to act in concert to drive keratinocyte-specific expression. We examined the proximal region in detail. After using CAT assays to narrow a transcriptional activation element to within 110 bp, we demonstrated the existence of a keratinocyte nuclear factor which binds to a 10-bp palindrome, 5'-GCCTGCAGGC-3', within this domain. Using methylation interference analysis, we identified the G residues important for factor binding, and showed that point mutations in these G residues not only blocked factor binding but also resulted in decreased transcriptional activity of an hK14-CAT gene. The factor was most abundant in keratinocytes, was expressed at lower levels in some simple epithelial cell lines, and was not detected in fibroblasts or lymphoma cells. Moreover, the 10-bp sequence was similar to sequences found in the 5' upstream sequences of several other genes expressed in keratinocytes, and at least one of these genes, the human K1 gene, contained a sequence that competed with the hK14 proximal element for binding factor. Collectively, our data suggest that both the sequence and the nuclear factor that we have identified may be involved in controlling keratinocyte-specific expression in vitro and in vivo.

Animals↗
PubMed1990

Activation of glycogenolysis by stimulation of the hepatic nerves in perfused livers of guinea pig and tree shrew as compared to rat: differences in the mode of action.

A study on the metabolic and hemodynamic actions of hepatic nerve stimulation in the perfused liver of guinea pig and tree shrew as compared to rat was performed, since the density of liver innervation was reported to be different. 1) Nerve stimulation resulted in an increase in glucose release and decrease in lactate uptake or in a shift to output as well as a decrease in portal flow in all three species. The change in glucose output was very similar, that in lactate balance and flow was smaller in tree shrew than in guinea pig and rat. Apparently, the metabolic and hemodynamic changes did not reflect the different densities of liver innervation. 2) The overflow of the neurotransmitter noradrenaline into the hepatic vein differed very clearly in the three animals. In the guinea pig and tree shrew the maximal increase in noradrenaline concentration measured in the effluent was about 6-7-fold higher than in the rat. 3) The content of noradrenaline in the liver in vivo was about five-fold higher in the guinea pig and again another four-fold higher in the tree shrew than in the rat. The contents of adrenaline and dopamine were very low in comparison to those of noradrenaline. The different hepatic noradrenaline contents of the three species investigated are in line with the anatomical findings on the different innervation density. 4) Inhibitors of eicosanoid synthesis reduced the nerve stimulation-dependent metabolic and hemodynamic alterations in guinea pig liver as in rat liver indicating a similar mechanism in these species. Apparently, prostaglandins might be involved as mediators or modulators of nerve actions also in the more densely innervated guinea pig liver and not only in the less densely innervated rat liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1990

Ultrastructural and histochemical observations on secretory phenomena in the resting human mammary gland.

Ultrastructure and histochemistry of clinically normal appearing tissue and secretions of non-lactating human mammary glands have been investigated in order to document and analyse secretory phenomena in the resting gland. The material studied originated from women of different ages (18-74 years) who underwent plastic surgery or surgery for various disorders of the breast. The epithelia of small ducts and of alveolar enlargements as well as acini contained moderate amounts of mitochondria and of cisterns of the rough endoplasmic reticulum; the transcisterns of the Golgi apparatus which were surrounded by smooth and coated vesicles, exhibited modest dilatations, the number of lysosomes increased with age; regularly glycogen particles and bundles of intracellular filaments (phi 5 nm) were to be observed. Typical casein vesicles and stages of apocrine secretion of milk fat globules were not seen. The following features indicated secretory activity: differently sized vesicles and granules with flocculent, dense, or light contents were regularly to be seen in the apical cytoplasm often immediately below the apical plasma membrane of the epithelia of the small ducts and even more frequently in the alveolar enlargements. Secretory products of fine granular or filamentous structure, probably containing proteins, were frequently found within the lumen. Different types of lipid and liposome-like particles were detected both in intracellular localization as well as in ductal lumina. As demonstrated by lectin histochemistry the secretory products also contained a considerable amount of carbohydrate components. The composition of the secretory products of the resting gland is of clinical interest since the chronical deposition of secretions, which among others possibly contain enzymes producing oxygen radicals, may lead to pathological changes of mammary gland tissue.

Adult↗
PubMed1989

Histaminergic system in the tree shrew brain.

This study mapped the histamine-immunoreactive neuronal system in the brain of the tree shrew (Tupaia belangeri) and compared its structure with that of the rat and guinea pig. The histamine-containing cell bodies lay in the posterior ventral hypothalamus in the tuberomammillary complex, as in the rodents. The morphology of this complex resembled that of the rat. The histaminergic axons projected to nearly all parts of the brain. The main ascending bundle ran ventromedially: the densest innervation was found in the ventral hypothalamus, preoptic area, septum, medial part of nucleus accumbens, and bed nucleus of the stria terminalis. High fiber densities were present in the amygdaloid nuclei and claustrum. Another pathway ran dorsomedially along the periventricular hypothalamus and sent fibers to all parts of the diencephalon. Part of these fibers followed the central gray to the midbrain and spread laterally below the inferior colliculus. Another descending pathway ran through the interfascicular and medial raphe nuclei to meet the pontine central gray. The densest fiber networks were seen in the dorsal tegmental and parabrachial nuclei, and around the locus coeruleus. Also the substantia nigra, interpeduncular and mesencephalic reticular nuclei, colliculi, and vestibular and raphe nuclei received a dense histaminergic innervation. The organization of the fibers in the tree shrew brain resembled more that in the guinea pig than that in the rat. As compared with the guinea pig, more fibers were present, particularly in the globus pallidus, central thalamus, and deep cerebellar nuclei. No fibers were seen in the outer layer of the piriform cortex. In Tupaia, a laminar organization of the fibers was evident in the hippocampus, in contrast to the rodents. Also, a dense periventricular fiber plexus was prominent.

Animals↗
PubMed1989

Serum immunoreactive erythropoietin in HIV-infected patients.

Serum immunoreactive erythropoietin (SIE) and hemoglobin levels were measured in 152 patients infected with the human immunodeficiency virus. Anemia was present in 18% of asymptomatic patients who tested positive for the human immunodeficiency virus, 50% of patients with a condition related to the acquired immunodeficiency syndrome (AIDS), and 75% of patients with AIDS. The mean SIE level for untreated AIDS patients (26.2 +/- 2.4 mU/mL) was greater than for patients who tested positive for human immunodeficiency virus or patients with an AIDS-related condition but not outside the normal range for SIE (4 to 26 mU/mL), and the incremental increase in SIE level for a given decline in hemoglobin level was much less in AIDS patients than in patients with uncomplicated iron deficiency anemia. Forty-two patients were treated with zidovudine, and the hemoglobin level fell 10 g/L or more in 48%. In contrast to the untreated patients, however, the mean SIE level rose 10-fold to 214 mU/mL, and the incremental change in SIE level for a given decline in hemoglobin level was markedly increased. In the zidovudine-treated patients, erythrocyte mean corpuscular volume also rose significantly from a mean of 88.1 fL to 102 fL. However, in only 1 patient was there a corresponding increase in reticulocytes and in none was there amelioration of anemia. The data indicate that SIE level is inappropriately low in anemic AIDS patients. The ability of these patients to produce erythropoietin is intact and can be expressed with zidovudine therapy. However, even very high levels of SIE fail to stimulate erythropoiesis adequately.

AIDS-Related Complex↗