Studies on the absorption, distribution and metabolism of 1-alpha-tocopherol in the rat.
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Biomedical subjects
Publications and source records attributed to F Weber.
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Because of the lack of non-invasive methods for measuring muscle blood flow, quantitative investigations of blood flow in the skeletal muscle of hypertensive subjects are rare. We therefore developed a new method for the determination of muscle blood flow noninvasively and quantitatively by a combination of computed tomography and venous occlusion plethysmography (strain-gauge method). At two sites on one forearm (p = site of the largest diameter, d = 1 cm proximal to the epicondyle lat.) the volumes of tissues [Vt = total volume, VM = muscle volume, VSk = bone volume, VR = residual volume = Vt - (VM + VSk)] were determined by computed tomograms and total forearm blood flow (Fp and Fd, respectively in ml/100 ml tissue x min) measured by strain-gauge plethysmography. After correcting for the bone volume at the different sites, Fp and Fd were transformed into the absolute influx rates of blood volume (Qp and Qd). From Qp and Qd and the different tissue volumes, the muscle blood flow (FM in ml/100 ml muscle x min) could be calculated: (formula; see text) Results thus derived were compared with data from the literature Cooper et al. (17). At rest there was neither a significant difference in Fp (own results: 3.62 +/- 1.67, Cooper: 3.25 +/- 1.42 ml/100 ml tissue x min, means +/- S.D.) nor in FM (4.08 +/- 2.07 and 3.66 +/- 1.57 ml/100 ml muscle x min, respectively), however, Fp and FM were significantly different (p less than 0.05). In the mean, FM was 13% greater than Fp, range: -40 to +38% (Cooper 15%, range: -17 to +43%). The individual difference could not be predicted by any of the parameters. Testing the procedure by means of a pharmacological agent (clonidine) with known effects on muscle blood flow (no change) and skin blood flow (decrease) revealed the correct reproduction of this hemodynamic pattern with our method. The usual identification of total with muscle blood flow would have led to false conclusions.
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Enhancers are regulatory DNA elements, usually about 200 base pairs (bp) long, which are able to stimulate transcription of linked genes in eukaryotic cells. This activation can be exerted over large distances, and from a position 5' or 3' to the gene. Enhancers have been identified in viral genomes and cellular genes. Using a transient expression assay, we have analysed transcription of the rabbit beta-globin gene and the thymidine kinase gene from herpes simplex virus with and without a simian virus 40 (SV40) enhancer. S1 nuclease mapping shows a high level of specific transcripts when the genes are linked to the enhancer. To determine whether this increased number of transcripts is due to a higher transcription rate, or perhaps to a shift from nonspecific to specific initiation, we have performed run-on transcription assays with isolated nuclei. Our results, presented here, demonstrate that the SV40 enhancer increases the RNA polymerase density within the linked gene. Therefore, enhancers apparently increase the rate of transcription initiation without influencing the specificity of initiation.
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We report here on three patients suffering from recessive dystrophic epidermolysis bullosa and one suffering from generalized atrophic benign epidermolysis bullosa, all of whom developed cutaneous squamous cell carcinoma. Our observations and a review of the literature suggest that squamous cell carcinoma in generalized atrophic benign epidermolysis bullosa is very infrequent and has a better outcome compared to skin cancer in recessive dystrophic epidermolysis bullosa. These differences could be explained by the distinct pathophysiology and clinical course of each of these variants of epidermolysis bullosa. In contrast to UV-induced skin cancer, the tumours in epidermolysis bullosa develop on distal extremities at sites of chronic wound healing. The cases reported here underline the exceptional importance of early histopathological assessment of suspicious skin lesions in patients with epidermolysis bullosa.
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Computed tomography and magnetic resonance (MR) studies were done in one case of Behcet disease and showed a focal lesion in the upper brain stem. Early institution of therapy was followed by a complete clinical remission and disappearance of the CT and MR changes. Computed tomography and MR are important modalities for the early detection of Behcet disease when reversibility of the pathological changes is still possible.
Calcineurin antagonists FK506 and CsA, administered to treat organ allograft rejection, exert specific effects on renal vasoconstriction and nephrotoxicity, possibly due to endogenous vasoconstrictor release such as ET-1. We investigated contribution of FK506 and CsA on regulation of prepro ET-1 gene transcription in HUVEC. To conclude on transcriptional regulation, ET-1 mRNA levels were quantified by Northern blot analysis upon stimulation with calcineurin antagonists, and newly transcribed luciferase gene, placed under the control of the rat ET-1 promoter, was quantified by reporter gene assays, where luciferase activity reflects ET-1 promoter activation. Calcium fluorometry was employed to examine calcium dependency of ET-1 promoter-dependent gene transcription. Northern blot analysis shows differential induction of prepro ET-1 mRNA in favour of CsA over FK506. Likewise, luciferase assays demonstrate stronger ET-1 promoter-dependent stimulation of the reporter gene by CsA than by FK506. Transcription of prepro ET-1 gene upon stimulation with both calcineurin antagonists is regulated by intracellular calcium levels. Lack of extra- or intracellular calcium prevents ET-1 promoter-dependent gene transcription and ET-1 mRNA induction. These observations demonstrate that calcineurin antagonists FK506 and CsA differ in quality to induce transcription of prepro ET-1 in HUVEC via calcium-dependent nuclear signalling events. To examine the contribution of ET-1 in nephrotoxicity upon CsA and FK506 immunosuppression the availability of endothelin receptor antagonists or endothelin converting enzyme inhibitors is required.
To determine the diagnostic efficacy of F-wave amplitude and F/M-ratio measurements in routine electrodiagnostic examinations, normal values were established for the ulnar nerve and systematically applied to a group of patients with various nosological entities (Mononeuropathies at the elbow, radiculopathies of C8, polyneuropathies, anterior horn cell disorders, plexopathies, syringomyelias, others). As a result, F/M-ratio can distinguish between the various pathological conditions (P = 0.02). Patients with radiculopathy and accompanying myelopathy were identified by increased F/M-ratio. It is concluded that F-wave amplitude analysis can give hints for additional central pathology in the individual case.
Liver drug metabolism is a major source of drug interactions. Three major human in vitro models are employed to detect drug interactions in the preclinical phases of drug development: recombinant enzymes, human liver microsomes and primary human hepatocyte cell cultures. Results obtained from these models may vary during the different phases of drug development. Identification of the metabolic pathways, enzymes involved in drug metabolism (mainly cytochrome P450s), enzyme induction or inhibition allow us to detect the major pharmacokinetic drug interactions which can occur in man and to identify specific populations at risk for such interactions. In vitro models are essential to decide if and which future drug interaction studies should be performed in man. However, the clinical relevance of the potential pharmacokinetic drug interactions detected by these in vitro models remains to be determined and confirmed by human studies.
The efficacy of postoperative pain treatment after dental surgery procedures depends not only on the type of substance used but also on the time it is taken and the dose administered. Direct postoperative administration of 400 mg Ibuprofen (2nd administration after 6 hours) resulted in considerably greater pain relief, without increasing the risk for the patient, than when the drug was taken as required.
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The authors analyse the short-term prognosis of ulcerative colitis from a series of 65 patients followed during ten years and treated with the same attitude. The results are compared to those of the most important published, from which they differ just a little. The medical treatment is effective in 84,6% of cases. The mortality of first attack is 6,1%. Only 1,4% of patients in our series are colectomised. It seems that the short-term prognosis has been slightly better during the last few years perhaps because of improvement in management and appearance of corticosteroids and/or salazosulfapyridine. The factors of bad prognosis in a first attack are its severity, its extension to the whole colon, its beginning after 60 years.
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This paper introduces some comments on the complete text of Good Pharmacovigilance Publishing Practices, which forms appendix number 2 of the Good Pharmacovigilance Practices now published by the French Drug Agency, as was Good Clinical Practices. Each good practice is printed in italic and presented in a frame; the following comments are designed to facilitate its application. The technical terms that are used in this text are presented according to the glossary in Good Pharmacovigilance Practices.