[Systemic effects of ophthalmic solutions].
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Biomedical subjects
Publications and source records attributed to P Netter.
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In the mitochondrial DNA of Saccharomyces cerevisiae, the genes cob-box and oxi3, coding for apocytochrome b and cytochrome oxidase subunit I respectively, are split. Several mutations located in the introns of the cob-box gene prevent the synthesis of cytochrome b and cytochrome oxidase subunit I (this is known as the 'box effect').-We have elucidated the molecular basis of this phenomenon: these mutants are unable to excise the fourth intron of oxi3 from the cytochrome oxidase subunit I pre-mRNA; the absence of a functional bI4 mRNA maturase, a trans-acting factor encoded by the fourth intron of the cob-box gene explains this phenomenon. This maturase was already known to control the excision of the bI4 intron; consequently we have demonstrated that it is necessary for the processing of two introns located in two different genes. Mutations altering this maturase can be corrected, but only partially, by extragenic suppressors located in the mitochondrial (mim2) or in the nuclear (NAM2) genome. The gene product of these two suppressors should, therefore, control (directly or indirectly) the excision of the two introns as the bI4 mRNA maturase normally does.
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High-angle x-ray diffraction was applied to the study of four meniscal fibrocartilages and 11 articular cartilages from patients suffering from various articular disorders. In eight samples microcrystals were seen, apatite most frequently, CaHPO4 in two instances, calcium pyrophosphate dihydrate (CPPD) in one. These results confirm the association of various crystals in a single joint, and favour their heterogenous partition on collagen fibres.
The goal of this experimental study was to examine the effect on articular tissue of tribasic aluminium phosphate (crystalline and amorphous forms) after intraarticular injection in rabbit and to compare it with that of various phlogistic compounds such as carrageenin, calcium hydrogen phosphate dihydrate and diamond powder, as a control. Synovium and cartilage were studied with light microscopy, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and energy dispersive micro-analysis (EDM). Crystalline and amorphous aluminium phosphate could induce a synovitis with articular effusion in rabbits. With TEM, lysosomal inclusions of phagocytosed material were observed. Through SEM coupled with EDM, aluminium associated with phosphate was found in cellular elements.
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We studied the concentrations of aluminum in the articular tissues of 5 hemodialysed patients treated with aluminum compounds. Aluminum crosses the synovial barrier, is found in synovial fluid (SF) and accumulates in the joint structures (synovial membrane and joint cartilage). The concentrations found in synovial tissue were 2.7 to 10 times control values, in SF 2.5 to 8 times the control concentrations and in cartilage 2.6 times the control concentrations. Transmission electron microscopy showed localization of aluminum in the lysosomal structures and wavelength dispersive microprobe analysis showed aluminum in cellular components associated with phosphate. The possible toxicity of aluminum to joints merits further investigations.
The therapeutic effectiveness of non-steroid anti-inflammatory (NSAI) drugs is partly determined by their passage across the synovial membrane. The synovium can be compared to a double barrier the permeability of which to NSAI drugs depends on the degree of inflammation of the joint and on the pharmacokinetic properties of the drugs (lipophilia, pka, protein-binding). A few hours after one single systemic dose, concentrations in the synovial fluid are higher than in serum. During chronic administration, concentrations of NSAI drugs with a short half-life vary less in synovial fluid than in serum. During steady state, free fractions of NSAI drugs with prolonged half-life may be similar in both compartments.
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Pulse polarography has been applied to the determination of aluminium in bone. The sensitivity, selectivity and reproducibility of the method are described. The results of bone aluminium concentrations in controls and in haemodialysed patients treated with aluminium compounds are discussed. Pulse polarography permits very precise measurements of aluminium impregnating bone.
Ill-considered use of the Scatchard model often leads to unjustified deductions. Since the main difficulty of this model is its number of parameters, new models are proposed that have only two parameters. After checking the models on simulated data, they were applied to real data on the binding of salicylates to albumin.
The diffusion of oxyphenbutazone into synovial and cerebrospinal fluids and synovium and joint cartilage was investigated in 25 patients receiving short-term treatment. In the synovial fluid, the mean oxyphenbutazone concentration, was 57.1 +/- 13.4% of the plasma level, due to its excellent diffusion into the joint cavity. In synovial tissue, the oxyphenbutazone level was higher in patients with severe inflammation than in those with no or little inflammation. Penetration into joint cartilage is less than into synovial tissue. In cerebrospinal fluid the concentration was close to the level of free plasma oxyphenbutazone. The findings show increased diffusion of oxyphenbutazone towards its site of action in inflammation.
The paper reviews in the first part some of the most important contributions to pharmacological anxiety research of related scientific disciplines, namely human pharmacopsychology, animal behavioral pharmacology, neuropharmacology and pharmacopsychiatry. In the second part the main methodological problems encountered in research on psychopharmacology of anxiety are treated. The problems discussed refer to the assessment of anxiety, to the definition of the anxiety state and to the problem of unspecific drug actions and of response variability to drugs.
In 45 headache patients the relationship between sensory suggestibility and three measures of treatment effect--ratings on (1) intensity of headaches; (2) efficacy of drugs, and (3) physician's competence--was investigated in a double-blind long-term crossover study. Subjects scoring high on sensory suggestibility clearly showed more relief of headaches upon the analgesic as well as upon the placebo. The physician's competence was rated higher by high-suggestible patients, whereas ratings on drug efficacy were low in all patients. The seemingly controversial behavior of high-suggestible patients was interpreted as a call for continuation of the physician's efforts in spite of the relief the patients already achieved.
Types of hyper- and hyposympathetic plasma catecholamine response and types of pronounced epinephrine and pronounced norepinephrine response were identified within samples of hyper- and normotensive subjects each. Hypersympathetic subjects emerged as more active and well-adapted than hyposympathetic ones in both groups. Among hypertensives, subjects producing high levels of epinephrine and low levels of norepinephrine scored higher on state and trait anxiety scales than those with a reverse catecholamine pattern, while no such differences could be demonstrated between respective normotensive types.
We have constructed a refined genetic and physical map of 38 oxi3 mutations. With the help of the rho- clones derived from 'short' and 'long' genes, pairwise crosses between mutants, estimations of their reversion frequencies and analyses of mitochondrially synthesized proteins, we have characterized and localized several mutants in the exon A4 and in the intron aI4. We present genetic and physical evidence that in the 'long' gene the exon A5 is split into at least three quite distinct exons, A5-1, A5-2 and A5-3 where numerous mutations are localized. We suggest that a novel 56 Kd polypeptide, which accumulates in some cis-dominant oxi3- mutants results from the translation of the upstream exons and the downstream aI4 intron.
We have established the DNA sequence of two cis-dominant mutations located in the fourth intron, a14, of the yeast mitochondrial gene oxi3. These mutations prevent the synthesis of subunit I of cytochrome oxidase. Both mutations affect a very short DNA sequence located several hundred base pairs from the intron-exon junctions. An identical sequence is found in the cob-box gene; and this sequence is critical for the excision of the cytochrome b intron. Our interpretation is that this short sequence represents a common signal that must be recognized by the box7-encoded mRNA maturase, in conjunction with the mitochondrial ribosome, to splice out the introns in the two nonhomologous genes, cob-box and oxi3.
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