Visual function and car driving: longitudinal results 5 years after cataract surgery in a population.

AIMS: To determine visual function in drivers who had cataract surgery 5 years previously, and to analyse longitudinal data, by comparing preoperative and postoperative changes in subjective driving ability and objective visual function. METHODS: All patients (810) who underwent cataract surgery, during a 1 year period, were prospectively studied. Data regarding present driving status were collected from self administered questionnaires and visual acuity (VA) data were measured before and after surgery. All patients who were alive 5 years later were invited to participate with a new eye examination and questionnaire. RESULTS: Before surgery 36 active drivers (16%) did not fulfil the visual requirements for driving; with improved glasses this number could be reduced to 24 (11%). 5 years after surgery, the corresponding figures were 5% and 3% (5/174), respectively. Before surgery 50% stated visual difficulties while driving in daylight and 79% in darkness. A few months and 5 years after surgery the corresponding figures were 6% and 5%, respectively, for daytime driving and 34% and 44%, respectively, for night-time driving. CONCLUSIONS: Long term results regarding cataract surgery in car drivers are beneficial. 5 years after surgery only a few patients drove not fulfilling the requirements, but there were a larger proportion of patients with problems driving in darkness compared with a few months after surgery.

Conformation-activity correlations for chemotactic tripeptide analogs incorporating dialkyl residues with linear and cyclic alkyl sidechains at position 2.

Five stereochemically constrained analogs of the chemotactic tripeptide incorporating 1-aminocycloalkane-1-carboxylic acid (Ac(n)c) and alpha,alpha-dialkylglycines (Deg, diethylglycine; Dpg, n,n-dipropylglycine and Dbg, n,n-dibutylglycine) at position 2 have been synthesized. NMR studies of peptides For-Met-Xxx-Phe-OMe (Xxx=Ac(7)c, I; Ac(8)c, II; Deg, III; Dpg, IV and Dbg, V; For, formyl) establish that peptides with cycloalkyl residues, I and II, adopt folded beta-turn conformations in CDCl3 and (CD3)2SO. In contrast, analogs with linear alkyl sidechains, III-V, favour fully extended (C5) conformations in solution. Peptides I-V exhibit high activity in inducing beta-glucosaminidase release from rabbit neutrophils, with ED50 values ranging from 1.4-8.0 x 10(-11) M. In human neutrophils the Dxg peptides III-V have ED50 values ranging from 2.3 x 10(-8) to 5.9 x 10(-10) M, with the activity order being V > IV > III. While peptides I-IV are less active than the parent, For-Met-Leu-Phe-OH, in stimulating histamine release from human basophils, the Dbg peptide V is appreciably more potent, suggesting its potential utility as a probe for formyl peptide receptors.

Monitoring free extracellular valproic acid by microdialysis in epileptic patients.

This report describes the first experiences with monitoring of valproic acid pharmacokinetics in patients with epilepsy by subcutaneous microdialysis. We could demonstrate good correspondence between total concentration in plasma and free concentration in plasma and dialysate. In this study the dialysate concentrations were not corrected for in vivo recovery because the aim was to explore the possibilities of the method in routine clinical work rather than to estimate absolute concentrations in extracellular fluid. In one patient, microdialysis was continued for 3 days without problems. The dialysis probe with a small portable pump could be carried without any notable interference with daily activities of patients in the ward. No side effects were noted. The results encourage further studies along two lines: to investigate the free-concentration effect relation for valproic acid and to monitor drug concentration under nonhospital conditions in order to study the interaction between daily activities and drug concentration.

Human basophil histamine release is differently affected by inhibitors of calmodulin, diacylglycerol kinase and peptidyl prolyl cis-trans isomerase in a secretagogue specific manner.

To assess the role of calmodulin in human basophil histamine release, we triggered leukocytes with different secretagogues in the presence of putative inhibitors of calmodulin. Calcium ionophore-induced histamine release was reduced or blocked by calmidazolium, CGS 9343B, felodipine, metofenazate, and Ro 22-4839. H 186/86, a felodipine-related dihydropyridine derivative, blocked A23187-but not ionomycin-triggered histamine release, suggesting a difference in the mode of action of these ionophores. In contrast, leukocyte histamine release triggered by the purported protein kinase C (PKC) activator, 1,2-isopropylidene-3-decanoyl-sn-glycerol (IpOCOC9), was enhanced by calmidazolium, CGS 9349B and metofenazate but not affected by felodipine or Ro 22-4839, whereas the response triggered by 4 beta-phorbol 12-myristate 13-acetate (PMA) was reduced by metofenazate and Ro 22-4839 but not consistently affected by calmidazolium, CGS 9343B or felodipine. The PMA-induced histamine release was enhanced by H 186/86. Anti-IgE- and FMLP-induced responses were either unaffected or slightly enhanced by the examined calmodulin antagonists. In comparison with the calmodulin antagonists, R 59022, an inhibitor of diacylglycerol kinase, failed to reduce calcium ionophore-triggered histamine release, whereas FK506, an inhibitor of peptidyl prolyl cis-trans isomerase (PPI), reduced both anti-IgE- and ionophore-triggered responses. These results indicate that calmodulin constitutes an obligate link in signal transduction pathways leading to human leukocyte histamine release if the trigger is a calcium ionophore but not when responses are induced by anti-IgE, FMLP or PMA; a calmodulin-dependent component may rather balance responses induced by IpOCOC9.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of human basophil histamine release by protein kinase C inhibitors differs with secretagogue and with inhibitor.

To assess possible involvement of protein kinase C (PKC) in human basophil degranulation, the present work compared effects of various purported PKC inhibitors on leukocyte histamine release triggered by different stimuli. The effects recorded varied with the inhibitor and the secretagogue used; moreover, with a given secretagogue, different inhibitors often displayed different activities. Thus, histamine release triggered by the PKC activator 4 beta-phorbol 12-myristate 13-acetate was blocked by K252a, staurosporine and the purported specific PKC inhibitor Ro 31-7549, and reduced by calphostin C, H-7, TMB-8 and W-7 but not affected by polymyxin B; it was augmented by 2.1 microM palmitoyl carnitine. The leukocyte response induced by another putative activator of PKC, 1,2-isopropylidene-3-decanoyl-sn-glycerol, was also enhanced by 2.1 microM palmitoyl carnitine, slightly increased by staurosporine, TMB-8 and W-7 but not affected by calphostin C, H-7, K252a or Ro 31-7549, whereas the hyperosmolar mannitol-induced response was reduced by H-7, calphostin C, TMB-8 and W-7 and slightly augmented by staurosporine. Anti-IgE-induced histamine release was blocked by staurosporine and K252a and reduced by calphostin C, sphingosine, TMB-8 and W-7 but not affected by H-7, polymyxin B or retinal. It was enhanced by Ro 31-7549. In contrast, leukocyte histamine release induced by calcium ionophore A23187 or by ionomycin was blocked by retinal, TMB-8 and W-7 and reduced by calphostin C and palmitoyl carnitine but enhanced by H-7, staurosporine and polymyxin B; K252a and Ro 31-7549 did not affect such responses. Formyl-methionyl-leucyl-phenylalanine-triggered histamine release was barely affected by any agent used. Thus, the specific PKC inhibitor Ro 31-7549 selectively blocked 4 beta-phorbol 12-myristate 13-acetate-triggered leukocyte histamine release. These results imply that examined secretagogues trigger human leukocyte histamine release through partly separate pathways probably involving different kinase activities (PKC isozymes?). Moreover, the distinct effect patterns recorded for most purported PKC inhibitors imply a functional selectivity between these compounds.

Inhibition by galanin and by high K+ of human basophil histamine release triggered by calcium ionophores but not responses induced by anti-IgE, chemotactic peptide or phorbol ester.

1. Galanin concentration-dependently blocked human leukocyte histamine release triggered by the calcium ionophores A23187 and ionomycin. Almost complete inhibition of release was recorded at 410 nM whereas 41 nM galanin mediated close to 50% inhibition of responses. 2. Pretreatment of the cells with pertussis toxin did not influence the inhibitory effects of galanin. 3. Leukocyte responses triggered by anti-IgE, the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP) or 4 beta-phorbol 12-myristate 13-acetate (PMA) were not affected by galanin. 4. Ionophore-induced basophil histamine release, but not responses triggered by anti-IgE, FMLP or PMA, was inhibited when cells were challenged in medium containing high potassium (120mM). 5. We conclude that galanin and a depolarizing medium selectively inhibit ionophore-induced basophil histamine release.

Modulation of human leukocyte histamine release by sn-1,2-isopropylidene-3-decanoyl-glycerol and decanoic acid cyclopentyl methylester in comparison with effects of synthetic diacylglycerols and a phorbol ester.

Previous studies have shown that the glyceride derivative, sn-1,2-isopropylidene-3-decanoyl-glycerol (IpOCOC9), can trigger human leukocyte histamine release. Approximately 25% of the total cellular histamine content is extruded in the presence of 206 microM of IpOCOC9; at 69 microM, however, the secretagogue action of the compound is marginal. The characteristics of the release induced by IpOCOC9 are closely similar to those reportedly recorded at hyperosmolar triggering of basophils with mannitol, and in many respects they also mimic those observed at phorbol ester-induced histamine release. The compound decanoic acid cyclopentyl methylester (DACPME), a structural analogue of IpOCOC9, fails to induce histamine release. IpOCOC9, but not DACPME, stimulates human polymorphonuclear leukocyte cytosolic Ca2+- and phospholipid-dependent histone III-S kinase activity (unpublished observations). The secretagogue action of IpOCOC9 has therefore tentatively, at least partly, been attributed to a direct protein kinase C activation. In the present studies, we examined the influence of IpOCOC9 and DACPME on histamine release triggered by an ensuing exposure to anti-IgE, the calcium ionophore A23187, formyl-methionyl-leucyl-phenylalanine (FMLP), or 4 beta-phorbol 12-myristate 13-acetate (PMA). It is shown that IpOCOC9-treatment of cells results in either enhancement or reduction of the release induced by anti-IgE or by A23187, whereas FMLP-induced release is consistently reduced and PMA-induced release consistently enhanced by such a treatment. Treatment of cells with DACPME enhances but does not reduce anti-IgE-triggered release, whereas FMLP-induced release is not affected. Pretreatment of the cells with other putative protein kinase C activators like PMA, sn-1-oleoyl-2-acetyl-glycerol (OAG), 1,2-dioctanoyl-glycerol (DiC8) or the glycerol derivative sn-1,2-diacetyl-3-decanoyl-glycerol (DiC2OCOC9) affects secretagogue-induced basophil histamine release according to specific patterns similar to but not identical with those recorded for IpOCOC9 and DACPME. Thus, e.g., DiC2OCOC9 consistently reduces but does not enhance anti-IgE-triggered release. These data show that limited structural changes of IpOCOC9 may qualitatively affect its modulating properties in the human basophil histamine release system.

Induction of human basophil histamine release by a novel protein kinase C activator, sn-1,2-isopropylidene-3-decanoyl-glycerol (IpOCOC9): partial characterization of secretagogue characteristics.

Human leukocytes were found to release histamine at exposure for the synthetic glyceride derivative sn-1,2-isopropylidene-3-decanoyl-glycerol (IpOCOC9). The following characteristics for the IpOCOC9-induced basophil histamine release were recorded. A. In the order of 25% of the cellular histamine content was extruded at 206 mumol/l and 45% at 690 mumol/l of the compound, respectively. B. Removal of extracellular Ca2+ variably affected IpOCOC9-triggered release. C. The presence of N-ethylmaleimide (10 mumol/l) or p-bromophenacylbromide (10 mumol/l) markedly reduced IpOCOC9-induced histamine release. D. The time course of the release triggered by IpOCOC9 was intermediate to those characterizing the release triggered by 4 beta-phorbol 12-myristate 13-acetate (PMA) and by formyl-methionyl-leucyl-phenylalanine (FMLP). E. Cells desensitized to IgE-receptor-mediated stimulation were hyperresponsive to stimulation with IpOCOC9. F. Cells treated with a low concentration of 2-deoxyglucose were not hyperresponsive to IpOCOC9. These data show that IpOCOC9, a PMN/leukocyte protein kinase C stimulator, acts as a non-cytotoxic secretagogue for human basophils with a mode of action which in some, but not all respects, mimics that of PMA. In particular, IpOCOC9-triggered release resembles that reported by other authors for hyperosmolar triggering of release by mannitol.

The glucocorticosteroid, budesonide, partially blocks histamine release from human lung tissue in vitro.

IgE-receptor dependent, but not A23187-induced, histamine release from passively sensitized chopped human lung tissue, or from a dispersed lung cell population obtained from the tissue after enzymatic digestion, is reduced after incubation overnight of cells/tissue with the glucocorticosteroid budesonide (10(-7) M). Since the inhibitory effect of budesonide is reduced in the continuous presence of diluted reagin-rich serum used for passive sensitization, but not in the presence of heat-inactivated serum, it is suggested that the glucocorticosteroid acts by reducing the binding of IgE-antibody to the target cell(s).

Immunologically induced pleural and peritoneal mast cell histamine release: difference in responsiveness in relation to secretagogue and rat strain used.

Responsiveness was compared for cell populations harvested from the peritoneal and pleural cavities of rats with respect to histamine release induced by specific antigen, anti-IgE, and Con A. Cell populations were obtained from Fischer, PVG or Sprague-Dawley (SD) rats, which were either untreated or immunized with 10 micrograms ovalbumin together with 100 mg alum intraperitoneally. Mast cell histamine release was examined with crude cell populations. The results show that differences in response capacity to the various secretagogues employed do exist between pleural and peritoneal cells in Fischer and PVG strains but under the present circumstances apparently not in SD rats. These differences vary in magnitude with the secretagogue employed and (for cells from immunized animals) with the time elapsed between immunization and test. In PVG rats, neither pleural nor peritoneal mast cell histamine release induced by antigen paralleled serum OA-IgE antibody levels. Furthermore, an increase in anti-IgE induced release of histamine from serosal mast cells occurred in parallel with a decrease in total serum IgE levels. These data indicate that the functional differences observed with respect to release properties of the two cell populations are due not only to intrinsic differences in mast cell populations but also to differences in reaginic antibodies sensitizing the cells.

Renal complications to left renal vein ligation in abdominal aortic surgery.

Postoperative renal complications have been investigated in 31 patients subjected to left renal vein ligation during abdominal aortic surgery (11 ruptured and 18 non-ruptured aneurysms, 2 occlusive diseases). A marked increase in s-creatinine values was found in all patients after left renal vein ligation. The increase was significantly longer (p less than 0.01) and higher (p less than 0.005) as compared with control patients subjected to abdominal aortic surgery without ligation of the left renal vein. A sustained increase in postoperative s-creatinine values was found in 6 patients, one of whom had a total loss of left kidney function. Left-sided nephrectomy was necessary in 2 patients to control bleeding from the kidney. Acute haemorrhagic infarction and subinfarction of the left kidney were seen in 2 patients. A restricted application of left renal vein ligation during abdominal aortic surgery is recommended.

Anti-IgE-and ConA-induced histamine release from human basophilic leukocytes: the existence of differences in relative responses within individuals.

Histamine release was induced from human blood leukocytes with Concanavalin A (ConA) and two different preparations of anti-IgE. A dose-response curve was constructed for each cell population and secretagogue. No qualitative difference in response pattern was observed with the two anti-IgEs; however, the relative release-inducing efficacy of ConA and anti-IgE seemed to vary with the individual providing the cells. These findings indicate that release induced by ConA is not completely equivalent to that induced by anti-IgE.

Inhibitory effect of glucocorticosteroids on anti-IgE-induced histamine release from human basophilic leukocytes: evidence for a dual mechanism of action.

Anti-IgE-induced histamine release from human leukocytes is inhibited when the cells before challenge are cultured overnight in the presence of glucocorticoids (GCSs). The present report suggests that the GCSs might exert their effect by at least a dual mechanism of action. Histamine release was induced by a suboptimum concentration of anti-IgE. When the release recorded in the presence of the steroid is plotted against the release recorded in its absence, the data points of several experiments fit a regression line characterized by two parameters: its slope and its intercept with the abscissa. Structure-activity examination with selected GCSs indicates that the orders of potency for affecting these two parameters are not identical. Furthermore, pulse experiments suggest that the cells require different times of contact with the steroid to express inhibition according to the two parameters. The removal of adherent cells or platelets did not markedly affect the degree of leukocyte histamine release or its inhibition by a given GCS, suggesting that the steroid interacts directly with the basophil. Finally, steroid-induced inhibition was not affected by the putative phospholipase A2-inhibitor p-bromophenacylbromide (BPB) or the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA).

Anti-IgE-induced histamine release from rat tissues passively sensitized in vivo with myeloma IgE differs with strain and mast cell source.

Four different strains of rats, BDII, E3, LE, and OM/N, each with a low basal serum level of IgE, were examined with respect to anti-IgE- and ConA-induced release of histamine from serosal mast cells and chopped lung tissue. Tests were performed before and three days after i.p. injection of a graded dose of myeloma IgE (IR 162)-containing ascitic fluid. There was a clearcut strain difference in response capacity with respect to ConA- and anti-IgE-induced release of histamine from serosal mast cells before myeloma IgE-injection. Response capacity increased in some but not all strains after myeloma IgE injection; increase in response capacity of serosal mast cells did not correlate to that of chopped lung tissue. Analogous findings were observed when two of the strains, LE and E3, were passively sensitized by i.p. injection with serum containing another myeloma IgE (IR2). These results indicate that differences exist between mast cells of different rat strains, and within strain between mast cells of various tissues in capacity to become sensitized to myeloma IgE.

Antigen-induced release of histamine from serosal mast cells, lung, and tracheal tissue: variation with tissue and rat strain in relation to serum IgE-antibody level.

Rats of the Brown Norway (BN)2, Fischer, PVG and Sprague Dawley (SD) strains were immunized intraperitoneally with graded doses of ovalbumin (OA) together with either alum or Silica gel. At specified times after immunization, in vitro histamine release from serosal mast cells and from chopped lung and tracheal tissue was determined after challenge with OA. The development of the capacity to respond in these tests seemed to vary within strain independently for mast cells, lung, and tracheal tissue with immunization dose of antigen and nature of adjuvant. These variations were not closely correlated to observed variations in serum levels of OA-IgE antibody or ratio OA-IgE to total IgE as determined by radioimmunoassay. Furthermore, variations between strains in response capacity did not correlate to inter strain variation in median serum OA-IgE antibody level. These results do not clearly conform to the possibility that one single class of IgE mediates anaphylactic reactivity of various tissues of the rat.

Anti-IgE and Con A-induced histamine release from mast cells of four rat strains: correlation with total serum IgE.

Anti-IgE- and Con A-induced histamine release from serosal mast cells were compared to each other and to total serum levels of IgE in non-immunized, alum-injected, and Silica gel-injected rats of the BN, Fischer, PVG, and SD strains. The results indicate that the degree of anti-IgE- and Con A-induced release is strain-dependent and varies with immunization conditions. Furthermore, there is a gross but not complete correlation between the degree of serosal mast cell histamine release induced by the two secretagogues. However, Con A- or anti-IgE-induced release could significantly be correlated to serum levels of total IgE only in the Fischer strain but not in the BN or the PVG strains. In the SD strain, Con A-induced release correlated to serum IgE levels in Silica gel-injected but not in alum-injected animals.

Anti-IgE-induced histamine release from human basophilic leukocytes: inhibition depends on nature and concentration of inhibitor and secretagogue.

Histamine release from human basophilic leukocytes was induced by increasing concentrations of anti-IgE in the presence of various concentrations of 2-deoxyglucose (2-DOG), the histamine H2-receptor agonist dimaprit, theophylline, or enprofylline (a new antiasthmatic xanthine derivative). The results show that the degree of inhibition produced by each agent differed with the concentration of anti-IgE used and with the nature and concentration of the inhibitor. These data indicate that great care should be used when characterizing an inhibitor of mediator release by simply giving a figure for the per cent inhibition of release observed in its presence.

A new method for induction of fibrous renal artery stenosis in the pig designed for the study of percutaneous balloon catheter dilatation.

An open surgical method for the creation of experimental renal artery stenosis by ligation with chromic catgut is described. Microscopic examinations at different intervals demonstrated the development of fibrosis throughout the arterial wall. These stenoses seem to provide a suitable model for the study of the effects of balloon catheter dilatation. Previously reported techniques for experimental artery stenosis induction are briefly reviewed.

Partial purification and characterization of cyclic nucleotide phosphodiesterases from human bronchial tissue.

DEAE-Sephadex chromatography reveals the presence in extracts of human bronchial tissue of at least three separate cyclic nucleotide phosphodiesterases: a cyclic GMP-specific high affinity enzyme, a non-specific low affinity enzyme, and a high affinity cyclic AMP-specific enzyme. The activity of each fraction was partially characterized with respect to kinetic parameters, thermal stability, and the influence of a number of inhibitors. Each activity was found to resemble the activity of the previously characterized corresponding enzyme from whole lung tissue extracts. A high affinity non-specific phospho-diesterase previously isolated from lung tissue is missing in extracts of bronchial tissue.