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PubMed1989

Inositol trisphosphate production in squid photoreceptors. Activation by light, aluminum fluoride, and guanine nucleotides.

The light-stimulated production of inositol triphosphate (IP3), via hydrolysis of phosphatidylinositol bisphosphate (PIP2), can be demonstrated in an in vitro preparation of isolated distal segments of squid photoreceptors. The retina is labeled with [3H]inositol (Szuts, E. Z., Wood, S. F., Reid, M. S., and Fein, A. (1986) Biochem. J. 240, 929-932), and the rhodopsin-containing distal segments are isolated in artificial cytosol. Within 2 s after a flash, IP3 levels increase 200% (corresponding to an intracellular increase of approximately 5 microM), and the lipid precursor PIP2 decreases by 50%. Inositol bisphosphate (IP2) levels increase later, as a breakdown product of IP3. IP3 response is light-dependent, saturating when 0.5% of the rhodopsin is photoactivated. Guanosine-5'-O-(3-thiotriphosphate (GTP gamma S) binding demonstrates that the plasma membrane of most of the photoreceptor distal segments is intact or only transiently permeable. Membrane permeabilization enhances light-activated GTP gamma S binding but abolishes the light-activated IP3 production. Receptor-mediated production of IP3 is believed to be the result of a receptor-G-protein-phospholipase C cascade (i.e. Cockcroft, S., and Gomperts, B. D. (1985) Nature 314, 534-536). To test for G-proteins, we incubated the photoreceptors in AlF4- (an activator of G-proteins) in the dark. IP3 and IP2 were produced with a corresponding decrease in PIP2. Incubation with GTP or GTP gamma S, in hypotonic buffer, which causes transient leakiness, increased dark levels by IP3 by 50%. Addition of GTP in isotonic buffer enhanced the light-induced increase of IP3. These results localize the light-stimulated phospholipase C activity to the distal segments and suggest that a G-protein couples rhodopsin to phospholipase C.

Aluminum↗

PubMed1989

Neural networks--an artificial intelligence approach to the analysis of clinical data.

This paper describes an approach to the pattern recognition problem of categorizing evoked response waveforms, using that branch of artificial intelligence known as neural networking. A total of 19 subjects (38 eyes) were exposed to a reversing chequerboard pattern, and the resulting Pattern electroretinogram (PERG) recorded. This was repeated for each of the subjects at contrast levels of 75%,50% and 25%, with the resulting response becoming less pronounced as the contrast level was decreased. The subjects were also given an Arden contrast sensitivity test, and the resulting scores recorded for each eye. The averaged responses from each of the 3 contrast levels for each of the 38 eyes tested were used as the input to a computer simulated 3-input per neuron cascaded neural network. The output and weighting parameters for the individual neurons were then varied until the network was able to optimally classify the PERG results on the basis of the Arden contrast sensitivity scores. The neural network was thus taught to recognize patterns in the PERG responses in much the same way that an experienced clinician might. A second neural network was similarly taught to classify the PERG responses on the basis of a clinician's subjective rating of each of the responses.

Adult↗

PubMedDate not supplied

The effect of heparin on three whole blood activated clotting tests and thrombin time.

Whole blood activated clotting time (ACT) can be determined by many different methods that use a variety of clotting cascade activators and end-points. This study compared the results of three whole blood ACT instruments at equivalent concentrations of heparin. Whole blood (9.8 ml) from 10 healthy adult volunteers without coagulation abnormalities was added to 0.2 ml of heparin solution producing heparin concentrations of 0, 0.1, 0.2, 0.4, 0.6, 0.8, and 1.0 U/ml. Coagulation status was determined in duplicate with the Hemochron 400 System (HC), the HemoTec Automated Coagulation Timer (HT), and the TriMed ACTivator (TM). Thrombin times or dilutions (TT) were also determined for each sample. Baseline values did not differ (p greater than 0.05); however, the HT and TM ACT values were significantly longer (p less than 0.05) than the HC ACT values at predicted heparin concentrations greater than 0.2 U/ml. Results from the HT and TM instruments were not significantly different. The HT and TM instruments both provided a greater ACT range over the heparin concentrations tested. Of the tests studied to monitor heparin therapy, mean scaled TTs showed the best correlation with predicted heparin concentrations.

Adult↗

PubMed1992

Human 55-kDa receptor for tumor necrosis factor coupled to signal transduction cascades.

The numerous biological activities of tumor necrosis factor (TNF) appear mediated by two types of receptors of 55 kDa (TR55) and 75 kDa (TR75) molecular mass. To test TR55 for its individual role in signaling across the membrane, a cDNA coding for the human TR55 was stably expressed in murine 70Z/3 pre-B cells, which lack binding sites for, and proved nonresponsive to human TNF. The transfected TR55 showed high affinity ligand binding and active internalization. It is demonstrated that the TNF signaling cascade, i.e. stimulation of protein kinase C, sphingomyelinase, and phospholipase A2, production of the second messengers diacylglycerol and ceramide, can occur completely through exclusive binding of TNF to TR55. The p55 TNF-binding site functions as an autonomous TNF receptor that mediates key signal transduction pathways, which may control the majority of TNF actions.

Animals↗

PubMed1988

Myocardial perfusion imaging for detection of silent myocardial ischemia.

Despite the widespread use of the exercise stress test in diagnosing asymptomatic myocardial ischemia, exercise radionuclide imaging remains useful for detecting silent ischemia in numerous patient populations, including those who are totally asymptomatic, those who have chronic stable angina, those who have recovered from an episode of unstable angina or an uncomplicated myocardial infarction, and those who have undergone angioplasty or received thrombolytic therapy. Studies show that thallium scintigraphy is more sensitive than exercise electrocardiography in detecting ischemia, i.e., in part, because perfusion defects occur more frequently than ST depression and before angina in the ischemic cascade. Thallium-201 scintigraphy can be performed to differentiate a true- from a false-positive exercise electrocardiographic test in patients with exercise-induced ST depression and no angina. The development of technetium-labeled isonitriles may improve the accuracy of myocardial perfusion imaging.

Coronary Disease↗

PubMed1988

Characterization of a monoclonal antibody MoAb bH6 reacting with a neoepitope of human C3 expressed on C3b, iC3b, and C3c.

Activation products of the complement cascade contain neoepitopes that are not present in the individual native components. Monoclonal antibodies detecting neoepitopes have been used for direct quantification of activation at different steps in the cascade. These methods are suggested to be more sensitive and reliable than conventional complement activation tests, which are hampered by precipitation or fractionation procedures. The present study describes production screening and characterization of a monoclonal antibody (MoAb) bH6. MoAb bH6 exhibited a significantly higher binding capacity to ELISA plates coated with zymosan-activated human serum than to plates coated with EDTA plasma. When fixed to the enzyme-linked immunosorbent assay (ELISA) plates, MoAb bH6 retained material from zymosan-activated serum that only reacted with anti-C3 antibodies. Crossed immunoelectrophoresis performed on zymosan-activated serum demonstrated that MoAb bH6 co-precipitated with anti-C3c antibodies. In experiments using highly purified cell-bound fragments MoAb bH6 showed reactivity with C3b and iC3b, but not with C3d. MoAb bH6 reacted in ELISA with purified C3c, but not with C3dg, both as capture antibody and in tests with the fragments absorbed to the solid phase. Thus, MoAb bH6 is highly specific for a neoepitope of human C3 expressed on the cleavage fragments of C3b, iC3b, and C3c.

Antibodies, Monoclonal↗

PubMed1989

Morphogen gradients and the control of body pattern in insect embryos.

The basic body plan of insects is set up in response to determinants initially localized at the anterior and posterior poles of the egg. Early in development, these determinants give rise to a series of morphogen gradients which in turn trigger a cascade of molecular signals determining the body pattern. This signalling process is outlined and recent experiments testing the roles of these gradient systems in determining anterior and posterior pattern are described. The results of these experiments suggest that anterior pattern is controlled by a single instructive gradient, whereas posterior pattern depends on the overlap of several gradients, each providing only one or a few distinct responses.

Animals↗

PubMed1992

cAMP modulates multiple K+ currents, increasing spike duration and excitability in Aplysia sensory neurons.

Enhancement of the defensive withdrawal reflex of Aplysia involves a prolongation of the action potentials of mechanosensory neurons, which contributes to facilitation of transmitter release from these cells. Recent reports have suggested that whereas cAMP-dependent modulation of K+ current increases sensory neuron excitability, a cAMP-independent decrease in K+ current may increase the action potential duration and, thus, facilitate transmitter release. We have tested this proposal using Walsh cAMP-dependent protein kinase inhibitor or activators of the cAMP cascade and found that cAMP plays a major role in the spike-broadening effects of facilitatory transmitter; however, broadening requires higher levels of activation of the cAMP-dependent kinase than does increasing excitability. A steeply voltage-dependent transient K+ current, termed IKV,early, and the slowly activating S-type K+ (S-K+) current are both reduced by activation of the cAMP cascade, although with different sensitivities to the second messenger, enabling excitability and spike duration to be regulated independently. Differences in cAMP sensitivity also suggested that the originally described S-K+ current actually consists of two independent components, a slowly activating component and a time-independent, "steady-state" current that is activated at rest.

Action Potentials↗

PubMed1989

Leukocyte stimulation of intimal lesion formation is inhibited by treatment with diclofenac sodium and dexamethasone.

This investigation tested the effect of anti-inflammatory agents acting at different levels of the arachidonic acid cascade on leukocyte migration into the vessel wall. An animal model of vasculitis was used in which leukocytes stimulate migration of smooth muscle cells from the media into the intima resulting in formation of intimal lesions. In this model, an endotoxin-soaked thread is implanted in the adventitia along the ventral side of the rat femoral artery. At 2 days, subendothelial and medial leukocyte accumulation occurs exclusively in the ventral half of the vessel. At 14 days, intimal lesions composed primarily of smooth muscle cells are localized to the ventral half of the vessel. Treatment with neither the lipoxygenase inhibitor L-651,392 nor the dual cyclooxygenase and lipoxygenase inhibitor BW755C affected leukocyte migration into the vessel wall or subsequent lesion formation. Treatment with the cyclooxygenase inhibitor diclofenac sodium greatly reduced both leukocyte accumulation and lesion formation, whereas leukocyte migration and lesion formation were nearly totally inhibited by treatment with dexamethasone. Thus, it has been demonstrated that although leukocyte accumulation in the vessel wall stimulates intimal lesion formation, pharmacologic inhibition of leukocyte accumulation prevents lesion formation.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1987

Role of HLA class I and class II antigens in activation and differentiation of B cells.

The monoclonal antibodies (MoAb) CR10-214, CR11-115, and Q1/28 to distinct monomorphic determinants of HLA class I antigens, the MoAb CL413 and PTF29.12 recognizing monomorphic determinants of HLA-DR antigens, the anti-HLA-DQw1 MoAb KS11, the anti-HLA-DPw1 MoAb B7/21, and the anti-HLA-DR,DP MoAb CR11-462 were tested for their ability to modulate human B-lymphocyte proliferation and maturation to IgM-forming cells. Purified tonsillar B cells were stimulated with Staphylococcus aureus bacteria of the Cowan first strain (SAC) or anti-human mu-chain xenoantibodies, as well as in growth factor- or T-cell-dependent activation cultures. The B-cell proliferative responses induced by SAC or by mitogenic concentrations of anti-mu-chain xenoantibodies were inhibited by some of the anti-HLA class I and anti-HLA class II monoclonal antibodies tested. The same antibodies were effective inhibitors of the proliferation of B cells stimulated with interferon-gamma (IFN-gamma) or interleukin-2 (IL-2) and with submitogenic concentrations of anti-mu-chain xenoantibodies. The proliferation induced by IL-2 of SAC-preactivated B cells was inhibited by some of the anti-HLA class II monoclonal antibodies, but not by the anti-HLA class I monoclonal antibodies tested. This inhibition appeared to reflect at least in part a direct effect on later events of the B-cell activation cascade, since some anti-HLA class II monoclonal antibodies still exerted considerable inhibitory activity when added together with IL-2 to SAC-preactivated B cells after the third day of culture. Anti HLA-DR, DQ, and DP monoclonal antibodies consistently inhibited the IgM production induced in B cells by T cells alone, T cells plus pokeweed mitogen (PWM), SAC plus IL-2, or IL-2 alone. In contrast, two of the three anti-HLA class I monoclonal antibodies tested inhibited the IgM production in cultures stimulated with SAC plus IL-2 and one the IgM production induced by IL-2 alone, but none of them had inhibitory effects on T-cell dependent IgM production. The results reported herein indicate that HLA class II molecules directly participate in different phases of the B-cell activation cascade. In addition, our data also suggest that HLA class I molecules can be involved in the events leading to B-cell proliferation and differentiation into immunoglobulin-secreting cells.

Antibodies, Monoclonal↗

PubMed1988

Effect of calcium ionophore A23187 and of leukotrienes B4 and C4 on the adherence of mononuclear leucocytes in multiple sclerosis.

The disturbances of the arachidonic acid metabolic cascade are supposed to play a significant part in some membrane alterations and in associated immunopathological changes in multiple sclerosis. Since the lipoxygenase derivatives of the arachidonic acid and the calcium ion influx were proved to participate in the mechanisms involved in the leucocyte adherence inhibition phenomenon, the effect of calcium ionophore A23187 and of leukotrienes B4 and C4 upon the adherence of mononuclear leucocytes of multiple sclerosis patients and of healthy controls was investigated in the present study using a modification of the leucocyte adherence inhibition assay. A23187, a potent stimulator of the arachidonic acid metabolism, induced the mononuclear leucocyte adherence inhibition in a dose-dependent manner. In multiple sclerosis patients without corticosteroid treatment and in those treated with lower prednison doses (up to 5 mg/day), the non-adherent response to A23187 stimulation was significantly lower than in the controls, whereas in multiple sclerosis patients treated with prednison doses varying from 20 to 90 mg/day the A23187-induced adherence inhibition reached non-significantly higher values compared to the controls. Leukotrienes B4 and C4 stimulated the adherence of the leucocytes in multiple sclerosis patients treated with higher prednison doses. Compared to controls, statistically significant differences were found using 1 nM and 100 nM LTC4. The findings obtained in this study with all probability reflect alterations of the membrane processes in multiple sclerosis leucocytes associated with calcium ion homeostasis and arachidonic acid metabolic cascade.

Adult↗

PubMed1988

[Chronic urticaria--still a vexing problem? Progress in diagnosis and therapy].

Despite the suggestion than an intolerance reaction could be a possible cause of chronic urticaria in some cases, the pathogenesis of this disease remains enigmatic. It is unlikely that an intolerance reaction to substances used in provocation testing is the cause of the daily rashes. It rather seems that the intolerance reaction is an indication of a certain instability of the mast cell membrane of other factors of the reaction cascade leading to the wheals. Fortunately, an effective symptomatic therapy is available in such cases where the cause cannot be detected and the trigger cannot be avoided. The modern, non-sedating H1-antihistamines have been tested in clinical-experimental studies as well as in a multicentric study in patients with chronic urticaria. In histamine-induced wheals, terfenadine was slightly superior to other non-sedating H1-blockers, when the grade of reduction of wheals and flare areas was taken as criterion. In clinical studies, another antihistamine, loratadine, was slightly, but statistically not significantly superior to terfenadine. In cases that cannot be effectively treated with H1-blockers alone, the additional administration of non-steroidal antiphlogistics (acetylsalicylic acid, indomethacin) is recommended. To avoid aggravation of the symptoms caused by the antiphlogistics, the drugs must be given in increasing dosages and after concurrent treatment with H1-blockers. With this combined therapy, about 50% of the patients present amelioration.

Chronic Disease↗

PubMedDate not supplied

The effects of drugs on the arachidonate cascade in experimentally burned rabbits.

Platelet reduction and renal dysfunction may occur after major thermal injury and be causally related to changes in the arachidonate cascade. In this article two new drugs, prostaglandin I2 analog OP-41483 (Venopirin) and thromboxane synthetase inhibitor OKY-046 (Cataclot), were tested in addition to aspirin in animal experiments with rabbits. The rabbits were divided into five groups and measurements made before and 8 and 24 hours after burn injury. The results indicate that platelet reduction and renal dysfunction occur within 8 hours after thermal injury in the no-therapy group and renal dysfunction could not be prevented completely even by adequate infusion therapy, but treatment with OP-41483 proved to suppress platelet reduction and improve renal function. Improvement in renal function was also noted in animals treated with aspirin or OKY-046, but platelet reduction could not be prevented by these drugs. Analysis of the time course of changes in thromboxane B2 level and 6-keto prostaglandin F1 alpha level disclosed that animals treated by infusion showed an elevation in thromboxane B2 and a significant elevation in the thromboxane B2/6-keto prostaglandin F1 alpha ratio, whereas animals treated with these three drugs showed a reduction in the thromboxane B2/6-keto prostglandin F1 alpha ratio. These results indicate that an effective measure for prevention of dysfunction of the organs after thermal injury is treatment with drugs that can modify the arachidonate cascade and cause an absolute or relative reduction in TXA2.

6-Ketoprostaglandin F1 alpha↗

PubMed1990

The first EGF-like domain from human factor IX contains a high-affinity calcium binding site.

It has been suggested that epidermal growth factor-like (EGF-like) domains, containing conserved carboxylate residues, are responsible for the high-affinity calcium binding exhibited by a number of vitamin K-dependent plasma proteins involved in the control of the blood coagulation cascade. These include the procoagulant factors IX and X, and the anticoagulants protein C and protein S. To test this hypothesis we have expressed the first EGF-like domain from human factor IX (residues 46-84) using a yeast secretion system, and examined calcium binding to the domain. Using 1H-NMR to measure a calcium-dependent shift assigned to Tyr69 we have detected a high-affinity calcium binding site (Kd = 200-300 microM). We suggest that other EGF-like domains of this type may have similar calcium binding properties. In addition, we have completely assigned the aromatic region of the NMR spectrum by NOESY and COSY analysis, and have used these data to discuss the effect of calcium and pH on the conformation of the domain with reference to a model based on the structure of human EGF.

Amino Acid Sequence↗

PubMed1991

The prophenoloxidase system and in vitro interaction of Trypanosoma rangeli with Rhodnius prolixus and Triatoma infestans haemolymph.

The presence of the prophenoloxidase (proPO) system in the haemolymph of Rhodnius prolixus and Triatoma infestans and the role played by Trypanosoma rangeli in the in vitro activation of proPO were tested. Both R. prolixus and T. infestans whole blood preparations showed a very active ProPO system. The proPO cascade of the two insect species were differentially activated by microbial-derived extracts: laminarin was a better activator of T. infestans haemolymph than of R. prolixus blood, and lipopolysaccharides from Shigella flexneri or Pseudomonas aeroginosa caused significant proPO activation of T. infestans haemolymph but not of R. prolixus preparations. For the two insect species, neither T. rangeli from culture nor parasite lysates were able to trigger proPO activation. The presence of the parasite in R. prolixus haemolymph/laminarin assays, however, significantly reduced the level of proPO activation to that of spontaneous activating controls. The immobilization of T. rangeli in vitro in haemolymph preparations occurred in both insect species and was dependent on the proPO activation intensity. Our results suggest that the susceptibility of R. prolixus to T. rangeli haemocoel infection may be explained, at least in part, by the suppression of the insect immune defence system i.e., inhibition of proPO in the presence of this protozoan parasite.

Animals↗

PubMed1991

Physical properties and clinical efficacy of two sodium cromoglycate inhalation aerosol preparations.

In this study, the particle size distribution and the droplet characteristics of the delivered aerosol cloud were first determined for two disodium cromoglycate inhalation aerosol preparations obtained from different manufacturers. In addition, the in vitro deposition properties and the clinical efficacy of these preparations were compared. The evaluation of the in vitro deposition was performed using a cascade impactor. The clinical efficacy was monitored by measuring the peak expiratory flow (PEF) values after the exercise test in fifteen asthmatic patients. The particle size and the spray characteristics of these two inhalation aerosol preparations were similar; the results of the in vitro test confirmed their similar physical properties. Both disodium cromoglycate preparations clearly alleviated the bronchoconstriction after the exercise test. According to the results of the clinical trial, supported by the laboratory scale studies, both disodium cromoglycate aerosols are of equal value in asthma inhalation therapy.

Administration, Inhalation↗

PubMed2025

Cost-effectiveness of alternative cascade screening strategies for familial hypercholesterolemia with realistic cascade screening acceptance rates and use of novel treatment.

BACKGROUND AND AIMS: Cascade screening (CS) for familial hypercholesterolemia (FH) has been found to be cost-effective in many published studies. However, most existing studies (i) ignored or overstated first-degree relative (FDR) participation rate (as 60-100 %), (ii) did not consider novel and expensive therapies, e.g. PCSK9 inhibitors (PCSK9i), and (iii) were conducted outside of Asia. This study, conducted in Singapore, where FDR participation rate is about 25 % among probands who have known pathogenic variants, aims to identify drivers of cost-effectiveness of CS protocols for FH. METHODS: Four CS protocols, which vary in the application of genetic tests, were examined using a hybrid decision tree-Markov model. Sensitivity analyses were conducted to identify drivers of cost-effectiveness. RESULTS: Cascade acceptance rates are key drivers of cost-effectiveness. Other drivers include age of proband, prevalence of FH among probands, health-related quality of life loss with cardiovascular disease, timeliness of starting treatment post-screening, treatment effectiveness, cost of PCSK9i and discount rate for cost and QALY. With cascade acceptance rates observed in Singapore, among various screening protocols examined, probabilities of being cost-effective ranged from 86 % to 95 % when no access to PCSK9i and ranged from 75 % to 98 % when PCSK9i are provided. The most cost-effective protocol differs depending on cascade acceptance rates and whether PCSK9i is provided. CONCLUSION: For better cost-effectiveness of CS for FH, health systems need to look for ways to improve proband's willingness to share contact of their relatives and relatives' willingness to be screened and to lower the cost of novel treatment. Other ways to improve cost-effectiveness include to select age groups for proband screening, improve screening detection rate among probands, and start timely treatment post-screening.

Humans↗

PubMed1986

The arachidonic acid cascade is involved in the masculinizing action of testosterone on embryonic external genitalia in mice.

We have evaluated whether the arachidonic acid cascade may be involved in the folding and fusion of the penis and scrotum in masculine differentiation, a possibility raised by recent observations of the involvement of the arachidonic acid cascade in the analogous embryonic processes of elevation and fusion of the palatal shelves and of folding and fusion of the neural tube. To test this hypothesis, during embryonic masculine differentiation in mice of the B10.A strain, we administered certain agents that produce blockade of masculinization. We report that arachidonic acid can reverse the inhibition of masculine development in male embryos produced by estradiol-17 beta or by cyproterone acetate, an androgen receptor-site blocker, and that such reversal can be prevented by an inhibitor of cyclooxygenase, such as indomethacin. We have also found that agents that block the arachidonic acid cascade at the level of phospholipase A2 (cortisone, phenytoin) or at the level of cyclooxygenase (indomethacin, aspirin) also block masculine differentiation and that such antimasculinization is reversed by arachidonic acid. The masculinization of male embryos is inhibited by indomethacin and aspirin, and the masculinization of female embryos produced by exogenous testosterone is prevented by indomethacin. These findings provide evidence that the mechanism by which testosterone organizes the genitalia involves a role of the arachidonic acid cascade leading to prostaglandins at a critical period of development and that interference with testosterone synthesis or action leads to a teratogenic deficiency of arachidonic acid during this time in the genital anlagen.

Animals↗