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PubMed1994

Analysis of ERG a-wave amplification and kinetics in terms of the G-protein cascade of phototransduction.

PURPOSE: To test rigorously the hypothesis that the a-wave of the electroretinogram (ERG) is proportional to the rod photocurrent by examining the applicability to a-waves of a recent model of the activation steps in the G-protein cascade of phototransduction. METHODS: ERGs were recorded in response to flashes of graded intensity, from six dark-adapted normal subjects and from two patients, one with retinitis pigmentosa (RP) and one with cone retinal dystrophy with rod involvement (CRD). The a-wave portions of the responses were analyzed with a model of the activation steps of the G-protein cascade. The model is characterized by a parameter, A, the amplification constant, with units of s-2 (per photoisomerization), which may be expressed as the product of physical and biochemical parameters of the transduction cascade. RESULTS: Each a-wave family was well described by the model. For the six normal subjects, we obtained A approximately 7 s-2, about 100-fold greater than in isolated amphibian rods at 22 degrees C, but close to the value for isolated primate rods. For the patient with RP, the maximum a-wave amplitude (amax) was considerably reduced, but the amplification constant was normal (A = 7.5 s-2). In contrast, the patient with CRD had a nearly normal amax but had an amplification constant about sixfold lower than normal (A = 1.1 s-2). CONCLUSIONS: The authors conclude that the a-wave is a direct reflection of the rod photo-current and that the rising phase kinetics are accurately described by a simple model of the G-protein cascade. They show that the small volume of the human rod outer segment is crucial to the achievement of high amplification, and they show how their observations constrain the possible pathologies of phototransduction in patients with retinal disease.

Adolescent↗

PubMed1998

Endothelin-1-induced contraction in cerebral vessels mediated by phospholipase C/protein kinase C cascade.

Endothelin (ET) vasoconstricts cerebral vessels potently, an effect mediated by ET(A) receptors on the smooth muscle, although the subsequent signaling cascade is unclear. We tested whether the action of ET-1 is mediated by the phospholipase C (PLC)/protein kinase C (PKC) cascade. Isometric force was measured in vitro in ring segments of rat basilar (BA) and middle cerebral (MCA) arteries and expressed as a percentage of the contraction to 124 mM K+. Concentration-effect curves for the constrictor effect of ET-1 (1 pM = 0.3 microM) in control segments or after 25 minutes preincubation with an inhibitor of PLC (neomycin 100 microM) or PKC (H7 10 microM) were constructed under resting tone. In untreated BA, 100 nM ET-1 induced a contraction of 119 +/- 5.3% that fell significantly to 97 +/- 2.8% and 98 +/- 6.7% after neomycin or H7 pretreatment, respectively. In MCA, 100 nM ET-1 induced a contraction of 105 +/- 3.2% that fell significantly to 93 +/- 6.3% and 64 +/- 8.1% after neomycin or H7, respectively. There was no significant shift of the ET-1 EC50 after PKC inhibition in either vessel or PLC inhibition in BA. In summary, the amplitude of ET-1-induced contraction in cerebral vessels is reduced significantly, whereas the sensitivity to the agonist is unchanged, after blocking PLC with neomycin or PKC with H7. This indicates noncompetitive inhibition. ET-1-induced contraction in cerebral vessels thus depends on activation of the PLC/PKC cascade.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2006

Aluminum sulfate significantly reduces the skin test response to common allergens in sensitized patients.

BACKGROUND: Avoidance of allergens is still recommended as the first and best way to prevent allergic illnesses and their comorbid diseases. Despite a variety of attempts there has been very limited success in the area of environmental control of allergic disease. Our objective was to identify a non-invasive, non-pharmacological method to reduce indoor allergen loads in atopic persons' homes and public environments. We employed a novel in vivo approach to examine the possibility of using aluminum sulfate to control environmental allergens. METHODS: Fifty skin test reactive patients were simultaneously skin tested with conventional test materials and the actions of the protein/glycoprotein modifier, aluminum sulfate. Common allergens, dog, cat, dust mite, Alternaria, and cockroach were used in the study. RESULTS: Skin test reactivity was significantly reduced by the modifier aluminum sulfate. Our studies demonstrate that the effects of histamine were not affected by the presence of aluminum sulfate. In fact, skin test reactivity was reduced independent of whether aluminum sulfate was present in the allergen test material or removed prior to testing, indicating that the allergens had in some way been inactivated. CONCLUSION: Aluminum sulfate was found to reduce the in vivo allergic reaction cascade induced by skin testing with common allergens. The exact mechanism is not clear but appears to involve the alteration of IgE-binding epitopes on the allergen. Our results indicate that it may be possible to diminish the allergenicity of an environment by application of the active agent aluminum sulfate, thus producing environmental control without complete removal of the allergen.

Journal Article↗

PubMed1991

In vitro deposition and clinical efficacy of two sodium cromoglycate inhalation powders.

In this study, the in vitro deposition as well as the clinical efficacy of two dry powder inhalation preparations containing 20 mg of disodium cromoglycate were evaluated. The preparations were Blacil and Lomudal administered either with I.S.F. or Spinmatic powder inhalers, respectively. The in vitro inhalation study was performed using the cascade impacted method. During the in vitro test, similar fractions of the drug doses were retained in both inhalation devices. A remarkably larger proportion of the pelletized drug powder from the Lomudal preparation was deposited in the imitated upper airway than from the Blacil preparation consisting of the mixture of micronized disodium cromoglycate particles and lactose as a carrier. On the other hand, a larger fraction of the drug dose was deposited in the imitated lung area after the administration of the Blacil preparation than from Lomudal. The clinical study was performed as an exercise test in sixteen asthmatic patients. The preparations tested were statistically equally effective. The decrease in all the values of the pulmonary function parameters (PEF, FEV1) was, however, smaller after the administration of disodium cromoglycate from Blacil than from Lomudal preparation. According to the results of this study, the cascade impaction test seems to be valuable for predicting the efficacy of inhalation powders.

Administration, Inhalation↗

PubMed1998

Internuclear cascade-evaporation model for LET spectra of 200 MeV protons used for parts testing.

The Linear Energy Transfer (LET) spectrum produced in microelectronic components during testing with 200 MeV protons is calculated with an intemuclear cascade-evaporation code. This spectrum is compared to the natural space heavy ion environment for various earth orbits. This comparison is used to evaluate the results of proton testing in terms of determining a firm upper bound to the on-orbit heavy ion upset rate and the risk of on-orbit heavy ion failures that would not be detected with protons.

Electronics↗

PubMed2002

Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling.

Aldosterone plays a pathological role in cardiac fibrosis by directly affecting cardiac fibroblasts. Understanding of the cellular mechanisms of aldosterone action in cardiac fibroblasts, however, is rudimentary. One possibility is that aldosterone promotes proliferation of cardiac fibroblasts by activating specific cellular signaling cascades. The current study tests whether aldosterone stimulates proliferation of isolated adult rat cardiac myofibroblasts (RCF) by activating Kirsten Ras (Ki-RasA) and its effector, the MAPK1/2 cascade. Aldosterone (10 nM) significantly increased RCF proliferation. This action was sensitive to the mineralocorticoid receptor (MR) antagonist spironolactone. Expression of MR in RCF and the whole rat heart was confirmed by immunoblotting. Aldosterone significantly increased absolute and active (GTP bound) Ki-RasA levels in RCF. Aldosterone, in addition, significantly increased phospho-c-Raf and phospho-MAPK1/2. The effects of aldosterone on Ki-RasA and phospho-c-Raf proteins were inhibited by spironolactone but not RU-486, suggesting that aldosterone acts via MR. Inhibitors of MEK1/2 and c-Raf prevented aldosterone-induced activation of MAPK1/2 and proliferation. These results show that aldosterone directly increases RCF proliferation through MR-dependent activation of Ki-RasA and its effector, the MAPK1/2 cascade. Activation of cardiac fibroblasts through such a cascade may play a role in the pathological actions exerted by aldosterone on the heart.

Aldosterone↗

PubMed1988

A predictive test for adverse reactions to contrast media. Preliminary results.

In a prospective study, whole blood samples drawn from patients prior to their being injected with contrast media were incubated with zymosan to activate the complement cascade. The samples were tested for various analytes, including C3a, thromboxane B2 (TxB2), beta thromboglobulin and platelet factor 4 (PF4). Of 207 patients receiving contrast media, only eight experienced reactions, which were mild. Levels of the platelet constituents were generally elevated in these patients. Specificity and sensitivity were 89% and 83%, respectively, for the combined TxB2 and PF4 radioimmunoassay data. Using the Wilcoxon-Mann-Whitney rank sum test, both PF4 and TxB2 were collected with RCM reactions at the R less than .05 level. Although preliminary, the results suggest that RCM reactions are predictable by the in vitro test procedures described.

Complement Activation↗

PubMed2006

Regulatory roles of psrA and rpoS in phenazine-1-carboxamide synthesis by Pseudomonas chlororaphis PCL1391.

Production of the secondary metabolite phenazine-1-carboxamide (PCN) by Pseudomonas chlororaphis PCL1391 is crucial for biocontrol activity against the phytopathogen Fusarium oxysporum f. sp. radicis lycopersici on tomato. Regulation of PCN production involves the two-component signalling system GacS/GacA, the quorum-sensing system PhzI/PhzR and the regulator PsrA. This paper reports that a functional rpoS is required for optimal PCN and N-hexanoyl-L-homoserine lactone (C(6)-HSL) production. Constitutive expression of rpoS is able to complement partially the defect of a psrA mutant for PCN and N-acylhomoserine lactone production. Western blotting shows that rpoS is regulated by gacS. Altogether, these results suggest the existence of a cascade consisting of gacS/gacA upstream of psrA and rpoS, which influence expression of phzI/phzR. Overproduction of phzR complements the effects on PCN and C(6)-HSL production of all mutations tested in the regulatory cascade, which shows that a functional quorum-sensing system is essential and sufficient for PCN synthesis. In addition, the relative amounts of PCN, phenazine-1-carboxylic acid and C(6)-HSL produced by rpoS and psrA mutants harbouring a constitutively expressed phzR indicate an even more complex network of interactions, probably involving other genes. Preliminary microarray analyses of the transcriptomics of the rpoS and psrA mutants support the model of regulation described in this study and allow identification of new genes that might be involved in secondary metabolism.

4-Butyrolactone↗

PubMed1998

Endotoxin activation of mitogen-activated protein kinase in THP-1 cells; diminished activation following endotoxin desensitization.

The signal transduction events occurring in monocytes in response to endotoxin (LPS) stimulation are incompletely delineated, although pertussis toxin (PT)-sensitive G proteins and the mitogen-activated protein kinase (MAPK) cascade have been implicated. Cellular desensitization in response to 18-h pre-exposure to 1 microgram/mL LPS alters signal transduction pathways of cellular activation and decreases production of certain inflammatory mediators such as thromboxane (Tx)B2, the stable metabolite of TxA2. We hypothesized that LPS stimulation of the human monocyte cell line THP-1 occurs via MAPK activation, and that LPS desensitization, induced by pre-exposure to LPS, is associated with altered signaling through the MAPK cascade. Involvement of a specific MAPK, ERK, in LPS-stimulated TxB2 production was further tested using a specific MAPK cascade inhibitor, PD98059 (PD). PD inhibited LPS and phorbol myristate acetate (PMA)-stimulated ERK activation as demonstrated by immunoblots using anti-activated ERK antibodies. PD significantly inhibited LPS and PMA-stimulated TxB2 synthesis to non-detectable levels, suggesting an involvement of MAPK in LPS-stimulated activation. Because PT-sensitive G proteins mediate LPS-stimulated signal transduction, their role in MAPK activation was tested. Pretreatment with PT inhibited basal and LPS-stimulated, but not PMA-stimulated ERK activation. Activation of ERK after LPS desensitization was also assessed. LPS pre-exposure resulted in a profound decrease in LPS-stimulated activation of ERK, but did not affect PMA activation of ERK. These data implicate the involvement of the MAPK cascade in LPS-stimulated activation of THP-1 cells and suggest coupling of Gi proteins and MAPKs in LPS-stimulated events. LPS desensitization is associated with decreased MAPK activation, but does not impair MAPK activation by PMA. Thus, LPS desensitization appears to selectively alter signal transduction upstream of ERK.

Carcinogens↗

PubMed1997

Screening for fragile X syndrome.

BACKGROUND AND AIM OF REVIEW. In 1991, the gene responsible for fragile X syndrome, a common cause of learning disability, was discovered. As a result, diagnosis of the disorder has improved and its molecular genetics are now understood. This report seems to provide the information needed to decide whether to use DNA testing to screen for the disorder. HOW THE RESEARCH WAS CONDUCTED. A literature search of electronic reference databases of published and 'grey' literature was undertaken together with hand searching of the most recent publications. RESEARCH FINDINGS. NATURAL HISTORY. Physical characteristics of fragile X syndrome include facial atypia, joint laxity and, in boys, macro-orchidism. Most affected males have moderate-to-severe learning disabilities with IQs under 50 whereas most females have borderline IQs of 70-85. Behavioural problems are similar to those seen with autism and attention-deficit disorders. Although fragile X syndrome is not curable there are a number of medical, educational, psychological and social interventions that can improve the symptoms. About 6% of those with learning disabilities tested in institutions have fragile X syndrome. Population prevalence figures are 1 in 4000 in males and 1 in 8000 in females. GENETICS. The disorder is caused by a mutation in a gene on the X chromosome which includes a trinucleotide repeat sequence. The mutation is characterized by hyper-expansion of the repeat sequence leading to down-regulation of the gene. In males an allele with repeat size in excess of 200, termed a full mutation (FM), is always associated with the affected phenotype, whereas in females only half are affected. Individuals with alleles having repeat size in the range 55-199 are unaffected but in females the sequence is heritably unstable so that it is at high risk of expansion to an FM in her offspring. This allele is known as a pre-mutation (PM) to contrast it with the FM found in the affected individual. No spontaneous expansions directly from a normal allele to an FM have been observed. SCREENING STRATEGIES. The principal aims of screenng for fragile X syndrome is to reduce the birth prevalence of the disorder, by prenatal diagnosis and selective termination of pregnancy, or by reducing the number of pregnancies in women who have the FM or PM alleles. Possible screening strategies are: routine antenatal testing of apparently low risk pregnancies, preconceptual testing of young women, and systematic testing in affected families ('cascade' screening). A secondary aim is to bring forward the diagnosis of affected individuals so that they might benefit from early treatment. Active paediatric screening and neonatal screening could achieve this but there is no direct evidence of any great benefit from early diagnosis. SCREENING TESTS. Cytogenetic methods are unsuitable for screening purposes. Southern blotting of genomic DNA can be used but is inaccurate in measuring the size of small PMs, there is a long laboratory turnaround time, and it is relatively expensive. The best protocol is to amplify the DNA using polymerase chain reaction on all samples, and when there is a possible failure to amplify, a Southern blot.(ABSTRACT TRUNCATED)

Costs and Cost Analysis↗

PubMed2005

Developmental cascades: linking academic achievement and externalizing and internalizing symptoms over 20 years.

A developmental cascade model linking competence and symptoms was tested in a study of a normative, urban school sample of 205 children (initially 8 to 12 years old). Internalizing and externalizing symptoms and academic competence were assessed by multiple methods at the study outset and after 7, 10, and 20 years. A series of nested cascade models was tested through structural equation modeling. The final model indicated 2 hypothesized cascade effects: Externalizing problems evident in childhood appeared to undermine academic competence by adolescence, which subsequently showed a negative effect on internalizing problems in young adulthood. A significant exploratory effect was consistent with internalizing symptoms containing or lowering the net risk for externalizing problems under some conditions. These 3 cascade effects did not differ by gender and were not attributable to effects of IQ, parenting quality, or socioeconomic differences. Implications are discussed for developmental models of cascades, progressions, and preventive interventions.

Achievement↗

PubMed1995

Dry-powder inhalers: evaluation of testing methodology and effect of inhaler design.

We have previously developed a spray dried formulation of a model protein (beta-galactosidase) of a size suitable for evaluation in dry powder inhaler devices. In this study, we wished to evaluate the roles of various methods available for the laboratory testing of dry powders for inhalation (cascade impactor, twin impinger, aerodynamic time of flight and image analysis). Secondly we wished to compare different inhaler devices using formulations with and without a carrier. Both the cascade impactor and twin impinger were appropriate methods for the testing of dry powder inhalers, and gave comparable estimates of respirable fraction. Image analysis and aerodynamic time of flight were suitable methods for determining the particle size of the dry powders, although the former was considerably more time consuming than the latter. The four inhalers evaluated differed greatly in terms of in vitro deposition properties. The presence of a carrier significantly improved respirable fraction with the poorer inhalers, but was less critical to the performance of the more efficient devices.

Equipment Design↗

PubMed1997

Risk assessment for heavy ions of parts tested with protons.

An internuclear cascade-evaporation code is used to model energy deposition in thin slabs of silicon. This model shows that protons produce a significant number of events with effective Linear Energy Transfer (LET) greater than 8 MeV cm2/mg and demonstrates that proton testing of microelectronic components can be an effective way to screen devices for low earth orbit susceptibility to heavy ions.

Computer Simulation↗

PubMed2004

The cAMP transduction cascade mediates olfactory reception in Drosophila melanogaster.

Two main second messenger systems depending on IP3 and cAMP have been related to olfaction in vertebrates as well as invertebrates. In Drosophila melanogaster, the availability of mutations affecting one or the other pathway (rdgB and norpA or rut and dnc, respectively) allowed showing of abnormal olfactory behavior phenotypes associated with olfactory transduction in complete living animals. However, because rut and dnc genes showed ubiquitous expression at olfactory receptor organs and some brain locations, the mutant behavior cannot be assigned exclusively to olfactory reception. In this report, overexpression of the dnc gene directed specifically to different olfactory receptor neuron subsets was used to produce dominant mutants. Abnormal olfactory behavior was found in 62.5% of the 8 lines studied in response to some odorants, depending on the affected neuronal subset. These results suggest that even for a small number of tested odorants (5), cAMP cascade is involved in olfactory reception to an important extent.

Animals↗

PubMed2000

Nickel-induced plasminogen activator inhibitor-1 expression inhibits the fibrinolytic activity of human airway epithelial cells.

One cause of debilitating pulmonary fibrosis is inhalation of insoluble metals. Human epidemiological and animal studies have associated inhalation of nickel dusts with increased incidence of pulmonary fibrosis. However, specific mechanisms for nickel-induced pulmonary fibrosis have yet to be elucidated. The current studies examine the hypothesis that particulate nickel promotes pulmonary fibrosis by inhibiting the fibrinolytic cascade. Since the urokinase-type plasminogen activator (uPA) initiates this cascade, this hypothesis was tested by investigating the effects of noncytotoxic levels of nickel subsulfide on the balance of uPA expression relative to expression of its inhibitor, PAI-1, in cultured human bronchial epithelial cells (BEAS-2B). Exposure to the metal decreased secreted uPA protein levels and activity without affecting uPA mRNA levels. In contrast, these same exposures stimulated transcription of PAI-1, causing prolonged increases in both mRNA and protein levels. Despite partial recovery of uPA protein levels, uPA activity remained depressed for more than 48 h after exposure to nickel due to the continued increase in PAI-1 expression. These data indicate that particulate nickel inhibits the fibrinolytic cascade by increasing the ratio of plasminogen inhibitor to activator. Sustained loss of uPA activity may contribute to nickel-induced pulmonary fibrosis in exposed populations.

Bronchi↗

PubMed2001

Evidence that the anti-spasmogenic effect of the beta-adrenoceptor agonist, isoprenaline, on guinea-pig trachealis is not mediated by cyclic AMP-dependent protein kinase.

1. The spasmolytic and anti-spasmogenic activity of beta-adrenoceptor agonists on airways smooth muscle is thought to involve activation of the cyclic AMP/cyclic AMP-dependent protein kinase (PKA) cascade. Here we have tested the hypothesis that PKA mediates the anti-spasmogenic activity of isoprenaline and other cyclic AMP-elevating agents in guinea-pig isolated trachea by utilizing a number of cell permeant cyclic AMP analogues that act as competitive 'antagonists' of PKA. 2. Anion-exchange chromatography of guinea-pig tracheae resolved two peaks of PKA activity that corresponded to the type I ( approximately 5%) and type II ( approximately 93%) isoenzymes. 3. Pre-treatment of tracheae with zardaverine (30 microM), vasoactive intestinal peptide (VIP) (1 microM) and the non-selective activator of PKA, Sp-8-CPT-cAMPS (10 microM), produced a non-parallel rightwards shift in the concentration-response curves that described acetylcholine (ACh)-induced tension generation. The type II-selective PKA inhibitor, Rp-8-CPT-cAMPS (300 microM), abolished this effect. 4. Pre-treatment of tracheae with Sp-8-Br-PET-cGMPS (30 microM) produced a non-parallel rightwards shift of the concentration-response curves that described ACh-induced tension generation. The selective cyclic GMP-dependent protein kinase (PKG) inhibitor, Rp-8-pCPT-cGMPS (300 microM), abolished this effect. 5. Pre-treatment of tracheae with isoprenaline (1 microM) produced a 10 fold shift to the right of the ACh concentration-response curve by a mechanism that was unaffected by Rp-8-Br-cAMPS (300 microM, selective inhibitor of type I PKA), Rp-8-CPT-cAMPS (300 microM) and Rp-8-pCPT-cGMPS (300 microM). 6. We conclude that the anti-spasmogenic activity of Sp-8-CPT-cAMPS, zardaverine and VIP in guinea-pig trachea is attributable to activation of the cyclic AMP/PKA cascade whereas isoprenaline suppresses ACh-induced contractions by a mechanism(s) that is independent of PKA and PKG.

Acetylcholine↗

PubMed1997

17Beta-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron.

Synapse loss, deposits of amyloid beta-peptide (Abeta), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to Abeta25-35 (Abeta) and FeSO4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na+/K+-ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17beta-estradiol or estriol largely prevented impairment of Na+/K+-ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17Beta-estradiol suppressed membrane lipid peroxidation induced by Abeta and FeSO4, but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17beta-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.

Amyloid beta-Peptides↗

PubMed1983

Possible involvement of lipoxygenase products of arachidonic acid pathway in ovulation.

The possible involvement of products of the lipoxygenase pathway of arachidonic acid cascade in ovulation was tested by intrabursal injection of nordihydroguaiaretic acid (NDGA); 5, 8, 11-eicosatriynoic acid (5, 8, 11-ETYA), 3 amino-1-(3 trifluromethyphenyl)-2-pyrazoline hydrochloride (BW755c) and (FPL 55712). All these drugs reduced the number of ova released from the treated ovaries in a dose-dependent manner, without affecting ovulation from contralateral ovaries. NDGA was most potent since it completely blocked ovulation from the treated ovaries in 17/38 rats receiving a dose higher than 0.15 mg/bursa. This effect of NDGA cannot be ascribed to its inhibition of ovarian PGE synthesis. Conversion of labeled arachidonic acid via the lipoxygenase pathway by preovulatory rat follicles was demonstrated by TLC chromatography. Collectively, these results suggest the involvement of products of lipoxygenase pathway of arachidonic acid in ovulation in the rat.

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