Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cascade testing”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 325 records · Page 18Linked to original sources
PubMed2003

Altered Sonic hedgehog signaling is associated with morphological abnormalities in the penis of the BB/WOR diabetic rat.

Erectile dysfunction (ED) is a common and debilitating pathological development that affects up to 75% of diabetic males. Neural stimulation is a crucial aspect of the normal erection process. Nerve injury causes ED and disrupts signaling of the Sonic hedgehog (Shh) cascade in the smooth muscle of the corpora cavernosa. Shh and targets of its signaling establish normal corpora cavernosal morphology during postnatal differentiation of the penis and regulate homeostasis in the adult. Interruption of the Shh cascade in the smooth muscle of the corpora cavernosa results in extensive changes in corpora cavernosal morphology that lead to ED. Our hypothesis is that the neuropathy observed in diabetics causes morphological changes in the corpora cavernosa of the penis that result in ED. Disruption of the Shh cascade may be involved in this process. We tested this hypothesis by examining morphological changes in the penis, altered gene and protein expression, apoptosis, and bromodeoxyuridine incorporation in the BB/WOR rat model of diabetes. Extensive smooth muscle and endothelial degradation was observed in the corpora cavernosa of diabetic penes. This degradation accompanied profound ED, significantly decreased Shh protein in the smooth muscle of the corpora cavernosa, and increased penile Shh RNA expression in the intact penis (nerves, corpora, and urethra). Localization and expression of Shh targets were also disrupted in the corpora cavernosa. Increasing our understanding of the molecular mechanisms that regulate Shh signaling may provide valuable insight into improving treatment options for diabetic impotence.

Animals↗
PubMed2004

Estrogen exerts neuroprotective effects via membrane estrogen receptors and rapid Akt/NOS activation.

The neuroprotective role of estrogen (E2) is supported by a multitude of experimental and epidemiological data, although its mode of action is not fully understood. The present work was conducted to study the underlying mechanisms of its neuroprotective action, using the rat cell line PC12, an established model for neuronal cell apoptosis and survival. Our results show that E2 (but not androgens or progestins) prevent growth inhibition and apoptosis of PC12 cells, induced by serum deprivation. Several mechanisms of action were investigated: 1) intracellular estrogen receptors (ERs) have been identified but do not appear to mediate the protective effect of E2. 2) The antioxidant properties of E2 cannot explain their protective actions at the concentrations used (10(-12)-10(-6) M). 3) Finally, membrane sites for E2 have been identified, and the underlying initial signaling cascade (2-30 min after E2) has been tested, showing Ca(2+) mobilization-->PI3K activation-->Akt phosporylation-->NOS activation. Inhibition of PI3K or NOS completely reversed the anti-apoptotic effect of E2. These results suggest a new mechanism of neuroprotective action of estrogen.

Animals↗
PubMed2001

Methylprednisolone and acute spinal cord injury: an update of the randomized evidence.

OBJECTIVES: Randomized trials are widely recognized as providing the most reliable evidence for assessing efficacy and safety of therapeutic interventions. This evidence base is used to evaluate the current status of methylprednisolone (MPSS) in the early treatment of acute spinal cord injury. METHODS: Medline, CINAHL, and other specified databases were searched for MeSH headings "methylprednisolone and acute spinal cord injury." The Cochrane Library and an existing systematic review on the topic were also searched. RESULTS: Five randomized controlled trials were identified that evaluated high-dose MPSS for acute spinal cord injury. Three trials by the NASCIS group were of high methodologic quality, and a Japanese and French trial of moderate to low, methodologic quality. Meta-analysis of the final result of three trials comparing 24-hour high-dose MPSS with placebo or no therapy indicates an average unilateral 4.1 motor function score improvement (95% confidence interval 0.6-7.6, P = 0.02) in patients treated with MPSS. This neurologic recovery is likely to be correlated with improved functional recovery in some patients. The safety of this regimen of MPSS is evident from the spinal cord injury trials and a systematic review of 51 surgical trials of high-dose MPSS. CONCLUSION: High-dose MPSS given within 8 hours of acute spinal cord injury is a safe and modestly effective therapy that may result in important clinical recovery for some patients. Further trials are needed to identify superior pharmacologic therapies and to test drugs that may sequentially influence the postinjury cascade.

Acute Disease↗
PubMed1998

Effects of a combined antithrombin III and protein C supplementation in porcine acute endotoxic shock.

Antithrombin III (ATIII) and protein C (PC) are major inhibitors of the coagulation cascade and might regulate the cytokine network. We tested the possibility that a combined supplementation using these two inhibitors might have synergistic effects on sepsis-induced disseminated intravascular coagulation and shock. Hemodynamics, coagulation parameters, tumor necrosis factor (TNF) alpha, and interleukin 6 levels were measured in pigs submitted to a bolus infusion of Escherichia coli endotoxin (lipopolysaccharide). Four groups were studied: control lipopolysaccharide, ATIII (100 IU/kg), PC (50 IU/kg), and ATIII-PC (same doses). The endotoxin infusion resulted in a typical hypokinetic shock with disseminated intravascular coagulation in all animals. Compared with the control group, a significant improvement in mean arterial pressure and systemic vascular resistance was observed in the PC and ATIII-PC groups. The increase in lactate levels was almost completely blunted in the PC group. A significant lesser increase in TNFalpha levels was observed in the ATIII-PC group. No effects were seen on interleukin 6 levels. Coagulation and fibrinolysis parameters were not improved by ATIII and/or PC, except for a lesser decrease in prothrombin time in the ATIII-PC group. We conclude that in this acute endotoxic model, a combined supplementation using PC and ATIII concentrates has favorable effects on hemodynamic parameters and TNFalpha levels, independently from the anticoagulant actions of these inhibitors.

Animals↗
PubMed1978

Activation of the alternative pathway of complement by grain. I. C3PA conversion and quantification of complement consumption by rye.

Ground whole rye and airborne rye dust of comparable size distribution were tested for their ability to activate the complement cascade via the alternative pathway. Precipitin-negative pooled normal human serum was incubated with increasing amounts of the two rye dusts. Electrophoresis of the resultant supernatant fluids demonstrated the conversion of the proactivator of the third component of complement to the gamma-migrating activator of the third component. This activation was completely prevented by pre-treating the serum with the chelator EDTA, while pre-treatment with EGTA allowed suboptimal arc conversion, strongly implying that complement was activated via the alternative pathway. Quantification of the supernanant fluids showed dose-dependent complement consumption as defined by both CH100 immunodiffusion and CH50 tube haemolytic techniques. Airborne rye dust showed a greater quantitative potential than ground whole rye for activating the alternative pathway. These results indicate the possibility of the direct action of airborne organic dusts on the induction of inflammatory sequelae in the lungs of both sensitized and unsensitized individuals.

Air Pollutants↗
PubMed2005

Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats.

The nucleus accumbens (NAc) plays a critical role in amphetamine-produced conditioned place preference (CPP). In previous studies inhibition or activation of cyclic adenosine monophosphate-dependent protein kinase (PKA) blocked NAc amphetamine-produced CPP. PKA activation unrelated to ongoing DA transmission may disrupt reward-related learning. Calcineurin (CN) down-regulates downstream PKA targets. Unlike PKA activation, CN inhibition may preserve and enhance reward-related learning. The PKA signalling cascade is negatively regulated by calcineurin (CN). We tested the hypothesis that post-training CN inhibition in NAc will enhance NAc amphetamine-produced CPP and that PKA activation will block CPP. Eight but not four or two 30-min conditioning sessions were sufficient to establish significant CPP. Immediate post-training, NAc injection of the calcineurin inhibitor FK506 (5.0 but not 1.0 microg in 0.5 microL per side) led to a significant amphetamine CPP in rats receiving four but not two training sessions; the 5.0-microg dose had no effect on rats trained with eight sessions. Injections of the PKA activator Sp-cAMPS (2.5 or 10.0 microg in 0.5 microL per side) failed to affect CPP following two or four training sessions and blocked CPP produced by a standard 8-day conditioning schedule. Results suggest that CN acts as a negative regulator in the establishment of NAc amphetamine-produced CPP, a form of reward-related learning.

Amphetamine↗
PubMed2000

NO regulates PDGF-induced activation of PKB but not ERK in A7r5 cells: implications for vascular growth arrest.

In addition to the well-documented role of nitric oxide (NO) as a vasodilator, NO has also been implicated in vascular smooth muscle cell (VSMC) growth arrest. Signaling mechanisms responsible for growth factor receptor-mediated VSMC proliferation include the extracellular signal-regulated kinase (ERK) and possibly the protein kinase B (PKB) cascade. Thus the present study was designed to test the hypothesis that, in A7r5 vascular smooth muscle-derived cells, platelet-derived growth factor (PDGF)-induced activation of either ERK or PKB is regulated by NO, which then modulates cellular proliferation and/or apoptosis. PKB-alpha was the predominant isoform of PKB expressed in A7r5 cells and was also expressed in rabbit carotid arteries and aortae. Phosphorylation of PKB-alpha and ERK induced by PDGF-BB was maximal within 5-15 min in A7r5 cells. Preincubation of A7r5 cells with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) resulted in a biphasic regulation of PDGF-stimulated PKB-alpha phosphorylation and bioactivity. Acute exposure to SNAP significantly augmented PDGF-induced activation of PKB-alpha, whereas prolonged incubation led to a marked diminution in PDGF-induced activation of PKB-alpha. In contrast, SNAP did not affect PDGF-induced activation of ERK at any time point. The cGMP-independent effects of SNAP on PDGF-induced activation of PKB-alpha were established with the use of an inhibitor of soluble guanylyl cyclase, ODQ, as well as a cell-permeable analog of cGMP, 8-bromo-cGMP. Prolonged treatment of A7r5 cells with SNAP led to a significant decrease in DNA synthesis without an appreciable increase in apoptosis. These data suggest that, after prolonged exposure to SNAP, NO selectively attenuates PDGF-induced increase in PKB-alpha activation, which in turn may contribute to diminished VSMC proliferation by mechanisms involving growth arrest but not apoptosis.

Animals↗
PubMed2006

Thermal reactions of blood vessels in vascular stroke and heatstroke.

Research on the pathophysiology and treatment of brain damage with special focus on thermal vascular responses is the subject of this minireview. Interruption of cerebral blood supply by vascular obstruction, temporary cardiac arrest or hyperthermia causes a sudden attack of vascular stroke or heatstroke with serious consequences. It may not induce immediate cell death, but can precipitate a complex biochemical cascade leading to a delayed neuronal loss. When testing thermal vasomotor responses by stepwise cooling of isolated carotid arteries, a temperature-proportional dilatation was observed while heating induced the opposite response: a marked vasoconstriction. General hyperthermia with an increased oxygen demand combined with a reduction of blood supply therefore is a serious consequence. At the cellular level an important mechanism involving hyperthermia is the temperature-dependent regulation of K(+) channel tone of vascular smooth muscle. Further, their inhibition through temperature elevation causes vasoconstriction. In heatstroke, which can induce platelet aggregation and the release of the vasoconstrictor serotonin, arterial cooling attenuates this response. General hypothermia is induced to prevent or attenuate neurological damage in stroke. The procedure is not without serious side effects. Therefore, rapid institution of selective brain cooling has been considered in adults and in infants with postpartum encephalopathy.

Animals↗
PubMed2005

Neuroprotection by sodium channel blockade with phenytoin in an experimental model of glaucoma.

PURPOSE: Sustained influx of intracellular sodium through voltage-gated sodium channels is an important event in the cascade leading to degeneration of axons. This study tested the hypothesis that sodium channel blockade with phenytoin would result in neuroprotection of retinal ganglion cells (RGCs) and optic nerve axons in an experimental model of glaucoma. METHODS: Chronic elevation of rat intraocular pressure (IOP) leading to optic nerve damage was induced using the episcleral vein occlusion model. Before induction of glaucoma, a subset of animals was placed on phenytoin-containing chow; this treatment continued for 8 weeks. Quantitative counts of backfilled RGCs and optic nerve axons was performed to examine the effects of phenytoin on glaucoma-induced adverse neurodegeneration. RESULTS: Elevated IOP resulted in a significant decrease in density of RGCs, as well as dropout of axons within the optic nerve at 8 weeks after induction. In phenytoin-treated animals, however, the loss of RGCs was significantly reduced compared to vehicle-treated glaucomatous animals. Axon loss in the optic nerve was also reduced in phenytoin-treated animals, compared to controls. CONCLUSIONS: Orally delivered phenytoin was effective in protecting neurons in an animal model of glaucoma, and merits further examination as a potential therapeutic strategy.

Administration, Oral↗
PubMed2000

Molecular biology of breast cancer metastasis. Genetic regulation of human breast carcinoma metastasis.

The present is an overview of recent data that describes the genetic underpinnings of the suppression of cancer metastasis. Despite the explosion of new information about the genetics of cancer, only six human genes have thus far been shown to suppress metastasis functionally. Not all have been shown to be functional in breast carcinoma. Several additional genes inhibit various steps of the metastatic cascade, but do not necessarily block metastasis when tested using in vivo assays. The implications of this are discussed. Two recently discovered metastasis suppressor genes block proliferation of tumor cells at a secondary site, offering a new target for therapeutic intervention.

Antigens, CD↗
PubMed2006

Postprandial transduodenal bolus transport is regulated by complex peristaltic sequence.

AIM: To study the relationship between the patterns of postprandial peristalsis and transduodenal bolus transport in healthy subjects. METHODS: Synchronous recording of chyme transport and peristaltic activity was performed during the fasting state and after administration of a test meal using a special catheter device with cascade configuration of impedance electrodes and solid-state pressure transducers. The catheter was placed into the duodenum, where the first channel was located in the first part of the duodenum and the last channel at the duodenojejunal junction. After identification of previously defined chyme transport patterns the associated peristaltic patterns were analyzed. RESULTS: The interdigestive phase 3 complex was reliably recorded with both techniques. Of 497 analyzed impedance bolus transport events, 110 (22%) were short-spanned propulsive, 307 (62%) long-spanned propulsive, 70 (14%) complex propulsive, and 10 (2%) retrograde transport. Short-spanned chyme transports were predominantly associated with stationary or propagated contractions propagated over short distance. Long-spanned and complex chyme transports were predominantly associated with propulsive peristaltic patterns, which were frequently complex and comprised multiple contractions. Propagated double wave contraction, propagated contraction with a clustered contraction, and propagated cluster of contractions have been identified to be an integralted part of a peristaltic sequence in human duodenum. CONCLUSION: Combined impedancometry and manometry improves the analysis of the peristaltic patterns that are associated with postprandial transduodenal chyme transport. Postprandial transduodenal bolus transport is regulated by propulsive peristaltic patterns, which are frequently complex but well organized. This finding should be taken into consideration in the analysis of intestinal motility studies.

Adult↗
PubMed1999

Regulatory role of protein tyrosine phosphorylation in platelet activating factor-induced signal transduction in platelets.

AIM: To study the role of protein tyrosine phosphorylation (PTP) in platelet activating factor (PAF)-induced platelet signal transduction cascade. METHODS: Washed rabbit platelets were used to test the inhibitory effect of genistein (Gen) on platelet aggregation and serotonin secretion. Intracellular Ca2+ ([Ca2+]i) and pH (pHi) were measured by a dual wavelength fluorophotometer with Fura 2-AM and BCECF-AM. PTP was determined with a specific anti-phosphotyrosine monoclonal antibody by Western blotting. RESULTS: Pretreatment with Gen (100 and 200 mumol.L-1) inhibited PAF (20 nmol.L-1)-stimulated platelet serotonin release by 23.7% +/- 2.0% and 41% +/- 8%, respectively. Similar inhibitory effects of Gen were observed on PAF-evoked increase of [Ca2+]i and intracellular alkalization. PAF also elicited a pronounced increase in PTP of several bands with M(r) 70,000, 60,000, 50,000, 42,000/40,000, and 34,000, which were suppressed markedly by Gen 200 and 400 mumol.L-1. Pretreatment with staurosporine (Sta) 20 nmol.L-1, BAPTA 200 mumol.L-1, and egtazic acid 2 mmol.L-1 to inhibit PKC activation, [Ca2+]i elevation, and Ca2+ influx respectively, also showed an inhibitory effects on the formation of PTP. CONCLUSION: PTP is involved in multiple signal transduction pathways induced by PAF, on which PKC activation and calcium mobilization play a regulatory role.

Animals↗
PubMed1999

Self-organizing map (SOM) of space acceleration measurement system (SAMS) data.

In this paper, space acceleration measurement system (SAMS) data have been classified using self-organizing map (SOM) networks without any supervision; i.e., no a priori knowledge is assumed regarding input patterns belonging to a certain class. Input patterns are created on the basis of power spectral densities of SAMS data. Results for SAMS data from STS-50 and STS-57 missions are presented. Following issues are discussed in details: impact of number of neurons, global ordering of SOM weight vectors, effectiveness of a SOM in data classification, and effects of shifting time windows in the generation of input patterns. The concept of 'cascade of SOM networks' is also developed and tested. It has been found that a SOM network can successfully classify SAMS data obtained during STS-50 and STS-57 missions.

Acceleration↗
PubMed2003

Application of spectrofluorometry for evaluation of dry powder inhalers in vitro.

Andersen cascade impactor (ACI) is commonly used for the testing of pharmaceutical aerosols, which has to be coupled with an instrument for quantitative analysis of drug depositing on each stage of the ACI. This procedure consumes much time in operation. Therefore, this study was aimed at speeding up the process of drug analysis in aerosol formulations after obtaining samples from the ACI. From the results obtained, it was proved that the validated spectrofluorometric method was accurate and sensitive. It was capable of giving similar results to those we obtained from HPLC-UV analysis. There was no interference from the amount of lactose carrier incorporated in the formulation in the step of salbutamol analysis indicating specificity of the method. As a result, samples were analyzed without further separation. The detection limit was 0.1 microg/ml. Hence, spectrofluorometry can be used as a substitute method to HPLC-UV in determining the small quantity of salbutamol after aerosolization from dry powder aerosols. The present study suggests that spectrofluometry can be a rapid and efficient method in the pharmaceutical analysis of aerosols.

Aerosols↗
PubMed1987

The dorsal skin-fold preparation of awake Syrian golden hamsters for assessment of microvascular permeability and microhaemodynamics with leukotriene C4.

This study has quantitated the effects of topically-applied leukotriene C4 (LTC4) upon vessel diameters, red blood cell velocities and vascular permeability to macromolecules in an animal model, namely, the dorsal skin-fold preparation of Syrian golden hamsters. Furthermore, we studied the efficacy of the leukotriene receptor blocking agent FPL 55712 in this preparation in order to establish a model for testing antiinflammatory compounds possibly involved in the lipoxygenase cascade.

Animals↗
PubMed1983

Combination estrogen and progestogen replacement therapy does not adversely affect coagulation.

Coagulation and fibrinolysis profiles of naturally menopausal women receiving conjugated estrogens (0.625 or 1.25 mg for 21 of 28 days) and medroxyprogesterone acetate (10 mg for seven of 28 days) for 18 months were compared with those of similar women receiving no hormone therapy. Tests indicative of the dynamics of the coagulation cascade, ongoing intravascular coagulation, and anticoagulation were performed. Hormone therapy had no effect on prothrombin times, activated partial thromboplastin times, or thrombin times. There was no evidence of intravascular coagulation in any of the groups as assessed by platelet counts, fibrinogen antigen and activity, and fibrin degradation products. Antithrombin III antigen and activity, alpha 1-antitrypsin antigen, and alpha 2-macroglobulin antigen, the natural inhibitors of coagulation, were also unaffected by hormone therapy. Plasminogen antigen levels were unaffected, but plasminogen activity was enhanced in the hormone-treated groups, suggesting a stimulatory effect on fibrinolysis. These data indicate that in terms of the coagulation system, healthy women can safely use a combined regimen of conjugated estrogens and medroxyprogesterone acetate.

Androstenedione↗
PubMed1993

NF-kappa B activation by ultraviolet light not dependent on a nuclear signal.

Exposure of mammalian cells to radiation triggers the ultraviolet (UV) response, which includes activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B). This was postulated to occur by induction of a nuclear signaling cascade by damaged DNA. Recently, induction of AP-1 by UV was shown to be mediated by a pathway involving Src tyrosine kinases and the Ha-Ras small guanosine triphosphate-binding protein, proteins located at the plasma membrane. It is demonstrated here that the same pathway mediates induction of NF-kappa B by UV. Because inactive NF-kappa B is stored in the cytosol, analysis of its activation directly tests the involvement of a nuclear-initiated signaling cascade. Enucleated cells are fully responsive to UV both in NF-kappa B induction and in activation of another key signaling event. Therefore, the UV response does not require a signal generated in the nucleus and is likely to be initiated at or near the plasma membrane.

Alleles↗
PubMed2000

Urinalysis to exclude and monitor nephrotoxicity.

A large number of compounds, which are in common usage in industry and medicine, are potentially nephrotoxic. Renal damage and disease resulting from toxic exposure is progressive and will, if unarrested, culminate in irreversible renal disease. There is, therefore, a need to develop a battery of tests with which to monitor and characterise the nephrotoxic cascade. A European-wide study compared biomarker profiles of adult male workers who were exposed to heavy metals or solvents. It became apparent that the urinary profiles varied with the nature of the toxin, reflecting the functional region of the kidney affected and also the severity of the damage. Children are a particularly vulnerable group and the investigation of range of biomarkers indicated that they were indeed susceptible to nephrotoxic pollutants in their environment. It is proposed that a small cohort of tests should be used to monitor the early (pre-clinical stages) of renal damage or dysfunction; these can be supplemented if necessary by additional specific tests. In the future better information on at-risk populations and genetic information will enable the determination of individual susceptibility to be assessed more precisely.

Adult↗