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PubMed1988

Activation of Na+/H+ exchange and the expression of cellular proto-oncogenes in mitogen- and phorbol ester-treated lymphocytes.

It has been suggested that an intracellular alkalinization, resulting from stimulation of Na+/H+ exchange, is a necessary step and perhaps the signal leading to cellular proliferation in cells stimulated by mitogens. This hypothesis was tested by measuring the early stages of the proliferative cascade in cells where antiport activity was precluded by omission of Na+ or by the addition of potent amiloride analogs. To circumvent possible nonspecific effects due to long incubations under these conditions, an early response to mitogens, the increased level of c-fos mRNA, was monitored. In rat thymic lymphocytes, the increase in the level of c-fos RNA induced by the combination of 12-O-tetradecanoylphorbol 13-acetate and ionomycin was unaffected by inhibition of the antiport with 5-(N-ethyl-N-propyl)amiloride. Increased c-fos RNA was also observed in the absence of Na+ and when alkalinization was prevented by means of nigericin. Similar results were obtained with phytohemagglutinin-stimulated human T lymphocytes. Moreover, although the lectin stimulated the antiport in these cells, an alkalinization was not observed, due to the concomitant occurrence of an acidifying process. It was concluded that the stimulation of the Na+/H+ antiport that accompanies the addition of mitogens is neither sufficient nor necessary for the initiation of cellular proliferation.

Amiloride↗
PubMed1994

Kinetic expression of endothelial adhesion molecules and relationship to leukocyte recruitment in two cutaneous models of inflammation.

BACKGROUND: Adhesive interactions between circulating leukocytes and endothelium is requisite for subsequent leukocyte extravasation at inflammatory sites. These adhesive events are mediated by a repertoire of proteins and carbohydrate moieties on both leukocyte and endothelial membranes. Understanding the kinetic expression of these adhesion molecules during an inflammatory cascade in vivo is important for the design and testing of rational therapeutic approaches directed at the blockade of adhesion molecule function in inflammatory disease. EXPERIMENTAL DESIGN: Two cutaneous inflammatory models were examined using healthy rhesus monkeys. Acute cutaneous injury was studied during a 72-hour period by intradermal injection of endotoxin (lipopolysaccharide) and subsequent biopsy. These tissues were then compared with those obtained from a cutaneous delayed-type hypersensitivity reaction (DHR), elicited by intradermal injections of mammalian tuberculin in sensitized animals and followed for up to 11 days. Expression of E-selectin, P-selectin, VCAM-1, and ICAM-1 was assessed using immunohistochemistry and compared with leukocyte localization and immunohistochemical expression of interleukin (IL) 1, IL-8 and tumor necrosis factor-alpha (TNF-alpha). Finally, relevant adhesion ligands on leukocytes were assessed using flow cytometry. RESULTS: The lipopolysaccharide model was characterized by early (0.5 hours) and sustained (up to 72 hours) expression of E-selectin on the superficial dermal vasculature, with maximal expression by 8 hours. The expression of VCAM-1 was either not detected or minimal. Neutrophil localization, as detected by elastase immunoreactivity, paralleled E-selectin expression with a 4- to 12-hour lag phase, being maximal by 24 hours. In contrast, DHR was characterized by the dual asynchronous expression of both E-selectin and VCAM-1. Localization of CD2+ lymphocytes, representing the predominant cell type recruited, kinetically followed the expression of E-selectin and VCAM-1, being maximal in number at approximately 48 hours after peak expression of both of these endothelial proteins. Neutrophil recruitment in lipopolysaccharide-induced injury was associated with immunohistochemical localization of TNF-alpha, IL-1, and IL-8, whereas only TNF-alpha was consistently detected in DHR. During DHR, blood lymphocyte expression of L-selectin, VLA-4 (CD49d; alpha chain), and lymphocyte function-associated antigen 1 (both CD11a (alpha chain) and CD18 (beta chain)) did not change. CONCLUSIONS: The results from this study demonstrate that cutaneous inflammatory infiltrates of varying cellular compositions are associated temporally and spatially with unique patterns of endothelial adhesion molecule and cytokine expression.

Animals↗
PubMed1995

Triclosan inhibits histamine-induced inflammation in human skin.

Previous studies indicate that triclosan reduces the pain and other symptoms after chemically-induced inflammation in the oral mucosa and skin when sodium lauryl sulfate (SLS) is used as an irritant. The aim of the present study was to examine whether triclosan has an effect on the inflammation in human skin caused by intradermal administration of histamine. 9 female volunteers participated in a double-blind study, and skin patch tests were performed in 2 series. In the 1st, the skin was pre-treated for 1 h with triclosan before the histamine was applied. In the 2nd, the histamine reaction was elicited first and triclosan applied subsequently. The effect of triclosan on the weals formed in the skin after histamine application was measured. It was found that triclosan reduced the size of the weals markedly when triclosan was applied after the weals were formed, and that pre-treatment of the skin had only a slight effect. It is assumed that triclosan has an effect on the cascade reactions of inflammation elicited by histamine. 2 other phenols tested in the same study had similar effects.

Administration, Cutaneous↗
PubMed2002

Parallel cascade recognition of exon and intron DNA sequences.

Many of the current procedures for detecting coding regions on human DNA sequences combine a number of individual techniques such as discriminant analysis and neural net methods. Recent papers have used techniques from nonlinear systems identification, in particular, parallel cascade identification (PCI), as one means for classifying protein sequences into their structure/function groups. In the present paper, PCI is used in a pilot study to distinguish exon (coding) from intron (noncoding; interspersed within genes) human DNA sequences. Only the first exon and first intron sequences with known boundaries in genomic DNA from the beta T-cell receptor locus were used for training. Then, the parallel cascade classifiers were able to achieve classification rates of about 89% on novel sequences in a test set, and averaged about 82% when results of a blind test were included. In testing over a much wider range of human nucleotide sequences, PCI classifiers averaged 83.6% correct classifications. These results indicate that parallel cascade classifiers may be useful components in future coding region detection programs.

Algorithms↗
PubMed2002

Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer's disease.

The amyloid and tangle cascade hypothesis is the dominant explanation for the pathogenesis of Alzheimer's disease (AD). A complete knowledge of the metabolic pathways leading to beta-amyloid (A beta) production and clearance in vivo and of the pathological events that lead to fibril formation and deposition into plaques is crucial for the development of an 'anti-amyloid' therapeutic strategy. Important advances in this respect have been achieved recently, revealing new candidate drug targets. Among the most promising potential treatments are beta- and gamma-secretase inhibitors, A beta vaccination, Cu-Zn chelators, cholesterol-lowering drugs and non-steroidal anti-inflammatory drugs. Now, the major question is whether these drugs will work in the clinic.

Alzheimer Disease↗
PubMed2005

The effect of glutamate receptor blockers on glutamate release following spinal cord injury. Lack of evidence for an ongoing feedback cascade of damage --> glutamate release --> damage --> glutamate release --> etc.

It is widely hypothesized that excitotoxicity of released glutamate following a CNS insult is propagated by the cyclic cascade: glutamate release --> damage --> glutamate release --> further damage --> etc. We tested this hypothesis by determining the effects of attempting to interrupt the loop by administering glutamate receptor antagonists and Na(+)-channel blockers on glutamate release following spinal cord injury (SCI). The effects of administering the NMDA receptor blockers MK-801 and memantine, the AMPA/kainate receptor blockers NBQX and GYKI 52466, the AMPA receptor desensitization blocker cyclothiazide and the sodium channel blockers riluzole, mexiletine and QX-314 on post-SCI were determined. Agents were administered into the site of injury by direct injection, by microdialysis or systemically. None of these agents had an appreciable effect on glutamate release following SCI. Thus, it is unlikely that the above cascade produces significant secondary glutamate release and ongoing damage following SCI, although such cascades may worsen other CNS insults. We attribute our results to overwhelming effects of much greater release by direct mechanical damage and reversal of transport following SCI.

Animals↗
PubMed2005

Model identification of signal transduction networks from data using a state regulator problem.

Advances in molecular biology provide an opportunity to develop detailed models of biological processes that can be used to obtain an integrated understanding of the system. However, development of useful models from the available knowledge of the system and experimental observations still remains a daunting task. In this work, a model identification strategy for complex biological networks is proposed. The approach includes a state regulator problem (SRP) that provides estimates of all the component concentrations and the reaction rates of the network using the available measurements. The full set of the estimates is utilised for model parameter identification for the network of known topology. An a priori model complexity test that indicates the feasibility of performance of the proposed algorithm is developed. Fisher information matrix (FIM) theory is used to address model identifiability issues. Two signalling pathway case studies, the caspase function in apoptosis and the MAP kinase cascade system, are considered. The MAP kinase cascade, with measurements restricted to protein complex concentrations, fails the a priori test and the SRP estimates are poor as expected. The apoptosis network structure used in this work has moderate complexity and is suitable for application of the proposed tools. Using a measurement set of seven protein concentrations, accurate estimates for all unknowns are obtained. Furthermore, the effects of measurement sampling frequency and quality of information in the measurement set on the performance of the identified model are described.

Algorithms↗
PubMed2007

Depolarization and neurotransmitter regulation of vasopressin gene expression in the rat suprachiasmatic nucleus in vitro.

Vasopressin (VP) transcription in the rat suprachiasmatic nucleus (SCN) in organotypic culture was studied by in situ hybridization histochemistry using an intron-specific VP heteronuclear RNA probe. The circadian peak of VP gene transcription in the SCN in vitro is completely blocked by a 2 h exposure to tetrodotoxin (TTX) in the culture medium, and this TTX inhibition of VP gene transcription is reversed by exposure of the SCN to either forskolin or potassium depolarization. This suggests that an intrinsic, spontaneously active neuronal mechanism in the SCN is responsible for the cAMP- and depolarization-dependent pathways involved in maintaining peak VP gene transcription. In this paper, we evaluate a variety of neurotransmitter candidates, membrane receptors, and signal-transduction cascades that might constitute the mechanisms responsible for the peak of VP gene transcription. We find that vasoactive intestinal peptide (VIP) and a VPAC2 (VIP receptor subtype 2) receptor-specific agonist, Ro-25-1553, are the most effective ligands tested in evoking a cAMP-mitogen-activated protein kinase signal transduction cascade leading to an increase in VP gene transcription in the SCN. In addition, a second independent pathway involving depolarization activating L-type voltage-gated calcium channels and a Ca-dependent kinase pathway [inhibited by KN62 (1-[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine)] rescues VP gene transcription in the presence of TTX. In the absence of TTX, these independent pathways appear to act in a cooperative manner to generate the circadian peak of VP gene transcription in the SCN.

Animals↗
PubMed1980

Assessment of a modified cascade centripeter.

The cascade centripeter of Hounam and Sherwood was modified to permit a wider selection of filters for use in stages 1 to 3. Tests with monodisperse aerosols showed that the calibration given by O'Connor adequately describes the modified device. An iterative procedure was devised which provides more detailed particle size data than is possible with conventional data analysis. In tests sampling urban aerosol, it was found that the centripeter is a practical alternative to the cascade impactor. Using filters selected for low and stable tare weight, a sample sufficient for weighing can be obtained in 4 to 6 hours. The main advantage of the centripeter is that the size-classified samples are obtained as uniform deposits on clean, dry filters.

Air↗
PubMed2025

What Should a Clinical Cardiologist Know About Cardiogenetics?

Inherited cardiovascular diseases are becoming increasingly prominent in clinical practice, significantly impacting diagnosis, risk assessment, and family screening strategies. Progress in genetic testing has broadened access to cardiogenetic evaluations, while also presenting new challenges in interpreting variants and incorporating findings into clinical care. This narrative review explores 20 essential questions that clinical cardiologists may face when dealing with suspected or confirmed inherited cardiac conditions. Organized as a practical, question-driven guide, it outlines when to consider a genetic cause, how to choose and interpret genetic tests, and how to manage patients regardless of their genetic test results. The review emphasizes variant classification based on American College of Medical Genetics and Genomics criteria, the importance of clinical context in interpreting uncertain results, and the principles behind family cascade screening. Particular attention is given to the management of relatives who carry a genetic variant but show no symptoms, and to the current limitations of genetic testing technologies (eg, performance). Ethical considerations, including the appropriate timing of testing in children minors, are also discussed. By connecting genetic insights with clinical cardiology, this review aims to support practical, informed decision making and promote effective collaboration with cardiogenetic specialists.

Humans↗
PubMed2001

Cyclic AMP imaging in neurones in brain slice preparations.

The second messenger cascade of cyclic AMP (cAMP) plays an important physiological role in neurones, modulating neuronal excitability and synaptic transmission. The fluorescent probe FlCRhR allows real time ratiometric imaging of cAMP changes inside cells (Nature 349 (1991) 694). Until now, the only way to introduce FlCRhR into cells was microinjection, which restricted the use of FlCRhR to large invertebrate neurones. This report describes the use of the patch-clamp technique to deliver FlCRhR into the cytosol of several types of neurones in brain slice preparations. Direct activation of adenylate cyclase by forskolin produced marked increases in fluorescence ratio, confirming that the probe can report cAMP increases. However, some neurones failed to exhibit a cAMP response and this lack of response was related to the nucleus integrity. Stimulation of membrane receptors positively coupled to adenylate cyclase elicited cAMP increases in various neuronal cell types. This is the first report of a cAMP response to neuromodulators measured by an imaging technique in neurones in brain slices. The method described here could find many applications such as testing the ability of agonists to specifically activate the cAMP cascade in identified neurones, studying the kinetics of the cAMP response and determining the subcellular localisation of cAMP changes.

Animals↗
PubMed2003

Micro-angiography for neuro-vascular imaging. II. Cascade model analysis.

A micro-angiographic detector was designed and its performance was previously tested to evaluate its feasibility as an improvement over current x-ray detectors for neuro-interventional imaging. The detector was shown to have a modulation transfer function value of about 2% at the Nyquist frequency of 10 cycles/mm and a zero frequency detective quantum efficiency [DQE(0)] value of about 55%. An assessment of the system was required to evaluate whether the current system was performing at its full potential and to determine if any of its components could be optimized to further improve the output. For the purpose, in this study, the parallel cascade theory was used to analyze the performance of the detector under neuro-angiographic conditions by studying the output at the various stages in the imaging chain. A simple model for the spread of light in the CsI(Tl) entrance phosphor was developed and the resolution degradation due to K-fluorescence absorption was calculated. The total gain of the system was found to result in 21 e(-) (rms) detected at the charge coupled device per absorbed x-ray photon. The gain and the spread of quanta in the imaging chain were used to calculate theoretically the DQE using the parallel cascade model. The results of the model-based calculations matched fairly well with the experimental data previously obtained. This model was then used to optimize the phosphor thickness for the detector. The results showed that the area under the DQE curve had a maximum value at 150 microm of CsI(Tl), though when weighted by the squared signal in frequency space of a 100-microm-diam iodinated vessel, the integral DQE reached a maximum at 250 microm of CsI(Tl). Further, possible locations for gain increase in the imaging chain were determined, and the output of the improved system was simulated. Thus a theoretical analysis for the micro-angiographic detector was performed to better assess its potential.

Algorithms↗
PubMed2002

Two temporal phases of light adaptation in retinal rods.

Vertebrate rod photoreceptors adjust their sensitivity as they adapt during exposure to steady light. Light adaptation prevents the rod from saturating and significantly extends its dynamic range. We examined the time course of the onset of light adaptation in bullfrog rods and compared it with the projected onset of feedback reactions thought to underlie light adaptation on the molecular level. We found that adaptation developed in two distinct temporal phases: (1) a fast phase that operated within seconds after the onset of illumination, which is consistent with most previous reports of a 1-2-s time constant for the onset of adaptation; and (2) a slow phase that engaged over tens of seconds of continuous illumination. The fast phase desensitized the rods as much as 80-fold, and was observed at every light intensity tested. The slow phase was observed only at light intensities that suppressed more than half of the dark current. It provided an additional sensitivity loss of up to 40-fold before the rod saturated. Thus, rods achieved a total degree of adaptation of approximately 3,000-fold. Although the fast adaptation is likely to originate from the well characterized Ca(2+)-dependent feedback mechanisms regulating the activities of several phototransduction cascade components, the molecular mechanism underlying slow adaptation is unclear. We tested the hypothesis that the slow adaptation phase is mediated by cGMP dissociation from noncatalytic binding sites on the cGMP phosphodiesterase, which has been shown to reduce the lifetime of activated phosphodiesterase in vitro. Although cGMP dissociated from the noncatalytic binding sites in intact rods with kinetics approximating that for the slow adaptation phase, this hypothesis was ruled out because the intensity of light required for cGMP dissociation far exceeded that required to evoke the slow phase. Other possible mechanisms are discussed.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Phonological activation of category coordinates during speech planning is observable in children but not in adults: evidence for cascaded processing.

There is a long-standing debate in the area of speech production on the question of whether only words selected for articulation are phonologically activated (as maintained by serial-discrete models) or whether this is also true for their semantic competitors (as maintained by forward-cascading and interactive models). Past research has addressed this issue by testing whether retrieval of a target word (e.g., cat) affects--or is affected by--the processing of a word that is phonologically related to a semantic category coordinate of the target (e.g., doll, related to dog) and has consistently failed to obtain such mediated effects in adult speakers. The authors present a series of experiments demonstrating that mediated effects are present in children (around age 7) and diminish with increasing age. This observation provides further evidence for cascaded models of lexical retrieval.

Adult↗
PubMed2002

Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines.

Adenocarcinoma of the mammary gland is the leading type of cancer in women. Among these breast cancers those that are estrogen-responsive respond well to existing therapeutic regimens while estrogen non-responsive cancers metastasize widely, demonstrate a high relapse rate, and respond poorly to therapy. Over-expression of the arachidonic acid-metabolizing enzymes cyclooxygenase-2 and lypoxygenases is frequently observed in breast cancer, particularly the non-estrogen-responsive type, suggesting a role of the arachidonic acid (AA) cascade in the growth regulation of these malignancies. Adenocarcinomas of the lungs, pancreas and colon also frequently over-express AA-metabolizing enzymes, and recent evidence suggests that the growth-regulating AA-cascade in these malignancies is under beta-adrenergic control. Our current experiments have therefore tested the hypothesis that in analogy to these findings adenocarcinomas of the breast are also regulated by beta-adrenergic receptors via stimulation of the AA-cascade. Analysis of DNA synthesis by [3H]-thymidine incorporation assays in three estrogen-responsive and three estrogen non-responsive cell lines derived from human breast cancers demonstrated a significant reduction in DNA synthesis by beta-blockers and inhibitors of cyclooxygenase or lipoxygenases in all cell lines. Analysis of AA-release in one of the most responsive cell lines demonstrated a time-dependent increase in AA-release in response to the beta-adrenergic agonist isoproterenol. Analysis by RT-PCR revealed expression of beta2-adrenergic receptors in all cell lines whereas beta1-adrenergic receptors were not found in two of the estrogen non-responsive cell lines. Our data suggest that a significant subset of human breast cancers is under control of beta-adrenergic receptors via stimulation of the AA-cascade. These findings open up novel avenues for the prevention and clinical management of breast cancer, particularly the non-estrogen-responsive types. Moreover, our findings suggest that cardiovascular disease and adenocarcinomas in a variety of organ systems, including the breast may share common risk factors and benefit from similar preventive and treatment strategies.

Adrenergic beta-Agonists↗
PubMed2004

Agrin-induced AChR aggregate formation requires cGMP and aggregate maturation requires activation of cGMP-dependent protein kinase.

Previously, it was demonstrated that agrin acting through the gaseous, signaling molecule, nitric oxide (NO), induces the formation of AChR aggregates on myotubes in culture. Soluble guanylyl cyclase (sGC), which is present at the neuromuscular junction, is a common target of NO. Therefore, we hypothesized that sGC and cGMP are involved in the agrin signaling cascade. Inhibition of sGC hindered AChR aggregation in both agrin- and NO donor-treated cultured myotubes; whereas, a cGMP analogue was able to induce the formation of AChR aggregates on naïve muscle cells. Due to the presence of cyclic GMP-dependent protein kinase (PKG) at the neuromuscular junction, we tested the ability of a PKG inhibitor to alter the agrin signaling cascade. PKG inhibition did not prevent nascent AChR aggregate formation; however, these aggregates were diffuse and composed of numerous microaggregates consistent with incomplete maturation. Thus, we conclude that cGMP is important for the initiation of AChR aggregation, while PKG is involved in the maturation of AChR aggregates.

Agrin↗
PubMedDate not supplied

Anti-inflammatory agents and inducibility of hepatic drug metabolism.

Two rat liver cytosolic aldehyde dehydrogenases, ALDH1 and ALDH3c, are of particular interest because they are inducible by different classes of xenobiotics. ALDHI is mainly increased by phenobarbital-type inducers; polycyclic aromatic hydrocarbons (PAHs), such as 3- methylcholanthrene (3MC), increase ALDH3c enzyme activity in all rat species currently tested. In addition, ALDH3c has been found to reflect the subfamily CYPIA of cytochrome P-450, as well as other enzymes functionally related to the aryl hydrocarbon receptor (the "Ah-receptor enzyme battery"), which is activated by the same type of inducers. In the present study we investigated whether the induction of ALDH3c might be connected with a chemically produced aseptic inflammation of the hepatocyte. To answer this question, we examined the relationship between the induction of ALDH3c by 3MC and the arachidonic acid cascade. Different non-steroid anti-inflammatory drugs (NSAIDs) were tested in combination with 3MC and in post-treatment. The 3MC-induced ALDH3c activity was significantly diminished by the co-administered anti-inflammatory agents. Two microsomal enzyme activities (ethoxyresorufin-O-deethylase, EROD; aryl-hydrocarbon-hydroxylase, AHH) were also decreased. Similar results were obtained with NSAIDs administered to animals pre- treated with 3MC, as far as the ALDH3c activity was concerned, but not for the microsomal enzyme activity (EROD and AHH). In conclusion, the induction of ALDH3c, after PAH treatment, may be related to an aseptic inflammation of the hepatocytes. This effect is reduced by commonly used steroid and non-steroid anti- inflammatory drugs, and although the mechanism of inhibition has not yet been elucidated, it appears likely that ALDH3c and CYP1A activities are associated with the "acute phase" response.

Aldehyde Dehydrogenase↗