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PubMed2000

Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can regress adenomas in patients with familial adenomatous polyposis (FAP), and the mechanism involves inhibition of cyclooxygenases (COX). Reactive intermediates formed during the arachidonic acid cascade, notably by COX-2, which is upregulated in polyps of FAP patients, may promote various stages of the polyp --> adenoma --> carcinoma sequence. Etheno-DNA adducts can be derived from reactive intermediates generated during arachidonic acid metabolism and lipid peroxidation. We tested this hypothesis in colonic polyps from FAP patients and colorectal tissue from cancer patients to see whether increased formation of etheno-DNA adducts occurs. Using an ultra-sensitive and specific immunoaffinity/(32)P-postlabelling method, 1, N(6)-ethenodeoxyadenosine (straightepsilondA) and 3, N(4)-ethenodeoxycytidine (straightepsilondC) were quantitated in epithelial cell DNA from asymptomatic colon, FAP polyps and colon tumor tissues. Mean adduct levels in FAP polyps were 65 straightepsilondA/10(9) and 59 straightepsilondC/10(9) parent nucleotides, being 2 to 3 times higher than in unaffected colon tissue (p < 0.02 for straightepsilondA; p < 0.05 for straightepsilondC). Adduct levels in colonic epithelia decreased in the order: FAP polyps > tumor-adjacent tissue > tumor, normal and tumor-distal tissue. Based on this study, requiring confirmation in a larger number of patients and in experimental models, we have demonstrated the formation of promutagenic etheno-DNA adducts in adenomatous polyps of FAP patients that may contribute to genetic instability and cancer progression.

Adenoma↗
PubMed1995

The MAP kinase cascade is not essential for transcriptional stimulation of osmolyte transporter genes.

Kidney derived MDCK cells are protected from the stress of hypertonicity by accumulating compatible osmolytes. Accumulation of the compatible osmolytes myo-inositol and betaine is driven by hypertonicity-induced stimulation of transcription of the genes coding for the myo-inositol cotransporter and the betaine cotransporter. We tested the importance of the mitogen-activated protein kinase pathway in transcriptional activation of the genes for the two osmolytes cotransporters because this kinase pathway is rapidly activated when cells are exposed to hypertonicity and a mitogen-activated protein kinase pathway is essential for the osmo-protective transcriptional response of yeast to hypertonicity. Eliminating the activation of mitogen-activated protein kinase did not block the hypertonicity induced increase in accumulation of osmolyte transporter mRNA.

Animals↗
PubMed1991

Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation (the CASCADE study).

This randomized study evaluates survivors of out-of-hospital ventricular fibrillation (VF) not associated with a Q-wave acute myocardial infarction who are deemed to be at a high risk of recurrence of VF. It compares the outcome of treatment with empirically administered amiodarone with the outcome of treatment with other antiarrhythmic agents guided by electrophysiologic testing or Holter recording, or both. The goal of therapy guided by electrophysiologic testing is to suppress inducible ventricular tachycardia (VT) or VF. Holter recording is used as the primary means of adjusting therapy only if patients are noninducible at the baseline electrophysiologic study. Patients are stratified according to cardiac diagnosis, ejection fraction, and whether they had previously received an antiarrhythmic agent that failed to suppress their arrhythmias. The primary end point of the study is total cardiac mortality. The first patient was enrolled in a pilot study on April 26, 1984. By October 1988, 142 patients had been enrolled in the full study and, as of May 1990, 199 patients have been enrolled. Compliance with therapy has been good, with no patients lost to follow-up and 8% of patients, equal in both drug groups, crossing over to alternate therapy. Baseline clinical characteristics remain similar in amiodarone and conventional drug groups. Pulmonary toxicity with amiodarone is 7% at 1 year, with no patients dying of pulmonary toxicity. In the first 142 patients, the overall 1-year cardiac mortality was 19%, with a 17% arrhythmic mortality (either VF or presumed arrhythmic death).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1995

TNF-alpha production as an in vitro assay predictive of cytokine-mediated toxic reactions induced by monoclonal antibodies.

When administered to patients, various biotechnology products may induce early toxic effects mediated by a cytokine cascade in which Tumor Necrosis Factor-alpha (TNF-alpha) plays a central role. The mechanisms of these toxic reactions have been extensively documented in the clinical model of the CD3 monoclonal antibody (mAb), OKT3. In order to develop a preclinical test for assessing the potential of mAbs or recombinant molecules to induce acute reactions when administered to patients, we investigated different in vitro culture systems for TNF-alpha secretion, using human blood cells. OKT3 and bacterial lipopolysaccharide (LPS) were used as positive controls. By comparing different culture conditions and kinetics, we concluded that 6-h supernatants of plasma-depleted whole blood contained high amounts of TNF-alpha in cultures stimulated by OKT3 or LPS, but not in those performed in the absence of exogenous stimulant or in the presence of mAbs which do not induce toxic reactions in vivo. This in vitro assay may be applied to the preclinical evaluation of the risk of cytokine-mediated toxicity in vivo. Owing to its simplicity, it could be used for preclinical investigation of inter-individual differences in the susceptibility to 'activation syndrome'.

Antibodies, Monoclonal↗
PubMed2005

Role of early case detection by screening relatives of patients with HFE-associated hereditary haemochromatosis.

Hereditary haemochromatosis is a primary inherited disorder of iron metabolism leading to progressive iron loading of parenchymal cells of the liver and other organs with diverse clinical manifestations, including cirrhosis, diabetes and skin pigmentation. This chapter will focus on HFE-associated hereditary haemochromatosis, which accounts for approximately 90% of cases in Caucasian populations. Penetrance is incomplete, with variable clinical expression. The majority of cases demonstrate biochemical expression, but a much lower proportion develop advanced disease. Clinical disease--especially hepatic fibrosis--is related to the level of body iron stores, which is reflected primarily in the liver. The available evidence indicates that adequate screening and diagnostic strategies ensure that early case detection and treatment occur prior to the development of irreversible end-organ damage. The most cost-effective methods of early case detection are family (cascade) screening and evaluation of potential cases by primary care physicians with a high index of clinical suspicion.

Genetic Testing↗
PubMed2005

Cascade models of synaptically stored memories.

Storing memories of ongoing, everyday experiences requires a high degree of plasticity, but retaining these memories demands protection against changes induced by further activity and experience. Models in which memories are stored through switch-like transitions in synaptic efficacy are good at storing but bad at retaining memories if these transitions are likely, and they are poor at storage but good at retention if they are unlikely. We construct and study a model in which each synapse has a cascade of states with different levels of plasticity, connected by metaplastic transitions. This cascade model combines high levels of memory storage with long retention times and significantly outperforms alternative models. As a result, we suggest that memory storage requires synapses with multiple states exhibiting dynamics over a wide range of timescales, and we suggest experimental tests of this hypothesis.

Animals↗
PubMed2005

Semi-synthetic mammalian gene regulatory networks.

In recent years gene network engineers have celebrated spectacular success: Genetic devices such as epigenetic toggle switches and oscillating networks have been engineered and pioneered a new ever-increasing scientific community known as synthetic biology. While synthetic biology was until recently restricted to network assembly and testing in prokaryotes, decisive advances have been achieved in eukaryotic systems based on current availability of different human-compatible transgene control technologies. Most prominent examples include the epigenetic gene network enabling metastable fully inheritable transgene expression states in mice, artificial regulatory cascades managing multi-level expression control and Boolean-type BioLogic gates supporting near-digital expression readout. The majority of transgene control networks available to date are fully synthetic and integrate artificial extracellular signals in a desired host metabolism-independent manner. Yet, in order to develop their full anticipated therapeutic potential, synthetic transgene control circuits need to be well interconnected with the host cell's regulatory networks in order to enable physiologic control of prosthetic molecular expression units. We have designed three semi-synthetic transcription control networks able to integrate physiologic oxygen levels and artificial antibiotic signals to produce expression readout with NOT IF or NOR-type Boolean logic or discrete multi-level control of several intracellular and secreted model product proteins. Subtle differences in the regulation performance of the endogenous oxygen-sensing system in CHO-K1 and human HT-1080 switched the semi-synthetic network's readout from a classic four-level (high, medium, low, basal) regulatory cascade to a network enabling six discrete transgene expression levels. These findings are in excellent correspondence with a mathematical model. Prosthetic networks, precisely embedded in host regulatory networks and co-fine-tuned by physiologic as well as pharmacologic input signals, will foster future advances in gene therapy and tissue engineering.

Animals↗
PubMed1996

Fibronectin and antithrombin as markers of pre-eclampsia in pregnancy.

INTRODUCTION: The differential diagnosis between pre-eclampsia and chronic hypertension is not easy, but is essential to proper management of a pregnancy. Patients presenting pre-pregnancy hypertension can be treated conservatively, if not a superimposed pre-eclampsia occurs, controlling pressure pharmacologically and completing the pregnancy with a natural delivery. In pre-eclampsia, hypertension is merely the visible sign of a process of endothelial damage and coagulation cascade activation which is often destined to emerge clinically on a dramatic scale. MATERIALS AND METHODS: The study involved 18 women with physiological pregnancies, 19 with pre-eclampsia and 13 with chronic hypertension since superimposed pre-eclampsia. The following laboratory tests were performed: PT, PTT, AT-III, proteins C and S, platelet count, D-dimer, fibrinogen and plasma fibronectin. The three groups were compared using the Kruskall Wallis test, the median test and, for multiple comparisons, the Mann-Whitney test. A 'P' value of < 0.01 was considered as statistically significant. RESULTS: The values for plasma fibronectin were higher in the pre-eclampsia group (410 mg/l (253-727)) than in controls (262 mg/l (183-385)) (P < 0.01) and values for AT-III were lower in the pre-eclampsia group (73% (40-100)) than in controls (93% (80-126) (P < 0.01) (Table 2). The groups with chronic hypertension revealed no such significant differences, however, in relation to the control group (fibronectin = 296 mg/l (198-530), AT-III = 86% (75-103)). CONCLUSIONS: Measuring antithrombin and fibronectin to monitor any onset of pre-eclampsia can help the obstetrician to avoid important diagnostic and therapeutic errors.

Adult↗
PubMed2004

Genome-wide gene-expression patterns of donor kidney biopsies distinguish primary allograft function.

Roughly 25% of cadaveric, but rarely living donor renal transplant recipients, develop postischemic acute renal failure, which is a main risk factor for reduced long-term allograft survival. An accurate prediction of recipients at risk for ARF is not possible on the basis of donor kidney morphology or donor/recipient demographics. We determined the genome-wide gene-expression pattern using cDNA microarrays in three groups of 36 donor kidney wedge biopsies: living donor kidneys with primary function, cadaveric donor kidneys with primary function and cadaveric donor kidneys with biopsy proven acute renal failure. The descriptive genes were characterized in gene ontology terms to determine their functional role. The validation of microarray experiments was performed by real-time PCR. We retrieved 132 genes after maxT adjustment for multiple testing that significantly separated living from cadaveric kidneys, and 48 genes that classified the donor kidneys according to their post-transplant course. The main functional roles of these genes are cell communication, apoptosis and inflammation. In particular, members of the complement cascade were activated in cadaveric, but not in living donor kidneys. Thus, suppression of inflammation in the cadaveric donor might be a cheap and promising intervention for postischemic acute renal failure.

Acute Kidney Injury↗
PubMed2004

Transgene-driven expression of the Doppel protein in Purkinje cells causes Purkinje cell degeneration and motor impairment.

The Doppel (Dpl) and Prion (PrP) proteins show 25% sequence identity and share several structural features with only minor differences. Dpl shows a PrP-like fold of its C-terminal globular domain and lacks the flexible N-terminal tail. The physiological functions of both proteins are unknown. However, ubiquitous Dpl overexpression in the brain of PrP knockout mice correlated with ataxia and Purkinje cell degeneration in the cerebellum. Interestingly, a similar phenotype was reported in transgenic mice expressing an N-terminally truncated PrP (DeltaPrP) in Purkinje cells by the L7 promoter (TgL7-DeltaPrP). Coexpression of full-length PrP rescued both the neurological syndromes caused by either Dpl or DeltaPrP. To evaluate whether the two proteins caused cerebellar neurodegeneration by the same mechanism, we generated transgenic mice selectively expressing Dpl in Purkinje cells by the same L7 promoter. Such mice showed ataxia and Purkinje cell loss that depended on the level of Dpl expression. Interestingly, the effects of high levels of Dpl were not counterbalanced by the presence of two Prnp alleles. By contrast, PrP coexpression was sufficient to abrogate motor impairment and to delay the neurodegenerative process caused by moderate level of Dpl. A similar situation was reported for the corresponding TgL7-DeltaPrP mice supporting the concept that Dpl and DeltaPrP cause cell death, possibly by interfering with a common signaling cascade essential for cell survival.

Animals↗
PubMed1983

Action of luteinizing hormone-releasing hormone: involvement of novel arachidonic acid metabolites.

Anterior pituitary cells were incubated in the presence of luteinizing hormone-releasing hormone and one of three inhibitors of arachidonic acid metabolism:indomethacin, an inhibitor of the cyclooxygenase system; nordihydroguaiaretic acid, an antioxidant that inhibits lipoxygenase; and icosatetraynoic acid, an acetylenic analogue of arachidonic acid that blocks all known pathways of arachidonic acid metabolism. Indomethacin was ineffective in blocking luteinizing hormone-releasing hormone-stimulated luteinizing hormone secretion. Nordihydroguaiaretic acid was only marginally capable of inhibiting luteinizing hormone-releasing hormone-stimulated luteinizing hormone secretion. Icosatetraynoic acid at 10 microM completely inhibited stimulated luteinizing hormone secretion. Addition of several epoxygenated arachidonic acid metabolites to cells in vitro resulted in secretion of luteinizing hormone equal to or greater than that induced by 10 nM luteinizing hormone-releasing hormone. The half-maximal effective dose for these compounds was approximately 50 nM. The 5,6-epoxyicosatrienoic acid was the most potent of the compounds tested. These studies suggest that luteinizing hormone-releasing hormone-stimulated luteinizing hormone release is closely coupled with the production of oxidized arachidonic acid metabolites. Moreover, one or more of the epoxygenated arachidonic acid metabolites might be a component of the cascade of reactions initiated by luteinizing hormone-releasing hormone that ultimately results in secretion of luteinizing hormone.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1995

The impact of chronic illness on the health and well-being of family members.

Examined is the impact of dementia on the physical and mental health of all family members caring for an ill parent/spouse. The sample included 97 spouses of patients diagnosed with either Alzheimer's disease or vascular dementia, 186 offspring, and 97 offspring spouses or "in-laws." Multiple regression tested the association between severity of the illness and family member health and well-being. Severity was significantly associated with health and well-being for spouses, offspring, and in-laws, regardless of the amount of caregiving, demonstrating the potential cascading effect of the illness through the family. Use of services displayed no direct association with spouse health and well-being, but service utilization interacted with illness severity. The relationship between severity of illness and spouse health was lower under conditions of high service utilization than under conditions of low service utilization.

Adult↗
PubMed1995

MK-801 blockade of Fos and Jun expression following passive avoidance training in the chick.

Training chicks on a one-trial passive avoidance task results in transient up-regulation of the N-methyl-D-aspartate (NMDA) receptor in the left intermediate medial hyperstriatum ventrale (IMHV) of the forebrain 30 min post-training. Injection of the non-competitive NMDA receptor inhibitor, (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten 5,10-imine maleate (MK-801), around the time of training renders chicks amnesic for the task. Training also results in enhanced expression of the immediate early gene (IEG) c-fos in the IMHV. To determine the relationship between NMDA receptor up-regulation and IEG induction during memory formation we have examined the expression of Fos, Jun and their related proteins 2 h following training in the presence/absence of the putative amnestic agent MK-801. Western blotting of IMHV samples revealed two protein bands with immunoreactivity to the Fos antibody at 47 and 54 kDa. Using an antibody to Jun, two immunoreactive bands were revealed at 39 and 54 kDa. All bands were enhanced in the left IMHV following passive avoidance training. Post-training intraperitoneal injections of MK-801 (75 mM) produced amnesia in approximately 50% of the birds when tested 1 h after training. Injection of MK-801 significantly attenuated expression of these proteins in birds rendered amnesic, but not in those that recalled the task. We conclude that NMDA receptor activation precedes immediate early gene expression in the memory formation cascade.

Amnesia↗
PubMed2004

Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury.

Tetracyclines exhibit significant anti-inflammatory properties, inhibit matrix metalloproteinases (MMPs), and are protective in models of ischemia-reperfusion injury (IRI). Both inflammatory cascades and MMP activation have been demonstrated to modulate microvascular permeability. Because increased microvascular permeability occurs during IRI in a variety of organ systems including the kidney, we hypothesized that minocycline, a semisynthetic tetracycline, would diminish microvascular leakage during renal IRI. To test this hypothesis, we used intravital 2-photon microscopy to examine leakage of fluorescent dextrans from the vasculature in a rodent model of IRI. Minocycline significantly reduced the extent of dextran (500 kDa) leakage from the renal microvasculature 24 h after ischemia. Although minocycline diminished leukocyte accumulation in the kidney following ischemia, areas of leukocyte accumulation did not correlate with areas of microvascular permeability in either the saline- or minocycline-pretreated animals. Minocycline diminished the perivascular increase in MMP-2 and MMP-9, as well as the increase in MMP-2 activity 24 h after ischemia. ABT-518, a specific inhibitor of MMP-2 and MMP-9, also significantly reduced the extent of dextran (500 kDa) leakage from the renal microvasculature 24 h after ischemia. Our results indicate that minocycline mitigates the renal microvascular permeability defect following IRI. This effect is spatially distinct from the effect of minocycline on leukocyte accumulation and may be related to diminished activity of MMPs on the integrity of the perivascular matrix.

Acute Kidney Injury↗
PubMed2006

Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma.

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Akt are important regulators of the phosphatidylinositol 3-kinase (PI3K) pathway and thus are important to the regulation of a wide spectrum of tumor-related biological processes. Akt regulates several critical cellular functions, including cell cycle progression; cell migration, invasion, and survival; and angiogenesis. Decreased expression of PTEN and overexpression of the Akt proto-oncogene, which is located downstream of PI3K, have been shown in a variety of cancers, including glioblastoma. Novel small-molecule inhibitors of receptors and signaling pathways, including inhibitors of the PI3K pathway, have shown antitumor activity, but inhibitors of Akt have not been examined. In this study, we tested our hypothesis that the pharmacologic inhibition of Akt has an antiproliferative effect on gliomas. We showed that two newly developed Akt inhibitors, KP-372-1 and KP-372-2 (herein called KP-1 and KP-2), effectively inhibited the PI3K/Akt signaling cascade. KP-1 and KP-2 blocked both the basal and epidermal growth factor-induced phosphorylation of Akt Ser473 at 125 and 250 nmol/L, which, in turn, reduced the activation of intracellular downstream targets of Akt, including GSK-3beta and p70s6k. Furthermore, the treatment of U87 and U251 glioma cells with 125 to 250 nmol/L KP-1 and KP2 for 48 hours inhibited cell growth by approximately 50%. This decrease in cell growth stemmed from the induction of apoptosis. Collectively, these results provide a strong rationale for the pharmacologic targeting of Akt for the treatment of gliomas.

Apoptosis Regulatory Proteins↗
PubMed2026

Engagement and Retention in Precision Public Health: A Cascade Analysis of Two Cluster Randomized Trials.

INTRODUCTION: When research fails to reach and engage all populations who might benefit from study findings, it can compromise scientific validity and ultimately health equity. Few studies have systematically examined factors driving study engagement through longitudinal intervention research. This project examined sociodemographic, geographic, and structural influences on engagement and attrition across the participation "cascade" (outreach, enrollment, retention) for two large-scale multilevel precision medicine and precision prevention trials for smoking and lung cancer screening. METHODS: Modified Poisson regression models were used to determine the factors associated with study engagement based on sociodemographic and geographical factors at each step in the cascade of participation, from initial outreach through retention at 12 months post-enrollment. Secondary analyses examined the cascade among the subset of patients who had active electronic patient portals and were approached via the portal. RESULTS: A total of 24,366 patients were approached for participation. Race, Social Vulnerability Index (SVI), insurance status, and distance from the study site were significantly associated with engagement at various points in the cascade. Black patients were more likely than White patients to be reached (48.9% vs 47.1%; p = 0.022) and to complete eligibility screening (52.8% vs. 38.4%; p < 0.001), but less likely to consent to participate (56.7% vs 69.8%; p < 0.001) and complete genetic testing (58.5% vs. 69.8%; p = 0.003). Patterns of engagement through electronic patient portal versus non-electronic recruitment channels also differed by race- and place-based factors, with Black patients being less likely than White patients to respond in the portal (8.8% vs 15.5%; p < 0.001), and patients who reside farther from the study site being more likely to respond in the portal compared to those who live closer (14.9% vs 12.5%; p < 0.001). CONCLUSIONS: These findings highlight the need for tailored, stage-specific engagement strategies to ensure representative participation in genomic and behavioral intervention research to advance the integration of genomics into public health practice.

Journal Article↗
PubMed2003

Adaptation in pheromone-sensitive trichoid sensilla of the hawkmoth Manduca sexta.

In extracellular tip recordings from long trichoid sensilla of male Manduca sexta moths, we studied dose-response relationships in response to bombykal stimuli of two different durations in the adapted and the non-adapted state. Bombykal-responsive cells could be distinguished from non-bombykal-sensitive cells in each trichoid sensillum because the bombykal-responsive cell always generated the action potentials of larger initial amplitude. The bombykal cell, which was recorded at a defined location within a distal flagellar annulus, can resolve at least four log(10)-units of pheromone concentrations but is apparently unable to encode all stimulus durations tested. Parameters of the amplitude-modulated sensillar potential and the frequency-modulated action potential responses were examined in different states of adaptation. Evidence is presented for the existence of several mechanisms of adaptation, which affect distinct steps of the transduction cascade. After adapting pheromone stimuli, the sensillar potential rises to a lower amplitude and declines faster compared with the non-adapted response. In addition, the frequency of the adapted action potential response is reduced. Only the time of rise of the sensillar potential is differentially affected by adapting pheromone stimuli of different duration. The time of rise does not increase after short, but only after long, adapting stimuli. Both short and long adapting stimuli shift the dose-response curves of the sensillar potential amplitude, as well as the initial slope of its rising phase, to higher stimulus concentrations by approximately one log(10)-unit. The shift in the dose-response curve of the action potential response is larger than for the sensillar potential response, suggesting that an additional adaptation mechanism acts at the level of action potential generation. Furthermore, a faster decline of the sensillar potential after short and long adapting stimuli suggests that the resting potential of the olfactory receptor neuron is stabilized.

Action Potentials↗
PubMed2006

[Pharmacogenetics of chronic heart failure--beta blockers].

BACKGROUND: Activation of the renin-angiotensin (RAS) cascade and sympathetic nervous systems adversely affect heart failure progression. ACE deletion allele (ACE D) of insertion/deletion polymorphism in the gene coding for angiotensin-1 converting enzyme is associated with increased renin-angiotensin activation. The aim of the study was to test pharmacogenetic associations of I/D ACE genotype with beta blockers therapy in patients with chronic heart failure. METHODS AND RESULTS: A total of 241 patients were included in the study, 63% with betablocker therapy and 37% without it. Using polymerase chain reaction (PCR) method, I/D genotype was detected in 2% agarose electrophoretic gel in UV light. Patients with chronic heart failure and with the II genotype of polymorphism I/D ACE were younger, with more frequent administration of betablockers and diuretics, with less regular administration of aspirin and with lower glycemia and plasma TNFalpha level. A significant difference in genotype distribution and allele frequency between patients with recommended dose and patients without betablockers therapy was proved, when a decrease of the D allele in patients with betablockers had been observed. Contemporary evaluating of AC inhibitor and betablocker therapy, a decrease of ID+DD genotypes in patients with lower than 50% recommended dose compared with the others was found. CONCLUSIONS: In this study, we proved statistically significant interactions between genotypes in I/D ACE polymorphism, betablocker administration, its dosing and pharmacogenetic interaction with ACE inhibitors in patients with chronic heart failure.

Adrenergic beta-Antagonists↗