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At least 865 records · Page 48Linked to original sources
PubMed2005

Tone choice and voice quality of dispreferred turns in the English of Finns.

Authentic Finnish-English speech data was collected as part of an English conversation class in a Finnish college. Intonation was coded utilizing the framework involving 'tone', 'key' and 'termination'. A categorization of voice quality was chosen (e.g., 'modal voice', 'creak', 'breathy', and 'tense'). The tempo of speech was transcribed with such descriptors as, e.g., 'fast' and 'slow'. The majority of dispreferred turns in the data represented mitigated disagreement, with structural complexity (involving, e.g., wordiness). The p tone was predominant: a low/mid key often accompanied mitigated disagreement. The r and r+ tones were virtually absent in the mitigated dispreferred turns. Instead, the speakers often used a very lax/breathy voice quality and a slow/decelerating tempo, often resulting in creak near a transition relevant place.

Affect↗
PubMed2006

Assessment and management of residential radon health risks: a report from the health Canada radon workshop.

Epidemiologic studies of uranium miners and other underground miners have consistently shown miners exposed to high levels of radon to be at increased risk of lung cancer. More recently, concern has arisen about lung cancer risks among people exposed to lower levels of radon in homes. The current Canadian guideline for residential radon exposure was set in 1988 at 800 Bq/m(3). Because of the accumulation of a considerable body of new scientific evidence on radon lung cancer risks since that time, Health Canada sponsored a workshop to review the current state-of-the-science on radon health risks. The specific objectives of the workshop were (1) to collect and assess scientific information relevant to setting national radon policy in Canada, and (2) to gather information on social, political, and operational considerations in setting national policy. The workshop, held on 3-4 March 2004, was attended by 38 invited scientists, regulators, and other stakeholders from Canada and the United States. The presentations on the first day dealt primarily with scientific issues. The combined analysis of North American residential radon and lung cancer studies was reviewed. The analysis confirmed a small but detectable increase in lung cancer risk at residential exposure levels. Current estimates suggest that radon in homes is responsible for approximately 10% of all lung cancer deaths in Canada, making radon the second leading cause of lung cancer after tobacco smoking. This was followed by a perspective from an UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) working group on radon. There were two presentations on occupational exposures to radon and two presentations considered the possibility of radon as a causative factor for cardiovascular disease and for cancer in other organs besides the lung. The possible contribution of environmental tobacco smoke to lung cancers in nonsmokers was also considered. Areas for future research were identified. The second day was devoted to policy and operational issues. The presentations began with a perspective from the U.S. Environmental Protection Agency, followed by a history of radon policy development in Canada. Subsequent presentations dealt with the cost-effectiveness of radon mitigation, Canadian building codes and radon, and a summary of radon standards from around the world. Provincial representatives and a private consultant were given opportunities to present their viewpoints. A number of strategies for reducing residential radon exposure in Canada were recognized, including testing and mitigation of existing homes (on either a widespread or targeted basis) and changing the building code to require that radon mitigation devices be installed at the time a new home is constructed. The various elements of a comprehensive national radon policy were set forth.

Air Pollutants, Radioactive↗
PubMed2003

Influence of seat foam and geometrical properties on BioRID P3 kinematic response to rear impacts.

As the primary interface with the human body during rear impact, the automotive seat holds great promise for mitigation of Whiplash Associated Disorders (WAD). Recent research has chronicled the potential influence of both seat geometrical and constitutive properties on occupant dynamics and injury potential. Geometrical elements such as reduced head to head restraint, rearward offset, and increased head restraint height have shown strong correlation with reductions in occupant kinematics. The stiffness and energy absorption of both the seating foam and the seat infrastructure are also influential on occupant motion; however, the trends in injury mitigation are not as clear as for the geometrical properties. It is of interest to determine whether, for a given seat frame and infrastructure, the properties of the seating foam alone can be tailored to mitigate WAD potential. Rear impact testing was conducted using three model year 2000 automotive seats (Chevrolet Camaro, Chevrolet S-10 pickup, and Pontiac Grand Prix), using the BioRID P3 anthropometric rear impact dummy. Each seat was distinct in construction and geometry. Each seat back was tested with various foams (i.e., standard, viscoelastic, low or high density). Seat geometries and infrastructures were constant so that the influence of the seating foams on occupant dynamics could be isolated. Three tests were conducted on each foam combination for a given seat (total of 102 tests), with a nominal impact severity of Delta V = 11 km/h (nominal duration of 100 msec). The seats were compared across a host of occupant kinematic variables most likely to be associated with WAD causation. No significant differences (p < 0.05) were found between seat back foams for tests within any given seat. However, seat comparisons yielded several significant differences (p < 0.05). The Camaro seat was found to result in several significantly different occupant kinematic variables when compared to the other seats. No significant differences were found between the Grand Prix and S-10 seats. Seat geometrical characteristics obtained from the Head Restraint Measuring Device (HRMD) showed good correlation with several occupant variables. It appears that for these seats and foams the head-to-head restraint horizontal and vertical distances are overwhelmingly more influential on occupant kinematics and WAD potential than the local foam properties within a given seat.

Accidents, Traffic↗
PubMed2005

Parkin gene therapy for alpha-synucleinopathy: a rat model of Parkinson's disease.

Parkin is known to mitigate alpha-synuclein-induced neuronal cell death in vitro, which suggests that the parkin gene therapy is a candidate for therapeutic strategies for Parkinson's disease (PD). In the present study, the parkin gene therapy was investigated for its ameliorative effects on alpha-synucleinopathy in substantia nigra (SN) of rats. A recombinant adeno-associated viral (rAAV) vector system has frequently been used for the gene transfer to rat SN, and we have previously demonstrated that this technique induced the alpha-synucleinopathy, which closely resembles pathogenetic changes in PD. Therefore, in the present study, the effect of parkin was examined by co-infection of rAAV-parkin with rAAV-alpha-synuclein into dopaminergic neurons in SN. At 13 weeks post-rAAV infection, alpha-synuclein overexpression induced dopaminergic neuron loss, while co-expression of parkin mitigated the alpha-synuclein toxicity. Moreover, alpha-synuclein-induced dopaminergic neuron loss consequently resulted in motor dysfunction, which was also mitigated by parkin. Taken together, our results indicate that the parkin gene therapy is effective against alpha-synucleinopathy, suggesting its potential suitability for patients with PD.

Animals↗
PubMed2003

Fighting arsenic at the grassroots: experience of BRAC's community awareness initiative in Bangladesh.

The study evaluates the arsenic mitigation project of BRAC in raising awareness of arsenic poisoning in rural communities in Bangladesh. Data came from selected project villages in south-western Bangladesh. Comparison villages were also selected from the same region. A total of 1240 randomly selected adults were interviewed in May 2000. Findings reveal that the mitigation project played a significant, positive role in raising awareness of the safe water options, signs of arsenicosis, mode of transmission and the type of treatment. Testing tube-well water for arsenic created curiosity, innovation and interest in the community, and the water treatment plant became a symbol of the arsenic campaign. The study concludes that the behavioural change aspects of the arsenic mitigation project have the potential to significantly improve the level of understanding about arsenic contamination in the traditional communities.

Adult↗
PubMed1992

Soil as a source of indoor 220Rn.

Two suggestions for sources of indoor 220Rn (thoron) have appeared in the literature: 1) building materials and outside air, and 2) soil beneath the house. Due to the difficulty of 220Rn measurement and limited data, both suggestions lack sufficient supporting evidence. We have investigated sources of indoor 220Rn in seven occupied houses in northern New Mexico, U.S. A two-filter system was used to measure indoor 220Rn levels continuously, and 220Rn progeny were measured with single filters and specialized alpha-track detectors. The amount of 220Rn entry from soil was curtailed by cutting off soil gas flow to the indoor air with subfloor depressurization mitigation systems. Four of the houses showed significant reductions in 220Rn with mitigation systems on. The average effect for these houses was to reduce indoor 220Rn levels by 70%. The other three houses had no clear reductions but in one of these houses, the mitigation system was not effective for stopping soil gas flow. Our results provide some of the most clear evidence to date supporting soil as an important source of indoor 220Rn.

Air Pollution, Indoor↗
PubMed1994

The use of computed radon entry rates to understand radon concentration in buildings.

The central role played by basement depressurization in drawing radon-contaminated soil gas into a structure has been demonstrated by calculating the radon entry rate from radon concentration and air infiltration measurements at different levels of basement depressurization in a single-family research house. The radon entry rate is found to be a linear function of basement depressurization in this house which indicates that the flow of soil gas into the structure is laminar. The radon entry rates calculated before and after using a mitigation procedure is shown to provide a better measure of the mitigation efficacy than the standard before and after mitigation radon measurements in a research house. In addition, an analysis of the possible flow characteristics of soil gas and uncontaminated air into a basement indicates that any attempt to predict long-term average radon exposure from short-term screening measurements will only be possible under severely restricted conditions.

Air Pollution, Indoor↗
PubMed1998

Indoor exposure to 222Rn: a public health perspective.

The objective of this study was to assess the lung cancer risk resulting from indoor radon exposure in the province of Quebec, Canada, and to evaluate the efficacy of mitigation measures to reduce this exposure. Concentrations of radon were determined in a representative sample of houses, and the corresponding lung cancer risk estimates were generated using the BEIR IV model, taking into account smoking, residential mobility, and regional variations in radon concentrations. Mean (geometric) radon concentrations in basements (n = 418) and on first floors (n = 319) were, respectively, 34.4 (95% CI-30.6 to 38.8) and 16.5 Bq m(-3) (14.2 to 19.3). A total of 109 deaths from lung cancer are predicted to occur as a result of this exposure in a cohort of 60,000 people. Detecting all residences with high radon concentrations (equal to or above 200 Bq m(-3)) and implementing mitigation measures in each of them would reduce by 4 the number of lung cancer deaths attributable to indoor radon exposure. A reduction of 0.05% in the prevalence of smoking would prevent as many deaths from lung cancer as would radon mitigation. From a public health perspective, in order to reduce mortality from lung cancer, most efforts should be focused on smoking, not on the relatively minor and hardly preventable population risk arising from household radon exposure.

Air Pollutants, Radioactive↗
PubMed2002

The role of sustainable agriculture and renewable-resource management in reducing greenhouse-gas emissions and increasing sinks in China and India.

This paper contains an analysis of the technical options in agriculture for reducing greenhouse-gas emissions and increasing sinks, arising from three distinct mechanisms: (i) increasing carbon sinks in soil organic matter and above-ground biomass; (ii) avoiding carbon emissions from farms by reducing direct and indirect energy use; and (iii) increasing renewable-energy production from biomass that either substitutes for consumption of fossil fuels or replaces inefficient burning of fuelwood or crop residues, and so avoids carbon emissions, together with use of biogas digesters and improved cookstoves. We then review best-practice sustainable agriculture and renewable-resource-management projects and initiatives in China and India, and analyse the annual net sinks being created by these projects, and the potential market value of the carbon sequestered. We conclude with a summary of the policy and institutional conditions and reforms required for adoption of best sustainability practice in the agricultural sector to achieve the desired reductions in emissions and increases in sinks. A review of 40 sustainable agriculture and renewable-resource-management projects in China and India under the three mechanisms estimated a carbon mitigation potential of 64.8 MtC yr(-1) from 5.5 Mha. The potential income for carbon mitigation is $324 million at $5 per tonne of carbon. The potential exists to increase this by orders of magnitude, and so contribute significantly to greenhouse-gas abatement. Most agricultural mitigation options also provide several ancillary benefits. However, there are many technical, financial, policy, legal and institutional barriers to overcome.

Agriculture↗
PubMed2003

The economics of abrupt climate change.

The US National Research Council defines abrupt climate change as a change of state that is sufficiently rapid and sufficiently widespread in its effects that economies are unprepared or incapable of adapting. This may be too restrictive a definition, but abrupt climate change does have implications for the choice between the main response options: mitigation (which reduces the risks of climate change) and adaptation (which reduces the costs of climate change). The paper argues that by (i) increasing the costs of change and the potential growth of consumption, and (ii) reducing the time to change, abrupt climate change favours mitigation over adaptation. Furthermore, because the implications of change are fundamentally uncertain and potentially very high, it favours a precautionary approach in which mitigation buys time for learning. Adaptation-oriented decision tools, such as scenario planning, are inappropriate in these circumstances. Hence learning implies the use of probabilistic models that include socioeconomic feedbacks.

Adaptation, Psychological↗
PubMed2002

An overview of the Salmonella enteritidis risk assessment for shell eggs and egg products.

This article summarizes a quantitative microbial risk assessment designed to characterize the public health impact of consumption of shell eggs and egg products contaminated with Salmonella Enteritidis (SE). This risk assessment's objectives were to: (1) establish the baseline risk of foodborne illness from SE, (2) identify and evaluate potential risk mitigation strategies, and (3) identify data gaps related to future research efforts. The risk assessment model has five modules. The Egg Production module estimates the number of eggs produced that are SE-contaminated. Shell Egg Processing, Egg Products Processing, and Preparation & Consumption modules estimate the increase or decrease in the numbers of SE organisms in eggs or egg products as they pass through storage, transportation, processing, and preparation. A Public Health Outcomes module then calculates the incidence of illnesses and four clinical outcomes, as well as the cases of reactive arthritis associated with SE infection following consumption. The baseline model estimates an average production of 2.3 million SE-contaminated shell eggs/year of the estimated 69 billion produced annually and predicts an average of 661,633, human illnesses per year from consumption of these eggs. The model estimates approximately 94% of these cases recover without medical care, 5% visit a physician, an additional 0.5% are hospitalized, and 0.05% result in death. The contribution of SE from commercially pasteurized egg products was estimated to be negligible. Five mitigation scenarios were selected for comparison of their individual and combined effects on the number of human illnesses. Results suggest that mitigation in only one segment of the farm-to-table continuum will be less effective than several applied in different segments. Key data gaps and areas for future research include the epidemiology of SE on farms, the bacteriology of SE in eggs, human behavior in food handling and preparation, and human responses to SE exposure.

Animals↗
PubMed2001

Risk and the neoliberal state: why post-Mitch lessons didn't reduce El Salvador's earthquake losses.

Although El Salvador suffered light losses from Hurricane Mitch in 1998, it benefited from the increased international aid and encouragement for advance planning, especially mitigation and prevention interventions. Thus, one would have supposed, El Salvador would have been in a very advantageous position, able more easily than its economically crippled neighbours, Honduras and Nicaragua, to implement the 'lessons of Mitch'. A review of the recovery plan tabled by the El Salvador government following the earthquakes of early 2001 shows that despite the rhetoric in favour of 'learning the lessons of Mitch', very little mitigation and prevention had actually been put in place between the hurricane (1998) and the earthquakes (2001). The recovery plan is analysed in terms of the degree to which it deals with root causes of disaster vulnerability, namely, the economic and political marginality of much of the population and environmental degradation. An explanation for the failure to implement mitigation and preventive actions is traced to the adherence by the government of El Salvador to an extreme form of neoliberal, free market ideology, and the deep fissures and mistrust in a country that follow a long and bloody civil war.

Disaster Planning↗
PubMed1994

High risk or low: how location on a "risk ladder" affects perceived risk.

Efforts to explain risk magnitude often rely on a "risk ladder" in which exposure levels and associated risk estimates are arrayed with low levels at the bottom and high ones at the top. Two experiments were conducted to test the hypothesis that perceived threat and intended mitigation vary with the location of the subject's assigned level on the risk ladder. Subjects were New Jersey homeowners, asked to assume a particular level of radon or asbestos contamination in their homes, to read a brochure explaining the risk, and then to complete a questionnaire. Both studies found that the difference between an assigned level one-quarter of the way up the ladder and the same level three-quarters of the way up the ladder significantly affected threat perception; the effect on mitigation intentions was significant in only one of the studies. Variations in assigned risk also affected threat perception and mitigation intentions. Variations in test magnitude (e.g., 15 fibers per liter vs. 450 fibers per cubic foot, roughly equivalent risks) had no effect, nor did the distinction between radon and asbestos affect the dependent variables. These findings suggest that communicators can design risk ladders to emphasize particular risk characteristics.

Analysis of Variance↗
PubMed2005

Modelling the spread of foot-and-mouth disease in Australia.

Preparedness for an incursion of an exotic animal disease is of key importance to government, industry, producers and the Australian community. An important aspect of Australia's preparedness for a possible incursion of foot-and-mouth disease is investigation into the likely effectiveness and cost-efficiency of eradication strategies when applied to different regional outbreak scenarios. Disease modelling is a tool that can be used to study diseases such as foot-and-mouth disease to better understand potential disease spread and control under different conditions. The Australian Government Department of Agriculture, Fisheries and Forestry has been involved with epidemiologic simulation modelling for more than 10 years, and has developed a sophisticated spatial model for foot-and-mouth disease (AusSpread) that operates within a geographic information system framework. The model accommodates real farm boundary or point-location data, as well as synthesised data based on agricultural census and land use information. The model also allows for interactions between herds or flocks of different animal species and production type, and considers the role that such interactions are likely to play in the epidemiology of a regional outbreak of foot-and-mouth disease. The user can choose mitigations and eradication strategies from those that are currently described in Australia's veterinary emergency plan. The model also allows the user to evaluate the impact of constraints on the availability of resources for mitigations or eradication measures. Outputs include a range of maps and tabulated outbreak statistics describing the geographic extent of the outbreak and its duration, the numbers of affected, slaughtered, and, as relevant, vaccinated herds or flocks, and the cost of control and eradication. Cost-related outputs are based on budgets of the value of stock and the cost of mitigations, each of which can be varied by the user. These outputs are a valuable resource to assist with policy development and disease management.

Animals↗
PubMed2026

The Moral of the Story-Perception of Leadership With Moral Distress in Registered Nurses: A Qualitative Systematic Review.

AIM: To understand how Registered Nurses perceive the impact of nursing leadership on managing moral distress and mitigating burnout. BACKGROUND: Moral distress and burnout are pervasive issues in nursing, compromising well-being, patient safety and workforce sustainability. Leadership is a critical factor in shaping workplace culture and mitigating these challenges, yet evidence remains limited. DESIGN: Qualitative systematic review. METHODS: A qualitative systematic review was conducted following JBI methodology and PRISMA guidelines. Comprehensive searches across MEDLINE, PsycINFO, Embase, CINAHL and Scopus identified 5927 articles, with two studies meeting the inclusion criteria. Data were appraised using the JBI Critical Appraisal Checklist and synthesised via meta-aggregation. Confidence in findings was assessed using the ConQual approach. RESULTS: Four major themes emerged: (1) Behind the barriers, (2) Breaking point, (3) Weathering the storm and (4) Leadership for lasting change. Leadership influenced nurses' psychological safety, ethical decision-making and resilience. Inadequate support amplified moral distress, and effective strategies included authentic communication, team solidarity and systemic interventions. CONCLUSIONS: Leadership plays a pivotal role in mitigating moral distress and burnout. Evidence highlights the need for structural changes and support to sustain registered nurses' well-being and retention. RELATIVE TO CLINICAL PRACTICE: Findings offer direction for leadership strategies that promote ethical workplaces, shared decision-making and mental health supports to enhance resilience and patient care. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Strengthening leadership capability is vital for workforce sustainability, care quality and nurse retention. REPORTING METHOD: Authors have adhered to relevant EQUATOR guidelines. PATIENT OR PUBLIC CONTRIBUTION: This study did not involve patients or the public in its design, conduct or reporting.

Leadership↗
PubMed2025

Adrenomedullin overexpression protects mice from experimental bronchopulmonary dysplasia and associated pulmonary hypertension.

Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) or BPD-PH is a lung disease of infants with significant morbidity. Adrenomedullin (Adm) is an angiogenic peptide that signals through calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2 (RAMP2). Adm deficiency potentiates hyperoxia-induced experimental BPD-PH in mice; however, whether Adm overexpression can mitigate this lung disease is unclear. Thus, we tested the hypothesis that Adm overexpression attenuates hyperoxia (HO)-induced murine experimental BPD-PH by using a novel transgenic mouse that overexpresses Adm globally (Admhi/hi mice). One-day-old Admhi/hi mice or their wild-type littermates (Adm+/+ mice) were exposed to HO ([Formula: see text] 70%) for 14 days and allowed to recover in normoxia (NO, [Formula: see text] 21%) for an additional 14 days. Controls were maintained in NO for 28 days. On postnatal day (P) 14, we harvested the lungs to determine the extent of Adm expression and apoptosis. On P28, we quantified alveolarization, lung vascularization, and PH. HO-exposed Adm+/+ mice demonstrated increased lung apoptosis, decreased alveolarization and lung vascularization, and indices of PH, indicating that neonatal HO exposure causes BPD-PH. However, Adm overexpression attenuated experimental BPD-PH, as evident by the decreased extent of hyperoxia-induced lung apoptosis and inflammation, alveolar and vascular simplification, pulmonary vascular remodeling, and PH in Admhi/hi mice than in Adm+/+ mice. Collectively, our results demonstrate that Adm overexpression attenuates HO-induced murine experimental BPD-PH, emphasizing the therapeutic potential of Adm for BPD-PH in preterm infants.NEW & NOTEWORTHY The deficiency of the proangiogenic peptide, adrenomedullin (Adm), exacerbates the severe infantile lung disorder, bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), in mice. However, whether Adm therapy can mitigate this disease is unclear. Our study, conducted with a rigorous methodology, suggests a potential solution. Using a novel mouse that overexpresses Adm to overcome the pharmacological limitations of the peptide, we demonstrate that Adm can mitigate this disorder, highlighting the therapeutic potential of Adm for human BPD-PH.

Animals↗
PubMed2026

Partially countering the physiological effects of fentanyl with naloxone or d-cysteine ethyl ester in adult goats.

Fentanyl is the leading contributor to opioid-involved overdose (OD) mortality in the United States. Despite the demonstrated efficacy, safety, and wide availability of naloxone (NAL), opioid-involved OD fatalities remain high. This suggests our understanding of the negative integrated physiological effects of fentanyl remains incomplete, and highlights the need to develop additional novel countermeasures. Here we tested whether the physiological and behavioral effects of intravenous fentanyl in adult female goats (n = 12) could be mitigated with NAL or the potential countermeasure d-cysteine ethyl ester (d-CYSee). As hypothesized, intravenous injections of high doses (HD) fentanyl caused immediate ventilatory suppression via reduced breathing frequency leading to hypoventilation and hypoxemia (&#x2265;10 min). HD fentanyl elicited immediate and sustained (&#x2265;90 min) increases in diaphragm, intercostal, abdominal, and laryngeal constrictor muscle activity along with an increased alveolar to arterial oxygen (A-a O2) gradient and hypertension. Intravenous NAL administered immediately following HD fentanyl mitigated most of these effects except the increased activation of respiratory pump and airway muscles. In contrast, d-CYSee administration immediately following HD fentanyl countered the initial hypoventilation but did not mitigate the increases in muscle activation and persistent hypoxemia. Neither treatment prevented acute withdrawal-like behaviors emerging >90 min after fentanyl administration. The data suggest that there are physiological effects of HD fentanyl that are NAL-insensitive, and d-CYSee can transiently normalize blood gases and counter opioid-induced respiratory depression (OIRD) in adult goats.NEW & NOTEWORTHY Here we determined whether any of the deleterious physiological effects of high-dose fentanyl could be countered by naloxone and/or d-cysteine ethyl ester (d-CYSee) in adult goats. Fentanyl induced hypoventilation and sustained increases in respiratory and airway muscle activity and hypoxemia. Naloxone reversed all fentanyl effects except tonic muscle activation, and d-CYSee reversed fentanyl-induced hypoventilation. These data suggest some effects of fentanyl are naloxone-insensitive and that d-CYSee may be a valuable countermeasure for OIRD.

Animals↗
PubMed2005

Novel role of lactosylceramide in vascular endothelial growth factor-mediated angiogenesis in human endothelial cells.

Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis associated with coronary heart disease, vascular complications in diabetes, inflammatory vascular diseases, and tumor metastasis. The mechanism of VEGF-driven angiogenesis involving glycosphingolipids such as lactosylceramide (LacCer), however, is not known. To demonstrate the involvement of LacCer in VEGF-induced angiogenesis, we used small interfering RNA (siRNA)-mediated silencing of LacCer synthase expression (GalT-V) in human umbilical vein endothelial cells. This gene silencing markedly inhibited VEGF-induced platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and angiogenesis. Second, we used D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of LacCer synthase and glucosylceramide synthase, that significantly mitigated VEGF-induced PECAM-1 expression and angiogenesis. Interestingly, these phenotypic changes were reversed by LacCer but not by structurally related compounds such as glucosylceramide, digalactosylceramide, and ceramide. In a human mesothelioma cell line (REN) that lacks the endogenous expression of PECAM-1, VEGF/LacCer failed to stimulate PECAM-1 expression and tube formation/angiogenesis. In REN cells expressing human PECAM-1 gene/protein, however, both VEGF and LacCer-induced PECAM-1 protein expression and tube formation/angiogenesis. In fact, VEGF-induced but not LacCer-induced angiogenesis was mitigated by SU-1498, a VEGF receptor tyrosine kinase inhibitor. Also, VEGF/LacCer-induced PECAM-1 expression and angiogenesis was mitigated by protein kinase C and phospholipase A2 inhibitors. These results indicate that LacCer generated in VEGF-treated endothelial cells may serve as an important signaling molecule for PECAM-1 expression and in angiogenesis. This finding and the reagents developed in our report may be useful as anti-angiogenic drugs for further studies in vitro and in vivo.

Cells, Cultured↗