Digital assessment of working memory and processing speed in everyday life: Feasibility, validation, and lessons-learned.

OBJECTIVES: Cognitive functioning is often impaired in mental and neurological conditions and might fluctuate throughout the day. An existing experience-sampling tool was upgraded to assess individual's cognition in everyday life. The objectives were to test the feasibility and validity of two momentary cognition tasks. METHODS: The momentary Visuospatial Working Memory Task (mVSWMT) and momentary Digit Symbol Substitution Task (mDSST) were add-ons to an experience sampling method (ESM) smartphone app. Healthy adults (n = 49) between 19 and 73 years of age performed the tasks within an ESM questionnaire 8 times a day, over 6 consecutive days. Feasibility was determined through completion rate and participant experience. Validity was assessed through contextualization of cognitive performance within intrapersonal and situational factors in everyday life. FINDINGS: Participants experienced the tasks as pleasant, felt motivated, and the completion rate was high (71%). Social context, age, and distraction influenced cognitive performance in everyday life. The mVSWMT was too difficult as only 37% of recalls were correct and thus requires adjustments (i.e. fixed time between encoding and recall; more trials per moment). The mDSST speed outcome seems the most sensitive outcome measure to capture between- and within-person variance. CONCLUSIONS: Short momentary cognition tasks for repeated assessment are feasible and hold promise, but more research is needed to improve validity and applicability in different samples. Recommendations for teams engaging in the field include matching task design with traditional neuropsychological tests and involving a multidisciplinary team as well as users. Special attention for individual needs can improve motivation and prevent frustration. Finally, tests should be attractive and competitive to stimulate engagement, but still reflect actual cognitive functioning.

An Experience Sampling Method Intervention for Dementia Caregivers: Results of a Randomized Controlled Trial.

OBJECTIVE: Ecological momentary interventions integrated with real-life assessments using the experience sampling method (ESM) could be promising to effectively support dementia caregivers in daily life. This study reports on the effectiveness of the ESM-based intervention "Partner in Sight." DESIGN, SETTING, PARTICIPANTS: A randomized controlled trial with 76 dementia caregivers was performed. Participants were randomly assigned to the intervention group ("Partner in Sight": ESM self-monitoring and personalized feedback), the pseudo-intervention group (ESM self-monitoring without feedback), or the control group (usual care). MEASUREMENTS: Effects were evaluated pre- and postintervention and at 2-month follow-up. Primary outcomes were retrospective measures of caregiver sense of competence and mastery. Secondary outcomes were retrospective measures of depression, anxiety, and perceived stress. Complementary ESM measures of positive and negative affect were collected pre- and postintervention. RESULTS: Both the experimental and pseudo-experimental groups showed an increase in retrospective sense of competence and a decrease in perceived stress at 2-month follow-up. At postintervention, the experimental group showed a decrease in momentary negative affect compared with the pseudo-experimental and control groups. No effects were found for retrospective mastery, depression, anxiety, and momentary positive affect. CONCLUSIONS: ESM interventions could be an important asset for increasing caregiver resources and could help caregivers to better adapt and manage difficult situations and to protect against negative emotions.

Animal health economics: an aid to decisionmaking on animal health interventions - case studies in the United States of America.

For animal disease events the outcomes and consequences often remain unclear or uncertain, including the expected changes in benefits (e.g. profit to firms, prices to consumers) and in costs (e.g. response, clean-up). Moreover, the measurement of changes in benefits and costs across alternative interventions used to control animal disease events may be inexact. For instance, the economic consequences of alternative vaccination strategies to mitigate a disease can vary in magnitude due to trade embargoes and other factors. The authors discuss the economic measurement of animal disease outbreaks and interventions and how measurement is used in private and public decision-making. Two illustrative case studies in the United States of America are provided: a hypothetical outbreak of foot and mouth disease in cattle, and the 2014-2015 outbreak of highly pathogenic avian influenza in poultry.

Lors d'un événement sanitaire, les résultats et les conséquences d'une intervention sont souvent incertains ou imprécis, y compris pour ce qui concerne l'évolution attendue des bénéfices (par ex. le profit pour les entreprises ou le prix payé par le consommateur) et des coûts (par ex. le coût de la réponse ou de l'assainissement). De plus, la mesure de l'évolution des bénéfices et des coûts suivant les différentes interventions utilisées pour lutter contre les maladies animales peut s'avérer inexacte. Par exemple, les conséquences économiques de différentes stratégies de vaccination visant à atténuer l'impact d'une maladie peuvent varier en ordre de grandeur du fait des restrictions imposées au commerce suite à la vaccination, ou d'autres facteurs. Les auteurs examinent l'évaluation économique des foyers de maladies animales et des interventions sanitaires ainsi que l'utilisation de ces évaluations dans les prises de décision du secteur privé et public. L'analyse est illustrée par deux études de cas aux États- Unis d'Amérique : l'hypothèse d'un foyer de fièvre aphteuse survenant dans la population bovine, et le foyer d'influenza aviaire hautement pathogène survenu en 2014­2015 chez les volailles.

A menudo los resultados o efectos de ciertos episodios zoosanitarios quedan poco claros o generan incertidumbre, por ejemplo sobre el modo en que en principio modifican los beneficios (réditos para las empresas, precios para el consumidor) y los costos (p.ej. de respuesta o de saneamiento de la explotación). Además, la medición de los cambios que experimenten los costos y beneficios a resultas de distintas intervenciones posibles para combatir un episodio zoosanitario puede resultar inexacta. Por ejemplo: las consecuencias económicas de estrategias alternativas de vacunación para mitigar una enfermedad pueden ser de magnitud variable dependiendo de la existencia de embargos comerciales u otros factores. Los autores examinan la cuantificación económica de los brotes de enfermedades animales y las intervenciones para combatirlos y explican cómo se utilizan esas mediciones para tomar decisiones en los sectores público y privado, ofreciendo como ejemplo casos situados en los Estados Unidos de América: un brote hipotético de fiebre aftosa en el ganado vacuno y el brote de influenza aviar altamente patógena que en 2014 y 2015 afectó a las aves de corral.

Dealing with daily challenges in dementia (deal-id study): an experience sampling study to assess caregiver functioning in the flow of daily life.

OBJECTIVE: Accurate assessment of caregiver functioning is of great importance to gain better insight into daily caregiver functioning and to prevent high levels of burden. The experience sampling methodology (ESM) is an innovative approach to assess subjective experiences and behavior within daily life. In this study, the feasibility of the ESM in spousal caregivers of people with dementia was examined, and the usability of ESM data for clinical and scientific practice was demonstrated. METHODS: Thirty-one caregivers collected ESM data for six consecutive days using an electronic ESM device that generated ten random alerts per day. After each alert, short reports of the caregiver's current mood state and context were collected. Feasibility was assessed by examining compliance and subjective experiences with the ESM. Usability was described using group and individual ESM data. RESULTS: Participants on average completed 78.8% of the reports. One participant completed less than 33% of the reports and was excluded from data analyses. Participants considered the ESM device to be a user-friendly device in which they could accurately describe their feelings and experiences. The ESM was not experienced as too burdensome. Zooming in on the ESM data, personalized patterns of mood and contextual factors were revealed. CONCLUSIONS: The ESM is a feasible method to assess caregiver functioning. In addition to standard retrospective measurements, it offers new opportunities to gain more insight into the daily lives of people with dementia and their caregivers. It also provides new possibilities to tailor caregiver support interventions to the specific needs of the caregiver. Copyright © 2016 John Wiley & Sons, Ltd.

A systematic review of Internet-based supportive interventions for caregivers of patients with dementia.

OBJECTIVE: Because of the expected increase in the number of dementia patients, the unlikelihood of a cure in the near future, and the rising cost of care, there is an increasing need for effective caregiver interventions. Internet interventions hold considerable promise for meeting the educational and support needs of informal dementia caregivers at reduced costs. The current study aims to provide an overview of the evidence for the effectiveness, feasibility, and quality of Internet interventions for informal caregivers of people with dementia. METHODS: A systematic literature search of five scientific databases was performed, covering literature published up to 10 January 2013. Twelve studies were identified. The quality of the included studies was assessed according to the Cochrane level of evidence and the criteria list of the Cochrane Back Review Group. RESULTS: The intervention types, dosage, and duration differed widely, as did the methodological quality of the included studies. The overall level of evidence was low. However, the results demonstrate that Internet interventions for informal dementia caregivers can improve various aspects of caregiver well-being, for example, confidence, depression, and self-efficacy, provided they comprise multiple components and are tailored to the individual. Furthermore, caregivers could benefit from interaction with a coach and other caregivers. CONCLUSIONS: Internet interventions for informal dementia caregivers may improve caregiver well-being. However, the available supporting evidence lacks methodological quality. More randomized controlled studies assessing interventions performed according to protocol are needed to give stronger statements about the effects of supportive Internet interventions and their most promising elements.

A role for histamine and substance P in immediate allergic responses in guinea pig airways: characterization of MDL 108,207DA, a dual H1/NK-1 receptor antagonist.

BACKGROUND: Histamine is a critical mediator of immediate hypersensitivity reactions. Sensory neuropeptides, such as substance P (SP), may also contribute to acute inflammatory responses. A compound which antagonizes both H1 and NK-1 receptors, such as MDL 108,207DA, may present a significant therapeutic advantage over pure antihistamines. METHODS: The binding affinity of MDL 108,207DA for H1 and NK-1 receptors was evaluated and its potency of antagonism evaluated in vitro. The in vivo antagonism of SP- or histamine-induced microvascular leakage in guinea pig airways was examined. A role for these mediators in antigen-induced microvascular leakage in ovalbumin-sensitized guinea pig airways was examined using MDL 108,207DA as well as the NK-1-selective antagonist FK888 and the H1-selective antagonist pyrilamine alone or in combination. RESULTS: The affinity of MDL 108,207DA for H1 and NK-1 receptors is similar to that of receptor-selective antagonists. The compound inhibits both receptors in vitro and in vivo with comparable potencies for each. The efficacy of FK888 in combination with pyrilamine and MDL 108,207DA on antigen-induced microvascular leakage in sensitized guinea pig airways supports a role for both SP and histamine in early allergic responses. CONCLUSION: The contribution of both SP and histamine to immediate hypersensitivity reactions supports the utility of NK-1 and H1 receptor antagonist therapy. MDL 108,207DA incorporates both activities into the same compound and, as a result, may be useful in the treatment of allergic diseases.

Implementation of the Bamako Initiative: strategies in Benin and Guinea.

Two West African countries, Benin and Guinea, have been reorganizing their peripheral health systems since 1986, with the goal of improving access to primary health care (PHC). A comprehensive approach evolve, based on improving effectiveness, optimizing efficiency, ensuring financial variability and promoting equity. These strategies were launched as the Bamako Initiative by the World Health Organization's Regional Assembly in 1987. This is the first in a series of five articles on the Bamako Initiative in Benin and Guinea. The strategies implemented in these two countries are discussed. Subsequent articles discuss the improved health indicators, impact on service costs efficiency, and community empowerment through local cost recovery and equity implications. The health center is the basis for a revitalized primary care system. From here, an integrated minimum health care package is readily accessible to meet basic community health needs. Through the Bamako Initiative program, drugs and other essential resources are always available, regular contract between the community health service providers and communities has increased, and the quality of care has improved while also becoming more efficient. Community health resources are managed locally through joint microplanning and monitoring, involving health personnel and village committees. Community ownership, fostered by local budgeting and decision making, is an essential pillar for the success of the system.

The Bamako Initiative in Benin and Guinea: improving the effectiveness of primary health care.

The objective of the health system revitalization undergone in Benin and Guinea since 1986 is to improve the effectiveness of primary health care at the periphery. Second in a series of five, this article presents the results of an analysis of data from the health centres involved in the Bamako Initiative in Benin and Guinea since 1988. Data for the expanded programme of immunization, antenatal care and curative care, form the core of the analysis which confirms the improved effectiveness of primary health care at the peripheral level over a period of six years. The last available national data show a DPT3 immunization coverage of 80% in 1996 in Benin and 73% in 1995 in Guinea. In the Bamako Initiative health centres included in our analysis, the average immunization coverage, as measured by the adequate coverage indicator, increased from 19% to 58% in Benin and from less than 5% to 63% in Guinea between 1989 to 1993. Average antenatal care coverage has increased from 5% in Benin and 3% in Guinea to 43% in Benin and 51% Guinea. Utilization of coverage with curative care has increased from less than 0.05 visit per capita per year to 0.34 in Guinea and from 0.09 visit per capita per year to 0.24 in Benin. Further analysis attempts to uncover the reasons which underlie the different levels of effectiveness obtained in individual health centres. Monitoring and microplanning through a problem-solving approach permit a dynamic process of adaptation of strategies leading to a step by step increase of coverage over time. However, the geographical location of centres represents a constraint in that certain districts in both countries face accessibility problems. Outreach activities are shown to play an especially positive role in Guinea, in improving both immunization and antenatal care coverage.

Affordability, cost-effectiveness and efficiency of primary health care: the Bamako Initiative experience in Benin and Guinea.

Since 1986 two West African countries, Benin and Guinea, have been actively reorganizing their peripheral health systems according to strategies subsequently called the "Bamako Initiative". Two preceding articles described the strategies implemented and the increased effectiveness of primary health care (PHC) witnessed over a period of six years. This article presents an analysis of cost and coverage data from biannual monitoring sessions between 1988 and 1993 in approximately 200 health centres in Benin and 214 in Guinea. In order to assess affordability, the total and per capita recurrent costs for operational health centres are analysed and then compared. The cost analysis reveals a mean total cost per health centre per year of slightly over US+11,000 in Benin and nearly US+9,000 in Guinea. The median cost per capita per year is approximately US+1.0 in Benin and between US+0.60 and US+0.80 in Guinea. Comparisons of these costs between regions, health centres and over time (as coverage levels evolved) show very little variation in either country. Cost-effectiveness is estimated by allocating these costs to immunization, antenatal and curative care and comparing them to the coverage achieved with these interventions. First, the cost-effectiveness of the Bamako Initiative (BI) system as a whole is analysed. The cost per fully vaccinated child is calculated at US+10.9 in Benin and US+8.8 in Guinea. The cost per woman receiving at least three antenatal visits is US+7 in Benin and US+4.7 in Guinea. For curative care, cost per full treatment is US+1.6 in Benin and half this amount in Guinea. Cost-effectiveness is variable between regions, health centres reveals that these differences in cost-effectiveness are mainly caused by the coverage levels achieved, since total costs are relatively stable. Finally the efficiency of drug management and prescriptions as well as of outreach for the expanded programme of immunizations (EPI) is estimated by relating specific drug and outreach activities costs to the number of beneficiaries. The average cost of drugs per treatment is around US+0.5 in Benin and around US+0.3 in Guinea. Cost analysis of outreach activities undertaken for EPI in Guinea revealed a similar average cost per child completely vaccinated for health centres with different intensities of outreach (approximately US+10) and an additional cost per child vaccinated attributable to outreach of US+1-2.

Local cost sharing in Bamako Initiative systems in Benin and Guinea: assuring the financial viability of primary health care.

The fourth in a series of five, this article presents and analyses data on cost recovery and community cost-sharing, two key aspects of the Bamako Initiative which have been implemented in Benin and Guinea since 1986. The data come from approximately 400 health centres and result from the six-monthly monitoring sessions conducted from 1989 to 1993. Community involvement in the financing of local operating costs in the two national scale programmes is also described. In Benin and Guinea, a user fee system generates the community financed revenue with the aim of covering local operating costs including drugs. Health worker salaries remain the responsibility of the government and donor funding covers vaccine and investment costs. Village health committees manage and control resources and revenue. The community is also involved in decision making, strategy definition and quality control. In Benin in 1993, community financing revenue amounted to about US$0.6 per capita per year and generally covered all local recurrent non salary costs except vaccines and left a surplus. Although total costs and revenues were slightly lower in Guinea for the same period, over-all user fee revenue (around US$0.3 per capita per year) covered local recurrent costs (not including salaries or vaccines). A comparison of costs and revenue between regions and individual health centres revealed important differences in cost recovery ratios. In Benin, some centres recovered more than twice the local costs targeted for community financing. Twenty-five per cent of centres in Guinea did not manage to cover their designated local recurrent costs. The longitudinal analysis showed that the level of cost recovery remained stable over time even as preventive care (and especially EPI) coverage rose significantly. To better understand the most important characteristics affecting cost recovery levels, best performing health centres in terms of cost-recovery levels in 1993 were compared to worst performing centres. This analysis showed that the size of the target population of the health centre is a key determinant of cost-recovery in both countries. In addition, in Guinea the utilization of curative care linked to geographical access and in Benin the average revenue per case linked to the number of deliveries proved to be additional factors of importance. In best performing centres, financial viability improved over time in both countries between 1990 and 1993. Finally, the implications of these conclusions for the planning of health centre revitalization in West Africa are discussed.

Health seeking behaviour and household health expenditures in Benin and Guinea: the equity implications of the Bamako Initiative.

Curative and preventive care utilization in Bamako Initiative health centres in Guinea and Benin increased significantly. Service based data and household survey results are compared and interpreted to evaluate the equity aspects of the Bamako Initiative programmes in these settings. Improvements in the use of preventive services are shared by the richer and poorer groups of the population. Inequities are more apparent regarding curative area. An important part of the population is not using Bamako Initiative Health Centres for financial reasons. However, the poor were found to use these Health Centres relatively more than richer socio-economic groups. Challenges of the future are identified and recommendations made as to how to tackle the problem of true indigence.

The peripheral NK-1/NK-2 receptor antagonist MDL 105,172A inhibits tachykinin-mediated respiratory effects in guinea-pigs.

1. Stimulation of sensory nerves causes release of tachykinins, including substance P (SP) and neurokinin A (NKA), which produce a variety of respiratory effects via NK-1 and NK-2 receptors, respectively. Hence, development of a compound which could potently and equivalently antagonize both receptors was pursued. 2. MDL 105,172A ((R)-1-[3-(3,4-dicholorophenyl)-1-(3,4,5-trimethoxybenzoyl)- 3-pyrrolidinyl]-4- phenyl-piperidine-4-morpholinecarboxamide) exhibited high affinity for NK-1 (4.34 nM) and NK-2 (2.05 nM) receptors. In vitro, the compound antagonized SP (pA2 = 8.36) or NKA (pA2 = 8.61)-induced inositol phosphate accumulation in tachykinin monoreceptor cell lines. 3. In anaesthetized guinea-pigs, MDL 105,172A inhibited SP-induced plasma protein extravasation (ED50 = 1 mg kg-1, i.v.) and [beta-Ala8]NKA 4-10-induced bronchoconstriction (ED50 = 0.5 mg kg-1, i.v.) indicating NK-1 and NK-2 antagonism, respectively. 4. Capsaicin was used to elicit respiratory effects in anaesthetized and conscious guinea-pigs; the latter were inhibited by MDL 105,172A following i.v. (ED50 = 1 mg kg-1) or oral (ED50 = 20 mg kg-1) administration. Hence, MDL 105,172A can inhibit pulmonary responses to tachykinins released endogenously in the airways. 5. At doses up to 200 mg kg-1, p.o., MDL 105,172A failed to inhibit repetitive hind paw tapping induced by i.c.v GR 73632, and NK-1 selective agonist, in gerbils, whereas CP-99,994 (0.87 mg kg-1, s.c.) completely ablated the effect. These data suggest that MDL 105,172A does not penetrate the central nervous system (CNS) and its tachykinin antagonism is restricted to the periphery. 6. MDL 105,172A is a non-peptide, potent, equivalent antagonist of NK-1 and NK-2 receptors. Its ability to inhibit both exogenously administered as well as endogenously released tachykinins support its use in examining the role of sensory neuropeptides in diseases associated with neurogenic inflammation including asthma.

Effect of MDL 105,212, a nonpeptide NK-1/NK-2 receptor antagonist in an allergic guinea pig model.

MDL 105,212 has been identified as a potent, nonpeptide NK-1 and NK-2 receptor antagonist that inhibits effects of substance P and neurokinin A in vitro and in vivo (Kudlacz et al., 1996). In the present study, the compound inhibited capsaicin-induced respiratory effects after p.o. administration (5-50 mg/kg) to conscious guinea pigs; nearly complete inhibition of dyspnea and cough was observed 1 hr after 50 mg/kg p.o., and efficacy persisted for approximately 11 hr. MDL 105,212 reduced pulmonary insufflation pressure and microvascular leakage in ovalbumin-sensitized animals in response to antigen-challenge relative to vehicle-treated animals. Attenuation of early-phase allergic responses may result from MDL 105,212 inhibition of antigen-induced histamine release from sensitized guinea pig lung observed in vitro. Airway hyperresponsiveness to methacholine occurred 24 hr after antigen-challenge in ovalbuminsensitized guinea pigs; this effect was inhibited by pretreatment with MDL 105,212 (50 mg/kg p.o.) 1 hr before ovalbumin exposure without affecting increased bronchoalveolar lavage eosinophil numbers. These data suggest that sensory neuropeptides play a role in some aspects of allergic airway responses and that tachykinin receptor antagonists may be useful in treatment of atopic respiratory diseases.

In vitro and in vivo characterization of MDL 105,212A, a nonpeptide NK-1/NK-2 tachykinin receptor antagonist.

We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.

Parainfluenza virus type-3 infection attenuates the respiratory effects of antigen challenge in sensitized guinea pigs.

Respiratory viral infections not only exacerbate asthma symptoms but may also be important in the pathogenesis of the disease. We therefore explored the effects of respiratory viral infection on the respiratory response of sensitized guinea pigs to antigen challenge. Lung tissue obtained from uninfected guinea pigs sensitized to ovalbumin aerosol released histamine upon incubation with the antigen in vitro. After antigen challenge in vivo, sensitized animals had significantly greater numbers of eosinophils in their bronchoalveolar lavage fluid than did nonsensitized animals and exhibited airway hyperresponsiveness to methacholine aerosol. When ovalbumin sensitization was initiated 7 days after inoculation with parainfluenza virus type-3 (PI-3), antigen challenge elicited little histamine release from infected lung tissue in vitro. Likewise, subsequent to antigen challenge in vivo, animals failed to exhibit airway hyperresponsiveness or an increased eosinophil population in bronchoalveolar lavage fluid. Similar effects were observed when sensitization was begun 19 days after PI-3 virus inoculation. The mechanism(s) responsible for the attenuated responses to antigen in PI-3 infected animals are unknown but may involve virus-induced effects on immune cells.

In vitro and in vivo effects of tachykinins on immune cell function in guinea pig airways.

The effects of sensory neuropeptides substance P (SP) and neurokinin A (NKA) on immune cell recruitment and macrophage activation were determined. Guinea pigs exposed to capsaicin aerosol exhibited eosinophil and neutrophil influx into their bronchoalveolar lavage (BAL) fluid 24 h after treatment; SP aerosol elicited eosinophil influx, whereas NKA aerosol exposure caused neutrophil recruitment. Inhalation of capsaicin, NKA or SP aerosols also enhanced superoxide production induced by zymosan in cultured alveolar macrophages. Incubation of alveolar macrophages with SP or NKA in culture for the same time (24 h) did not potentiate the response to zymosan. Hence, tachykinin-mediated airway effects may not be the result of direct actions on target cells but rather involve alternate mechanisms and mediators which do not necessarily reflect in vitro data.

Circulating factors contribute to elevation of intracellular cyclic-3',5'-adenosine monophosphate and depression of superoxide anion production in polymorphonuclear leukocytes following thermal injury.

We have previously demonstrated that bactericidal activity and superoxide anion (O2-) production are depressed concomitantly in polymorphonuclear leukocytes (PMNs) following thermal injury in a guinea pig model, and the bactericidal defect is related to elevation of intracellular cyclic-3',5'-adenosine monophosphate (cAMP). The purpose of the present investigation was to determine the relationship between elevation of intracellular cAMP and depression of O2- production in PMNs following thermal injury and determine the involvement of circulating factors in the development of these alterations. The kinetics of O2- production and dose responses to formylmethionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA) were depressed in peripheral PMNs following thermal injury in this experimental model. Sera obtained during the period of PMN dysfunction induced depression of O2- production in response to fMLP and elevation of intracellular cAMP in normal PMNs. Pretreatment of normal PMNs with nonsteroidal anti-inflammatory drugs (NSAID; indomethacin or piroxicam) inhibited the elevation of intracellular cAMP mediated by sera from the injured animals but had no effect on the depression of O2- production observed under similar conditions. Treatment of PMNs from injured animals with NSAID under conditions known to reduce the cAMP content of the cells and correct the bactericidal defect did not normalize O2- production. Studies utilizing sera from two thermally injured patients confirmed findings in the guinea pig model of serum-mediated elevation of intracellular cAMP and depression of O2- production in normal PMNs and effects observed with NSAID. These results suggest that circulating factors contribute to the elevation of intracellular cAMP and depression of O2- production in PMNs following thermal injury. Whereas the increase in intracellular cAMP may be involved in the depression of O2- production, our results suggest that there is not a direct link between these alterations.

Bactericidal defect of neutrophils in a guinea pig model of thermal injury is related to elevation of intracellular cyclic-3',5'-adenosine monophosphate.

PG of the E series inhibit major effector functions of polymorphonuclear leukocytes (PMN) by elevating intracellular cAMP. The present study investigated the involvement of this mechanism in the bactericidal defect of PMN induced by thermal injury in a guinea pig model. Peripheral and peritoneal exudate PMN harvested from thermally injured guinea pigs at 1 or 2 days postburn had decreased bactericidal activity against Pseudomonas aeruginosa and a marked increase in cAMP content. Production of PGE1 by these cells in the absence of exogenous PMN activators was also increased. Treatment of PMN in vitro or in vivo with nonsteroidal anti-inflammatory drugs (indomethacin, ibuprofen, and piroxicam) restored bactericidal activity to normal and concomitantly reduced cAMP content and PGE1 production. A concomitant reduction in cAMP content and PGE1 production was also observed as bactericidal activity of PMN returned to normal under natural conditions during 4 to 7 days postburn. The enhancement of PMN bactericidal activity mediated by NSAID was fully counteracted by purified PGE1, theophylline, and by cAMP itself. These results suggest that the bactericidal defect of PMN induced by thermal injury is related to elevation of cAMP and that PGE1 plays a significant role in this phenomenon.

Nonsteroidal anti-inflammatory drugs correct the bactericidal defect of polymorphonuclear leukocytes in a guinea pig model of thermal injury.

We conducted studies to determine the effects of parenteral therapy with indomethacin, ibuprofen, and piroxicam on key immunologic and hematologic alterations induced by thermal injury. Drugs (10-20 mg/kg) or placebo were administered intramuscularly to thermally injured guinea pigs at 3 h postburn and then daily for nine days postburn. All three drugs inhibited production of 6-keto prostaglandin F1 alpha and thromboxane B2 in wound fluid and concomitantly restored the bactericidal activity of polymorphonuclear leukocytes (PMNLs) against Pseudomonas aeruginosa to normal. Indomethacin also increased the proliferative response of splenic lymphocytes to concanavalin A; however, ibuprofen and piroxicam had no effect on this response. None of the drugs affected the extent of systemic complement consumption, thrombocytopenia, leukocytosis, or leukopenia in the injured animals. These results suggest that the PMNL bactericidal defect induced by thermal injury is preventable or reversible and that the mechanisms responsible for this defect are inhibitable by nonsteroidal anti-inflammatory drugs.