Risk factors associated with first symptomatic infection of {\it Cryptosporidium parvum\/} in an infant population in Bilbeis, Egypt

Diarrhea disease is a leading cause of morbidity and mortality, especially in children in developing countries. An estimate of the global mortality caused by diarrhea among children under five years of age was 3.3 million deaths per year. Cryptosporidium parvum was first identified in 1907, but it was not until 1970 that this organism was recognized as a cause of diarrhea in calves. Then it was as late as 1976 that the first reported case of human Cryptosporidiosis occurred. This study was conducted to ascertain the risk factors of first symptomatic infection with Cryptosporidium parvum in a cohort of infants in a rural area of Egypt. The cohort was followed from birth through the first year of life. Univariate and multivariate analyses of data demonstrated that infants greater than six months of age had a two-fold risk of infection compared with infants less than six months of age (RR = 2.17; 95% C.I. = 1.01-4.82). When stratified, male infants greater than six months of age were four times more likely to become infected than male infants less than six months of age. Among female infants, there was no difference in risk between infants greater than six months of age and infants less than six months of age. Female infants less than six months of age were twice more likely to become infected than male infants less than six months of age. The reverse occurred for infants greater than six months of age, i.e., male infants greater than six months of age had twice the risk of infection compared to females of the same age group. Further analysis of the data revealed an increased risk of Cryptosporidiosis infection in infants who were attended in childbirth by traditional childbirth attendants compared to infants who were attended by modern childbirth attendants (nurses, trained midwives, physicians) (RR = 4. 18; 95% C.I. = 1.05-36.06). The final risk factor of significance was the number of people residing in the household. Infants in households which housed more than seven persons had an almost two-fold risk of infection compared with infants in homes with fewer than seven persons. Other risk factors which suggested increased risk were lack of education among the mothers, absence of latrines and faucets in the homes, and mud used as building material for walls and floors in the homes. ^

Joining the dots - understanding the complex interplay between the values we place on wildlife, biodiversity conservation, human and animal health: A review.

The value of wildlife has long been ignored or under-rated. However, growing concerns about biodiversity loss and emerging diseases of wildlife origin have enhanced debates about the importance of wildlife. Wildlife-related diseases are viewed through these debates as a potential threat to wildlife conservation and domestic animal and human health. This article provides an overview of the values we place on wildlife (positive: socio-cultural, nutritional, economic, ecological; and negative: damages, health issues) and of the significance of diseases for biodiversity conservation. It shows that the values of wildlife, the emergence of wildlife diseases and biodiversity conservation are closely linked. The article also illustrates why investigations into wildlife diseases are now recognized as an integral part of global health issues. The modern One Health concept requires multi-disciplinary research groups including veterinarians, human physicians, ecologists and other scientists collaborating towards a common goal: prevention of disease emergence and preservation of ecosystems, both of which are essential to protect human life and well-being.

Prevalence and diversity of Chlamydiales in Swiss ruminant farms.

Chlamydia and Chlamydia-related bacteria are known to infect various organisms and may cause a wide range of diseases, especially in ruminants. To gain insight into the prevalence of these bacteria in the ruminant environment, we applied a pan-Chlamydiales PCR followed by sequencing to 72 ruminant environmental samples from water, feed bunks and floors. Chlamydiales from four family-level lineages were detected indicating a high biodiversity of Chlamydiales in ruminant farms. Parachlamydiaceae were detected in all three types of environmental samples and was the most abundant family-level taxon (60%). In contrast, only one bacterium from each of the following family-level lineages was identified: Chlamydiaceae, Criblamydiaceae and Simkaniaceae. The observed high prevalence of Parachlamydiaceae in water samples may suggest water as the main source of contamination for ruminants as well as their environment due to spoilage. The absence of reported infections in the investigated ruminant farms might indicate that either detected Chlamydiales are of reduced pathogenicity or infective doses have not been reached.

A STUDY OF THE ATTITUDES OF ELDERLY CONSUMERS TOWARD DENTAL CARE AND ORAL HEALTH

This paper describes a study of the attitudes of elderly consumers toward dental care and oral health. Four hundred and two respondents ages 60-97 were interviewed with a 62 item questionnaire. Attitudes were measured regarding: quality of care, sufficient utilization of care, priority of oral health, patient-provider interaction, individual control over health, powerful others control of health, and chance as the locus of control over health. Analysis of variance was performed on the sample of males and females separately. Fifty-four hypotheses were tested on each sex. Race and self-concept were excellent predictors of attitude for both sexes and SES (socioeconomic status) and self-reported health were good predictors for females. There was no statistically significant relationship between the frequency with which the elderly utilize dental care and their attitudes toward the quality of care they receive. Foremost reason for non-utilization was that of no felt need. Those selecting this reason were likely to be Anglo females, wearers of dentures, in good health. Those selecting cost as the foremost reason for non-utilization were Black, in fair health, of either sex, missing some teeth, but with no dentures. Overall attitudes toward quality of dental care were positive, despite the fact that this group was exposed to dental care in its infancy. This may suggest that the elderly recognize the importance of technological advances in dentistry. Women with low income and education levels were more likely to have positive attitudes about quality of care than other females. Attitudes about interaction between patient and provider were overall negative. The sample scored high on individual control over health, and scored lower, but nonetheless positively, on feelings that persons other than themselves are most essential to maintaining health. Overall these elderly persons did not agree that they relied on chance in matters of health. Those who did choose this locus were female, with lower SES and health status. Though males scored high on internal control of health, those with lowest scores were Mexican-American or had never been married. Sex and ethnicity were the best predictors of attitude across all measures in the study.^

Biochemical and genetic analysis of two protein kinases JNKK2 and MEKK3

Mitogen-activated protein kinase (MAPK) cascades are conserved eukaryotic signaling modules consisting of a MAPK, a MAPKK and a MAP3K. MAPK cascades are involved in many cellular responses including proliferation, differentiation, apoptosis, stress and immune responses. ^ The first part of this thesis describes the cloning and biochemical analysis of JNKK2, a member of MAPKK gene family. Our results demonstrate that JNKK2 is a specific JNK activator and activates the JNK-dependent signal transduction pathway in vivo by inducing c-Jun and ATF2-mediated gene expression. We also found that JNKK2 is specifically activated by a MAP3K MEKK2 through formation of MEKK2-JNKK2-JNK1 triple complex module. JNKK2 is likely to mediate specific upstream signals to activate JNK cascade. ^ The second part of this thesis describes biochemical and gene disruption analysis of MEKK3, a member of MAP3K gene family. We showed that overexpression of MEKK3 strongly activates both JNK and p38 MAPKs but only weakly activates ERK. MEKK−/− embryos die at about embryonic day (E) 11. MEKK3−/− embryos displayed defects in blood vessel development in the yolk sacs, and in the myocardium and endocardium development at E9.5. The angiogenesis in the head, intersomitic region and placenta was also abnormal. These results demonstrate that MEKK3, a member of MAP3K MEKK/STE11 subgene family, is essential for early embryonic cardiovascular development. Furthermore, it was found that disruption of MEKK3 did not alter the expression of vascular endothelial growth factor-1 (VEGF-1), angiopoietin-1, -2 and their respective receptors Flt-1, Flk-1, Tie-1, Tie-2. Finally, MEKK3 was shown to activate myocyte-specific enhancer factor 2C (MEF2C), a crucial transcription factor for early embryonic cardiovascular development through the p38 MAPK cascade, suggesting that MEF2C is one of the key targets of the MEEKK3 signaling pathway during early embryonic cardiovascular development. ^

Development of a protective vaccine against Helicobacter pylori

Helicobacter pylori, which colonizes the stomach and causes the most common chronic infection in man, is associated with peptic ulceration, gastric carcinoma and gastric lymphoma. Studies in animals demonstrated that mucosal immunization could induce immune response against H. pylori and prevent H. pylori infection only if powerful mucosal adjuvants such as cholera toxin (CT) or heat-labile toxin of E. coli (LT) were used along with an H. pylori protein antigen. Adjuvants such as CT or LT cannot be used for humans because of their toxicity. Finding non-toxic alternative adjuvants/immunomodulators or immunization strategies that eliminates the use of adjuvants is critical for the development of efficacious human Helicobacter vaccines. We investigated whether several new adjuvants such as Muramyl Tripeptide Phosphatidylethonolamine (MTP-PE), QS21 (a Quil A derivative), Monophosphoryl lipid A (MPL) or heat shock proteins (HSP) of Mycobacterium tuberculosis could be feasible to develop a safe and effective mucosal vaccine against H. pylori using a murine model. C57/BL6 mice were immunized with liposomes incorporating each adjuvant along with urease, a major antigenic protein of H. pylori, to test their mucosal effectiveness. Since DNA vaccination eliminates both the use of adjuvants and antigens we also investigated whether immunization with plasmid DNA encoding urease could induce protective immunity to H. pylori infection in the same murine model. We found that oral vaccination with liposomal MTP-PE (6.7 m g) and urease, (100 m g) induced antigen-specific systemic and mucosal immune response and protected mice against H. pylori challenge when compared to control groups. Parenteral and mucosal immunizations with as little as 20 m g naked or formulated DNA encoding urease induced systemic and mucosal immune response against urease and partially protected mice against H. pylori infection. DNA vaccination provided long-lasting immunity and serum anti-urease IgG antibodies were elevated for up to 12 months. No toxicity was detected after immunizations with either liposomal MTP-PE and urease or plasmid DNA and both were well tolerated. We conclude that immunization liposomes containing MTP-PE and urease is a promising strategy deserving further investigation and may be considered for humans. DNA vaccination could be used to prime immune response prior to oral protein vaccination and may reduce the dose of protein and adjuvant needed to achieve protective immunity. ^

Glucocorticoid alterations in the human type-1/type-2 cytokine balance and the role of CD28/B7 costimulation

We have recently reported that psychological stress is associated with a shift in the human type-1/type-2 cytokine balance toward a type-2 cytokine response. The mechanisms of these cytokine alterations are unknown, but likely involve glucocorticoid (GC) modulation of cytokine production. Therefore we sought to characterize the effects of GC on the in vitro human type-1/type-2 cytokine balance. We hypothesized that GC induce a type-2 cytokine shift through modulation of critical regulatory cytokines and alterations in the CD28/B7 costimulatory pathway. ^ We first sought to characterize the effect of the GC, dexamethasone (DEX), on type-1 (IFN-γ, IL-12) and type-2 (IL-4, IL-10) cytokine production by human peripheral blood mononuclear blood cells (pBMC) stimulated with a variety of T-lymphocyte and monocyte stimuli. DEX, at concentrations mimicking stress and supraphysiologic levels of cortisol, decreased IFN-γ and IL-12 production and increased IL-4 and IL-10 production, indicating a shift in the type-1/type-2 cytokine balance toward a type-2 response. Furthermore, both CD4+ and CD8+ T-lymphocytes were susceptible to the cytokine modulating effects of DEX. Furthermore, in the absence of the monocyte, the DEX-induced alterations in T-lymphocyte cytokine production were reduced, indicating that the interaction between the monocyte and T-lymphocyte plays a significant role. ^ We next determined the role of regulatory cytokines, known to modulate the type-1/type-2 cytokine balance, in the DEX-induced cytokine alterations. The addition of the recombinant IL-12p70 and IFN-γ, but not the neutralization of IL-4, IL-10 or IL-13 using monoclonal antibodies, attenuated the DEX-induced type-1/type-2 cytokine alterations. These data suggest that the DEX-induced cytokine alterations are mediated, at least in part, through the initial inhibition type-1 cytokines. Lastly, we investigated the role of the CD28/B7 costimulatory pathway in these cytokine alterations. DEX decreased the expression of CD80 and CD86 on THP-1 cells, a monocyte cell line, and the expression of CD28 and CTLA-4 on PHA-stimulated pBMC. The DEX-induced decrease in CD28 and CTLA-4 expression was attenuated by rhIL-12. Finally, CD28 activation attenuated the DEX-induced decrease in IFN-γ production, suggesting that modulation of the CD28/B7 costimulatory pathway may contribute to the DEX-induced type-1/type-2 cytokine alterations. ^

Social capital and adolescent health risk behavior in El Salvador

An emerging body of research suggests that the social capital available in one's social environment, as defined by supportive and caring interpersonal relationships, may provide a protective effect against a number of youth risk behaviors. In exploring the potential protective effect of social capital at school and at home on adolescent health and social risk behavior, a comprehensive youth risk behavior study was carried out in El Salvador during the summer of 1999 with a sample of 984 secondary school students attending 16 public rural and urban schools. The following dissertation, entitled Social Capital and Adolescent Health Risk Behavior in El Salvador, presents three papers centered on the topics of social capital and risk behavior. ^ Paper #1. Dangers in the Adolescent River of Life: A Descriptive Study of Youth Risk Behavior among Urban and Rural presents prevalence estimates of four principal youth risk behavior domains—aggression, depression, substance use, and sexual behaviors among students primarily between the ages of 13 and 17 who attend public schools in El Salvador. The prevalence and distribution of risk behaviors is examined by gender, geographic school location, age, and subjective economic status. ^ Paper #2. Social Capital and Adolescent Health Risk Behavior among Secondary School Students in El Salvador explores the relationship between social resources (social capital) within the school context and several youth risk behaviors. Results indicated that students who perceived higher social cohesion at school and higher parental social support were significantly less likely to report fighting, having been threatened or hurt with a weapon, suicidal ideation, and sexual intercourse than students with lower perceived social cohesion at school and parental social support after adjusting for several socio-demographic variables. ^ Lastly, paper #3. School Health Environment and Social Capital : Moving beyond the individual to the broader social developmental context provides a theoretical and empirical basis for moving beyond the predominant individual-focus and physical health concerns of school health promotion to the larger social context of schools and social health of students. This paper explores the concept of social capital and relevant adolescent development theories in relation to the influence of social context on adolescent health and behavior. ^

Integrin mediated growth and apoptosis in human gastric adenocarcinoma

Integrins are important as the primary cell adhesion molecule providing information about the extracellular microenvironment to the interior of the cell to influence cellular behavior such as differentiation, proliferation and apoptosis. Apoptotic death due to loss of adhesion is termed anoikis. In this study we have obtained a parental human gastric adenocarcinoma cell line that yielded two variant lines that had differing responses to lack of adhesion. The STAD.APO cell line undergoes apoptosis when denied adherence and the STAD.ARR cell line enters into cell cycle arrest under the identical suspended conditions. We have shown that cyclin A and cyclin D mRNA and protein are down regulated when cells are denied adherence for 24 hours in tissue culture wells previously coated with poly-HEMA. To test whether cyclin A was able to rescue cells from cell cycle arrest and/or anoikis by overriding the cell cycle machinery we transfected the full length cDNA in to each cell type. Surprisingly we found that anoikis and cell cycle arrest due to suspended conditions was not affected by overexpression of cyclin A protein, but that growth under adhered conditions was reduced compared to vector alone control transfectants. Further, we transfected other cell lines; ST7, gastric cancer, MDA-MB-4.35, breast cancer, and HPB T-cell leukemic and in no case were suspended culturing conditions overcome by cyclin A. This result indicates an additional level of regulation for the cell cycle machinery. Additionally, soluble collagen was shown to be able to save from anoikis and also from cell cycle arrest while the β1 specific mAb 33B6 was only able to save from anoikis. Immunofluorescent studies show that soluble collagen creates clusters of β1 with FAK and also β1 with actin in the STAD.ARR cells but does not in the STAD.APO cells. This result indicates that the phenotypes under suspended conditions between these cell lines may diverge at their requirements for integrin ligation. Additionally we characterized the nature of anoikis by showing cytochrome c release, caspase 3, p21 and p53 activation in STAD.APO cells. Thus, our results have implications in the understanding of integrin biology and neoplastic progression. ^

17-beta estradiol and progesterone-induced alterations in human type-1/type-2 cytokine balance and the role of costimulatory and apoptotic mechanisms

Evidence suggests that sex-based differences in immune function may predispose women to numerous hypersensitivity conditions such as Systemic lupus erythematosus (SLE), Hashimoto's thyroiditis and asthma. To date, the exact mechanisms of sexual dimorphism in immunity are not fully characterized but sex hormones such as 17-β estradiol (E2) and progesterone (PR) are believed to be involved. Since E2 and PR may modulate the production of critical regulatory cytokines, we sought to characterize their effects on the in vitro human type-1/type-2 cytokine balance. We hypothesized that E2 and/or PR vary cytokine production and influence costimulatory molecule expression and apoptosis. We first described the effect of E2 and/or PR on type-1 (IFN-γ and IL-12) and type-2 (IL-4 and IL-10) cytokine production by human peripheral blood mononuclear cells (PBMC) treated with various T-lymphocyte and monocyte stimuli. E2 and/or PR were each used at concentrations similar to those found at the maternal-fetal interface during pregnancy. At this dose, E2 increased IFN-γ and IL-12 production and PR decreased IFN-γ production and tended to increase IL-4 production. Furthermore, the combination of E2+PR decreased IL-12 production. This suggests that E2 shifts the type-1/type-2 cytokine balance towards a type-1 response and that PR and E2+PR shift the balance towards a type-2 response. Next, we used intracellular cytokine detection to demonstrate that E2 and/or PR are capable of altering cytokine production of CD3+ T-cells and the CD3+CD4+ and CD3+CD8+ subsets. In addition, we used the H9 T-lymphocyte cell line and the THP-1 monocyte cell line to show that E2 and/or PR can induce cytokine effects in both T-cells and monocytes independent of their interaction. Lastly, we determined the effect of E2 and/or PR on costimulatory molecule expression and apoptosis as potential mechanisms for the cytokine-induced alterations. E2 increased and PR decreased CD80 expression on THP-1 cells and PR and E2+PR decreased CD28 expression in PBMC and Jurkat cells. Furthermore, E2, PR and E2+PR increased Fas-mediated apoptosis in Jurkat cells and E2 increased FasL expression on THP-1 cells. Thus, E2 and/or PR may alter the cytokine balance by modulating the CD28/CD80 costimulatory pathway and apoptosis. ^

Vasculogenesis: A process of vessel formation and its role during Ewing's sarcoma development

Vasculogenesis is the process by which Endothelial Precursor Cells (EPCs) form a vasculature. This process has been traditionally regarded as an embryological process of vessel formation. However, as early as in the 60's the concept of postnatal vasculogenesis was introduced, with a strong resurface of this idea in recent years. Similarly, previous work on a mouse skin tumor model provided us with the grounds to consider the role of vasculogenesis during tumor formation. ^ We examined the contribution of donor bone marrow (BM)-derived cells to neovascularization in recipient nude mice with Ewing's sarcoma. Ewing's sarcoma is a primitive neuroectodermal tumor that most often affects children and young adults between 5 and 30 years of age. Despite multiple attempts to improve the efficacy of chemotherapy for the disease, the 2-year metastases-free survival rate for patients with Ewing's sarcoma has not improved over the past 15 years. New therapeutic approaches are therefore needed to reduce the mortality rate. ^ The contribution of BM endothelial precursor cells in the development of Ewing's sarcoma was examined using different strategies to track the donor-derived cells. Using a BMT model that takes advantage of MHC differences between donor and recipient mice, we have found that donor BM cells were involved in the formation of Ewing's sarcoma vasculature. ^ Cells responsible for this vasculogenesis activity may be located within the stem cell population of the murine BM. These stem cells would not only generate the hematopoietic lineage but they would also generate ECs. Bone marrow SP (Side Population) cells pertain to a subpopulation that can be identified using flow cytometric analysis of Hoechst 33342-stained BM. This population of cells has HSC activity. We have tested the ability of BM SP cells to contribute to vasculogenesis in Ewing's sarcoma using our MHC mismatched transplant model. Mice transplanted with SP cells developed tumor neovessels that were derived from the donor SP cells. Thus, SP cells not only replenished the hematopoietic system of the lethally irradiated mice, but also differentiated into a non-hematopoietic cell lineage and contributed to the formation of the tumor vasculature. ^ In summary, we have demonstrated that BM-derived cells are involved in the generation of the new vasculature during the growth of Ewing's sarcoma. The finding that vasculogenesis plays a role in Ewing's sarcoma development opens the possibility of using genetically modified BM-derived cells for the treatment of Ewing's sarcomas. ^

The immune response to the VlsE antigenic variation protein of Borrelia burgdorferi

The spirochete Borrelia burgdorferi (Bb) is the causative agent of Lyme disease. During infection, a strong immune response is elicited towards Bb by its host; however, the organism is able to persist and to disseminate to many different tissues. The vls locus is located on the linear plasmid lp28-1, a plasmid shown to be important for virulence in the mouse model. During infection, vlsE undergoes antigenic variation through a series of gene conversions, which results in the insertion of sequences from the silent, unexpressed cassettes into the vlsE cassette. We hypothesize that this antigenic variation is important in the spirochete's ability to persist within mammals by allowing it to evade the immune system. To define the role of vls in immune evasion, the immune response against VlsE was determined by using a recombinant form of VlsE (VlsE1-His) as an antigen to screen patient sera. Lyme patients produce antibodies that recognize VlsE, and these antibodies are present throughout the course of disease. Immunization with the VlsE1-His protein provided protection against infection with Bb expressing the same variant of VlsE (VlsE1), but was only partially protective when mice were infected with organisms expressing VlsE variants; however, subsequent VlsE immunization studies yielded inconsistent protection. Successful immunizations produced different antibody reactivities to VlsE epitopes than non-protective immunizations, but the reason for this variable response is unclear. In the process of developing genetic approaches to transform infectious Bb, it was determined that the transformation barrier posed by plasmids lp25 and lp56 could be circumvented by replacing the required lp25 gene pncA. To characterize the role of vlsE in infectivity, Bb lacking lp28-1 were complemented with a shuttle plasmid containing the lp25 encoded virulence determinant pncA and vlsE. Complemented spirochetes express VlsE, but the gene does not undergo antigenic variation and infectivity in the mouse model was not restored, indicating that either antigenic variation of vlsE is necessary for survival in the mouse model or that other genes on lp28-1 are important for virulence. ^

Occupational beryllium exposure: Reconciling federal policies, regulations and contractor implementation guides to protect worker health

Beryllium is a widely distributed, highly toxic metal. When beryllium particulates enter the body, the body's defense mechanisms are engaged. When the body's defenses cannot easily remove the particulates, then a damage and repair cycle is initiated. This cycle produces chronic beryllium disease (CBD), a progressive, fibrotic respiratory involvement which eventually suffocates exposed individuals. ^ Beryllium disease is an occupational disease, and as such it can be prevented by limiting exposures. In the 1940s journalists reported beryllium deaths at Atomic Energy Commission (AEC) facilities, the Department of Energy's (DOE) predecessor organization. These reports energized public pressure for exposure limits, and in 1949 AEC implemented a 2 μg/m3 permissible exposure limit (PEL). ^ The limits appeared to stop acute disease. In contrast, CBD has a long latency period between exposure and diagnosable disease, between one and thirty years. The lack of immediate adverse health consequences masked the seriousness of chronic disease and pragmatically removed CBD from AEC/DOE's political concern. ^ Presently the PEL for beryllium at DOE sites remains at 2 μg/m 3. This limit does not prevent CBD. This conclusion has long been known, although denied until recently. In 1999 DOE acknowledged the limit's ineffectiveness in its federal regulation governing beryllium exposure, 10 CFR 850. ^ Despite this admission, the PEL has not been reduced. The beryllium manufacturer and AEC/DOE have a history of exerting efforts to maintain and protect the status quo. Primary amongst these efforts has been creation and promotion of disinformation within peer reviewed health literature which discusses beryllium, exposures, health effects and treatment, and targeting graduate school students so that their perspective is shaped early. ^ Once indoctrinated with incorrect information, professionals tend to overlook aerosol and respiratory mechanics, immunologic and carcinogenic factors. They then apply tools and perspectives derived from the beryllium manufacturer and DOE's propaganda. Conclusions drawn are incorrect. The result is: health research and associated policy is conducted with incorrect premises. Effective disease management practices are not implemented. ^ Public health protection requires recognition of the disinformation and its implications. When disinformation is identified, then effective health policies and practices can be developed and implemented. ^

The contribution of A3 adenosine receptor signaling to pulmonary inflammation and mucus secretion in the mouse

Adenosine has been implicated in chronic lung diseases such as asthma and COPD. Most physiological actions of adenosine are mediated through G-protein coupled adenosine receptors. Four subtypes of adenosine receptors have been identified, A1, A2A, A2B, and A 3. However, the specific roles of the various adenosine receptors in processes central to asthma and COPD are not well understood in part due to the lack of adequate animal models that examine the effect of adenosine on the development of lung disease. In this study we have investigated the expression and function of the A3 adenosine receptor in pulmonary eosinophilia and mucus production/secretion in adenosine deaminase (ADA)-deficient mice in which adenosine levels are elevated. ADA-deficient mice develop features of asthma and COPD, including lung eosinophilia and mucus hyperplasia in association with elevated lung adenosine levels. The A3 receptor was found to be expressed in eosinophils and mucus producing cells in the airways of ADA-deficient. Disruption of A3 receptor signaling in ADA-deficient mice by genetic removal of the receptor or treatment with MRS 1523, a selective A3 adenosine receptor antagonist, prevented airway eosinophilia and mucus production. Although eosinophils were decreased in the airways of ADA-deficient mice with disrupted A3 receptor signaling, elevations in circulating and lung interstitial eosinophils persisted, suggesting signaling through the A3 receptor is needed for the migration of eosinophils into the airways. Further examination of the role of the A3 receptor in mucus biology demonstrated that the A3 receptor is neither required nor is overexpression of the receptor in clara cells sufficient for mucus production in naive mice. Transgenic overexpression of the A3 receptor did elucidate a role for the A3 receptor in the secretion of mucus into the airways of ovalbumin challenged mice. These findings identify an important role for the A3 adenosine receptor in regulating lung eosinophilia and mucus secretion in inflammatory lung diseases. Therefore, the A3 adenosine receptor may represent a novel therapeutic target for the treatment and prevention of asthma. ^