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Streptococcus pneumoniae is the most common cause of severe pneumonia in the elderly. However, the impact of aging on the innate inflammatory response to pneumococci is poorly defined. We compared the innate immune response in old vs. young adult mice following infection with S. pneumoniae. The accumulation of neutrophils recovered from bronchoalveolar lavage fluid and lung homogenates was increased in aged compared with young adult mice, although bacterial outgrowth was similar in both age groups, as were markers of microvascular leak. Aged mice had similar levels of IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor following S. pneumoniae infection, compared with young mice, but increased levels of the chemokines CXCL9, CXCL12, CCL3, CCL4, CCL5, CCL11, and CCL17. Moreover, levels of IL-10 were significantly lower in aged animals. Neutralization of IL-10 in infected young mice was associated with increased neutrophil recruitment but no decrease in bacterial outgrowth. Furthermore, IL-10 neutralization resulted in increased levels of CCL3, CCL5, and CXCL10. We conclude that aging is associated with enhanced inflammatory responses following S. pneumoniae infection as a result of a compromised immunomodulatory cytokine response.
- pneumonia
- neutrophil
- chemokine
- inflammation
- aging
the bacterium Streptococcus pneumoniae is the leading cause of community-acquired pneumonia (CAP) and the most frequent cause of infectious disease-related admittance to the intensive care unit (32, 33). It has been estimated that S. pneumoniae affects 5–6 million people in the USA each year, resulting in 1 million hospitalizations. Furthermore, lower respiratory tract infections account for the highest number of infectious disease-related deaths worldwide, of which S. pneumoniae is the predominant etiological agent (4). Age is a major risk factor for S. pneumoniae infections, with the majority of cases occurring in the very young or in the elderly (51). Pneumonia often results in the development of septicemia, acute respiratory distress syndrome, and respiratory failure, and these complications are also more common in the elderly (11, 22). However, why the frequency of pneumococcal infection is higher and the disease more severe in the elderly remains poorly defined.
Even though current vaccine regimens have improved clinical outcome in children, age-related immunosenescence hinders vaccine efficacy and enhances disease susceptibility (33, 37). Immunosenescence is a well-recognized phenomenon in the elderly that has been directly related to an increased risk of infectious disease (1, 19). Age-related alterations in the adaptive immune system include an increased production of autoantibodies and decreased production of pneumococcal-specific antibodies (39, 45), decreased T cell proliferative responses (12, 31), and a diminished T cell repertoire (35). These factors are likely to enhance infectious disease susceptibility, exemplified by a higher incidence of infection to a broad spectrum of pathogens, such as influenza virus and S. pneumoniae (6, 8, 19), by the reactivation of tuberculosis (23, 38), and a decrease in vaccine efficacy (39).
In contrast to the changes in adaptive immunity, age-related alterations in innate immunity are less well defined. Defects in innate immune cell function maybe associated with age, although innate leukocyte numbers in the elderly reflect those of young adults. Immunosenescence may affect specific functional aspects of innate immune cells (16), such as altered cytokine production and poor responses to inflammatory stimuli (3, 9, 19), including defective TLR2 activation (3). The innate immune system plays a pivotal role in controlling host-pathogen interactions and preventing invasive disease following S. pneumoniae colonization of the nasopharynx (27). In particular, alveolar macrophages and recruited neutrophils are thought to be important factors for the control of pneumococcal invasion (26).
The present study aims to address whether the innate immune response of aged mice differs from that of young adult mice in response to S. pneumoniae infection. We compared the inflammatory response following infection with S. pneumoniae in young adult mice with aged mice and characterized the neutrophil and macrophage response in bronchoalveolar lavage (BAL) fluid and whole lung homogenates. The levels of proinflammatory cytokines, the immunomodulatory cytokine IL-10, and several chemokines were measured. Because of significant differences in IL-10 production between young and aged mice, the effect on pneumococci-induced inflammation, cytokine production, and chemokine levels were assessed following neutralization of IL-10 in young mice. Taken together, these data demonstrate that the innate immune response to S. pneumoniae in aged mice is associated with heightened inflammation and diminished IL-10-mediated immunoregulation. These findings have important implications for our understanding of the mechanisms involved in the dysregulation of innate immune responses during aging.
Bacterial strain and infection model.
The D39 strain (serotype 2) of S. pneumoniae was used for all experiments, a virulent strain that is fully infective in mouse lungs. S. pneumoniae was cultured on Columbia agar (Oxoid) containing 5% defibrinated horse blood (TSC Biosciences) at 37°C or in Todd-Hewitt medium (Oxoid) containing 5% yeast extract (Oxoid). Growth in liquid medium was assessed by measuring optical density at 580 nm with a spectrophotometer. Bacteria were grown to mid-log phase and numerated by performing serial dilutions and counting colony-forming units (cfu) on Columbia agar.
Young adult female Balb/c mice (6–7 wk old) or aged female Balb/c mice (24 mo old) were housed in identical specified pathogen free conditions, in accordance with the Home Office, UK regulations. Mice were infected intranasally with 50 μl 5 × 106 cfu of S. pneumoniae, strain D39 (serotype 2), under general anesthesia (isoflurane). Mice were euthanized 2, 4, 8, 24, or 48 h following infection, depending on the study, and blood, BAL fluid, and whole lungs were removed postmortem.
Cell isolation and analysis.
BAL fluid was obtained by making an excision in the trachea and inserting a plastic cannula. The lungs were inflated three times with 750 μl sterile saline and the fluid was withdrawn; 100 μl BAL fluid was used for bacterial colony counts. The BAL fluid was centrifuged at 300 g for 5 min to collect the cell pellet. The supernatant was removed and stored at −20°C until analyzed. The cell pellet was resuspended in 500 μl PBS (GIBCO) and total leukocytes were counted by use of a hemocytometer. Cytospin preparations were performed on 200 μl of the cell suspension, centrifuged onto glass slides at 700 rpm for 7 min. Cytospins were then stained with a rapid Romanowski stain (Thermo-Fisher). Differential cell counts were performed by optical microscopy.
Whole lungs were homogenized into a single cell suspension. Lungs were passed through a 40-μm nylon filter (BD Biosciences) with 6 ml of sterile PBS (GIBCO), and 100 μl of the neat cell suspension was used for bacterial colony counts. The cell suspension was centrifuged at 300 g for 5 min to obtain a cell pellet. The lung supernatant was removed and stored at −20°C until used. The cell pellet was resuspended in 1 ml of sterile PBS and counted by use of a hemocytometer.
Bacterial culture.
Bacteria recovered from BAL fluid, whole lung homogenates, and blood were counted by performing serial dilutions and were cultured on Columbia agar containing 5% defibrinated horse serum as described. Cultures were incubated at 37°C for 18 h; cfu were counted and numbers transformed into log-10 values.
Flow cytometric analysis of lung cells.
Leukocyte recruitment into lung tissue was analyzed by flow cytometry, and 100 μl containing 2 × 105 cells from homogenized lung tissue were used for each stain. Cells were centrifuged at 400 g for 2 min and resuspended in staining medium containing PBS, 4% bovine serum albumin (Sigma), and 0.1% sodium azide (Sigma). The following antibodies specific to mouse surface markers were used: Ly6G-PE (clone 1A8, BD Biosciences), CD11b-APC (BD Biosciences), and CD11c-PerCP (BD Biosciences). Isotype controls (BD Biosciences) and Fluorescent Minus One (FMO) control stains were performed. Flow cytometry analysis was performed on a FACSVerse (BD Biosciences) and analyzed with FlowJo software (Tree Star). The total leukocyte population was gated based on FSc and SSc and neutrophils were analyzed based on their specific expression of Ly6G and CD11b (Ly6GhighCD11bhiCD11clo population). Differential cell counts were calculated based on the percentage of neutrophils within the total leukocyte population.
Protein, cytokine, and chemokine analysis.
BAL fluid was used to analyze endothelial-epithelial barrier permeability and surrogate markers of coagulopathy. Endothelial-epithelial barrier permeability was measured by analyzing the amount of serum albumin recovered in BAL fluid with an ELISA (Bethyl Laboratories). Coagulopathy was assessed by measuring thrombin-anti-thrombin (TAT) complexes (EnymeResearch) or activated protein C (APC) (Antibodies Online) recovered from BAL fluid by ELISA. Neutrophil elastase (ELA2) was measured by ELISA (Caltag-MedSystems) and the ELA2-to-neutrophil ratio for BAL fluid was calculated. The levels of cytokines and chemokines were analyzed in supernatant derived from whole lung homogenates. The proinflammatory cytokines IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor (G-CSF) and the immunomodulatory cytokine IL-10 were all measured by ELISA (PeproTech). Chemokines were measured by use of a multiarray ELISA platform (Qiagen).
IL-10 neutralization in vivo.
Mice were intranasally infected with 50 μl 5 × 106 cfu of S. pneumoniae strain D39 (serotype 2). In addition, the inoculum contained 10 μg of functional grade anti-IL-10 antibody per mouse (eBioscience) or poly-Ig control (PeproTech). This antibody has been shown to inhibit 50% the biological activity of IL-10 (at a concentration of 4 ng/ml of antibody in the presence of 1 ng/ml antigen), as reported by the manufacturers. Animals were euthanized 2, 4, 8, 24, or 48 h following challenge, as described, and BAL fluid, lung tissue, and blood were removed postmortem.
Statistical analysis.
Data were analyzed by one-way analysis of variance (ANOVA) with Newman-Keuls posttest to compare all groups, or with two-way ANOVA across time courses, or with a Student's t-test when comparing two groups. A P value of less than 0.05 was considered significant.
Enhanced inflammation in aged mice following S. pneumoniae infection.
To assess whether there are age-related differences in the innate immune response to S. pneumoniae, young adult mice (6–7 wk) or aged mice (24 mo) mice were challenged with 5 × 106 cfu of the D39 S. pneumoniae strain and euthanized 24 h later. Infection with S. pneumoniae resulted in an acute inflammatory response in both young and aged animals. The total number of cells recovered from the BAL fluid (Fig. 1A) and from whole lung homogenates (Fig. 1B) of aged mice were higher than those recovered from young mice. Differential cell counts revealed that the number of neutrophils isolated from the BAL fluid and lung homogenates were significantly higher in aged mice compared with young mice following infection (Fig. 1, C and D), indicating that aged mice mount a heightened innate inflammatory response to S. pneumoniae. Furthermore, although macrophage numbers were slightly increased in aged mice following infection, macrophage numbers at baseline were similar between young and aged mice in both BAL fluid and lung homogenates (Fig. 1, E and F).
We next determined the effect of age on the ability of the host to control bacterial outgrowth. The bacterial cfu recovered from the BAL fluid of aged and young mice were comparable (Fig. 1G), as was the bacterial burden based on cfu recovered from whole lung homogenates (Fig. 1H). In addition, neither young mice nor aged mice developed septicemia after 24 h, since no bacteria were recovered from blood (data not shown).
Considering that aged mice had significantly increased neutrophil numbers in the BAL fluid compared with young mice, but no corresponding decrease in bacterial cfu, we next assessed neutrophil function by measuring neutrophil elastase production in BAL fluid of infected mice. Aged mice had a decrease in the ELA2-to-neutrophil ratio compared with young mice (Fig. 1I), indicating reduced capacity to produce ELA2 in aged neutrophils.
Aged mice do not exhibit increased barrier permeability.
We next aimed to investigate whether aged mice display evidence of increased endothelial-epithelial barrier permeability or coagulopathy. Serum albumin levels, recovered from BAL fluid, increased following S. pneumoniae infection in both young and aged mice, although there was no difference between the two age groups (Fig. 2A), indicating that increased neutrophil influx does not result in increased barrier permeability. To assess potential differences in coagulation, APC and TAT were measured in BAL fluid. There was no difference in APC levels in young compared with old mice (Fig. 2B). However, aged mice had a small but significant increase in BAL fluid TAT levels (Fig. 2C), indicating that aged animals exhibit an enhanced procoagulant state.
Decreased IL-10 production in aged mice.
To determine whether the heightened inflammatory response in aged mice was associated with an increase in pulmonary cytokine levels, we measured several proinflammatory cytokines and the immunomodulatory cytokine IL-10 in lung tissue. Although the levels of IL-1β, TNF, and G-CSF increased following infection with S. pneumoniae in both young and aged mice, no differences between the two age groups were detected (Fig. 3, A–C). The levels of IFN-γ and IL-17 did not significantly increase following infection, although baseline levels were higher in aged mice compared with young (Fig. 3, D and E). In contrast, baseline levels of IL-10 were higher in young compared with aged mice (Fig. 3F), whereas young mice exhibited increased IL-10 levels following infection with S. pneumoniae. Taken together, these data suggest that the heightened inflammatory response in aged mice is associated with reduced IL-10 levels rather than an increased proinflammatory cytokine response.
Elevated chemokine production in aged mice.
We next measured the levels of several chemokines in lung tissue. Aged animals exhibited enhanced production of a number of chemokines following infection with S. pneumoniae compared with young animals (Fig. 4). Baseline levels of these chemokines were low or undetectable in PBS-instilled mice regardless of age. Increased production of CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES), CCL11 (Eotaxin), CCL17 (TARC), CXCL9 (MIG), and CXCL12 (SDF-1) were detected in aged mice compared with young mice (Fig. 4), suggesting that the increased neutrophil margination into the lungs of aged mice may be associated with increased levels of several chemokines. Of note, although the known neutrophil chemoattractants CXCL1 (KC) and CCL2 (MCP-1) increased following infection, the levels were similar in aged vs. young mice (Fig. 4, A and I).
IL-10 modulates the inflammatory response to S. pneumoniae.
We next aimed to determine the relationship between IL-10 and the modulation of the inflammatory response following S. pneumoniae infection. Young adult mice were infected with 5 × 106 cfu of S. pneumoniae with or without 10 μg of a neutralizing anti-IL-10 antibody given within the intranasal challenge volume. Compared with IgG control antibody-treated mice, those that received anti-IL-10 had an increase in total cell (Fig. 5, A and B) and neutrophil numbers (Fig. 5, C and D) recovered from the BAL fluid and lung tissue, although macrophage numbers were similar (Fig. 5, E and F). These data indicate that IL-10 modulates the magnitude of the neutrophil influx into the lungs of S. pneumoniae-challenged mice.
To assess whether the anti-IL-10 neutralizing antibody was inducing inflammation itself, mice were treated with anti-IL-10 antibody or control antibody via the intranasal route in the absence of concurrent bacterial infection. No differences in the total cell or neutrophil numbers (Fig. 5G) were observed 2, 4, or 8 h after treatment. Furthermore, no differences in IL-1β production between control antibody and anti-IL-10 antibody were detected (Fig. 5H) indicating an absence of inflammation.
No decrease in bacterial outgrowth in the absence of IL-10.
We next measured S. pneumoniae recovered from BAL fluid and lung homogenates following treatment with anti-IL-10 antibody. No difference in bacterial counts was observed in recovered BAL fluid (Fig. 6A) or lungs (Fig. 6B) at 4, 24, or 48 h compared with control mice following infection with S. pneumoniae, suggesting that the control of bacterial outgrowth is independent of IL-10. Bacteremia was not detected at any of the time points (data not shown), measured by cfu counts from the blood. Furthermore, neutralization of IL-10 at the point of infection with S. pneumoniae resulted in elevated neutrophil and macrophage numbers in the BALF up to 48 h postinfection compared with control antibody-treated mice (Fig. 6, C and D), despite a significant decrease in bacterial numbers within the BAL fluid and lung at this time point.
In addition, IL-10 treatment did not alter barrier permeability as determined by serum albumin levels in recovered BAL fluid (Fig. 7A) 24 h after infection with S. pneumoniae. No differences in the levels of IL-1β or TNF were detected following anti-IL-10 treatment compared with IgG controls (Fig. 7, B and C), suggesting that IL-10 is not involved in modulating these cytokines, consistent with the data obtained for young vs. aged mice.
IL-10 regulates CCL3, CCL5, and CXCL10 production.
To determine whether IL-10 has a modulatory effect on chemokine production, the levels of several chemokines were assessed following infection. Of all the chemokines tested, treatment with anti-IL-10 neutralizing antibody only led to a significant increase in the pulmonary levels of CCL3, CCL5, and CXCL10 (Fig. 8). Increased expression of CCL3 and CCL5 following anti-IL-10 treatment is consistent with the enhanced chemokine response in aged mice compared with young mice (Fig. 4). These data indicate that IL-10 modulates the expression of a subset of chemokines associated with the innate immune response following infection with S. pneumoniae.
S. pneumoniae is the leading cause of CAP, accounting for more than 1 million hospitalizations in the US and 1 million childhood deaths worldwide each year (2). Although vaccination has been successful at reducing disease burden in infants, immunocompromised patients are still at risk of developing invasive disease (20, 40). In particular, the elderly population (>65 years of age) represents a substantial and growing group of individuals who are at particular risk of developing life-threatening pneumococcal pneumonia (6, 29). As global demographics shift toward an expanding elderly population, understanding host-pathogen interactions in aging individuals is therefore paramount.
In the present study we specifically focused on the acute phase of S. pneumoniae infection and compared the innate immune response in aged vs. young mice. Aged mice exhibited an enhanced inflammatory response to the pneumococcus, as demonstrated by higher numbers of total leukocytes, neutrophils, and macrophages recovered from the BAL fluid and lung tissue following challenge. The enhanced neutrophil response may be of particular relevance to the pathogenesis of disease due to the pivotal role that these cells play in host defense (30). The increased macrophage response in aged mice further suggests a dysregulated innate immune response in these animals. Moreover, alveolar macrophages often marginate and adhere to the epithelium during acute inflammatory reactions (25), as seen in young mice in this study, a process that may be defective in aged mice. Indeed, macrophages from aged animals have previously been shown to be less responsive to inflammatory signals (24). Alternatively, the increased number of macrophages in aged mice may be due to the underlying proinflammatory state, which may result in increases in both resident and recruited macrophage populations. However, it is accepted that there are some limitations in using aged mice to model responses in elderly humans, as not all age-related changes can be modeled accurately. For example, aged mice are not exposed to a lifetime of environmental insults and do not possess many of the comorbidities associated with aged humans. Despite these caveats, this model does represent a useful means of studying acute inflammation in the lung to understand how the aging process affects innate immune responses to bacterial pathogens.
Taking into account the enhanced recruitment of neutrophils in aged mice, we next assessed how this would affect bacterial clearance. Despite higher neutrophil numbers, pneumococcal clearance from the lungs was not enhanced in aged compared with young mice. This may be explained by the finding that the relationship between neutrophil recruitment and pathogen clearance is not linear. An increase in neutrophil numbers therefore does not necessarily mean that the pneumococcus will be cleared more effectively. This may also reflect discrepancies between neutrophil accumulation and normal function, whereby a decline in bacterial killing may further compromise host defense (18). Neutrophil function has previously been demonstrated to be compromised in aged mice, so that bacteria are cleared less efficiently. Indeed, neutrophils from aged mice have a reduced phagocytic killing potential (46) and are less capable of generating reactive oxygen species (53). Neutrophils from aged humans also have reduced phagocytic activity (13), which may be related to lower CD16 expression (5) or to defective Fcγ-receptor-mediated uptake of opsonized microbes (15). In addition, elderly neutrophils are less effective at phagocytosing and killing pneumococci opsonized by immunoglobulin (46). In the present study we further demonstrate that ELA2 production per neutrophil is compromised in aged mice, which could explain the unaffected bacterial counts, despite increased cell numbers, in our model. It may be the case that aged individuals recruit more neutrophils into sites of infection to compensate for a reduced antimicrobial capacity.
Because of the potential for enhanced tissue damage as a result of excessive neutrophilia, we next assessed endothelial-epithelial barrier permeability in young and aged mice. Although aged mice recruited more neutrophils, endothelial-epithelial barrier permeability, as measured by serum albumin levels in the BAL fluid, was not correspondingly increased. There is some debate as to whether neutrophil migration directly contributes to barrier permeability, whereas it has been suggested that the activation of neutrophils is required for bystander tissue damage to occur (10, 47, 54). Although barrier integrity was compromised following S. pneumoniae challenge, this was not directly associated with the observed neutrophil influx. This apparent paradoxical observation may be accounted for by the poor functionality of neutrophils derived from aged compared with young animals (46, 53). Indeed, the release of proteinases, such as matrix metalloproteinases, ELA2, and other granule-derived enzymes, has been shown to contribute, and even be required for, the tissue damage associated with neutrophil recruitment into the lung (55–57). We further found that BAL fluid TAT complex levels were elevated in aged compared with young mice, suggesting that aging is associated with an enhanced pulmonary procoagulant state in these animals. Coagulation markers in the circulation have been shown to increase in patients hospitalized with CAP, although no correlations were made with clinical outcome (28, 34).
To account for the heightened recruitment of leukocytes into the lungs following S. pneumoniae challenge in aged mice, we next analyzed the levels of several proinflammatory cytokines. We found that IL-1β, TNF, G-CSF, IFN-γ, and IL-17 levels were similar in young and old mice. However, IL-10 levels were significantly lower in aged mice compared with young mice at baseline levels and in response to S. pneumoniae infection. IL-10 is an immunosuppressive cytokine capable of modulating both innate and adaptive immune responses. Initially recognized as a regulatory cytokine produced by T cells, it is now known to be expressed by a variety of cells, including macrophages, neutrophils, and epithelial cells and has diverse modulatory effects on the immunopathology induced by infectious microorganisms (42). However, aging is associated with chronic inflammation, termed inflammaging (14), which may modulate the phenotype of both immune and nonimmune cells. However, the cell-specific changes in propensity for IL-10 production remain poorly defined and findings have often been paradoxical. For example, the T cell system in aged humans is biased toward an inflammatory Th17 phenotype under basal condition but shifts toward a regulatory T cell phenotype upon stimulation, indicating that an imbalance exists between pro- and anti-inflammatory immune responses (43). There may also be tissue-specific differences in the aging immune system, as exemplified by decreased production of TGF-β and IL-10 in the gut mucosa (41). The reduced levels of IL-10 in aged mice may therefore suggest a lack of immunoregulation in the lungs following bacterial infection, thereby contributing to enhanced recruitment of neutrophils and inflammatory disease.
To further evaluate the contribution of IL-10 on the acute phase of S. pneumoniae infection, we inhibited IL-10 with a specific neutralizing antibody. This treatment caused a similar result in young mice to that observed in aged mice, with increased neutrophil recruitment to BAL and lungs, similar levels of proinflammatory cytokines, and an increase in some chemokines (CCL3 and CCL5). These data indicate that IL-10 plays an important functional role in regulating the recruitment of neutrophils into infected lungs. This heightened recruitment occurred despite a significant reduction in bacterial burden by 48 h postinfection, further suggesting a lack of resolution of inflammation in these aged animals. However, bacterial lung burden was not altered after anti-IL-10 treatment, despite the corresponding increase in neutrophils, comparable to the findings in aged mice following S. pneumoniae infection. This suggests that bacterial clearance may be independent of IL-10, whereas the extent of neutrophilic inflammation is dependent on IL-10. Previous reports have been somewhat conflicting regarding the role of IL-10 in host defense against S. pneumoniae. Some report that IL-10 actually impairs host defense against S. pneumoniae (50, 52), whereas others report that IL-10 is protective in models of septic peritonitis (49). Further studies have shown that the absence of IL-10 results in immunopathology independent of pathogen load (17, 21), an observation that the present study supports. These findings and the data reported herein indicate that the balance between host defense and the regulation of excessive inflammation is highly complex.
Chemokines play an instrumental role in directing leukocyte trafficking into sites of inflammation. CXCL1 (KC) is considered to be the archetypal neutrophil chemoattractant, which is the murine functional homologue of human CXCL8 (IL-8). Even though aged mice recruited higher numbers of neutrophils than young mice, there were no differences in the levels of CXCL1. This suggests that excessive neutrophil influx in aged mice may be dependent on other chemokines. Of the chemokines tested, CCL3, CCL4, CCL5, CCL11, CXCL9, and CXCL12 were all elevated in the lungs of aged mice, suggesting they might be involved in mediating the heightened inflammatory response of aged mice. Furthermore, inhibiting IL-10 resulted in an increase in CCL3 and CCL5, two of the chemokines that were increased in aged mice following pneumococcal infection. This would suggest that IL-10 modulates the expression of these chemokines following challenge with S. pneumoniae and that these chemokines may be important in mediating the enhanced inflammatory response of aged mice. IL-10 has previously been shown to modulate neutrophil and eosinophil recruitment in a mouse model of ovalbumin sensitization (58). In a mouse model of LPS-induced inflammation, IL-10 was shown to regulate the expression of CCL3 and CXCL2 and decrease neutrophil accumulation into air spaces (44). This likely reflects the dynamic relationship between various pro- and anti-inflammatory mediators during an innate immune response to a bacterial infection. The way in which the immune system responds to a microorganism is therefore a critical factor that determines the severity of disease (36).
Although the present study suggests that aged mice have a heightened innate immune response to bacterial infection, several questions regarding the role of IL-10 in this process, and the functional capacity of aged neutrophils, remain. For example, restoring the levels of IL-10 in aged animals to similar levels in young adult mice would provide important information regarding the role of this cytokine in regulating inflammation during the aging process. Extending these studies to strains of mice that are more susceptible to S. pneumoniae infection, such as C57BL/6 or CD1, may also help to delineate how IL-10 regulates the host response to this pathogen. Further studies on the microbicidal capacity of aged neutrophils would also be useful to determine whether these cells have reduced functionality in aged mice. In addition, studies designed to address the effect of IL-10 on neutrophil recruitment and on the regulation of the pulmonary chemokine network would be informative and should form the basis of future research activity in this area.
To summarize, we provide evidence that aged mice respond to S. pneumoniae infection with a heightened pulmonary innate immune response compared with young adult mice, represented by increased neutrophil recruitment, even though this did not seem to affect lung protective immunity. We further show that IL-10 production in response to S. pneumoniae is reduced in aged mice and is associated with increased chemokine production. These data support the notion that loss of IL-10 production with age, during an innate immune response within the lung, is associated with enhanced inflammatory responses to this common pathogen. This study also supports the immune dysregulation theory of aging, whereby normal regulatory components of the immune system, in this case IL-10, are lost, resulting in an underlying proinflammatory state (7). This study also supports the concept of inflammaging (14), whereby age-related diseases are often associated with chronic inflammation. A similar mechanism might underlie the greater degree of morbidity and mortality reported in elderly patients during S. pneumoniae pneumonia compared with younger subjects (6, 48), although we accept there are physiological differences between aged mice and elderly humans. As global demographics shift toward an aged population, understanding the mechanisms underlying the fine control of innate immune responses to S. pneumoniae during aging may reveal new molecular targets that could improve outcome in elderly individuals.
This work was supported by funding from the Rosetrees Trust (Grant No. A420 to R. C. Chambers and A. E. Williams) and the NIHR UCLH Biomedical Research Centre (Grant No. BRC/76HI/RC to R. C. Chambers and A. E. Williams), The Wellcome Trust (Grant No. 097216/Z/11/Z to R. J. José and R. C. Chambers); and the NIHR UCLH Biomedical Research Centre (to J. S. Brown).
No conflicts of interest, financial or otherwise, are declared by the author(s).
A.E.W. and R.C.C. conception and design of research; A.E.W. and R.J.J. performed experiments; A.E.W. analyzed data; A.E.W., R.J.J., J.S.B., and R.C.C. interpreted results of experiments; A.E.W. prepared figures; A.E.W., R.J.J., J.S.B., and R.C.C. drafted manuscript; A.E.W., J.S.B., and R.C.C. edited and revised manuscript; A.E.W., R.J.J., J.S.B., and R.C.C. approved final version of manuscript.
- Copyright © 2015 the American Physiological Society
Licensed under Creative Commons Attribution CC-BY 3.0: © the American Physiological Society.


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Registration of vehicles in the UK is predominately referred to as 'road tax' even though road tax was actually abolished some 74 years ago. Registration is in fact a 'vehicle exercise duty' (VED) . There has been much incorrect and emotive talk in the UK media about cyclists should pay road tax and not 'freeload' on the system. This arguement as usual, ignores that most cyclists would be paying VED on a vehicle that they are presumably not driving on that day (thereby making room for cars), the fact that in the UK roads are not funded from VED and finally if you drive a car with low emissions such as a Toyota Prius, you don't pay VED anyway. You can find more detail on the website at http://ipayroadtax.com/
The problem with, or perhaps the intent of emotive campaigns is to dismiss rationale discussion and play on emotive but illogical prejudices. For cyclists this can mean a motorist deliberately using their vehicle as a weapon to 'teach them a lesson'. I think we have all witnessed this on occasions. Time to buy one of their tee shirts perhaps?

subset: commoncrawl


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Journalists in Gambia have been reminded of their duties to follow journalism standards in reporting on the upcoming elections, the Daily Observer reported. According to Afrique en Ligne, Gambia will have a general election in late November.
According to the Daily Observer, Independent Electoral Commission communication officer Joseph Colley told the journalists at a Sept. 21 "media capacity building programme on election reporting" that journalists should have "fair access" to candidates. Colley added that the commission doesn't plan to set "financial limits on party political advertising in the print media."
Colley advised journalists to report "fair, accurate and comprehensive" articles, avoid presenting propaganda, and quickly correct any errors. He also recommended journalists "be equally critical in their analysis and reporting."


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January 20, 2012 in Games (E)
[prMac.com] Montreal, Canada - 1 Last Try Games today is pleased to introduce Evil Square 1.0 for iOS, their new geometry based puzzle Game, where players must arrange a collection of regular and irregular cubes and pyramids so that all the pieces fit perfectly within a black square grid. Shapes are of various sizes, colors, and 3D deformations, but each has a flat base with either three or four sides. When correctly completed, the flat bases of the assembled shapes form a perfect square, with no gaps or overlaps. Featuring two modes of play, automatic positioning, tap to rotate a quarter turn, and drag to position, Evil Square is for players of all ages. The game challenges the puzzle solver to visualize and experiment with the way irregular shapes, having few 90-degree angles, fit together.
Evil Square includes four puzzle packs with 20 puzzles each. Players can choose either Classic Mode or Evil Mode. In Classic Mode, players are scored by the amount of time they take to complete each puzzle. They can ask for up to three hints per puzzle, with a 30-second penalty for each hint. In Evil Mode, the puzzles are completely different, and players have a maximum of two minutes to complete each puzzle. There are no hints available in Evil Mode. In addition, players progress from puzzle to puzzle, but if they fail at any time, they are required to start over from the beginning.
The colors and shading of each 3D shape are realistic and add visual flair to gameplay. The puzzles quickly become quite challenging, requiring fitting together 5 - 12 differently shaped and sized pieces. As players reach higher levels, the playing grid increases in size, allowing for more puzzles of greater complexity. Fortunately, only the bases of each shape must fit together; the third dimension, height, does not affect gameplay.
There is a major emphasis on rectilinear thinking and visualization in modern society. Books, television screens, houses, furniture, and many mass produced objects reflect the primacy of the box and the 90-degree angle. Evil Square is a game that challenges the player to manipulate, both mentally and physically, three and four-sided shapes that do not possess the structural right angles we are accustomed to. These puzzles are difficult at higher levels, and they provide much entertainment and mental exercise.
Feature Highlights:
* Move and rotate pieces to fit perfectly into the square
* 1 touch game play
* Stunning HD graphics
* Easy, intuitive touch controls
* Hint system
* Visual progression
* Perfect for all ages
* Play for a minute or play for hours
* Evil Mode allows only 2 minutes with no hints
* Openfeint Leader boards and more
"Evil Square is a diabolical puzzle game where fitting together a few simple shapes is harder than you ever thought possible," commented Isaac Papismado of 1 Last Try Games. "Evil Square made it to the Top 25 in two categories (Puzzle and Board) in Canada in just two days."
Device Requirements:
* iPhone, iPad, or iPod touch
* Requires iOS 4.0 or later
Pricing and Availability:
Evil Square 1.0 is $0.99 (USD) and available worldwide exclusively through the App Store in the Games category. Review copies are available on request.
Based in Montreal, Canada, Indie developer Isaac Papismado is the owner of 1 Last Try Games. Isaac focuses on developing iPhone games and apps. Copyright (C) 2011-2012 1 Last Try Games. All Rights Reserved. Apple, the Apple logo, iPhone, and iPod are registered trademarks of Apple Inc. in the U.S. and/or other countries. Other trademarks and registered trademarks may be the property of their respective owners.


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It's hard for me to do long toss before tryouts and in mid winter around janurary because it is cold. No one around where I live is that dedicated to play long toss. Could I buy A bucket of balls and then just throw them from the out field to the fence and stuff like that to work on long toss?
Does long toss Improve MPH of your pitch?
Also what should I do when long tossing in like january and it is snowing or there is snow on the ground I need a plan I can do.
I guess you could throw it against the fence, just dont miss When you do long toss don't lob it or throw it too high because you want to try and throw it on a line.
Not the best video ever but this is Roy Halladay and a short Long Toss video.
You can see how he releases it and all that but watch when it shows you the catcher. The ball looks like it comes in straight at him at he catches near his chest.
I don't now if or how it improves velocity but you gotta wait for someone a lot smarter than me to answer. Hope this helps.
Why should I do short long toss instead of Long Toss to a far distance?
IS this good Could I use this? And just throw it to the fence.
Long toss is going to improve arm strength, but not necesssarily hand speed, which translates directly to velocity. Arm strength will help with durability and stamina in a game though.
I'd prefer doing a number of throws at a certain distance, rather than doing timed minutes.
Defintely. You could let a ball get by you and lose out on a few throws if you do it timed. If your talking about those minutes as general guidelines, thats fine. But if you feel like you need to throw more at a certain distance, do it.
Ok I'm prob going to throw againest a fence starting January I'm going to throw 3 time a week for a while then go to 4 maybe.
When doing long toss can I just do it with my pitching motion instead of crow hop? I saw chein ming wang do this at a red sox vs new york game I went to before he went to the bullpen. Could I use my wind-up and go from short toss to 160 feet out using pitching motion?
I will try to get a good program unless someone can figure a program without time and put throws into it?
I'm in total agreement with everyone else so far, it's better to do a set number of throws rather then an alotted time.
As some have said if a ball gets by you you've lost time, another factor is you will more then likely rush yourself if you're on the clock and something will suffer, mechanics, quality of throws etc.
Here's the program that I'd do if I were you RiStar...
You can go three times a week to start..
10 throws at 45 ft, especially if it's cold, take what's needed just to feel like you can go back to the next distance. Atleast 10
8 throws from 60 feet
6 throws from 75 feet
5 from 90
3 from 105
3 from 120
3 from 135
3 from 150
2 from 170 working on keeping it on a line and full extension
2 from 190
2 from 210
That's 37 throws, not counting the warmups to get out to over 200' while keeping the ball on a line. When you get out here, if you feel good still you can throw a few more until the arm is fatigued. You really shouldn't need more than 5-10 more at this distance to feel a little tired in the arm. No need to go out too much further if your keeping the ball on a line. Then I'd bring it in to about 120' for a cooldown for about 5-8 throws, nice and easy. Wouldn't be a bad idea to throw a couple changeups from here either, just to get a feel. There ya go!
the two types of long toss that i use are to loosen the arm and to add strength. when getting loose i really throw in a general motion not a pitching motion and not trying to throw the ball on a line. other days when i feel 100% i will use my pitching motion and throw it on a line as far as i can (my coach want us to throw at a certain distance, but honestly why would i want to limit my throwing distance, idk ?). i also have a similar problem with weather and finding a throwing partner to come outside all year round. being from MI the weather is horrible, something that i found that in the long run does save money when throwing into a fence or mattress or wall ect.. is something correct me if i am wrong called an "all weather" ball. at first i was a skeptic but after using several of them for long periods of time they are great for unideal throwing conditions.
Ok I will do that in January hammer I will try to get to 120 with wind-up and then past that i will crow hop but the most i will get to is about 180 at most.
Cool. Just remember that it's off season training, so respect how your arm is feeling. Some days you may be able to push it, some times maybe you just need some blood flow.
Hammer I know what you mean since i will prob be working out 4 times or more a week and could be a little sore.
What exercises would you suggest to increase hand speed?
I think long toss might help more with arm speed then arm strength.
Ristar your off on this one.
Long toss is the best and one of the only ways to gain arm strength. However it will not increase hand speed all that much. Hand Speed comes mostly from mechanics, genetics, and some of trunk strength.
I've seen guys throw a ball OVER 400 feet and they top at 89 mph. I've also seen guys who rarely long toss and couldn't throw it nearly as far throw 95.
Just look at qb's in the nfl, they have tremendous arm strength especially the guys who can throw the football 70 or more yards. But I bet they couldn't throw a lick on the pitching mound.
Hand speed comes down to getting the most out of your body, period.
if it's too cold to go outside you can throw a version of long toss into the end of a batting cage. just throw the ball near the top of the end in the stretch out phase, and then lower your target in the pull down phase. i just have my guys pick a spot a little higher than a strike and throw at that spot with a running crow hop.
progressive, monitored throwing is a good safe way to build arm strength.
I disagree. I say that guy that threw 400 had poor mechanics pitching or was throwing with a 40 MPH gust that day for long toss. Bret Favre threw 95 in high school, or so Ive heard.
If Brett Favre threw 95 then he had hand speed...
The guy that threw over 400 feet had great mechanics and great command, he was our closer.
Ask anybody that's been to the professional level, long toss will not translate into hand speed. You may get 1 mph, that's about it.
There's a big difference between hand speed and arm strength.
I agree, kind of. I personally believe that long toss can be great for conditioning and that would be its primary benefit. The link between long toss and velocity may lie in two factors. The 1st being to condition the tissues involved so that they actually can withstand the rigors of high velocity throwing. The 2nd being to strengthen/train all of the other musculature involved in pitching at high speeds, such as the legs and core. I would actually credit Roger for these thoughts but I'll let him chime in if he wishes to correct me on his thoughts on it.
What's your definition of "arm"? Which muscles of the "arm" require strength for pitching?


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Sullivan County Community College organic chemistry lab
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It's protected activity if a manager reports to HR that another manager has been treating subordinates who belong to a protected class more harshly than other subordinates.
Punishing the reporting manager for doing so could be retaliation.
Recent case: Joseph O'Leary took a job as vice president at Accretive Health. Soon, O'Leary started keeping a close eye on one of the managers who worked for him when he learned that she had bragged about her sexual exploits at a company dinner. He thought her behavior might constitute sexual harassment, although none of the other diners appeared offended.
The woman was generally known as a bully. But O'Leary began to notice that, while she tended to treat everyone brusquely, she treated black subordinates the worst. He reported to HR and other executives his suspicions that she discriminated on the basis of race and was a sexual harasser.
Shortly after, O'Leary was fired for poor performance. He sued, alleging retaliation for reporting sexual and racial harassment.
The court said O'Leary hadn't engaged in protected activity when he reported the alleged sexual harassment because no reasonable employee would think the dinner talk was sexual harassment. However, the court said he had engaged in protected activity when he reported the disparate treatment black employees received from their supervisor. (O'Leary v. Accretive Health, No. 10-1418, 7th Cir., 2011)
Final note: Accretive Health won anyway because it fired O'Leary for poor performance, not his protected activity.
Related Articles...
- How to Fire an Employee the Legal Way: 6 Termination Guidelines
- How to head off race bias lawsuits: Have the hiring manager also handle firing
- When providing benefits, make sure they go to everyone entitled to them
- Harassment among the orchids yields settlement in Oxnard
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White Rabbits – "The Plot" (Mp3)
This has everything a great song should have for a CW soundtrack: youthful energy, a propulsive rhythm, several ?whoa-oh-oh-oh-oh-whoa-oh-oh?s,? and that great line ?he?s not impressed.? It conveys a scenester ennui, both commenting on the rich kid slacker type and the iconoclast – apart of, yet detached from that scene. But who knows? When I hear this song I crank my speakers to 13, jumping up until exhaustion sets in and letting my balls hang out. Then sadness creeps in at the thought of this playing during a climactic showdown between Supes and Lex on Smallville. It?d be a hell of a showdown though, yeah?
By the by, if you are saying to yourself "young folks?? What the hell is he talking about?? Maybe this will help.? It was featured in like seven Fall television premieres.
Hell of a song though, yeah?


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2016 Election: Talk about a bad a start to a political convention. The release of almost 20,000 emails hacked out of Democratic National Committee servers has forced the head of the DNC to resign, sparked protests from Bernie Sanders supporters, and showed the media in cahoots with Democrats. Now, in desperation, the Clinton campaign is claiming that this is somehow all Donald Trump's fault.
The breech, first exposed in mid-June, let hackers gather emails from seven top DNC officials over the first six months of the year.
It's proved to be a treasure trove of embarrassing information showing how the DNC, which publicly insisted that it wasn't pulling for Clinton, was, in fact, pulling for Clinton at the highest levels.
In May, for example, DNC Chief Financial Officer Brad Marshall pushed to "get someone to ask...does he (Sanders) believe in God ... This could make several points difference with my ... Southern Baptist peeps." DNC Chief Executive Office Amy Lacey responded with an "Amen."
In one email, DNC chair Debbie Wasserman Schultz called Sanders a "damn liar" and in another berates him for having "no understanding of what we do."
Even before these emails emerged, there were signs that the DNC was tipping the scales. In fact, Mika Brzezinski, co-host of MSNBC's Morning Joe, in May called on Wasserman Schultz to resign over how she and the DNC had treated Sanders. That sent Wasserman Schultz into a blind fury demanding, in an email to NBC's Chuck Todd, that "this must stop."
In the wake of these revelations, Sanders called for Wasserman Schultz resign, which she later announced she would do once the convention was over.
The revelations also reignited the already uber-passionate Sanders' supporters, who had all along felt the process had been rigged against him. On Sunday, more than a thousand Sanders' supporters protested in Philadelphia — making it already larger than any of the protests mounted in Cleveland during the GOP convention.
The leaked emails uncovered other embarrassing tidbits, such as the DNC's decision to create a fake Craigslist job posting to embarrass Donald Trump. When asked about it by her underlings, communications director Luis Miranda's only response was that "as long as all the offensive sh-t is verbatim I'm fine with it."
Then there's the revelation that a Politico reporter shared his entire story with the DNC to get its approval before showing it to his editor. (Just try to imagine any reporter giving the RNC the chance to review and amend a story before publishing it.) There are emails showing NBC's Todd all too willing to intervene in Wasserman Schultz's tirade against Brzezinski. And emails showing DNC officials talking breezily about how they could "utilize reporters to drive a message."
The Clinton campaign's response has only made matters worse. On Sunday, campaign spokesman Robby Mook told ABC News that "experts are telling us that Russian state actors broke in to the DNC" and "some experts are now telling us that this was done by the Russians for the purpose of helping Donald Trump." Experts? Who are these experts? Mook isn't saying.
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Admiral Sir Kenneth Eaton
Admiral Sir Kenneth Eaton GBE KCB BA FREng
After reading Engineering at Cambridge, Admiral Eaton served in the Royal Navy throughout the cold war. From witnessing an H Bomb test at Christmas Island in the Pacific in 1957 to the fall of the Berlin Wall and the upheaval in the Soviet Union in the early 1990's he was in the forefront of naval technological and electronic developments.
Promoted to Flag Rank Sir Kenneth became Controller of the Navy, the most senior engineer in the Royal Navy and a member of the Admiralty Board. He was accountable for the Procurement of all new ships, submarines and ordnance for the Royal Navy and consequently for a large slice of the Defence budget. A Weapons Engineer, his responsibilities covered everything from small survey ships to the Trident submarine programme, from submarine nuclear power plants to computer systems, and from guided missiles to ballistic missiles and their warheads.
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He was Chairman of the Mary Rose Trust at Portsmouth during the planning phase of the new museum and having always been interested in maritime history, he remains Chairman of the Society for Nautical Research.


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Another Palestinian Arab blood libel?
Palestinian Authority (P.A.) farmers, police, and media accuse Israelis in Samaria of releasing wild boars to uproot Arabs' crops. The Arabs did not explain how Israelis could tame wild boars and direct them to damage Arabs' crops but not Israelis' crops. Actually, boars have damaged Israeli crops near Haifa.
They also had claimed that Jews in Jerusalem breed and released rats to harm Arabs there. Again, how do rats distinguish Arabs from Jews?
They also claimed that Israel spreads disease. Again, how does one confine bacteria to the other side of borders? Israel works on eradicating disease. Some Arab states refuse to cooperate with Israel on that effort of mutual benefit.
The Arab accusations are like the weird blood libel charges that Jews, contrary to Jewish ethics and culinary practice which abhors blood in meat, kill Christian children to drink their blood. Now you see the kind of people that confront Israel. EXAMINER via Religion of Peace
I guess the fact that most Jews, like Muslims, do not even eat pork escapes these morons.
RELATED VIDEOS: Islam and the Jews


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I would like to wish you all the merriest of Christmases. Hoping your holiday is filled with beauty, laughter, peace, and the reminder that today is about more than gifts under a tree or in a stocking, but today is the day we choose to celebrate the miracles for all miracles: the birth of the hope of the world, Jesus.
God bless you all and Merry Christmas


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Terry Pratchett?(27 Posts)
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SEATTLE, Oct. 25, 2016 /PRNewswire/ -- The University of Washington's Population Health Initiative, which aims to bring together the research and resources of the UW and partners around the Puget Sound and beyond to improve the health and well-being of people around the world, has received a significant vote of support from the Bill & Melinda Gates Foundation, the university announced Tuesday.
In May, the UW launched an initiative to develop a 25-year vision to improve population health locally and globally by focusing on three key areas: human health, environmental resiliency, and social and economic equity. The Bill & Melinda Gates Foundation has awarded a $210 million gift that will serve as a catalyst for the vision, funding construction of a new building to house several UW units working in population health, as well as serving as a place for faculty, students and collaborators from the many university departments and global partners that are part of the effort to come together in their work.
"Melinda and I are pleased to make this investment in the University of Washington to help dramatically accelerate their 25-year vision to achieve positive health outcomes for populations around the world. UW has long been a partner in our foundation's global health and development efforts and this grant underscores our confidence in the school's students, faculty and multi-disciplinary resources to advance their Population Health Initiative," Bill Gates said.
The UW's Population Health Initiative recognizes that the health of an individual or a community involves more than just the absence of disease. Issues from poverty and equity, to health care access, to climate change and government policies all combine to affect the health and well-being of populations around the world, creating health disparities between countries and even within communities. The initiative builds on the UW's public mission of service to improve health around the world.
"We believe we have a moral imperative to bring together the tremendous knowledge and resources of the UW and the Puget Sound region and channel them towards improving health and well-being here in Washington and around the world," UW President Ana Mari Cauce said. "We are grateful and honored to receive this generous support from the Gates Foundation, which recognizes that the UW is among a small subset of institutions equipped to tackle the health challenges we face on a global scale."
Over the next quarter century, the Population Health Initiative will expand the UW's ability to turn the diagnosis of patients, populations and the planet into actionable policies, reforms, interventions and innovations. The University will strengthen its commitment to reducing the diseases, afflictions, and health disparities that detract from and shorten the lives of far too many people both locally and globally. Recognizing that factors such as air pollution and access to clean water contribute to health disparities, the UW will work toward ways to meet the challenge of environmental sustainability, particularly in those communities most likely to be harmed by climate change. And the UW will strive to address the social and economic inequities that often leave communities here and around the world mired in poverty and poor health.
The new building will serve as a hub for collaboration on population health across a range of disciplines at the University. When completed, it will house the Department of Global Health, Institute for Health Metrics and Evaluation, and portions of the School of Public Health – all of which are currently spread out in various locations across Seattle – and provide a central gathering place for partners from around the University, region and world. The location of the building has not yet been determined. However, several sites on the main Seattle campus are under active consideration.
The Gates Foundation gift is among the largest single contributions in the UW's history and will dramatically accelerate the 25-year vision of collaboration among diverse fields in the health sciences and beyond, including education, engineering, environmental sciences, law, the arts, humanities, social sciences, business and others.
The gift comes at a time when the University is launching its most ambitious philanthropic campaign in its history, "Be Boundless — For Washington, For the World," aimed at transforming lives and expanding opportunity. The campaign launched on Oct. 21 and seeks to raise $5 billion by 2020.
To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/university-of-washington-population-health-initiative-receives-transformative-gift-from-the-bill--melinda-gates-foundation-300350379.html
SOURCE University Of Washington


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Bach Flower Remedy - Consultations
You can either choose your own Bach Flowers or consult with me. Dr Bach made the system easy enough for everyone to use, but if the situation is quite complex or chronic you may wish to use my knowledge and experience.
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Hors d'oeuvres
No matter if you are hosting a company event, private party or even wedding, our Hot or Cold Appetizers will fit the bill very nicely. Our clients rave about the high quality and presentation. DJ's has you covered.
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Petite Meatballs
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Chinese Egg Rolls
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Bite-Sized Pastas make an excellent addition to an Hors d'oeuvre Buffet
Chicken Pesto Baskets
Petite Fillo Cups filled with shredded Rotisserie Roasted Chicken Breast in our house-made Pesto with a Cranberry Raisin Garnish
Cucumber Rounds
Topped with your choice of Chicken Salad, Smoked Salmon Mousse, or Roasted Red Pepper Mousse
Jumbo Shrimp Display
with Cocktail Sauce
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Traditional Deviled Eggs
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Petite Finger Sandwiches
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Garden Vegetable Display With Dip
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Listing is for 1 yard of fabric.
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The leader of the Catholic Church in England and Wales has labelled the government's social reform a "disgrace".
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Thursday, August 23, 2007
I'm also nervous because I know nothing about how to take care of little girls. With Braydon, I was told to cover him with a diaper or wipe while I changed him. I only had him pee on me once, and that was my own fault. We were in NY visiting my family when he was 3 months old, and I was changing him downstairs. My dad was in the room, and I saw Braydon squeezing his cheeks tight, and I thought it was hilarious, so I held him up for my dad to see. He laughed too, and just as he laughed, Braydon released his cheeks and peed on me. Apparently he was squeezin' em for a reason. But anyways, with girls I heard they can get infections, and you have to wipe them a certain way. Even at daycare, all of my babies were boys when I was in the baby room. I guess I'll just have to learn, huh?
Anyways, I've come to accept the fact that its a girl. I even bought her an outfit to come home in. It's not pink, but it has a little pink on it. I'll be 21 weeks tomorrow and I'm itching for her to be here. I can't wait to hold her and count her fingers and toes.
2 comments:
- bethany said...
I just have to say...I know how you feel. I've ALWAYS wanted a little boy. I was so afraid I'd be horribly disappointed when I found out that we were having a girl, and I was, a little. I had a hard time buying girly clothes, and to be honest, I still don't like pink. (But she looks great in pink, lol.) I can dress her in jeans and t-shirts and hoodies, and that's ok. :) I discovered that I love her more than anything. I wouldn't trade her for a boy even if I could! Sure, I hope someday I have a little boy. But I know that I'll learn how to be a girl mama, and even if she wants to do ballet and have "princess"-themed things, I'll learn how to do it with her. I know you will learn the same things! And it will be so much fun watching B be a big brother to his little sister. :)
- August 23, 2007 at 10:54 AM
So i know how you feel. i was so anti girly i didn't actually discover i had breasts till college i don't think. i am anti anything pink and the idea that parents would tell their daughters they are a princess not only made the feminist inside me rage but it also made me need that pink pepto before i hurled. ellas outfit to come home from the hospital in was a little BLUE dress with the littlest amount of pink i could find.
As i write this my daughter is prancing about in a "princess dress" with tulle - yes tulle. some lady from alexs work gave her these overtly girly dresses that turned into dress up clothes(yes she does that) because i cant bear anyone in public getting the impression i might have bought them lol.
Ella and i are currently undergoing a search for a dinosaur shirt that isnt made for a boy. now i dont mind her dressing in boys clothes, she has lots. BUT WHY IS IT THAT GIRLS CANT LIKE DINOSAURS!! all the little girls shirts say things like little princess and cutie pie. if you ever see one get one for both of our girls ok?
much to my initial dismay she came up with the princess thing herself. but i realized when your little girl looks up at you and says "look mommy, i a pwincess" you just cant do anything except say "yes, baby you are"
you will get it all even if you weren't born with it. oh and NEVER EVER underestimate the peeing abilities of a little girl! see you tomorrow. Aprille
- August 24, 2007 at 10:27 AM


text: PrintPackagingWebsites Taylor Robinson Craig Steere NECA Assure Cosmetics Water Corporation LGIS Regional Development Authority COMO The Treasury COMO The Treasury Turner Design was commissioned to assist with the rollout of the Como Hotel branding (logo produced in Singapore). As well as promotional brochures and postcards, hundreds of printed items were required for the launch including stationery, luggage tags, breakfast menus, valet parking tags and Guest compendiums. PREVIOUS / NEXT


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Est.1993 (317) 585-1060
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What kind of couples are appropriate for an Intensive?
Although any couple can participate in an Intensive, often it is the couple in a crisis who prefer this method. The distress of the relationship has taken a toll on them and they want to find some resolution and do so as quickly as possible.
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MLB's Lewis to be honored with WISE Award
MLB's Lewis to be honored with WISE Award
But Lewis, who is senior vice president of diversity and strategic alliances for Major League Baseball, really wants him to be in New York City on June 8. That's the day Lewis will be honored at the Marriott Marquis Hotel as one of three recipients of the 2011 WISE Woman of the Year Award during the 17th annual luncheon.
As a longtime Milwaukee resident, Lewis' father is a really big baseball fan, and an even bigger admirer of Commissioner Bud Selig.
One way or another, he'll watch his daughter win the award she's admittedly most proud to have earned.
"I can't think of any award we would try so hard to get my dad to be there for," Lewis said. "I'm more than thrilled -- really, really, really humbled, because it means a lot to a lot of people. It means we've done a good job for them [Women in Sports & Events] to think this way."
Most recently in a long list of achievements geared toward workforce diversity in her two-plus decades at MLB, Lewis was critical in starting the two-day Selig Business Conference -- a massive trade fair that will take place at the Georgia Aquarium May 12-13 as part of the Civil Rights Game events.
Lewis' father, Emcee Williams, will be 92 in May. He still lives at home and is still in pretty good health. In fact, Lewis worked it out so that her father can bring a group of his friends as special guests at various Brewers games this season.
"He's so excited," Lewis said. "But I tell him, 'Dad, you have to wait.'"
Lewis' mother, Alma Williams, passed away eight years ago from cancer. Before then, Emcee and Alma visited the same deli and dry cleaners as Selig and ran into him frequently. And every time they did, Selig would make sure to stop and say hello.
Those trips don't happen anymore for Emcee, and neither does much traveling at all. But he still brags about his daughter's involvement with baseball.
"He thinks it's just so special that baseball actually pays me to make sure there's a more diverse representation," Lewis said. "He just thinks it's incredible."
WISE, described as the leading voice and resource for professional women in the sports and events industries, was founded in 1993 and has 10 chapters across the country. According to a release issued by the organization, WISE "aims to offer its members the opportunity to gain valuable industry insights and connections that can give them a competitive advantage in their current position, and as they advance in their careers."
Every year, the organization's national board creates a Women of the Year ballot based off recommendations, then sends an email blast to its 1,200 members for voting.
After being listed at least two previous times, Lewis finally got over the hump this year, joining Stacey Allaster (chairman and CEO of the Women's Tennis Association) and Lisa Baird (chief marketing officer of the United States Olympic Committee) as winners.
"This one specifically is very special, because of the selection process and because of the caliber of women who have received it in the past," Lewis said. "It has always meant a lot to me. The thought of joining this unique club of extraordinary people -- it's the most special honor I've ever received."
The WISE winners, according to a release issued by the organization, were selected because they "are visible leaders and continue to be an influential voice for women in the industry," they "have broken down barriers and helped create connections and new opportunities for other women," and they "exemplify professional excellence and are role models for others."
"[Lewis] has great achievements and has proven to be a leader and is well-respected," WISE founder and national president Sue Rodin said. "Aside from her career accomplishments, she's also very supportive of WISE and what it does."
Lewis did her undergraduate studies at the University of Wisconsin-Oshkosh, got her MBA at Northwestern University and began working at MLB while serving as manager of human resources with the Cubs in 1987 -- at a time when professional sports leagues didn't really have HR representation.
Lewis then moved to MLB's Central Office in New York in 1995, and along the way has steered several initiatives geared toward diversity in the workplace. Perhaps most notably, she now manages the leadership of MLB's Diverse Business Partners Program -- the leading supplier-diversity program in sports, which has resulted in more than $800 million being spent with thousands of minority- and women-owned businesses.
"Wendy kind of goes under the radar," MLB executive vice president of baseball development Jimmie Lee Solomon said. "She does a tremendous job. On behalf of minority and women in businesses, she has basically been responsible for MLB spending tens of millions of dollars in that sector. That, in large part, is a tribute to her hard work."
And as a tribute to that, Lewis will be one of several notable winners of a prestigious honor.
Her biggest fan plans on being there to see it.
"I'm just so excited of just the thought of it," Emcee said about Lewis wanting him there. "I appreciate it very much."
Alden Gonzalez is a reporter for MLB.com. Read his columns and his blog, listen to his podcast and follow him on Twitter. This story was not subject to the approval of Major League Baseball or its clubs.


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Allen and Hester,Ester or Sarah McKee Oh
Looking for info on Allen McKee B. 1813 in NY.died between 1860 and 1870 and wife or wifes Hester or Ester and Sarah last names unknown.Their children where Clarinda b.1836 Caroline b. 1841 Leornorab. 1844 Deaf Pricsilla b. 1847 Charles b.????? and my gggrandfather James Dwight b.1839 and died 1870. All of the children where born in Noble Co. Ohio. Also looking for info on two of James Dwight's childrenMartha A. or J. b. 1867 and James Dwight b.1870 died 1916 in Stark Co. Ohio in a Railroad accident.James Dwight's known children where Gladyus, Emily, Louis, Anna and ??????Any info would help. Thanks Ann Marie
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Re: Allen and Hester,Ester or Sarah McKee Oh
Re: Allen and Hester,Ester or Sarah McKee Oh
Charley McKee 4/15/01


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This may be the only way to go in the future. The "new rules" will only disallow any doping or gene doping that disrupts the "spirit" of the particular sport. For instance, archery and shooting require an athlete to control their nerves, so no beta blockers allowed that would reduce tremors or nervousness. But if you're running, lifting weights or pedaling a bike, use your knowledge to do whatever it takes to go faster, lift more, etc.
Lance Armstrong, Marion Davis, Barry Bonds, and Roger Clemens never failed a drug test. Armstrong was tested over a thousand times. Snitching was the only thing that busted them. There are hundreds still doping who will never be caught. Who cares what these fools want to do to their bodies? We're getting closer and closer to the absolute maximum "records" the human body can achieve. There has already been legal doping going on for years; athletes have been using altitude chambers to train in which gives them more oxygen capacity (like EPO). What about this guy; is this enhancing the human body?
We are now using drugs to allow students to perform better on tests; we are calming youngsters with drugs. The human genome can be sequenced for a single human for a few thousand dollars and will be a few hundred bucks in less than a decade. We can turn genes on and off. We will be able to enhance genes that cause faster acceleration or develop more muscle mass. How can we make that illegal?
I predict the only way that athletic records can be broken in the future will be by enhanced athletic bodies using knowledge of gene therapy and drugs.
What do I care? I won't be around to witness the new freak show anyway, but running the 100m in 8 seconds will still fill stadiums.
Maybe by then they will find a way to not have acne-scarred backs and raisin-sized testicles.


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Is this common? It seems relatively quick, and all the 95-100s I've read have way better (and way more) hubs than I do.
I don't know, it seems a little strange but I wont complain. My hub score usually fluctuates a lot but it has stayed at 95 for about the last six days like you said. So who knows. Maybe it has something to do more new changes to hubpages, if you haven't noticed yet.
If you have read a lot of hubs that increases it, too much forum activity decreases it. The Cabin Girls theory anyway !
maybe that's what is wong with me...my profile score is crap despite the high fan base, hub turnout, and hub scores...
I already hate you.
Well, then it seems that I am in good company?
I was joking. I still hate you.
I think the weather also plays a major role in hubscores.
lucky you, congrats! it's a good question. my score dropped six points within seven hours.
when i first started I had a constant 90 plus ranking too. Seems to be part of the system
Hub Profile scores are like the weather here in NC. "If you don't like it, give it a few minutes, it'll change."
How does Hubber score work anyway? Is it randomly generated? Just to give us the ups and downs? Maybe it is, because HubPages never tell us.
absolutely. I really want insights how hub score is generated. This is my 4th day and I already have score=61. What is the criteria? How this score helps? if I remain inactive for 20 days, would it die?
I have seen some hubs with this topic, cant recall the full details but I can tell you that..In summary it is a combination of your hub quality, exposure(traffic) and a few other minor detailsJust search for it and you shall find
http://hubpages.com/faqthanks for the tip, with little try i found the details on above link.
I'm still skeptical... I don't know, but I'll keep plugging along. If it stays high, I will just attribute it to the 30 in 30 HUB CHALLENGE!
by Audrey Hunt3 years ago
Just had a big drop on my profile score. And all my hubs were featured along with a steady 10 Editors Choice. I say 'were' because 3 were just unfeatured and I don't know what to do about that. My...
by Missing Link4 days ago
I'm thinking the answer is probably yes?If you have hubs that have been deemed "not featured", for one reason or another, will that factor into lowering your overall score/rating as a HubPages member? ...
by M. Toni2 years ago
I've been on here for a few years, and I guess I never really understood the point of these scores. They don't seem to provide any real value to the user and I can't convince myself that they add value because they...
by LindaSmith13 years ago
I took a hiatus for awhile from Hub Pages! However, in the past week or so, I have added new hubs participated in forums, asked a question or two, participated with the Hub Hopper, have read some Hubs, yet my...
by Erin3 years ago
Hi ya'll. I'm a newbie and am wondering what hub scores ranging from 47 to 56 mean? What is a "good" hub score and how does that impact things?Thanks so much!!!
by Marisa Wright3 years ago
I'd like to suggest we get rid of Hubber Score - and perhaps even Hub Scores. They:- are constantly misunderstood;- cause a lot of upset and grief in the forums; and- encourage newbie Hubbers to direct their...
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The Canadian Network for Innovation in Education (CNIE) is a national organization of professionals committed to excellence in the provision of innovation in education in Canada. Our inclusive culture welcomes all of those interested in examining innovation in education from our K-12 systems, post-secondary organizations, private training and professional development and those involved in industry – our goal is to provide a space for dialogue, collaboration and innovation!
Hello! – Bonjour! – Aanii/Boozhoo! Laurentian University's Centre for Academic Excellence Le centre d'excellence universitaire de l'Universitaire Laurentienne invites you to | vous invite à CNIE-RCIÉ 2018 May 15 – 17, 2018 | 15 – 17 mai 2018 Laurentian University … Continue reading
Connections July 2017 – Vol. 22, No. 2 COL is pleased to share the latest issue of our newsletter, Connections. In this issue: • Regional Consultations on OER • Top 4 trends in Higher Education • Open textbooks and costs: … Continue reading
CNIE is partnering with 7th Annual Summit on Education Technology Strategies for Colleges, Universities & K-12 Schools| Marriott Downtown Eaton Centre| 11th – 12th April 2017 Canadian Network for Innovation in Education (CNIE) is pleased to announce partnership with the … Continue reading


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About Keep it Local
We want our public services delivered by local non-profit organisations, not big national companies
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Keep it Local
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Faced with limited choices when it comes to providing quality, cost-effective public services, commissioners are being pushed into inefficient, centralised services and mega contracts in a bid to answer austerity's challenges.
But there is a better way: Our Keep it Local campaign calls for locally-commissioned and delivered public services which provide substantially better outcomes and value than standardised, one-size-fits-all services.
We have developed two key resources around keeping it local:
The handbook for pioneering councillors and commissioners across the country who prioritise local commissioning and delivery, leading to improved services for local people, savings for councils and economic resilience in their communities.
Based on our five key principles of how to Keep it Local, the guide busts myths around commissioning locally and showcases the benefits of working with community anchor organisations.
Download the How to Keep it Local: Five step guide for councillors and commissioners guide.
This briefing paper outlines the steps we need to take to finally make decentralisation stick and harness the potential of place-based strategies to save money and create better services.
It draws on Locality's experience of working with communities, local authorities and central government to innovate from the ground up. It also introduces case studies of social policy experiments that have been successful across Europe, as part of Locality's work with the InnoSI research programme.
Read more about the How to Keep it Local: Innovation in Action Policy Briefing Paper here.
To share, learn and be inspired with bi-monthly newsletters, local councillors and commissioners are encouraged to sign up to our Keep it Local Network here.
If you're a supporter of the Keep it Local approach, please share the new five step guide with your local councillors and commissioners!
Increasing pressure on public services, coupled with ongoing austerity measures, have fostered a belief that public service efficiency can only be driven by a combination of centralising, outsourcing and standardisation of services. However, packaging services up into standard price, one-size-fits all mega-contracts delivered by large national providers fails to meet people's needs and wastes money.
In 2014 we published the first comprehensive assessment of the demand placed on public services. Saving money by doing the right thing showed that the way our public services are currently delivered is wasteful and inefficient, and highlighted 'diseconomies of scale'.
Locality is now working with six pioneering local authorities (Bradford, Bristol, Calderdale, Dorset, Hackney, Shropshire) and community anchors in their areas to test these ideas in practice and showcase better commissioning solutions. The action research project, supported by the Friends Provident Foundation, will: