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CD40 is an important signaling and activation antigen found on certain bone marrow-derived cells. Recently, CD40 has also been shown to be expressed by nonhematopoietic cells, including certain human fibroblasts, but not others. Little is known about the function of CD40 on fibroblasts. The current study investigates the hypothesis that CD40 is expressed on orbital fibroblasts and represents a pathway for interaction between these fibroblasts and CD40 ligand-expressing cells, such as T lymphocytes and mast cells. We report here that orbital connective tissue fibroblasts, obtained from normal donors and from patients with severe thyroid-associated ophthalmopathy (TAO), express functional CD40. CD40 is upregulated ∼10-fold by interferon-γ (500 U/ml) treatment for 72 h. These fibroblasts become activated through triggering of CD40 with CD40 ligand (CD40L). This is evidenced by nuclear translocation of nuclear factor-κB and induction of the proinflammatory and chemoattractant cytokines interleukin-6 and interleukin-8, respectively. These data support the concept that cognate interactions between orbital fibroblasts and infiltrating T lymphocytes, via the CD40-CD40L pathway, may promote the tissue remodeling observed in TAO and other inflammatory diseases of the orbit. Disruption of the CD40-CD40L interaction may represent a therapeutic intervention to reduce the inflammatory components of TAO, which remains a vexing clinical problem.
- fibroblasts
- thyroid-associated ophthalmopathy
- cellular activation
- interleukin-6
- interleukin-8
the connective tissue of the human orbit can manifest dramatic inflammation in thyroid-associated ophthalmopathy (TAO) (30). TAO is synonymous with Graves' ophthalmopathy. In this disease process, tissues become infiltrated with activated T lymphocytes and mast cells and accumulate excessive amounts of the nonsulfated glycosaminoglycan hyaluronan (7). Hyaluronan is synthesized by many cell types. However, fibroblasts are a major source of this and other glycosaminoglycans (30). It is believed that orbital fibroblasts have a primary role in the pathogenesis of TAO. During the tissue remodeling associated with TAO, infiltrating T lymphocytes are thought to initiate, through unknown signaling pathways, biosynthesis of inflammatory mediators and hyaluronan, two cardinal features of TAO (22). It would therefore appear essential that conduits for molecular communication between orbital fibroblasts and infiltrating T lymphocytes be fully characterized if further insights are to be gained into the mechanism underlying the disease. Moreover, elucidation of the pathways utilized for lymphocyte-fibroblast cross talk could allow the formulation of specific therapeutic strategies designed to interrupt inflammation.
One candidate pathway for communication between orbital fibroblasts and T lymphocytes is the CD40-CD40 ligand (CD40L) costimulatory pathway. This system conveys signals for activation and differentiation between hematopoietic cells. It has been implicated recently in T lymphocyte costimulation (4, 28). Triggering through surface CD40, a 50-kDa member of the tumor necrosis factor-α (TNF-α) receptor gene superfamily, is a powerful stimulus for B lymphocyte activation, proliferation, immunoglobulin (Ig) production, and isotype class switching (6). CD40 is also expressed by non-B lymphocyte hematopoietic cells, including interdigitating dendritic cells, Langerhans cells, dendritic cells, and monocytes (4). CD40L, a member of the TNF-α cytokine gene superfamily, is the counterreceptor for CD40 and is primarily expressed on the surface of activated T lymphocytes and mast cells (34). In addition to being an important signaling mechanism for B lymphocytes, the CD40-CD40L intercellular ligand interaction can provide a necessary "second signal" to help drive cytokine production and clonal expansion of naive T lymphocytes (26).
Observations in patients with X-linked hyper-IgM syndrome provide evidence for the importance of the CD40-CD40L pathway in immune responses. These patients possess mutations in the gene encoding CD40L, resulting in the disruption of CD40-CD40L signaling. The loss of T lymphocyte "help" renders B cells functionally deficient, with abnormal Ig class switching and a profound inability to respond to bacterial antigens (2). The CD40-CD40L pathway has also been shown to play a major role in autoimmune diseases that have significant B lymphocyte involvement. For example, treatment with anti-CD40L antibodies are effective in preventing the onset of disease in murine models of collagen-induced arthritis, experimental autoimmune encephalomyelitis, and lupus nephritis (8, 24).
CD40 expression is not limited to bone marrow-derived cells. It has been demonstrated to be expressed and functional on epithelial cells, such as human epidermal keratinocytes (15), thymic epithelium (13), and activated vascular endothelial cells (21). Very relevant to the current study is the observation of CD40 expression on nontransformed human fibroblasts derived from lung, foreskin, periodontal, and synovial tissue (12). CD40 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR), and the protein was detected on cultured fibroblasts using flow cytometry. In tissue sections, immunostaining suggested fibroblast display of CD40. In contrast, some dermal fibroblasts failed to express CD40 (12).
The current studies were conducted to determine whether CD40 is expressed by orbital fibroblasts derived from normal tissue and tissue obtained from donors with TAO. We demonstrate here that CD40 is expressed by orbital fibroblasts from either source and that these fibroblasts can be activated through CD40 to mobilize nuclear factor-κB (NF-κB) and to express proinflammatory cytokines. We hypothesize that the CD40-CD40L coreceptor system, described for B-T lymphocyte communication, is an important pathway through which communication between orbital fibroblasts and T lymphocytes and mast cells can occur. This pathway may be relevant to the pathogenesis of inflammatory diseases in the orbit, such as TAO. Moreover, the demonstration of functional CD40 on fibroblasts represents a potentially important target for therapy design.
Cell culture.
Normal and TAO orbital primary fibroblasts were isolated from surgical explants as described in an earlier publication (33). TAO fibroblasts were initiated from surgical explants from individuals undergoing decompressive surgery for severe Graves' ophthalmopathy. Normal orbital strains were derived from individuals undergoing eye surgery for conditions not affecting the soft tissues of the orbit. Procurement of these tissues was approved by the Institutional Review Board of Albany Medical College. The fibroblasts were maintained in minimal essential medium with Eagle's salts (MEM; Life Technologies, Gaithersburg, MD) supplemented with 10% fetal bovine serum (FBS; Hyclone, Logan, UT) and gentamicin (50 μg/ml; Life Technologies). These cells are morphologically consistent with a fibroblast phenotype and express vimentin and collagen, two markers of fibroblasts. They do not, however, express CD45, factor VIII, or smooth muscle actin. Fibroblasts were passaged every 10–14 days and reseeded at 3 × 105cells/75-cm2 flask (Costar, Cambridge, MA). Adherent monolayers of fibroblasts were dissociated with a 1:1 solution of sodium EDTA (0.1% wt/vol; Sigma Chemical) and trypsin (0.05% wt/vol; Worthington Biochemical, Freehold, NJ). All fibroblasts were maintained in a humidified 7% CO2 incubator. All experiments used cells between passages 2 and13.
Fibroblasts were untreated or treated with recombinant human interferon-γ (IFN-γ, 500 U/ml; Genzyme, Cambridge, MA) for 48 h and then scraped with a rubber policeman for extraction of total RNA with Tri-Reagent (1 ml/106 cells; Molecular Research Center, Cincinnati, OH), following the manufacturer's protocol. RNA was solubilized in nuclease-free water by heating to 55°C for 10 min. The concentration of total RNA was quantitated by spectrophotometry, and 5 μg of RNA were reverse transcribed using Moloney murine leukemia virus reverse transcriptase (200 U/reaction; Life Technologies) and an oligo(dT) primer (Pharmacia, Piscataway, NJ), as previously described (12). Reverse transcriptase was withheld from replicate samples, which served as negative controls. PCR reactions for human CD40 and β-actin consisted of cDNA obtained above (2 μl), reaction buffer (Boehringer Mannheim Biochemicals), deoxynucleotides (1 μM each), specific primers (1 μM each), and Taq DNA polymerase (2.5 U; Boehringer Mannheim Biochemicals) in a total volume of 50 μl. The human CD40 primer sequences were 3′-CGT ACA GTG CCA GCC TTC TTC and 5′-ATG GTT CGT CTG CCT CTG CAG, yielding a 330-base pair (bp) product; the human β-actin primer sequences were 3′-CTC CTT AAT GTC ACG CAC GAT TTC and 5′-GTG GGG CGC CCC AGG CAC CA, which generated a 539-bp product. Samples underwent 30 cycles of amplification in a PTC-200 DNA Engine thermal cycler (M. J. Research, Watertown, MA), and each cycle included denaturation at 94°C for 30 s, annealing at 63°C for 30 s, and primer extension at 72°C for 60 s. The products were electrophoresed on 2% agarose gels and visualized with ethidium bromide staining. A 100-bp ladder (Life Technologies) was used for size determination.
Flow cytometry analysis.
Fibroblasts were prepared for flow cytometry by washing a suspension of cells in phosphate-buffered saline (PBS) with 0.1% sodium azide and 1.0% bovine serum albumin (BSA). Cells were incubated with anti-human CD40 monoclonal antibody (G28-5, 100 μl of hybridoma supernatant; American Type Culture Collection) or anti-HLA-DR (L243, 100 μl of hybridoma supernatant; American Type Culture Collection) for 30 min on ice. After the cells were washed, fluorescein isothiocyanate-conjugated goat anti-mouse Ig (1:50 dilution; Cappel Research Products, Durham, NC) was added for 30 min on ice. Samples stained with only the secondary antibody served as negative controls. Once washed, the cells were resuspended in PBS with 0.1% sodium azide and 1.0% BSA and analyzed on a flow cytometer (Elite, Coulter, Hialeah, FL). We have demonstrated that trypsin treatment, under the conditions used to disrupt fibroblast monolayers, fails to alter the detection of surface CD40 or HLA-DR (data not shown). Viable cells were gated on the basis of forward light scatter, and the data were analyzed with the Cytologo software program (Coulter). All experiments were repeated a minimum of three times, and representative results are presented.
Electrophoretic mobility shift assays.
Orbital fibroblasts were allowed to proliferate to confluence in 100-mm tissue culture dishes covered with MEM supplemented with 10% FBS. The fibroblasts were pretreated with IFN-γ (500 U/ml, Genzyme) for 72 h. The cultures were then washed extensively and incubated overnight with MEM containing 1% FBS. The cells were then stimulated for 2 h at 37°C with medium alone, control insect cell membranes containing glutathione S-transferase (GST), or insect cell membranes containing human CD40L. Membranes were generously provided by Dr. Marilyn Kehry (Boehringer Ingelheim, Ridgefield, CT) and were prepared as described previously (19). Recombinant human TNF-α (50 U/ml; Genzyme) was used to trigger the cells as a positive control for NF-κB mobilization. The cells were harvested, nuclear extracts were prepared as described by Andrews and Faller (1), and protein concentrations were normalized by the bicinchoninic acid protein assay (Pierce, Rockford, IL). To assess NF-κB binding activity, 25 μg of nuclear extract were incubated with32P-labeled double-stranded oligonucleotide probe representing the consensus sequence for the NF-κB binding sites following the supplier's instructions (Promega, Madison, WI). Samples were electrophoresed on 4% polyacrylamide gels, and the DNA-protein complexes were visualized by autoradiography.
Cytokine production.
Orbital fibroblasts were seeded into 96-well tissue culture plates (5,000 cells/well) and, once established, were untreated or treated with IFN-γ (500 U/ml) for 72 h in MEM containing 10% FBS. The fibroblast monolayers were then washed extensively with fresh culture medium at 37°C and incubated in triplicate for 72 h with medium alone, control insect cell membranes containing GST, or insect cell membranes containing human CD40L. Culture medium was harvested, and the concentration of IL-6 and IL-8 was determined by specific enzyme-linked immunosorbent assay (ELISA). Media samples were appropriately diluted with sample buffer so as to fall within the linear sensitivity range of the ELISAs.
For detection of human IL-6, Immulon 3 flat-bottomed 96-well plates (Dynatech, Chantilly, VA) were coated overnight at 4°C with 2 μg/ml anti-human IL-6 (capture antibody, Pharmingen, San Diego, CA) diluted in 0.1 M sodium bicarbonate (pH 8.2). The plates were then washed three times with PBS-Tween [1× PBS, 0.05% Tween 20 (vol/vol), and 0.1% sodium azide]. Plates were blocked with ELISA buffer (1× PBS, 5% BSA, 5% calf serum, and 0.1% sodium azide) for 2 h at room temperature. The plates were washed three times with PBS-Tween. Media samples and IL-6 standard (500 ng/ml to 0 pg/ml; Pharmingen), diluted in ELISA buffer, were then incubated on the plates for 2 h at 37°C. The plates were washed three times with PBS-Tween. Detection antibody (2 μg/ml of biotinylated anti-human IL-6; Pharmingen) was diluted in ELISA buffer and then incubated on the plates for 1 h at room temperature. Plates were washed three times and incubated at 37°C for 1 h with streptavidin-alkaline phosphatase (1:500 dilution in ELISA buffer; Southern Biotechnologies, Birmingham, AL). After the plates were washed three times, they were incubated with 1 mg/ml of p-nitrophenyl phosphate diluted in DEA buffer [2% (vol/vol) diethanolamine, 10 μM magnesium chloride, and 30 μM sodium azide, pH 9.8]. The reaction was stopped with 3 N NaOH. The optical density of each well was read at 405 nm with a Dynatech plate reader.
The assay for human IL-8 resembles that for IL-6 with the following exceptions: the capture antibody (anti-human IL-8; Endogen, Cambridge, MA) was used at a concentration of 1 μg/ml. The recombinant IL-8 standard (Biosource, Camarillo, CA) was used in a dilution series from 600 to 0 pg/ml. The biotinylated detection antibody (anti-human IL-8; Endogen) was used at a final concentration of 0.5 μg/ml. The detection antibody was directly added to the wells 15 min after addition of samples and IL-8 standards. The plates were then incubated for 1 h at room temperature.
Standard curves were plotted on the basis of a dilution series of the recombinant cytokine standards and used to determine the concentrations of IL-6 and IL-8 in the experimental samples. All experiments were repeated a minimum of three times, and results from representative experiments are presented.
CD40 mRNA expression by normal and TAO orbital fibroblasts.
Primary human orbital fibroblasts were isolated to examine the expression and function of CD40. Previous reports have demonstrated that fibroblasts from human lung tissue constitutively express CD40 mRNA and protein. In addition, it was shown that the proinflammatory cytokine IFN-γ induces hyperexpression of this surface antigen (28). RT-PCR analysis was performed on total RNA extracted from normal and TAO fibroblasts treated without or with IFN-γ (500 U/ml) for 48 h. Equivalent amounts of RNA were reverse transcribed, and the resulting cDNA was then amplified for 30 cycles with primers specific for CD40 and the housekeeping gene β-actin. Samples prepared without reverse transcriptase failed to yield any CD40 or β-actin product (data not shown). A representative ethidium bromide-stained gel showing the amplification products from normal orbital fibroblast RNA (±IFN-γ) is shown in Fig.1 A. The amplification products from TAO orbital fibroblast RNA (±IFN-γ) are depicted in Fig.1 B. It is clearly demonstrated that normal and TAO orbital fibroblasts express CD40 mRNA constitutively, and the intensity of the bands suggests that the amount of steady-state CD40 mRNA is elevated in the IFN-γ-treated samples, using β-actin expression as a control. From the results shown and multiple repetitions of this experiment, it does not appear that there is a significant difference in the level of CD40 mRNA expression between normal and TAO orbital fibroblasts, under control or IFN-γ-treated conditions.
Surface expression of CD40 and HLA-DR by normal and TAO orbital fibroblasts.
The next step in the analysis of CD40 expression by normal and TAO orbital fibroblasts was to verify the findings regarding expression of CD40 mRNA by flow cytometric detection of basal and IFN-γ-induced surface CD40 protein expression. Fibroblasts were cultured in the presence or absence of IFN-γ for 72 h and then stained with a monoclonal antibody specific for CD40. Histograms showing background staining (control) and CD40 expression by untreated and IFN-γ-treated normal orbital fibroblasts are presented in Fig.2 A. The log fluorescence intensity of staining is plotted vs. cell number for each sample analyzed. CD40 is constitutively expressed on the surface of the fibroblasts compared with background staining profiles. Stimulation with IFN-γ results in a dramatic 10-fold increase in the expression of CD40 on normal orbital fibroblasts. Figure2 B shows the flow cytometry histograms obtained for CD40 staining of TAO orbital fibroblasts treated similarly. TAO fibroblasts also display detectable basal levels of CD40 comparable to those of normal orbital fibroblasts and are also stimulated by IFN-γ to upregulate CD40 expression.
In addition to enhancing CD40 expression, IFN-γ can induce expression of HLA-DR, a human major histocompatibility complex (MHC) class II molecule required for specific engagement and activation of T lymphocytes. IFN-γ is known to upregulate HLA-DR on a variety of cell types including orbital fibroblasts (10). Histograms of HLA-DR expression by normal and TAO orbital fibroblasts, treated without or with IFN-γ, are shown in Fig. 2. Neither fibroblast type expresses HLA-DR in the absence of IFN-γ; however, when stimulated with IFN-γ for 72 h, virtually all cells stained positively.
CD40L triggers mobilization of NF-κB in orbital fibroblasts.
To address whether CD40 on orbital fibroblasts is functional, its signal transduction capacity was investigated. Although little is known about CD40 signaling in nonhematopoietic cell types, CD40 on B lymphocytes is known to mobilize the ubiquitous transcription factor NF-κB (23). Therefore, electrophoretic mobility shift analysis of NF-κB binding activity in nuclear extracts from IFN-γ-treated normal and TAO orbital fibroblasts was performed. The cells were stimulated for 2 h with control insect cell membranes containing GST (control) or insect cell membranes containing human CD40L. Nuclear proteins were extracted from the treated cells, and equivalent amounts of protein were incubated with32P-labeled double-stranded oligonucleotide probe representing the consensus sequence for the NF-κB binding site. An induction of NF-κB binding activity (arrow) was observed after stimulation with CD40L of normal and TAO orbital fibroblasts (Fig. 3). Supershift studies with anti-p65 antisera confirmed that the upper band is a p65-containing NF-κB complex (data not shown). A constitutively shifted lower band was detected in all extracts. This band is a putative p50/p50 homodimer thought to be transcriptionally inactive. The specificity of the protein-DNA complex was confirmed by incubation of the nuclear extract with 200-fold excess unlabeled NF-κB probe before addition of 32P-labeled probe (data not shown). The detected shift in CD40L-treated cells is similar to that seen after treatment with the potent NF-κB-mobilizing agent TNF-α (Fig. 3) (3). Densitometric analysis of the shifted bands vs. the basal level of NF-κB binding activity revealed no significant difference between the normal and TAO fibroblasts (data not shown). These results indicate that orbital fibroblasts, primed with the proinflammatory cytokine IFN-γ to optimize CD40 expression, display functional CD40 molecules on their surface that can be activated with CD40L to translocate NF-κB into the nucleus.
Cross-linking CD40 on orbital fibroblasts activates production of IL-6 and IL-8.
To determine the functional consequence of CD40-mediated signal transduction in the orbital fibroblasts, we investigated IL-6 and IL-8 expression after triggering of CD40 with CD40L. IL-6 and IL-8 are potent proinflammatory cytokines, the promoter regions of which possess NF-κB binding sites. IL-6 is a pleiotropic cytokine, often expressed at high levels at sites of inflammation, and has been shown to be an autocrine growth factor for mouse fibroblasts (11). Confluent monolayers of orbital fibroblasts were pretreated for 72 h in medium alone or with IFN-γ to upregulate surface CD40 expression. The cells were then stimulated for 72 h with fresh medium, control insect cell membranes, or membranes containing human CD40L. Media samples were then harvested for cytokine-specific ELISA. Induction of IL-6 after activation of CD40 in orbital strains from three normal and three TAO tissues (±IFN-γ) is shown in Fig. 4. The concentration of cytokine detected in the conditioned medium was corrected for the background secretion of cytokine observed in untreated fibroblasts. Orbital fibroblasts express low levels of IL-6 and have detectable IL-6 mRNA under basal culture conditions (data not shown). Fibroblasts stimulated with CD40L, without IFN-γ, expressed higher levels of IL-6 than did controls. A far more robust induction of IL-6 production occurred when the fibroblasts were primed with IFN-γ before CD40 engagement (Fig. 4 A). Although levels of IL-6 varied in all six fibroblast strains tested, the pattern of induction remained the same (Fig.4 B).
IL-8 was selected for analysis because it is a chemoattractant agent for human T cells and neutrophils and is released from hematopoietic and nonhematopoietic cells at sites of tissue injury and chronic inflammation (9, 36). IL-8 production after activation of CD40 is shown in Fig. 5. Orbital fibroblasts secrete a low level of IL-8, and IL-8 mRNA can be detected by RT-PCR under basal conditions (data not shown). There was an upregulation of IL-8 in response to CD40L in fibroblasts not primed with IFN-γ. A more dramatic induction of IL-8 occurred when orbital fibroblasts were pretreated with IFN-γ before CD40L stimulation (Fig.5 A). As with IL-6, the pattern of IL-8 induction remained consistent for all six strains tested (Fig.5 B).
A time course from 12 to 72 h was performed for the CD40L-induced secretion of IL-6 and IL-8. Elevated levels of both cytokines were detected as early as 12 h, but maximal cytokine secretion was observed at 72 h (data not shown). These data strongly suggest that IL-6 and IL-8 secretion is not a direct result of the rapid CD40L-induced NF-κB mobilization (Fig. 3). Cytokine synthesis may be a downstream consequence of CD40-mediated activation of orbital fibroblasts.
CD40 has been recently detected on nonlymphoid cells, such as keratinocytes, endothelial cells, and fibroblasts; however, certain primary human fibroblasts, such as those from the skin of the abdominal wall, do not express CD40 (15, 16, 21). Here we have examined the expression of CD40 by orbital fibroblasts. Normal and TAO orbital fibroblasts were found to display this surface antigen. Moreover, CD40 engagement with its natural ligand resulted in the activation of intracellular signaling and a dramatic upregulation of IL-6 and IL-8 expression. We hypothesize that orbital fibroblasts interact with infiltrating T lymphocytes via the CD40-CD40L costimulatory pathway. This in turn promotes fibroblast activation, which can result in the tissue remodeling observed in orbital inflammatory conditions such as TAO.
RT-PCR analysis of total RNA extracted from normal and TAO orbital fibroblasts revealed a detectable basal level of CD40 mRNA expression (Fig. 1). Similar to pulmonary, gingival, and foreskin fibroblasts, there was an apparent increase in the steady-state level of CD40 mRNA when the orbital fibroblasts were stimulated with IFN-γ (12). This finding was confirmed by flow cytometry (Fig. 2). In addition to enhancing CD40 expression, IFN-γ treatment also induced expression of HLA-DR on the orbital fibroblasts. This finding is consistent with our earlier studies (18). Despite being isolated from tissues in two very different states (inflamed vs. noninflamed), the two types of fibroblasts have similar basal levels of CD40 and HLA-DR is absent. Moreover, IFN-γ induces HLA-DR expression and relatively similar levels of CD40. It can therefore be inferred that any increase in surface expression of CD40 and HLA-DR on orbital fibroblasts in situ is not an imprinted characteristic induced by the disease process but, rather, represents a transient activation of these fibroblasts in the setting of an inflammatory mircroenvironment.
Orbital fibroblasts are heterogeneous with respect to expression of the surface antigen Thy-1. Thy-1 is expressed on 54–71% of the cells in primary cultures of orbital fibroblasts, with the remainder of the cells staining negatively (32). This expression profile is stable in culture, and representative clones of orbital fibroblasts can be isolated that faithfully retain Thy-1-positive and Thy-1-negative expression status. Thy-1 heterogeneity indicates a complexity of orbital tissue, which may provide insight into the mechanisms of tissue remodeling associated with inflammatory diseases of the orbit. Interestingly, normal and TAO orbital fibroblasts homogeneously express CD40. This suggests that all fibroblasts in the orbit are capable of receiving and transducing signals via CD40. CD40 expression is therefore not a criterion for rationalizing functional heterogeneity observed in orbital fibroblasts (32). However, CD40-mediated activation may be a key signaling conduit for orbital fibroblasts. The signal may be processed independently or in conjunction with one or more other signals to elicit a desired cellular response. This would then provide a mechanism for fibroblast subpopulations to serve distinct functions in the orbit.
The ubiquitous transcription factor NF-κB has been identified as a major signaling pathway utilized in CD40-mediated events in hematopoietic cells, such as induction of proinflammatory cytokine synthesis (3, 23). Little is known about CD40-mediated cell signal transduction and cellular activation in fibroblasts. It was hypothesized that NF-κB is mobilized after fibroblasts are triggered through CD40. Indeed, we have verified that CD40 engagement of orbital fibroblasts with insect cell membranes containing human CD40L results in the translocation of an NF-κB complex to the cell nucleus. These findings are significant, because nuclear mobilization of NF-κB is a conduit for cellular activation relevant to the transcriptional upregulation of many genes involved in inflammatory and specific immune responses (3).
Our results suggest that the cytokine milieu surrounding the orbital fibroblast in situ may represent a critical determinant of the cellular responses mediated through the CD40-CD40L pathway. Of particular relevance would appear to be the tissue concentration of IFN-γ. This cytokine is known to upregulate cellular adhesion molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, which can promote fibroblast adhesion to T lymphocytes (10, 14, 25). During the inflammation and tissue remodeling associated with TAO, large numbers of infiltrating T lymphocytes have been detected in orbital tissue. In addition, T lymphocytes with cytolytic properties have been isolated from TAO tissue (7, 22). Little is known about the cytokine milieu present in TAO; however, one study demonstrated by immunostaining the presence of IL-1α, TNF-α, and IFN-γ (17). The actual concentrations of these cytokines were not determined. These observations, in conjunction with our results, suggest that an inflammatory environment rich in IFN-γ-producing infiltrating cells, such as T lymphocytes, may provide a priming effect for interstitial fibroblasts and elevate CD40 expression on fibroblasts in inflamed tissue. This might in turn condition the fibroblasts to be hyperresponsive to CD40 engagement and, therefore, result in the amplified induction of proinflammatory cytokines.
IL-6, the human promoter of which contains an identifiable NF-κB site, is of significant interest with regard to TAO. A recent report by Salvi and colleagues (27) demonstrated elevated serum levels of IL-6 in patients with Graves' disease compared with normal subjects. These authors also observed higher levels of serum soluble IL-6 receptor in patients with active inflammatory TAO than in patients with inactive orbital disease. Thus IL-6 may have a pathogenic role in TAO. The degree of T lymphocyte infiltration detected in TAO tissue (7, 30) suggests that a chemoattractant signal for T lymphocytes, such as IL-8, might emanate from orbital cells. We hypothesized that activation of CD40 on orbital fibroblasts may represent an important mechanism for the upregulation of local IL-6 and IL-8 expression in the orbit. Data presented here support this hypothesis by clearly demonstrating that engagement of CD40 on orbital fibroblasts by CD40L results in the induction of IL-6 and IL-8 proteins (Figs. 4 and 5). No difference was observed in the induction of either cytokine in normal and TAO fibroblasts.
Human orbital fibroblasts exhibit a set of phenotypic attributes in culture that distinguish them from many types of extraorbital fibroblasts. They are particularly susceptible to certain actions of proinflammatory cytokines with regard to the induction of plasminogen activator inhibitor type 1 (5, 20, 29), hyaluronan synthesis (31, 33), and the upregulation of prostaglandin endoperoxide H synthase 2 (35). The latter may represent the molecular basis for the intense inflammatory response observed in certain orbital disorders such as TAO (30). It is therefore critical to compare the magnitude of CD40L-dependent cytokine expression in orbital fibroblasts with that in fibroblasts derived from other tissues. Future studies will examine whether CD40 signaling influences the expression of prostaglandin endoperoxide H synthase 2 and the synthetic rate of hyaluronan, independently and in conjunction with proinflammatory cytokines.
In conclusion, data in this report support the hypothesis that the fibroblast CD40 is an important mediator of cognate interactions between infiltrating CD40L-expressing immunocompetent cells and fibroblasts. These interactions may play a pivotal role in regulating normal tissue function and may underlie many aspects of remodeling associated with inflammation in the orbit. Anti-CD40L antibodies have been shown to be effective in preventing the onset of disease in murine models of collagen-induced arthritis, experimental autoimmune encephalomyelitis, and lupus nephritis (8, 24). We propose that strategies utilizing recombinant fusion proteins or monoclonal antibodies, targeting the disruption of the CD40-CD40L interactions between fibroblasts and lymphocytes, may represent powerful therapeutic strategies for TAO and other autoimmune diseases.
We thank Chantal K. Turner for expert technical assistance.
Address for reprint requests: R. P. Phipps, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 704, Rochester, NY 14642.
This work was supported in part by National Institutes of Health Grants CA-11198, DE-11047, AG-56002, EY-08976, EY-11708, and P30-ES-01247, a Merit Review Award from the Department of Veterans Affairs, and the Rochester Area Pepper Center. G. D. Sempowski is supported by National Institute of Dental Research Grant DE-07202.
Present address of G. D. Sempowski: Duke University Medical Center, Box 3258, Durham, NC 27710.
- Copyright © 1998 the American Physiological Society


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I have not posted here in quite a few months but this site has been invaluable to me, so I am hoping for some guidance.
I am still in the divorce process - our temporary orders give him time with the kids every weekend. I do not have a full weekend with them. My grandparents are out of state are very elderly and dying. They want to see their great - grandkids one last time. Taking them to visit means STBXH has to give me permission as it would be during some of his parenting time. I do not have enough consecutive time with them to make a visit without using some of his time. He will not agree. My attorney basically said if he does not agree I will be violating the custody order and he could file contempt on me, so I need to decide if it is worth it. I feel that it is. Is there anything I am missing? Any advice? Thank you so much in advance.
Also a good point to anyone else doing up their agreement; having visitation EVERY weekend can't work; both parents need to have a couple of uninterrupted time with the kids now and then.
I hope you can work it out.
WH says marriage is over: May 15, 2009.
EA#2 July 20, 2009. Legally sep: Aug 16, 2009. DIVORCED!!!! Signed Nov 23, final Dec 24, 2010, adultery listed.
His choice then is not to allow or deny you the time, but choose his option of making up the time.
If he gets ugly and threatens you if you go, then take him to court for his threats and his bullying.
I am sorry. This is an unfortunate situation.
If you are still working on your final orders, save all your emails re: you asking for the time and offering him a full weekend, and his referral. It will show him not willing to work with you, and you offering a good compromise.
I truly hope you don't end up with this schedule forever. Every other day is too hard on you, and on the kids down the road. He will find it doesn't work at some point too; just right now he knows he can hurt you by saying no.
Your parents don't get to tell you what to do. They clearly have NFI about what is at risk here.
Your small children seeing your elderly grandparents one last time is not worth risking losing custody or giving X any sort of advantage.
Custody is permanent. Those kids are your Number One priority and if your parents can't see that then they have rocks in their heads.
He is a piece of shit for doing this but it is a good reminder that they WILL do whatever they CAN do to stick it to us.
I am hoping your permanent orders are not every weekend. My girls are 5.5 and 3 and we have a 2//2/3 schedule which alternates weekends and also allows for all handovers to be done via daycare/school (one drops off on a Mon AM the other picks up after school.
Is it possible for someone in your family to set up the great grandparents with a Skype connection. Then your children could "see" their great grandparents on a regular basis.
I totally agree that your schedule is unworkable. You need to ask your lawyer to ensure your permanent orders are NOT based on these temporary orders. I have never heard of orders which don't ensure vacation time either. Please look into having these essential points changed in the final orders.
We must let go of the life we have planned, so as to accept the one that is waiting for us.

subset: commoncrawl


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4th of July Firework Shows In Lafayette And Acadiana
As the anniversary of our nation's independence nears, cities and towns across Acadiana are preparing for their annual fireworks shows. July 4 is always a fun holiday because it involves BBQ, swimming, socializing, and of course, firework shows. The tents selling fireworks are already set up for areas that allow fireworks, and always remember to practice safe firework handling and watch out for the children.
If your town doesn't allow residents to use fireworks, but you still want to see the explosions in the sky, here is a list of firework shows launching this 4th of July holiday:
Freedom Fest: Red, White, and BOOM
July 4, 2013
412 Travis Street
Lafayette, LA 70503
5:00 p.m.
visit website
Independence Day Celebration
July 3, 2013
101 Waterview Road
Youngsville, LA 70592
5:30 – 9:15p.m. (Fireworks at 9:00p.m.)
visit website
Erath 4th of July Celebration
June 30 – July 4, 2013
400 City Park Drive
Erath, LA 70533
6:00 p.m.
visit website
Erath 4th of July Parade
July 4, 2013
Downtown Erath
9:00 p.m.
New Iberia
Fourth of July Parade
July 4, 2013
East Main Street
New Iberia, LA 70560
6:00 p.m.
Celebration on the Cane- Red, White, and Blue!
July 4, 2013
Church Street
Natchitoches, LA 71457
5:00 p.m. – 9:00 p.m.


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Mixed Response Greets Bills to Amend Election Laws
COMPILED by ALEXANDER NURNBERG
Published: June 29, 2006
A summary of the top stories in Russian newspapers appears Monday through Friday.
Three bills amending the law on how elections are conducted in Russia were passed in their first or second readings by the State Duma, the country's lower house of parliament, on Wednesday.
The first two bills would forbid members of parliament from changing their party allegiance, and remove an effective "none-of-the-above" option on ballot papers, several newspapers reported. Both these bills "target tactics deemed threatening to the Kremlin and the pro-Kremlin United Russia party," the Moscow Times wrote.
The first bill would effectively prevent parties from aligning in a coalition against United Russia, Kommersant said, while the second would hide dissatisfaction from voters with candidates, several newspapers have written.
Izvestia, which is owned by state-controlled Gazprom, noted that the "against all candidates" clause on ballot papers did not exist in "the overwhelming majority of developed countries." In "Austria, Bulgaria, Brazil, Great Britain, Germany, Greece, and Italy," the paper said, those who do not like the candidates running simply do not vote. "They demonstratively do something else drink, let's say, beer or wine and curse their politicians to the high heavens."
According to Kommersant, Vladimir Pligin presented the case against the "none-of-the-above" clause. "He decided not to talk in detail about the bill," the paper wrote, "but it was approved anyway."
The loudest response in national newspapers was prompted by the third bill, however. It bans "extremist" candidates from running in elections. And it broadens the list of criteria defining extremist activity.
According to Rossiskaya Gazeta, the government newspaper, "the authors of this legislative initiative understood: if in region after region displays of extremism and xenophobia are being seen, then the law supposed to act against them is not perfect. And parliamentarians began to improve the law from its very first article."
But several other newspapers echoed Vremya Novostei's assessment that this was the "most anti-democratic" move in the legislative packet. Among the activities now labeled extremism, that paper wrote, is "public defamation of officials read: criticism of the authorities."
The bill was predicted by most papers to be passed, in any event, before the end of the Duma's spring session this year.
Pavel Krasheninnikov, a member of the ruling United Russia party, admitted that there were problems with this bill's wording. Its clause forbidding incitement of religious, national or racial hatred, for example, would strictly turn any "authors of plays or films about Hitler or Mussolini" into extremists, he said.
That said, Gazeta noted, "these observations did not stop Mr. Krasheninnikov from supporting the document" in parliament.
THE HEAT IS WORSE THAN THE COLD: Anatoly Chubais, the head of Russian United Energy Systems, has warned that during the present hot weather in Moscow the city's electricity network is again under threat. In January of this year there were blackouts in parts of Moscow due to temperatures plummeting to minus -20 degrees Fahrenheit or colder, and now, as temperatures in the city have risen into the high '80's, there may be worse "accidents" or even "a full shutdown" in the network. Electricity usage increases during very hot weather, with the use of air conditioners, and though this is still lower than the winter demand caused by heating devices, transformers warm up naturally, and overhead wires sag and sometimes hit trees, causing short circuits that could bring down the whole system.
RUSSIA PLANS TO USE MORE NUCLEAR POWER: A program to increase the use of atomic energy in Russia has been put forward by the country's atomic energy agency, Rosatom, at a time when "the whole world" is considering nuclear power, in the wake of "growing fear about energy security." The program would require "a whole range of new laws to be passed" by parliament, but lawmakers certainly "will pass them, because the president has already signed the proposal." Russia is faced by a gas deficit as soon as 2010, the paper writes, since demand is growing both within the country and for exports at a rate higher than gas can be extracted.
PROTESTING MUSCOVITES LENT GOVERNMENT EAR (PERHAPS) : Homeowners in the Butovo region south of Moscow, who refused to vacate their old wooden houses and be moved into new apartments so that the city government could build high-rises on their land, will "finally" be given a chance to talk to city officials. Over the next four days the authorities will talk personally with every "problematic family," of which there are 71, Deputy Mayor Vladimir Resin said. However, the deputy mayor "does not hide the fact" that luxury private houses will be built in the area, "so that the 'national needs', with which they justified seizing the land, turn out to be pretty doubtful."
G8 FOREIGN MINISTERS ARRIVE: A meeting Thursday between foreign ministers from the Group of Eight industrial nations "will set the tone" for the upcoming summit of world leaders in St. Petersburg this July, the paper said. A "particularly big challenge" will be faced by Secretary of State Condoleezza Rice, the paper writes, in "persuading Russia to step up pressure on Iran while many American officials are criticizing the Kremlin for squeezing democratic reformers at home and tampering in the politics of nearby countries." Relations have been tense between Russia and America since a speech made in Vilnius, Lithuania, by Dick Cheney in May, in which he accused Russia of "intimidation and blackmail" and of backpedaling on democracy.
OPPOSITION PREPARES RIVAL SUMMIT: Opposition leaders will hold a Moscow summit to rival the G8 meeting in St. Petersburg in July, in an attempt to draw the world's attention to what they call "The Other Russia", or "an alternative national viewpoint on everything happening in Russia," as the paper puts it. Garry Kasparov, the former world chess champion and opposition leader, has himself invested in the project, which is otherwise being supported by two foreign funds and donations from private Russian citizens. But "while the opposition is preparing large-scale events, its popularity in society has fallen somewhat," the paper writes. Polls indicate that only 56 percent of Russians believe that the country ought to have any political opposition at all.


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Richard Broersma Jr wrote: >> Please change the field name of B.ctid from hasbandctid to ctid. >> The name should be "ctid" for the driver to detect the field is for versioning. >> A.ctid isn't needed. > > It works now! However, I have a question. If I have a view with more than two joined tables will > i need to reference the ctid from each table after the first update statement? The ctid of the target table of the rule's last statement should be referenced. For example, in your case the command UPDATE "public"."vhusband" SET "name"=E'hello44',"tiesize"=52 WHERE "id" = 10 AND "ctid" = E'(0,47)' is issued by MS Access. The where condition "id" = 10 AND "ctid" = E'(0,47)' is added to each statment in the rule when the command is executed. So it's very siginificant that the contents of "id" and "ctid" are not changed until the last statement is called. Please note that the ctid field is modified autmatically when the table is updated. regards, Hiroshi Inoue
Next: From: Hiroshi Inoue Date: 2006-12-12 03:41:44 Subject: Re: Update-able View linked to Access Previous: From: Richard Broersma Jr Date: 2006-12-12 01:34:50 Subject: Re: Update-able View linked to Access


text: RT Book, Whole DB /z-wcorg/ DS http://worldcat.org ID 28089903 LA English T1 To the people of the United States : the Executive Committee of the New England Emigrant Aid Company respectfully ask your attention to the following facts ... A1 New England Emigrant Aid Company., Executive Committee., PB Buell & Blanchard, printers PP Washington, D.C. YR 1856 AB A report to the Senate of the United States by the Chairman of the Committee on Teritories on March 12, 1856, contained many errors and misrepresentations and this open letter denied publically those errors by stating the position and work of the New England Emigrant Aid Company. The text is similar to "To the honorable Senate of the United States" and "To the people of Missouri" by the same group. It was signed by William B. Spooner, J.M.S. Williams, Eli Thayer, S. Cabot, Jr., R.P. Waters, L.B. Russell, C.J. Higginson, and Edward E. Hale.


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Buy San Francisco 49ers tickets online by selecting the event from the San Francisco 49ers schedule below. At our website you'll find great deals for sold out and premium tickets for San Francisco 49ers events as well as event schedules and information. Should you have any questions about ordering tickets to San Francisco 49ers , please don't hesitate to contact us.
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Peter New
Location: New York, New York
Member since 2/24/2012
- 2 total posts
- 1 comment
- 1 question
Questions from Peter New
How Do People Get Multiple Sessions with Fraxel Dual?
How can people possibly do multiple sessions of Fraxel Dual? I did 1 session and the whole 7-10day process was more than I can possibly imagine to deal with. I have not seen... READ MORE
Recent comments from Peter New
Any updates on the progress recovery? Before or after pictures? READ COMMENT


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ANKARA Turkey (Dec. 15)
The Palestine problem must be solved "with justice and according to United Nations resolutions," and Communist subversion in the Middle East must be combatted if peace and stability are to be restored to the region, Turkish Foreign Minister Fatin Rustu Zorlu told newsmen here this week-end before emplaning for the NATO conference in Paris.
It is obvious, Mr. Zorlu said, that these "two dangers now threatening the Middle East are directly and indirectly linked to each other." He expected the issue to be discussed at the parley.
(In Ottawa, Prime Minister John Diefenbaker told Parliament yesterday that the Arab-Israel dispute will be examined at the NATO summit meeting.)


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Time: January 9, 2010 from 1pm to 4pm
Location: The Buckeye Tavern
Street: 3741 Brookside Road
City/Town: Macungie, Pa. 18062
Website or Map: http://BuckeyeTavern.com
Phone: 610-966-2506
Event Type: emergency, meeting, &, luncheon
Organized By: SACC-Smart Alecs Car Club of the Lehigh Valley
Latest Activity: Jan 5, 2010
We are calling this meeting to address the problem of our dealership in Devon Pa. closing.We have 50 Smart Alecs and probably another 15 Smarts in the Lehigh Valley. We now have to go to N.J. for service. we must get the attention of the Penske Group to rectify this problem.We will discuss what direction we will take to deal with being abandoned by Smart. All concerned Smarties welcome, for info. contact


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2008-07-17 / Top News
Commissioner to retire early; special election to be held
MONTEREY - Following a series of publicized criticism about her job performance, Highland's commissioner of revenue Bobbie Griffin announced Monday she intends to retire Sept. 1, more than three years before the end of her second term in office.
You must be an online subscriber to view this story.
Full versions of news stories from the current issue and our extensive archives are available to online subscribers only. You can buy single issues from the link below.


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Kristen Stewart's 'Twilight' Premiere Looks
From debuting on the "Twilight" red carpet in 2008 in a cute and edgy Balenciaga dress to looking glam from head to toe in a sparkling blue J. Mendel gown in 2011, it could be nearly impossible for Kristen Stewart to outdo herself at Monday's "Breaking Dawn - Part 2" premiere.
She's worn classic designers, including Oscar de la Renta, but Stewart also likes to test out newer designers, like Stella McCartney and even Victoria Beckham -- whose orange shift dress she wore recently on "Live with Kelly and Michael."
When it comes to those "Twilight" world premieres ("Twilight"'s version of the prom), Stewart has historically gotten decked out with the rest of the cast and has arguably never made a fashion faux pas.
As it appears, Stewart has favored Balenciaga over the years -- and now has her own fragrance with the fashion house. She does like to mix it up, but if any one designer has the advantage to dress her for the premiere, Balenciaga is it.
No matter who she's wearing -- or how she's smelling -- it's probably safe to predict the 22-year-old actress will be turning heads as she makes her last turn on the "Twilight" red carpet on Monday.
[Related: Take the 'Twilight' Ultimate Fan Poll]
"The Twilight Saga: Breaking Dawn — Part 2" opens in theaters November 16. Yahoo! Movies is live-streaming the red carpet premiere on Monday November 12 at 7:30 p.m. ET/ 4:30 p.m. PT. The online event will incorporate fan participation through Yahoo! Movies' various social media sites, including Facebook and Twitter.
Watch Stewart, Pattinson and the rest of the 'Twilight' gang talk to Yahoo! Movies about 'Breaking Dawn - Part 2':
Insider Access: 'Twilight' Cast Talk 'Breaking Dawn - Part 2'


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A pervert who made lewd comments to a woman and touched himself on a train is wanted by the police.
The man sat opposite a woman in her 30s on a train from Enfield Chase to Hornsey on Wednesday, May 21, and began to touch himself inappropriately and shout insults at the woman as she got off the train.
The incident took place between 2.30pm and 3pm.
British Transport Police have identified a man on CCTV footage and are appealing for any information into the incident.
PC Ruth Taylor, who is investigating, said: "As well as being completely inappropriate, this behaviour was hugely intimidating for the victim. Everyone should be able to travel on the rail network without fear of becoming a victim of any offensive behaviour, including that of a sexual nature.
"We take sexual offences on trains, Tubes and at stations very seriously, and I would encourage anyone who has experienced or witnessed anything similar to follow this woman's brave example by reporting it.
"The man was also seen touching himself inappropriately and began shouting insults at the woman, as she left the train at Hornsey station."


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To celebrate the start of the men's and women's college basketball tournament, appliance and electronics retailer Hhgregg is kicking off its March into Hhgregg event,"which will award more than $50,000 in prizes from LG Electronics.
From now through April 7, Hhgregg shoppers can enter daily online, via smartphone, on Facebook and in-store. Winners will be selected instantly, weekly, and one grand prize winner will be selected on April 8.
To promote the giveaway, Hhgregg teamed up with YouTube sensation and Frisbee trick shot master Brodie Smith and Butler University mascot Blue III at Hinkle Fieldhouse. To see the video and learn more about the promotion, visit hhgregg.com/March.
"This tournament is one of the biggest events of the year, so we want to give our customers the chance to win the latest technology in televisions and appliances from LG," said Julie Lyle, chief marketing officer. "The online and in-store entries for this giveaway allow customers to enter at the place and time that is most convenient for them, while giving us the chance to interact with our customers in-person and online."
The grand prize winner will receive a package from LG worth more than $18,000, including a 55" 1080p OLED Smart 3D TV, a 3D Smart Blu-ray player, a stainless steel kitchen suite including a French door refrigerator, double oven gas range, dishwasher and microwave and a front-load washer/dryer pair. Also, more than 45 prizes of televisions and appliances will be awarded to online winners.
In-store associates will also be awarding instant prizes to customers including Blu-ray players, Hhgregg $100 gift cards, big screen TVs and more. To enter, customers can visit the nearest Hhgregg store and chat with an associate about the latest LG televisions and appliances. The associate will then award customers with a game card to enter online to win.


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Minneapolis, Minnesota-based metallers SEVENTH CALLING have lined up the following dates:Sep. 24 - Backstage Lounge - Gainesville, FL
Sep. 25 - Club Underground - Jacksonville, FL
Sep. 26 - State Theatre - Tampa, FL
Nov. 06 - Dingbatz - Clifton, NJ
Nov. 07 - The Haunt - Yonkers, NY
Nov. 08 - Sterling Hotel - Allentown, PA SEVENTH CALLING is currently recording its sophomore album, "Deliverance". This follows up the group's Melissa Records debut entitled "Monuments" which was released 2007. Some of the new material can be found at the group's official MySpace page. These recordings are the first to feature the current SEVENTH CALLING lineup, which consists of the following:
Steve Handel - Lead Vocals, Guitar
Jamie Strobach - Drums
Michael Poplees - Bass Guitar
Alex Ritchey - Lead Guitar


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What is Labiaplasty?
Doctor Answers 26
What is a Labiaplasty
Labiaplasty is a procedure to help improve the aesthetic appearance of the external genitalia. This area is typically comprised of the clitoral hood, labia majora, and labia minora. A labiaplasty refers to improvement in the size and appearance of the labia minora, which can become darkened, enlarged, and sagging from pregnancy or a number of other reasons. A labiaplasty can remove the darkened folds and excess labia minora to help create a more symmetric cleaner appearance of your external genitalia. When we consult with patients for labiaplasty in our Jacksonville plastic surgery practice, we ask patients to demonstrate the specifics of what they desire to be improved. We then create a customized surgical plan to help them achieve the look and feel of what they hope to achieve with labiaplasty surgery.
Results of Labiaplasty
When referring to labiaplasty, I am discussing labia minora reductions.
Our first priority is to have a woman express her desires and aesthetic as well as her functional goals in the course of the intial consultation.
We ask patients to show us their areas of concern by using a mirror with a Q-tip as a pointer, to indicate their desired results.
I then review the surgical options, explain any particular aspects which cannot be performed, and then discuss reasonable expectations.
Labia are rarely symmetric. Our overall goal in treating asymmetry is to diminish the disparity between the two sides. Not all aspects of the labia can be corrected to achieve symmetry, this includes qualities such as size, shape, color, texture, thickness, projection, etc.
Results of labiaplasty are specific to the individual anatomy of a patient's labia minora
The labia minora and labia majora comprise the external anatomy of the female genital area.
In some cases, the labia minora may be large and stretched as a result of normal development, labor, or age. In this case, a labiaplasty is performed to reduce the size of the labia in order to acheive a more suitable shape and dimension of this very important part of a female body.
There are three important goals to surgery:
- Maintaining sensitivity in the area
- Acheiving beautiful aesthetic form
- Reducing the labia minora without causing the function of the labia minora to diminish, namely, keeping the vagina and introitus moist.
For questions about the procedure, speak to a board certified plastic surgeon.
You might also like...
It is important to discuss these questions with your provider and find a board certified plastic surgeon.
In my San Francisco area practice we perform labiaplasties typically under local anesthesia and conscious sedation. The procedure is relatively short and patients have little post-operative discomfort.
There are dissolving sutures left in place and the incisions heal quite quickly. Patients typically are back to their routine (including sexual intercourse) at 3-4 weeks.
I hope this helps.
You should expect to look better with very little discomfort
Labiaplasty is surgery on the labia minora (inner lips) and/or labia majora (outer lips). This surgery helps reduce the size and improve the appearance of the labia. It also can remove excess skin from around your clitoris which may help with sexual satisfaction. In addition to this, a vaginoplasty can be done where the entrance to the vagina is tightened. Adjunct procedures can be added such as g-spot injections to help achieve orgasm.
Because so much of sexual satisfaction is tied up in how we feel about ourselves and our bodies, this surgery not only makes you look better, but also feel better about your body.
Patients in my practice say that the recovery is easy with very little pain. People are back to work in two days without difficulty.
In my practice, we work with a Gynecological surgeon to address other issues as well, such as stress incontinence and vaginal prolapse.
All this is done in our office facility, which is AAAASF approved.
What is Labiaplasty?
Enlarged or protruding labia minor (inner vaginal lips) is a common problem and concern for women. They can occur for a number of reasons including increasing age, childbirth or often just naturally. Enlagred labia can be the cause of concern for many women as they can experience pain, discomfort, humiliation and hygiene problems. Labia reduction surgery, or labiaplasty, can alleviate these problems. During this procedure excess tissue of the labia minora is trimmed down to a more aesthetically pleasing and functional size.
Women usually return to work and normal activities within 2- 5 days, while more strenuous activities will take about 3 weeks.
Learn more: http://www.drdonaplasticsurgery.com.au/body/vaginal-rejuvenation-surgery-sydney/
Labiaplasty, plastic surgery on the labia, can be performed alone or with vaginoplasty. Surgery can be performed on the labia major, or the labia minor. Labiaplasty changes the size or shape of the labia, typically making them smaller or correcting an asymmetry between them. Hope this was helpful, best of luck!
Dhaval M. Patel
Double board certified
Plastic surgeon
Hoffman Estates
Labiaplasty surgery
Learn more: https://www.austinurogynecology.com/labiaplasty/
What is Labiaplasty?
Learn more: http://drmathewplant.com/labiaplasty-toronto/
Labiaplasty Explanation and Video
The term vaginal rejuvenation is a broad term that can be used to encompass several procedures with the overall goal of improving the appearance of the vaginal area.
The most common method for rejuvenation is trimming the labia minora (inner lips) this will remove the excess skin that may hang below the vagina.
The second method is fat grafting to the labia majora (outer lips) this will add volume to the area and improve the deflated appearance that women can have after having children or after weight loss.
The two methods can be done together to give the patient the best overall aesthetic result.
The cost depends on which of these procedures is performed and whether the procedure is performed under local anesthesia or with some type of anesthesia.
I would recommend that you consult your board certified plastic surgeon so that you can be evaluated and discuss your options.
Learn more: http://www.miamiplasticsurgery.com/plastic-surgeons-miami-fl/physicians-profiles-drfranco.html
These answers are for educational purposes and should not be relied upon as a substitute for medical advice you may receive from your physician. If you have a medical emergency, please call 911. These answers do not constitute or initiate a patient/doctor relationship.


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Regime shifts in European real interest rates
No abstract is available for this item.
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As the access to this document is restricted, you may want to look for a different version under "Related research" (further below) or search for a different version of it.
Volume (Year): 139 (2003)
Issue (Month): 1 (March)
Pages: 66-81
|Contact details of provider:
| Web page: http://www.springer.com
Postal:Kiellinie 66, D-24105 Kiel
Phone: +49 431 8814-1
Fax: +49 431 8814528
Web page: https://www.ifw-kiel.de/
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|Web: http://www.springer.com/economics/international+economics/journal/10290/PS2
References listed on IDEAS
Please report citation or reference errors to , or , if you are the registered author of the cited work, log in to your RePEc Author Service profile, click on "citations" and make appropriate adjustments.:
- Rose, Andrew Kenan, 1988. " Is the Real Interest Rate Stable?," Journal of Finance, American Finance Association, vol. 43(5), pages 1095-1112, December.
- Fama, Eugene F, 1975. "Short-Term Interest Rates as Predictors of Inflation," American Economic Review, American Economic Association, vol. 65(3), pages 269-282, June.
- Robert B. Davies, 2002. "Hypothesis testing when a nuisance parameter is present only under the alternative: Linear model case," Biometrika, Biometrika Trust, vol. 89(2), pages 484-489, June.
- Hamilton, James D, 1989. "A New Approach to the Economic Analysis of Nonstationary Time Series and the Business Cycle," Econometrica, Econometric Society, vol. 57(2), pages 357-384, March.
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Does your congregation want to share details about a Sunday service, fundraiser or special event? Send details to firstname.lastname@example.com and include the time, date, location and contact information with each entry.
Martial arts classes
What: Sword of the Spirit Christian Ministries practices the team martial art of Tabikap. Group membership is free and Sword of the Spirit Christian Ministries encourages all above the age of 12 to participate.
When: Saturdays at 10 a.m.
Where: 27150 Bouquet Canyon Road, Santa Clarita, CA 91350
Contact: www.sotscm.org/ or email Jeremy Meagher at email@example.com
Lutheran sermon series
What: Bethlehem Lutheran Ministries continues a six-week sermon series by Pastor John Koczman. The sermon, "Seeking Shelter," is a fresh look at the 23rd Psalm.
When: 8, 9:30 and 11 a.m. Sundays through Feb. 26
Where: 27265 Luther Drive, Canyon Country 91351
Contact: www.followthestar.com
Santa Clarita Church of Christ
What: The Church of Christ hosts its Sunday service. All are welcome.
When: 10 a.m. Sundays
Where: Rancho Pico Junior High School, 26250 W.Valencia Boulevard Valencia 91381
Contact: www.scvcoc.com
Unitarian service
What: The Rev. Stefanie Etzbach-Dale leads the congregation's 10th anniversary celebration by looking at the milestones, challenges and achievements in its journey.
When: 10:30 a.m. Sunday
Where: SCV Senior Center, 22900 Market St., Newhall 91329
Contact: uuofscv.org
Methodist Bible study
What: Santa Clarita United Methodist Church hosts its weekly lectionary Bible study, during which church members and visitors can read the Scripture in preparation for Sunday worship. Visitors welcome.
When: 8 a.m. Sundays
Where: Santa Clarita United Methodist Church, 26640 Bouquet Canyon Road, Saugus 91350
Contact: (661) 297-3783 or www.scumc.org
Methodist service
What: Pastor Stan Fix preaches "Pre-Game Analysis" based on Jeremiah 12:1, 2, 5; Corinthians 9:24-27. Holy Communion will be served. All are welcome and congregants are encouraged to donate canned soup for local food pantries.
When: 10 a.m. Sunday
Where: Friendly Valley Community Church (United Methodist), 19246 Ave. of the Oaks, Newhall 91321
Contact: (661) 251-1311
NorthPark couples program
What: NorthPark Community Church hosts "Couple's Garden," a mid-week program to help spouses connect and improve their relationships.
When: 6:45-8 p.m. on Feb. 8, 15 and 29
Where: 28310 Kelly Johnson Parkway, Valencia 91355
Contact: northpark.com
Presbyterian service
What: The First Presbyterian Church of Newhall hosts a kickoff Super Bowl Sunday with the traditional singing of "Drop kick me Jesus the the goal post of Life." Singing to be followed by sermon, "Thinking Clearly...about Spiritual Growth."
When: 9 a.m. and 10:45 a.m. on Feb. 5
Where: First Presbyterian Church of Newhall, 24317 Newhall Ave, Newhall 91351
Contact: Presby-
Interdenominational Bible study
What: Joy of Living Bible Study is an evangelical and interdenominational Bible study for women. All are welcome to join women in an interdenominational, in-depth study of God's word in an informal, small-group setting. Child care available.
When: 9:30-11:30 a.m. Wednesdays
Where: Grace Baptist Church, 22833 Copperhill Drive, Santa Clarita 91350
Contact: Fran Padgett at (661) 254-1039 or email@example.com
Lutheran Bible study
What: Bethlehem Lutheran Church hosts "Meals That Matters," a weekly family Bible study group. Appropriate for all ages. Child care is provided.
When: Meal at 6 p.m. and Bible study at 7 p.m.
Where: 27265 Luther Drive, Canyon Country 91351
Contact: www.follow
Church programs
What: Open Door Ministries launches its new programs. The church is sponsored by the Evangelical Lutheran Church in America and supported by the Episcopal and United Methodist churches.
When: Thursdays: noon Bible study with topic "How the Bible came to be"; 1:30 p.m. pain management support group; 2:45 p.m. Prayer and Healing Ministry with Pastor Christine Buma; 3:30 p.m. intergenerational choir with musician Tommy Osuna; Sunday worships at 10:45 a.m.
Where: 3808 Mt. Pinos Way, Frazier Park 93225
Contact: (661) 242-3667 or email@example.com
Episcopal book group
What: St. Stephen's Episcopal Church hosts a series of book discussions on C.S. Lewis' "The Four Loves." Free, open to everyone and no reservation is required.
When: 9-9:50 a.m. on Feb. 12 and 19 and 7 p.m. on Feb. 15
Where: St. Stephen's Upstairs Lounge, 24901 Orchard Village Road, Santa Clarita 91350
Contact: (661) 259-7307
Blood drive
What: The Unity Center of Santa Clarita Mosque and the First Presbyterian Church of Newhall sponsor a blood drive to benefit the American Red Cross.
When: 10 a.m. to 4 p.m. on Feb. 26
Where: Mobile blood drive vehicle, 24352 Walnut St., Newhall 91321
Contact: Jamshed Yazdani at (661) 259-8009; Carole Wheeler at First Presbyterian (661) 259-4615


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Aiming to tap the vast market of small to midsize businesses, software maker Peregrine Systems on Monday said it has agreed to acquire software provider Remedy in a deal valued at around $1.08 billion in cash and stock.
San Diego, Calif.-based Peregrine provides inventory management and purchasing software intended to help companies manage systems such as information technology, telecommunications and transportation fleets. The company, which also provides software for corporate help desks, said it plans to fold Remedy's core line of CRM (customer relationship management) software and other products into its own, in an effort to sell customers a broader application suite. --Melanie Austria Farmer, Special to ZDNet News


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Russell US Equity Index Series
Leading US equity benchmarks for institutional investors
A trusted index data set that segments the market for academic integrity and usability. Since their launch in 1984, the Russell US Equity Index family — which includes the Russell 1000, Russell 2000 and Russell 3000 Indexes as well as their growth/value style components — has been widely adopted by institutional investors for their straightforward methodology.
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- Quarterly Report: Russell 2000 – Small Cap Perspectives
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Six months later, what did we learn from the oil disaster in the Gulf?, CNN, October 19, 2010:
It was May when a fishing boat carrying Ed Overton and other scientists pulled away from what would become the largest accidental oil spill in history. The ocean was soupy and brown. The air tasted like gas. Some reporters looked green in the face. The oil stretched nearly from horizon to horizon.
Overton, sitting on a beanbag in the back of the boat, was upset. ... But, even then, Overton saw a sparkle in the muck:
Maybe we all will learn something from this experience, he said. ...
"It's a staggering amount of money that this thing is going to end up costing BP," he said, "so I think everybody has learned their lesson pretty strongly."
'Slime highway' of BP oil suspected on Gulf floor, MSNBC, September 13, 2010:
Ed Overton, a Louisiana State University chemist who has analyzed the spill for NOAA...


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Today there is a bit more news on the 500 ducks killed at a Syncrude tailings pond in Alberta. This is not the first such incident. Researchers with the Boreal Songbird Initiative have recorded many bird deaths in tailings ponds over the past 30 years.
-At least 15 species of waterfowl have already been documented as having been killed on Syncrude Tar Sands tailings ponds along with an amazing 22 species of non-waterfowl.The duck deaths are a major embarrassment and potential legal liability for Syncrude and other companies invested in boreal tar sands mining. Even before the incident, tar sands lobbyists had been trying to overturn a recent provision in U.S. law that forbid the use of liquid fuels with a higher carbon lifecycle than conventional gas. Canadian government ministers have been trying to reassure the Canadian and American publics that they are investigating the incident very seriously despite Syncrude's public apology.
-Research at tailings ponds in the late 1970's based on once a week surveys of two Syncrude tailings ponds observed at least 100-300 birds killed annually. Since this was based only on birds observed floating or on the sides of the ponds once a week there was clearly a larger number of birds that sunk or were unobservable so these numbers represent a minimum mortality from only two tailings ponds.
-At single tailings pond sites, research has documented tens of thousands of waterfowl and other wetland-dependent birds migrating over in periods of weeks during spring and fall migration.
-Based on research at the Alberta tar sands tailings ponds it is well documented that birds are most likely to land on the ponds at night, under weather conditions that restrict visiblity and when surrounding natural lakes and ponds are frozen under such conditions there is a very high risk of large numbers of casualties because waterfowl and shorebirds and other wetland dependent birds normally travel in flocks that can regularly number into the hundreds and sometimes into the thousands or tens of thousands. The conditions under which these large mortality events are likely to occur are also periods when it is unlikely that the ponds are monitored in order to observe mortality events. Because of this it is highly likely that mortality events like this may have occurred more frequently than reported.


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Otolaryngologists, often referred to as ear, nose, throat (ENT) physicians, diagnose and treat diseases and disorders of the ear, nose and throat, plus related parts of the head and neck, including the sinuses, mouth, voice box (larynx) and the soft tissues of the neck.
Whether you're looking to battle a balance disorder, having trouble hearing, or simply sick of seasonal allergies, the ENT specialists at Good Shepherd Medical Associates can help you or your family with treatment for many conditions.
View All Specialties and Services
You are leaving the www.goodshepherdhealthsystem.com website. GSHS provided this link for your convenience and is not responsible for the content, links, privacy or security of information on non-GSHS sites.


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Can't be Hindu or Muslim nationalist: J-K court
Gujarat chief minister Narendra Modi's remark that he was a 'Hindu nationalist' had stirred a debate earlier this year, but the Jammu and Kashmir HC has ruled that any person claiming affiliation with any form of religious nationalism shall be barred from contesting elections.india Updated: Oct 12, 2013 02:18 IST
BJP prime ministerial candidate Narendra Modi's remark that he was a 'Hindu nationalist' stirred a debate earlier this year, but the Jammu and Kashmir high court has ruled that any person claiming affiliation with any form of religious nationalism shall be barred from contesting elections.
"In our constitutional scheme, a citizen of India is only an Indian. No person can claim himself to be a Hindu nationalist, Muslim nationalist, Sikh nationalist, Buddhist nationalist or a Christian nationalist," justice Muzaffar Hussain Attar said in the ruling on Thursday.
"The constitutional provision is loud and clear (about it) and in unambiguous terms forbids using such expression," he added.
Justice Attar said a very serious and potential threat is posed to the very existence of the idea of India by "the fringe elements, who take cover under various types of 'isms' other than Indianism".
Attar's observation came while hearing a petition filed by Sanjay Tickoo, president of the Kashmiri Pandit Sangarsh Samiti (KPSS), a body of Kashmiri Pandits who stayed back in the valley in the face of armed rebellion in 1990s.
Tickoo had moved a petition on safeguarding the Hindu temples in the valley saying "the 'secular' character of the Constitution would require the state and its authorities to protect the religious places".
The petition said some non-Kashmiri Mahants had illegally allowed use of religious properties for commercial purposes and sought action against them.
The judge has directed the chief secretary "to take all required steps in accordance with law for protection of religious places of Hindus."
Earlier this year, Modi described himself as a 'Hindu nationalist' because he was a born Hindu.
"I am a nationalist. I'm patriotic. Nothing is wrong. I am born Hindu. Nothing is wrong. So I'm a Hindu nationalist," he said in Gujarat in July this year during an interview with an international news agency. His remarks ruffled many a feather.
However, justice Attar said, "A person, who persists in use of such expression/s and, in fact, believes in such a thought, has to be dealt with according to constitutional mandate and other laws of the land."


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PS I Love Music
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Mead's developed energy policy over two yearsMay 14, 2013 By Mead Gruver, The Associated Press
Among other things, it recommends creation of an "energy campus" in which different fuel sources could be blended in production.
CHEYENNE -- Gov. Matt Mead on Monday unveiled a state energy policy two years in the making that calls for maintaining Wyoming's position as the top energy-exporting state while preserving its wild, scenic and pristine landscapes.
Mead's report outlines four priorities: Economic competitiveness, efficient regulation, natural resource conservation and developing new technologies.
Lack of a national energy policy, Mead said, inspired him to develop the state policy. At least a dozen agencies play a role in federal energy development oversight, the 63-page report pointed out.
"Before we started throwing stones about that, I started thinking we in Wyoming needed to have an energy strategy," Mead said. "We hope they can take a cue from us."
Wyoming's coal, oil, natural gas, wind and uranium industries make it the second-leading state, after Texas, for total energy production. As the least-populated state, Wyoming exports more energy than any other, including Texas.
Specifics of the state policy include requiring baseline groundwater testing before oil or gas drilling occurs, something long sought by environmental groups. Such testing would seek to avoid inconclusive finger-pointing about groundwater contamination that occurs near petroleum development, as has been the story for more than five years with pollution in the Pavillion area.
Mead's policy also calls for Wyoming to promote development of liquid natural gas for export as well as compressed natural gas to power vehicles.
Wyoming will encourage creating a statewide network of pipelines to carry carbon dioxide to boost pressure -- and production -- in aging oil fields. Developing "hybrid" industrial sites is another goal.
"This might mean combining coal, natural gas and wind in a large energy campus to produce liquid fuels, chemicals and power," the report said. "In the long-term, small, modular nuclear plants could be part of this value-added conversion process."
Wyoming will continue to assert influence over managing potentially threatened or endangered species, such as sage grouse, that could get in the way of energy development if they ever came under federal protection.


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Best copycat martini recipes
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party this year. We scoured the best looking recipes from throughout the web and various
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Starbucks Frappuccino recipe from GroupRecipes.com. I have a series of drinks and desserts of your favorite Starbucks items.
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In a poll released by Rice University on Thursday, Annise Parker pulled further ahead of her opponent, Gene Locke.
The Houston Chronicle reports, "A Rice University survey released Thursday and conducted Dec. 7-9, showed Parker leading with 49 percent of the vote compared to 36 percent for Locke."
A Zogby poll released earlier in the week gave her a 5 point lead. Three other earlier polls also have given Parker the lead. She was endorsed by The Houston Chronicle.
Dallas Voice coverage of the election will continue through election night. I will be heading down to Houston in the morning and reporting live from the George Brown Convention Center with all the latest election results and pictures and quotes from the Parker election party.


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The King's Arms
Bexhill Road, Ninfield, Battle, East Sussex, TN33 9JB
Bexhill Road, Ninfield, Battle, East Sussex, TN33 9JB
At The King's Arms in Battle, the day's first meal is now bigger and better value than ever.
For just £4.29, you can eat as much as you like with our unlimited cooked breakfast. Just grab a plate and feast on these hunger-banishing favourites:
Plus, for just £1.69 extra you can help yourself to unlimited tea and Fairtrade filter coffee.
Full details of our unlimited breakfast and other brilliant brekkies are on our breakfast page. We serve breakfast from 8am - 11.30am, Monday to Sunday, so visit soon and fuel up for the day ahead.


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Results 11 to 13 of 13
September 17th, 2013 09:18 PM #11
My take on it would be, combine the 3 boys in the master if it's the biggest room (unless it's some sort of fancy master suite I don't think it matters in the least what you call the room, lol, people can get really touchy about silly things like that though). You guys would go in the second biggest room and the twins would get the small room.
Over the next 4-5 years work on setting up the attic as a room. Then the 2 oldest would be in one room, next 2 boys would get second room, girl would get the small room, and you two would have the last room (which room who takes I'd imagine would depend on your needs at the time, but I suppose the oldest boys would get the attic and you'd get the master back).
When to separate them I think will depend on their personalities. I don't think I'd have them share past about 8 years old, but if they love sharing then you could extend it past 4 or 5.
As for decorating a b/g twin nursery, I think there's a lot of options depending on what you like.
Personally, I'd probably do a chair rail with a coral color on top and robin's egg blue or bright sage green on the bottom (with pops of yellow). Then you could do maybe an animal theme--like circus or zoo.
Last edited by kala_way; September 17th, 2013 at 09:23 PM.Top Names: Benedict Calvin & Noelle Geneva
Olivia/Livy : Darah/Bethel : Eve/Verity
Eli/Solomon : Luke/Zane: Levi/Phineas
Due in January!
October 17th, 2013 08:09 PM #13Mom of James Daniel (13) William Joseph (12), Elise Marie (10), Zachary Allan (4), and George Thomas (2)
http://letterstoauntkay.com/ [making the blog private; PM me to subscribe]
TTC mid 2018? Or adopt?
Audrey; Rose; Patricia 'Patsy'; Vera Colette; Sylvia Amy; Mary Kathleen; Linnea "Lindy"; Anna; Tabitha; Caroline; Adele; Dahlia; Ida; Celia; Rosemary Laura; Rosalind, Bridget; Sally; Serena/Seri/Sarah; India
Calvin; Franklin; Adam; David; Theodore Maxwell; Henry
November 17th, 2013 09:24 PM #15Senior Member
- Join Date
- Jul 2009
- Location
- Ontario Canada
- Posts
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It seems a straightforward assignment for Kinsey: baby-sit Reba until she settles in, make sure she follows all the rules of her parole. Maybe all of a week's work. Nothing untoward, the woman seems remorseful and friendly. And the money is good. But life is never that simple, and Reba is out of prison less than 24 hours when one of her old crowd comes circling around.
Readers have come to expect the unexpected from Sue Grafton, and R is for Ricochet is no exception. In it, a complex and clever money-laundering scheme is just a cover for a novel that is all about love: love gone wrong, love betrayed, love denied. And love avenged. For Reba Lafferty, its moral is clear: Sometimes what you hand out in life comes back to bite you in the ass. Sometimes the good guys win, even when they lose.
Don't miss the other titles in the Kinsey Millhone Alphabet Mystery Series.
©2004 Sue Grafton; (P)2004 Random House, Inc. Random House Audio, a division of Random House, Inc.
"Sexy adventure....Grafton as usual creates believable and enduring characters and a strong sense of place in her town of Santa Teresa circa 1987." (Publishers Weekly)
"Fun to listen on a trip. Nothing earthshattering."
It was entertaining while driving.
V is for vengeance.
Very similar.
It was to Austin and back.
This is the kind of book that is interesting and entertaining when you are on a drive. No deep inner meaning or guide to the meaning of life, but a good distraction while driving. It's a good story and keeps your attention while the miles pass. I had 30 minutes left when I got home and made time to finish the book that day.
"A fun book."
Judy Kaye does a great job of reading this story. Her voice, and inflections, as with the other Sue Grafton books make them a joy to listen to. This book follows in the tradition of Grafton?s other ?alphabet books?, they are fun, entertaining and a good balance of adventure and a continuing soap opera of Kinsey?s life. I enjoy listening to these as I drive to eat up the miles. This book is a bit more sexual than I remember the others and there are a few moments that if you have little kids in the car, that might not be appropriate. Overall a good choice to purchase.
Report Inappropriate Content
If you find this review inappropriate and think it should be removed from our site, let us know. This report will be reviewed by Audible and we will take appropriate action.


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Just when we thought Gisele Bündchen wouldn't share another photo of her on set after receiving backlash from a past photo, she shared another one!
This time, Tom Brady's wife is posing while seated on the floor in a beige bodysuit. Not only is her pose diva-ish, so is her attitude. She cleary doesn't care who's fixing her hair, just as long as it's perfect for the photo shoot for Brazilian jewelry designer Joias Vivara.
"Fotografando @vivaraonline 📷 Shooting @vivaraonline," she captioned the pic posted May 29.
Just last month, the 33-year-old model shared another photo of her getting her hair and makeup done. At least it looks like her beauty squad was having fun!
"Already feeling butterflies in my stomach! #gettingready for @colccioficial fashion show," she captioned the photo.
And this past December, she posted a picture of her getting her hair, nails and makeup done—all while breastfeeding! The photo then went viral and rumors of her being a diva on set started.
"What would I do without this beauty squad after the 15 hours flying and only 3 hours of sleep #multitasking #gettingready," she captioned the photo.
In a past interview with the New York Post, Ted Southern, a designer who makes angel wings for Victoria's Secret, commented on what it's like to work with Gisele.
13 Times Gisele Bundchen Has Single-Handedly Annoyed the World — With GIFs and Memes!
"She's really tough. She's always screaming, 'What the f--k is this?'" he said, shedding some light on what really happens behind the scenes.


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BluePhoenix Solutions (NASDAQ: BPHX), the leader in value-driven IT modernization solutions, announced today that it has been awarded a contract valued approximately at two million dollars to modernize critical business systems for an international transportation company based in the US. The customer selected BluePhoenix to modernize mainframe hosted control, financial and fleet management applications and databases to the Windows platform. The main drivers for the modernization were reduction of costs associated with legacy technologies, application enhancement, improving the agility and building a modern and productive end user interface environment. "We are very pleased to be awarded with this contract. It is yet another testimony that enterprises are increasingly recognizing the potential for significant cost savings and efficiency gains from IT modernization. We are well-positioned to deliver the solutions that address these needs" said Yaron Tchwella, CEO, BluePhoenix Solutions. "In our engagements with customers around the world, we are able to demonstrate operational costs reductions, improved business agility and better efficiencies. In today's competitive markets, IT modernization is one of the areas that can help enterprises maintain their competitiveness as a result of lower cost structure, agility, time to market and reduced risk due to resource shortage." About BluePhoenix Solutions BluePhoenix Solutions (NASDAQ: BPHX) is the leading provider of value-driven legacy IT modernization solutions. The BluePhoenix portfolio includes a comprehensive suite of tools and services from global IT asset assessment and impact analysis to automated database and application migration, rehosting, and renewal. Leveraging over 20 years of best-practice domain expertise, BluePhoenix works closely with its customers to ascertain which assets should be migrated, redeveloped, or wrapped for reuse as services or business processes, to protect and increase the value of their business applications and legacy systems with minimized risk and downtime. BluePhoenix provides modernization solutions to companies from diverse industries and vertical markets such as automotive, banking and financial services, insurance, manufacturing, and retail. Among its prestigious customers are: Aflac, Capita Group, CareFirst, Citigroup, Danish Commerce and Companies Agency, Desjardins, Los Angeles County Employees Retirement Association, Rabobank, Rural Servicios Informaticos, SDC Udvikling, TEMENOS, Toyota, and Volvofinans. BluePhoenix has 14 offices in the USA, UK, Denmark, Germany, Italy, The Netherlands, Romania, Russia, Cyprus, South Korea, Australia, and Israel.
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Outlook Express to Outlook Conversion SimplifiedExport Outlook Express to Outlook even with little computer knowledge. With DBX Converter, perform DBX to PST conversion easily.
Need to migrate Outlook Express to Outlook? DBX file conversion process with DBX Converter is so easy to perform that you will really feel pleased after buying this simple and intuitive product.
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Give us a call to get our secret deals 1-800-468-3578
Property Location
Located in Mezraia, Djerba Les Dunes is by the sea and within the region of Borj El K'bir Fort and Houmt Souq Harbour. This spa hotel is within the region of El Ghriba Synagogue and Guellala Museum.
Make yourself at home in one of the 245 air-conditioned guestrooms. Rooms have private balconies or patios. Satellite television is provided for your entertainment. Bathrooms have shower/tub combinations and hair dryers.
Relax at the full-service spa, where you can enjoy massages, body treatments, and facials. You're sure to appreciate the recreational amenities, including an outdoor pool, an indoor pool, and a sauna. Additional features at this hotel include complimentary wireless Internet access, gift shops/newsstands, and tour/ticket assistance.
Enjoy a satisfying meal at a restaurant serving guests of Djerba Les Dunes. Relax with a refreshing drink at one of the 3 bars/lounges.
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Featured amenities include dry cleaning/laundry services, a 24-hour front desk, and multilingual staff.


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Alabama's Ingram could land in New Orleans
Published: March 16th, 2011 | Tags: Reggie Bush, Cameron Heyward, Cameron Jordan, Craig Heyward, Mark Ingram, New Orleans Saints, Ryan Kerrigan
The Saints were on the clock on "Path to the Draft" on Wednesday, and Mike Triplett of the New Orleans Times-Picayune joined the show to discuss where the team could be heading in the draft. The Saints could be in a tough spot with a potential 26 unrestricted free agents and one of the highest payrolls from last season. And the team would like to lock up QB Drew Brees long term.
So, where are they going with the 24th overall pick? The usual names of defensive studs were thrown around: Cameron Heyward — the son of former Saints star Craig "Ironhead" Heyward — Cameron Jordan and Ryan Kerrigan, to name a few.
Vould the team be in the market for a running back? Triplett expects Reggie Bush to be in the team's plans but believes Alabama's Mark Ingram could be an intriguing pick for the Saints.


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Sun, May 26, 2013 at 2:35 AM
How I feel
I Miss you
I Love You
I want you
I need you
I owe you
I wanna kiss you
I wanna hold you
I wanna make love to (only if you want me to)
I wanna hold your hand
I wanna make you laugh
I want to be your comfort
I wanna be more than just your friend (the question is do you believe in 2nd chances)
I wanna hear your voice
I'm thinking about you right now at this very moment . I know you are sleeping aww so cute I miss all the times we had together good and bad I miss them heart to heart talks how we both understand each other when we were hurt or down. how we always would help each other out DAMN!! *Stops and looks at your picture and smiles* xoxoxoxoxoxoxo
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