text:
Topical administration of orbital fat-derived stem cells promotes corneal tissue regeneration
- Ko-Jo Lin†1,
- Mei-Xue Loi†1,
- Gi-Shih Lien2,
- Chieh-Feng Cheng1,
- Hsiang-Yin Pao3,
- Yun-Chuang Chang3,
- Andrea Tung-Qian Ji3 and
- Jennifer Hui-Chun Ho1, 3, 4Email author
DOI: 10.1186/scrt223
© Lin et al.; licensee BioMed Central Ltd. 2013
Received: 31 December 2012
Accepted: 20 May 2013
Published: 14 June 2013
Topical administration of eye drops is the major route for drug delivery to the cornea. Orbital fat-derived stem cells (OFSCs) possess an in vitro corneal epithelial differentiation capacity. Both the safety and immunomodulatory ability of systemic OFSC transplantation were demonstrated in our previous work. In this study, we investigated the safety, therapeutic effect, and mechanism(s) of topical OFSC administration in an extensive alkali-induced corneal wound.
Corneal injury was created by contact of a piece of 0.5 N NaOH-containing filter paper on the corneal surface of a male Balb/c mouse for 30 s. The area of the filter paper covered the central 70% or 100% of the corneal surface. OFSCs (2 × 105) in 5 μl phosphate-buffered saline (PBS) were given by topical administration (T) twice a day or by two intralimbal (IL) injections in the right cornea, while 5 μl of PBS in the left cornea served as the control.
Topical OFSCs promoted corneal re-epithelialization of both the limbal-sparing and limbal-involved corneal wounds. In the first three days, topical OFSCs significantly reduced alkali-induced corneal edema and stromal infiltration according to a histopathological examination. Immunohistochemistry and immunofluorescence staining revealed that transplanted cells were easily detectable in the corneal epithelium, limbal epithelium and stroma, but only some of transplanted cells at the limbal epithelium had differentiated into cytokeratin 3-expressing cells. OFSCs did not alter neutrophil (Ly6G) levels in the cornea, but significantly reduced macrophage (CD68) infiltration and inducible nitrous oxide synthetase (iNOS) production during acute corneal injury as quantified by a Western blot analysis. Continuous topical administration of OFSCs for seven days improved corneal transparency, and this was accompanied by diffuse stromal engraftment of transplanted cells and differentiation into p63-expressing cells at the limbal area. The therapeutic effect of the topical administration of OFSCs was superior to that of the IL injection. OFSCs from the IL injection clustered in the limbal area and central corneal epithelium, which was associated with a persistent corneal haze.
Topical OFSC administration is a simple, non-surgical route for stem cell delivery to promote corneal tissue regeneration through ameliorating acute inflammation and corneal epithelial differentiation. The limbal area serves as a niche for OFSCs differentiating into corneal epithelial cells in the first week, while the stroma is a potential site for anti-inflammation of OFSCs. Inhibition of corneal inflammation is related to corneal transparency.
Corneal injury Inflammation Mesenchymal stem cells Orbital fat-derived stem cells Topical administrationIntroduction
Both a limbal cell deficiency and corneal stromal injury affect long-term corneal transparency due to corneal opacity[1]. During corneal tissue injury, inflammation is harmful to epithelial cell migration, and inflammatory cell infiltration in the stroma aggravates corneal edema and scarring[2]. The cornea is physiologically re-epithelialized by the proliferation and differentiation of limbal stem cells in the basal layer of the limbal epithelium[3, 4], and extensive loss of limbal epithelial cells leads to a persistent corneal epithelial defect and pannus formation[5]. Damage to the corneal stroma represents corneal ulceration, and this is complicated by corneal opacity due to scar formation[6].
Corneal transplantation is a way to replace scar tissue using the full or partial thickness of a donor's central cornea[7], but it fails to regenerate limbal stem cells. Moreover, the donor source and graft rejection are major limitations of corneal transplantations[8]. Limbal transplantation is a surgical procedure that removes autologous limbal epithelium from the contralateral eye to replenish diseased limbal epithelium[9]; disruption of healthy limbal stem cells is inevitable. Recently, replacement of the corneal epithelium under a limbal cell deficiency is achieved by ex vivo cultured cells, including limbal stem cells[10, 11], conjunctival epithelial cells[12], and oral mucosal cells[13]. However, long-term graft survival is always a challenge with autologous conjunctival or oral epithelial cell transplantation due to a lack of stem cell properties of those cells. Stem cell transplantation is a new therapeutic strategy for corneal tissue regeneration that relies on their multipotency.
In terms of stem cell therapy, healthy limbal stem cell preservation and immune tolerance of stem cells are two critical issues for successful corneal regeneration[14, 15], and it is imperative to use immune-tolerant allogenic stem cells. Among stem cells, only mesenchymal stem cells (MSCs) possess the immunomodulatory ability and are well-tolerated during allogenic transplantation[16]. We have successfully isolated and purified multipotent stem cells from human orbital fatty tissues[17]. Orbital fat-derived stem cells (OFSCs) are MSCs isolated from human orbital fat tissue[18]. In our previous study, we have demonstrated that the growth kinetics of OFSCs is similar to bone marrow-derived MSCs (BM-MSCs), while more than 260 surface markers of OFSCs are consistent with BM-MSCs[17, 19, 20]. OFSCs lack immunogenecity, and the safety and immunomodulatory ability of systemic OFSC transplantation has been demonstrated in our previous xenotransplant model[20]. In addition, OFSCs possess the osteogenic, chondrogenic and adipogenic differentiation capacity, and may differentiate into corneal epithelial cells upon contact with human corneal epithelial cells in vitro[17]. Therefore, development of a technically non-surgical, non-invasive method to deliver OFSCs and allow OFSCs to directly contact corneal epithelial cells will be valuable for corneal tissue regeneration.
In this study, extensive corneal injury was created by NaOH, an alkali chemical reagent. Alkali-induced corneal injury leads to corneal/limbal epithelial defects, and induces further stromal tissue melting and severe corneal inflammation, which subsequently results in corneal edema, ulceration in the early stage, and corneal opacity/scarring in the late stage[21]. We created two sizes of corneal wounds, that is, one was a limbal-sparing central corneal injury and the other was total corneal damage, including the limbal area. OFSCs were topically administrated to the corneal surface, and the therapeutic effect was evaluated by the size of the corneal defect, the corneal thickness, stromal infiltration and corneal transparency. In this experiment, the mechanism and the niche of OFSCs before and after corneal re-epithelialization were explored. In addition, differences in limbal-involved corneal injury between topical OFSCs and an intralimbal injection of OFSCs were also compared.
Material and methods
Animals with the corneal injury
Male Balb/c mice were purchased from BioLASCO (Taipei, Taiwan). Animals were maintained in the animal facility of Wan Fang Hospital, Taipei Medical University (WFH-TMU, Taipei, Taiwan). All experimental protocols were approved by the animal use and care committee of WFH-TMU. An eight-week-old mouse's cornea was covered by round filter paper, which had been rinsed by 0.5 N NaOH before covering the mouse corneal surface for 30 s. Mice were separated into two groups: filter paper in group A covered 70% of the central corneal area (5.9 mm in diameter) and in group B, filter paper covered 100% of the corneal area (7 mm in diameter). Corneal epithelial cells were smoothly removed with a no. 15 Bard-Parker scalpel blade after alkali damage.
Isolation, expansion of OFSCs
Isolation and culture of OFSCs were carried out as described previously[17]. Briefly, during blepharoplastic surgery, 0.5 to approximately 1 ml of redundant orbital fat tissues was removed from the intraorbital cavity. All samples were removed with informed consent and followed regulations of the Institutional Review Board of WFH-TMU. Tissues were fragmented, digested and filtered. The suspension was centrifuged, cells from the pellet were plated at a very low density, and colony-forming cells were maintained in MesenPro medium (Invitrogen, Carlsbad, CA, USA). OFSCs were mesenchymal stem cells which were negative for CD34, CD133, CD31, CD106, CD146, CD45, CD14, CD117 and HLA-DR and positive for CD58, CD90, CD105, CD29, CD49b, CD49e, CD44, CD49d and HLA-ABC[17]. The tri-lineage differentiation capacity of these cells was checked before this study.
Topical and intra-limbal OFSC transplantation
Six mice were used in Group A. After 70% of corneal injury to both eyes, the right eye was applied with topical OFSCs (T) and the left eye with PBS. Night mice were used in Group B for the topical (T) administration of OFSCs. After 100% of corneal injury for both eyes took place, topical OFSCs were given to the right eyes while topical PBS (six mice) or no treatment (dry control, three mice) to the left eyes. In addition, three mice without corneal injury received topical OFSCs on the right eyes and topical PBS on the left eyes.
For evaluation of the intra-limbal (IL) injection, 100% corneal injury was created on three mouse corneas. IL injection of OFSCs was performed in the right eye and PBS in the left eye. One mouse without corneal injury received IL OFSCs in the right eye and IL PBS in the left eye.
Before treatment, OFSCs were detached and re-suspended in PBS(Gibco, Grand Island, NY, USA). For topical (T) administration, 2 × 105 human OFSCs with or without quantum dots (Invitrogen) labeling in 5 μl of PBS were applied to the right corneal surface twice a day until the day of sacrifice, while 5 μl of PBS applied to the left eye twice a day served as the control. For the IL injection, 2 × 105 quantum dots (Invitrogen)-labeled OFSCs in 5 μl of PBS were injected into the lateral side of the right limbal epithelium on the first day, and a repeat injection on the nasal side of the right limbal epithelium was given on Day 6, while 5 μl of PBS was injected into the left limbal epithelium at the same time.
Quantification the area of corneal injury
The cornea wound was examined on days 0, 1, 2, 3 and 7. Before being photographed, the epithelial defect was stained with a topical fluorescent strip (HAAG-STREIT, Koeniz, Switzerland), and images were captured with a digital camera (Canon, Tokyo, Japan) under a cobalt-blue light source from a direct ophthalmoscope (Welch Allyn, Skaneateles Falls, NY, USA). The injured area of the cornea was determined using the software Image Pro-Plus version 6.0 (Media Cybernetics, Rockville, MD, USA) and calculated as a percentage of the residual epithelial defect.
Histological and immunohistochemical (IHC) staining
Mice were sacrificed at the end of day 2, 3 or 7 after injury. The eyeball was removed en bloc and fixed in formalin, then prepared in paraffin-embedded blocks for sectioning at a thickness of 10 μm. Tissue sections were stained with hematoxylin and eosin (H&E) (Sigma-Aldrich, St. Louis, MO, USA). For IHC staining, tissue sections were incubated with rabbit antibody against human immunoglobulin G (hIgG) (1:800, Abcam, Cambridge, MA, USA), or rabbit antibody against human beta-2 microglobulin (hβ2M) (1:800, Abcam) at 4°C for 1 h, followed by goat antibodies against rabbit IgG (Dako Cytomation, Glostrup, Denmark) for another 40 to approximately 60 minutes. Tissue sections were assessed by microscopy (Leica Microsystem, Wetzlar, Germany). Images were acquired with MetaMorph version 4.6 (Molecular Devices, Sunnyvale, CA, USA).
Immunofluorescence staining
For cytokeratin 19 (CK19) and CK3 staining, frozen section tissue slides were fixed in cold methanol for 30 minutes, followed by two PBS washes. After being blocked in 5% skim milk at room temperature for 1 h, slides were incubated with a mouse antibody against human/mouse CK19 (1:500, Millipore, Billerica, MA, USA), a mouse antibody against human/mouse CK3 (1:500, Millipore), rabbit antibody against human p63 (1:150, Abcam), or rabbit antibody against hIgG (1:800, Abcam) at room temperature for 1 h, followed by incubation with DyLight 488-conjugated goat anti-mouse IgG (1:500, Jackson ImmunoResearch Laboratories, Inc. West Grove, PA, USA), or DyLight 594-conjugated goat anti-rabbit IgG (1:500, Jackson ImmunoResearch Laboratories, Inc.) at room temperature for 30 minutes. Nuclei were then stained with 4,6-diamidino-2-phenylindole (DAPI, 1:1,000), and samples were assessed under a fluorescence microscope (Leica Microsystem). Images were acquired using MetaMorph version 4.6 (Molecular Devices).
Western blot analysis
Total protein was obtained from mouse cornea with Cell Lysis Buffer (Sigma-Aldrich) containing freshly added protease inhibitors (Sigma-Aldrich). Protein concentrations were determined with a Bio-Rad Protein Assay (Bio-Rad Laboratories, Hercules, CA, USA). Electrophoresis was performed using 30 μg of total protein by 10% sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidenedifluoride membranes (Millipore). Nonspecific binding was blocked by 5% skim milk in TBST buffer (50 mMTris–HCl, pH 7.4; 150 mMNaCl, and 0.1% Tween 20) at room temperature for 1 h. The membrane was then probed with a rabbit polyclonal antibody (pAb) to inducible nitrous oxide synthetase (iNOS, 1:2000, Abcam), a rabbit monoclonal antibody (mAb) to CD68 (1:1,000, Epitomics, Burlingame, CA, USA), a rabbit pAb to tissue growth factor-beta (TGF-β, 1:4,000, Abcam), a mouse mAb to tumor necrosis factor-alpha (TNF-α, 1:1,000, Abcam), a rat mAb to lymphocyte antigen 6 complex (Ly6G, 1:1,000, Abcam), a mouse mAb to vascular endothelial growth factor (VEGF, 1:1,000, Abcam), a rabbit pAb to hIgG (1:800, Abcam), a mouse mAb to mouse and human β-actin (1:200, Sigma-Aldrich), or a mouse mAb to α-tubulin antibodies (1:104, Sigma-Aldrich) at 4°C overnight. After three washes with TBST (for 15 minutes each), the membrane was incubated with a horseradish peroxidase (HRP)-conjugated secondary antibody against to rabbit IgG (1:5,000, Santa Cruz Biotechnology, Santa Cruz, CA, USA) or against to mouse IgG (1:5,000, Abcam) at room temperature for 1 h. After three more TBST washes, protein signals were detected by enhanced chemiluminescence (ECL; NEN Life Science, Boston, MA, USA) and their intensities were measured by densitometry (Image Pro-Plus version 6.0, Media Cybernetics).
Statistical analysis
Values are shown as the mean ± standard error. Statistical analyses were performed using the Statistical Package for Social Science version 16 software (SPSS, Chicago, IL, USA). Results of comparisons of the area of corneal injury at each time point between the PBS and OFSCs groups or between the dry control and OFSCs groups, and corneal protein expression between the PBS and OFSCs groups were analyzed by Student's t-test, and P < 0. 05 was considered a statistically significant difference.
OFSCs promote corneal wound healing
Mice were divided into two groups. A 70% central corneal injury (limbal-sparing) was created in group A, and 100% corneal damage (limbal-involved) was created in group B. Topical 2 × 105 OFSCs in 5 μl PBS (OFSCs-(T)) was administrated to the right corneal surface twice a day, and topical 5 μl PBS (PBS-(T)) was given to the left cornea twice a day.
For limbal-involved corneal wounds (group B), OFSCs accelerated corneal wound healing but a central corneal haze was found in the first three days (Figure 1C). In mice with a 100% corneal epithelial defect after alkali-injury, areas of the epithelial defect under PBS treatment were 74.8% ± 4.32% of the total cornea on Day 1, 59.6% ± 9.37% on Day 2, 42.0% ± 2.74% on Day 3, and 29.3% ± 6.78% on Day 7; while they were 64.2% ± 4.59% on Day 1, 40.2% ± 3.06% on Day 2, 15.0% ± 7.83% on Day 3, and 7.9% ± 2.34% on Day 7 with topical OFSC treatment (Figure 1D). Compared with PBS control, the dry control on a 100% corneal injury showed no significant difference on both corneal haze (Figure 1B, Dry-D3) and residual corneal defect (Figure 1D) in the first seven days.
Topical OFSCs' initial contact with the corneal epithelium, limbal epithelium, and stroma
Initial corneal epithelial differentiation of OFSCs is observed in the limbal epithelium
OFSCs reduce alkali-induced acute inflammation and corneal edema
OFSCs inhibit macrophage infiltration and iNOS production during acute corneal inflammation
Intra-limbal injection of OFSCs is not sufficient to clear the cornea
Stromal engraftment of topical OFSCs contributes to corneal transparency
Topical application of OFSCs in the first three days was insufficient to improve corneal transparency in the limbal-involved corneal wound (Figure 1C), so the long-term effect of OFSCs needed to be investigated. For safety consideration, multiple rounds of topical OFSCs on the normal corneal surface did not attack the corneal epithelium (Figure 7A). In the limbal-involved corneal wound, a large corneal epithelial defect and marked corneal opacity were observed under PBS treatment for seven days (Figure 7B), and continuous topical OFSC administration for seven days reduced the wound size and improved the corneal transparency (Figure 7C). Fluorescent staining revealed that diffuse quantum dot-labeled OFSCs were found in the corneal stroma, but no longer in the central corneal epithelium (Figure 7D). Limbal sections showed that some of the hβ2M-expressing cells differentiated into p63 positive cells (Figure 7E).
For the first time, we proved the concept that multiple rounds of topical OFSCs is a simple, non-surgical strategy to promote corneal tissue regeneration. In the first three days, the therapeutic effects of topical OFSCs are mainly through inflammation inhibition (Figures 1 and4), but little by directional corneal epithelial cell differentiation (Figure 3). Inhibition of macrophage infiltration and iNOS production (Figure 5) accounts for the amelioration of acute corneal inflammation and promotion of corneal re-epithelialization. OFSCs remain in the limbal epithelium, corneal epithelium and stroma in the first three days (Figure 2), and the limbal epithelium is favored for corneal epithelial differentiation (Figures 3,6E and7E). However, the corneal stroma potentially serves as a niche for OFSC engraftment, and this is related to improvements in the corneal transparency (Figures 6 and7).
OFSCs, the same as BM-MSCs, lacked immunogenicity and were well-tolerated after intravenous injections in our previous studies[20, 30]. This time, we explored whether topical administration (Figure 7A) and IL injections (Figure 6A) were safe routes to deliver MSCs into corneal tissues. Clinically, the addition of topical steroids or non-steroid anti-inflammatory drugs benefits corneal re-epithelialization and prevents corneal scar formation[31, 32]. Systemic transplantation of a high dose of MSCs reduce ethanol-induced inflammatory damage to the cornea by secretion of TNF-α-stimulated gene/protein 6 with minimal engraftment[33], which shows that systemic administration is not an efficient way to deliver stem cells to the cornea, a physiologically avascular tissue. However, the abundant paracrine effect of MSCs contributes to inhibition of inflammation. It has been reported that BM-MSCs expanded on an amniotic membrane can reconstruct an alkali-damaged cornea by inhibiting inflammation and angiogenesis[34]. Alternatively, topical administration of stem cells provided stem cells with direct contact with the corneal epithelium and stroma on a damaged cornea (Figures 2 and7D), and low-dose OFSCs resulted in good corneal protection (Figures 1,3,4 and7).
Neutrophils and macrophages, known as immune cells, are responsible for innate immunity, and infiltrate into an acutely inflamed cornea[35]. Macrophages play the central role in acute inflammation because they produce various proinflammatory cytokines, and also recruit and activate T-lymphocytes[35, 36]. Macrophage-produced iNOS and VEGF cause a vicious cycle with alkali-induced corneal inflammation[26, 36]. According to our data, OFSCs inhibited macrophage infiltration and subsequent iNOS production in the cornea (Figure 5B,F) without altering VEGF production (Figure 5E), indicating that macrophages are target cells regulated by OFSCs during acute inflammation. Further studies on interactions between OFSCs and macrophages in regulating acute tissue inflammation are ongoing in our lab.
In our previous study, we found that cell-cell interactions between corneal epithelial cells and stem cells were crucial for corneal epithelial cell differentiation of OFSCs[17]. When we applied OFSCs to the corneal surface with a large epithelial defect, most of the transplanted cells remained in the limbal epithelium, corneal epithelium and stroma during the first few days (Figure 2). Notably, only some of the OFSCs in the limbal epithelium rapidly differentiated into CK3-expressing cells, but no CK19 signals in transplanted cells were found in the limbal area in the first three days (Figure 3), while human p63-expressing cells were detectable at limbal area seven days later (Figures 6E and7E) rather than in the first three days (data not shown), implying that the limbal environment possibly induces OFSC differentiation and transdifferentiation into a corneal epithelial linage. The underlying mechanism should be determined.
Wound healing is essential for tissue regeneration. However, the cornea is the window of the eye, and the transparency of the cornea determines visual acuity. Corneal tissues are physiologically composed of the corneal epithelium, stroma and endothelium. Clarity of the cornea depends on an intact corneal epithelium, tight packing of epithelial cells, constant water content, and regular arrangement of keratocytes and keratocyte-produced extracellular matrix in the stroma[1, 37, 38]. In this study, corneal opacity was not a complication of the limbal-sparing corneal injury (Figure 1A). When OFSCs were applied to the limbal-involved corneal wound, marked central opacity was observed on Day 3 (Figure 1C), and a clear cornea did not occur until Day 7 (Figure 7C), suggesting that improved corneal clarity occurs after re-epithelialization.
We further delivered OFSCs into the limbal epithelium of a damaged cornea to avoid OFSCs directly contacting the corneal stroma. It was shown that cells transplanted via an IL injection clustered at the injection site and in the central corneal epithelium (Figure 6D), and this was associated with marked corneal opacity (Figure 6C, right). After seven days of continuous topical OFSC administration, transplanted cells were only detectable in the stroma and no longer in the corneal epithelium (Figure 7D), illustrating that stromal engraftment of OFSCs contributes to corneal transparency. It has been reported that an intrastromal injection of MSCs significantly increased the corneal thickness and transparency and lowered light scattering in keratocyte-dysfunctional mice by their similar phenotype with keratocytes and expression of keratocyte-unique keratan-sulfated keratocan and lumican after transplantation[39]. Recently, Agorogiannis et al. report a case using 3 × 106 autologous MSCs topically applied to the bottom of a corneal ulcer for a persistent sterile corneal epithelial defect[40]. The corneal stroma is connective tissue maintained by keratocytes, which are quiescent mesenchymal cells of neural crest origin[41], and the embryonic origins of keratocytes and orbital fat tissues are the same. It is speculated that the stroma serves as a niche for long-term OFSC engraftment. In addition, topical administration of OFSCs to the cornea with an epithelial defect provides a diffuse distribution of OFSCs in the stroma, and which favors direct OFSC-keratocyte interactions in comparison with an intrastromal injection. Future studies on developing bioactive stem cell eye drops are ongoing in our lab.
Topical administration of allogenic OFSCs is a simple, non-invasive method of delivering stem cells for corneal tissue regeneration. Inflammatory inhibition and corneal epithelial differentiation by OFSCs are responsible for corneal wound healing in the first few days, and corneal stroma engraftment of OFSCs at a late stage is associated with corneal transparency.
Authors' information
KJL and MXL are chief residents in the Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University. GSL is the Vice Superintendent of Wan Fang Hospital and Associate Professor in Department of Internal Medicine, Taipei Medical University. CFC is a Visiting Staff member in the Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University. HYP, YCC and ATJ are research assistants in the Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University. JHH is the Director of the Center for Stem Cell Research and a Consultant Ophthalmologist in the Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University. JHH is also an Associate Professor in Graduate Institute of Clinical Medicine, Taipei Medical University.
- β2M:
Beta-2 microglobulin
- BM-MSCs:
Bone marrow-derived mesenchymal stem cells
Enhanced chemiluminescence
Horseradish peroxidase
- IgG:
Immunoglobulin G
- iNOS:
Inducible nitrous oxide synthetase
- Ly6G:
Lymphocyte antigen 6 complex
- MSCs:
Mesenchymal stem cells
- OFSCs:
Orbital fat-derived stem cells
Phosphate-buffered saline
mixture of Tris-buffered saline and Tween 20
- TGF-β:
Transforming growth factor-beta
- TNF-α:
Tumor necrosis factor-alpha
Vascular endothelial growth factor.
The authors acknowledge the financial support from Wan Fang Hospital, Taipei Medical University (100-wf-eva-13 to CFC and JHH), and support from research grants (NSC101-2314-B-038-022-MY3 and NSC101-2120-M-010-002 to JHH) from the National Science Council, Taiwan. The authors also acknowledge the research grant support from Taipei Medical University and SteminentBiotherapeutics, Inc., (A-101-023 and 99TMU-ICC-011 to JHH).
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- Kitano A, Okada Y, Yamanka O, Shirai K, Mohan RR, Saika S: Therapeutic potential of Trichostatin A to control inflammatory and fibrogenic disorders of the ocular surface. Mol Vis. 2010, 16: 2964-2973.PubMedPubMed CentralGoogle Scholar
- Gronert K: Resolution, the grail for healthy ocular inflammation. Exp Eye Res. 2010, 91: 478-485. 10.1016/j.exer.2010.07.004.PubMedPubMed CentralView ArticleGoogle Scholar
- Roddy GW, Oh JY, Lee RH, Bartosh TJ, Ylostalo J, Coble K, Rosa RH, Prockop DJ: Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-α stimulated gene/protein 6. Stem Cells. 2011, 29: 1572-1579. 10.1002/stem.708.PubMedView ArticleGoogle Scholar
- Ma YL, Xu YS, Xiao ZF, Yang W, Zhang C, Song E, Du YQ, Li LS: Reconstruction of chemically burned rat corneal surface by bone marrow-derived human mesenchymal stem cells. Stem Cells. 2006, 24: 315-321. 10.1634/stemcells.2005-0046.PubMedView ArticleGoogle Scholar
- Ruberti JW, Klyce SD, Smolek MK, Karon MD: Anomalous acute inflammatory response in rabbit corneal stroma. Invest Ophthalmol Vis Sci. 2000, 41: 2523-2530.PubMedGoogle Scholar
- Lee ES, Ju HK, Moon TC, Lee E, Jahng Y, Lee SH, Son JK, Baek SH, Chang HW: Inhibition of nitric oxide and tumor necrosis factor-alpha (TNF-alpha) production by propenone compound through blockade of nuclear factor (NF)-kappa B activation in cultured murine macrophages. Biol Pharm Bull. 2004, 27: 617-620. 10.1248/bpb.27.617.PubMedView ArticleGoogle Scholar
- Müller LJ, Pels L, Vrensen GF: Novel aspects of the ultrastructural organization of human corneal keratocytes. Invest Ophthalmol Vis Sci. 1995, 36: 2557-2567.PubMedGoogle Scholar
- Kao WW, Funderburgh JL, Xia Y, Liu CY, Conrad GW: Focus on molecules: lumican. Exp Eye Res. 2006, 82: 3-4. 10.1016/j.exer.2005.08.012.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu H, Zhang J, Liu CY, Wang IJ, Sieber M, Chang J, Jester JV, Kao WW: Cell therapy of congenital corneal diseases with umbilical mesenchymal stem cells: lumican null mice. PLoS One. 2010, 5: e10707-10.1371/journal.pone.0010707.PubMedPubMed CentralView ArticleGoogle Scholar
- Agorogiannis GI, Alexaki VI, Castana O, Kymionis GD: Topical application of autologous adipose-derived mesenchymal stem cells (MSCs) for persistent sterile corneal epithelial defect. Graefes Arch Clin Exp Ophthalmol. 2012, 250: 455-457. 10.1007/s00417-011-1841-3.PubMedView ArticleGoogle Scholar
- Pinnamaneni N, Funderburgh JL: Concise review: stem cells in the corneal stroma. Stem Cells. 2012, 30: 1059-1063. 10.1002/stem.1100.PubMedPubMed CentralView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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Tecmo Koei Will Re-Release La Corda d'Oro 3 With Full Voice Acting
By Spencer . June 24, 2013 . 12:29am19. La Corda d'Oro 3 Full Voice Special has full voice acting, which is a feature fans have been waiting for. The team also listened to requests to have events for certain sub characters and added those to Full Voice Special.

subset: commoncrawl


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A Study of Torcetrapib/Atorvastatin vs Atorvastatin Alone or Placebo in Patients With High Cholesterol
This study has been completed.
Information provided by (Responsible Party):
ClinicalTrials.gov Identifier:
First received: August 26, 2005
Last updated: February 15, 2012
Last verified: February 2012
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
Detailed Description:
The Torcetrapib project was terminated on December 2, 2006 due to safety findings.
A study to look at lipid levels in subjects taking the study drug, Atorvastatin alone or placebo.
Condition | Intervention | Phase |
Hyperlipidemia |
Drug: torcetrapib/atorvastatin Drug: atorvastatin Drug: placebo |
Phase 3 |
Study Type: | Interventional |
Study Design: | Allocation: Randomized Intervention Model: Parallel Assignment Masking: Double-Blind Primary Purpose: Treatment |
Official Title: | A Phase 3, Double Blind, Placebo-Controlled, Randomized, Parallel Group, Multicenter Study of the Efficacy, Safety and Tolerability of Fixed Combination Torcetrapib/Atorvastatin Administered Orally Once Daily for 6 Months, Compared to Atorvastatin Alone or Placebo in Subjects With Mixed Dyslipidemia (Fredrickson Types IIa and IIb). |
Resource links provided by NLM:
Further study details as provided by Pfizer:
Primary Outcome Measures:
- LDL and HDL levels
Secondary Outcome Measures:
- other lipid parameters
Estimated Enrollment: | 3800 |
Study Start Date: | July 2004 |
Study Completion Date: | August 2006 |
Primary Completion Date: | August 2006 (Final data collection date for primary outcome measure) |
For additional information please call: 1-800-718-1021
Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- subjects with elevated cholesterol
Exclusion Criteria:
- Women who are pregnant or lactating, or planning to become pregnant.
- Intolerance to statin therapy resulting in withdrawal
- Subjects taking any drugs known to be associated with an increased risk of myositis in combination with HMG-CoA reductase inhibitors
- Subjects with any other medical condition or laboratory abnormality which could affect subject safety, preclude evaluation of response, or render unlikely that the subject would complete the study
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00138762
Show 154 Study Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00138762
Show 154 Study Locations
Sponsors and Collaborators
Study Director: | Pfizer CT.gov Call Center | Pfizer |
More Information
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on March 28, 2017
Responsible Party: | Pfizer |
ClinicalTrials.gov Identifier: | NCT00138762 History of Changes |
Other Study ID Numbers: |
Study First Received: | August 26, 2005 |
Last Updated: | February 15, 2012 |
Additional relevant MeSH terms:
Hyperlipidemias Dyslipidemias Lipid Metabolism Disorders Metabolic Diseases Atorvastatin Calcium Torcetrapib Anticholesteremic Agents |
Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on March 28, 2017


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The City of Montreal honoured former Expos catcher Gary Carter on May 21, renaming a street in honour of the Hall of Famer who died of brain cancer in February 2012 at age 57.
Faillon St. W., located near Uniprix stadium, which used to be known as Jarry Park when the Expos played there, will now be Gary Carter St.
Carter's widow Sandy and daughter Kimmy Carter Bloemers weren't be on hand for the street ceremony in Montreal because they found out about the event on short notice. However, they plan to be in Montreal the weekend of June 15 for the official opening of the Gary Carter baseball park in the north-end Ahuntsic district.
MLB Headlines
Montreal street re-named to honor Gary Carter
Montreal Gazette | May 22


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Submitted to Photo Challenge: The Letter C
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Window washers: cleaning the clouds away.
3 responses
Carol Arntsen Masiak gave props (1 May 2012):
wonderful and congrats on making the JPG blog!
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Congratulations on making the JPG blog!
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Featured in the Best Of Photo Challenge: The Letter C (jpgmag.com)


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The Record Book
• Individual Records
• Team Records
UVA Athletics Information
- Top Videos
Jeff White
O-Line Looking to Raise Its GameFootball3/24/17Guard Jack McDonald and tackle Jack English are the returning starters on the offensive line for Virginia, which starts spring practice Tuesday.Weber Hitting Right Notes on DiamondBaseball3/23/17Sophomore Andy Weber starts at second base for No. 16 Virginia, which hosts ACC rival Duke this weekend at Davenport Field.Successful Season Ends on Excruciating NoteMen's Basketball3/19/17Virginia's fourth consecutive appearance in the NCAA tournament ended with a 65-39 second-round loss to Florida in Orlando, Fla.
Jeff White
Director of News Content
A 1985 graduate of UVA, White worked at the Richmond Times-Dispatch until July 2009. He was honored six times as the state's Sportswriter of the Year.
More Headlines
DiCamillo Finishes Runner-Up At NCAA Championships
Wrestling | 3/18/2017
Virginia senior George DiCamillo matched the best individual finish in program history, finishing...
DiCamillo Advances To Finals Of NCAA Championships
Wrestling | 3/17/2017
Redshirt senior George DiCamillo advanced to the NCAA Championships finals and earned All-America...
DiCamillo, Mueller Advance To NCAA Quarterfinals
Wrestling | 3/16/2017
George DiCamillo and Jack Mueller both advanced to the quarterfinals of the NCAA Championships to...
Virginia Opens NCAA Wrestling Championships Thursday
Wrestling | 3/15/2017
The Virginia wrestling team looks to close out the 2016-17 season with a strong performance as...
Brackets, Seeds Announced For 2017 NCAA Championships
Wrestling | 3/8/2017
George DiCamillo and Jack Mueller both earned national seeds with the release of the brackets for...
Six Cavaliers Place At ACC Championships Saturday
Wrestling | 3/4/2017
George DiCamillo finished second at the ACC Championships, leading a group of six Cavaliers to...
Virginia Wrestles At ACC Championships Saturday
Wrestling | 03/03/2017
The Virginia wrestling team begins the postseason on Saturday (March 4) when it competes at the...
Jeff White: DiCamillo's Legacy Secure at UVA
Wrestling | 03/01/2017
Saturday in Raleigh, N.C., George DiCamillo will try to become the first four-time ACC champion...
Online Stores
AuctionsCavalier Team Shop


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sponsored by
Ari Vidali
CEO and Founder of Envisage Technologies
Ari is involved in building next-generation training systems, cloud-based learning, records management, automation of high-liability training operations, and pervasive readiness technologies. He is a committee member of the National Congress for Secure Communities and an advisory board member of IADLEST. He has consulted for Federal Agencies, Homeland Security, Public Safety, Military, and Law Enforcement on technology, security, legally defensible records, compliance, and training.
There is an ongoing debate about how long anyone should stay in SWAT. There are two schools of thought. One view is officers should stay in SWAT as long as they are qualified, pass the requirements, and want to remain a team member. The other view is officers should only stay in SWAT for a set amount of time (five years), and then rotate out. Both schools of thought have very different reasons for their beliefs.
You are a SWAT team commander/leader, and you have a dilemma. You have a major mission coming up soon, and you need to pick the right people for the right jobs. For many SWAT commanders, this doesn't present any problem. Every member of their teams is up to speed—trained, experienced, reliable, and trusted.
Law enforcement training covers practically every conceivable aspect of use of force. However, an area that is glossed over by many agencies is policy, training, and tactics for dealing with vicious dogs.
Vicious dog attacks account for more than 100 fatalities and thousands of serious injuries every year. Police are usually the first responders to vicious dog reports and are often attacked by these dogs.
There is a quiet debate in SWAT that starts with the question: Which team is the "best?" Followed by: Which teams are "better."
The only time SWAT teams compete against each other is during SWAT competitions for "bragging rights." And while such competitions are important, SWAT's real opponents are the bad guys. That's the competition you can't afford to lose.


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Molecular Imaging Is Helping To Reduce Post-surgical Infections
Scientists at UCLA's David Geffen School of Medicine are working with bioluminescent, fluorescent, and positron emission tomography (PET) technologies to reduce ...
August 30, 2016
Nearly 750 million people around the globe suffer from some form of chronic kidney disease (CKD). Caused primarily by high blood pressure or diabetes, CKD claims more than a million lives each year. Those who have the disease, including millions of children, require lifetime medical care that ranges from strict diets and medications to dialysis and transplants. There is no cure for the disease, but researchers may now be one step closer. 1
What do Twists, Snails, and CKD all have in common? For a team of research scientists based at the M.D. Anderson Cancer Center, University of Texas (UT), Austin, and Göttingen University Medical Center, Georg August University in Göttingen, Germany, understanding how to control two of the mechanisms that regulate EMT (epithelial mesenchymal transition) may provide the key to developing novel treatments for CKD as well as many other fibrosis-associated diseases, including cancer. 2
EMT is a process whereby epithelial cells, which form the membranous tissue covering our internal organs and other internal surfaces of the body, morph into a variety of other cell types, including mesenchymal stem cells that become migratory and invasive. This process is known to occur in wound healing, the initiation of metastasis for cancer progression, and in organ fibrosis, including kidney fibrosis. In short, kidney, or renal, fibrosis is caused by the excessive accumulation of extracellular connective tissue resulting from kidney injuries and the organs' inability to regenerate. This excessive tissue causes scarring and ultimately end-stage renal failure requiring dialysis, kidney transplantation, with potential fatal consequences. 3
To investigate the impact of EMT on the development of CKD, the UT research team overexpressed or deleted both Snail and Twist genes in the tubular epithelial cells of specially bred mice. This enabled the scientists to prompt or suppress the EMT process to weigh its effect on the development of kidney fibrosis. Using Opal® Multicolor Immunohistochemistry (IHC) Research Kits, tissue from various downregulated and upregulated samples were stained and scanned using the Vectra® Automated Multispectral Imaging System. The instrument is considered among the most advanced and reliable tools for objective and high-throughput biomarker quantitation and colocalization study using multiplexed immunohistochemistry. 4 As the UT research progressed, five random fields per slide were selected for each mouse. YFP+ (yellow fluorescent protein) tubular cells were then scored and quantified based on the presence or absence of small integral membrane proteins, such as water channel proteins that are depleted during EMT, using inForm® Tissue Finder Software, which automates the detection and segmentation of specific tissue types using patented user-trainable algorithms developed to recognize morphological patterns. 5
Turning to biopsied renal tissue from humans, the UT researchers then probed the EMT-related genes in samples that exhibited renal fibrosis as well as normal kidney tissue. The results showed that protein levels of select tubular epithelial cells (TECs) were deregulated in those samples from fibrotic kidneys. Similar findings were discovered in the TEC cell line where there was evidence of a robust induction of EMT. While the researchers noted more research is needed, these initial results suggest that damaged kidneys could release an EMT program that further damages TECs. In fact, compromised kidneys may "result in a vicious cycle of damage and host response, leading to chronic fibrosis," the researchers said. Equally important, the team's research findings "support the notion of targeting the EMT program as a viable therapeutic strategy for protecting functional parenchyma in kidney fibrosis" in the future. 6
Not reported, but widely understood, is the fact that the UT research, methodology, and stunning cellular images generated by the PerkinElmer Vectra® Automated Multispectral Imaging System are equally applicable and significant to the ongoing study of EMT in all human organs, including cancer progression research– and that could well prove to be a huge leap forward in developing effective new treatments for all forms of fibrosis-based diseases.
The PerkinElmer instruments included in this article are for research use only. Not for use in diagnostic procedures.
Scientists at UCLA's David Geffen School of Medicine are working with bioluminescent, fluorescent, and positron emission tomography (PET) technologies to reduce ...
PerkinElmer and University of Colorado scientists review the current state of high-content (3D) imaging technologies that are advancing rapidly in the biological...
Amid increased complexity of regulations, PerkinElmer's QSight™ Pesticide Analyzer solution provides labs with more uptime and competitive advantage to meet regu...
A review of the growing dangers associated with antibiotics in milk and PerkinElmer's latest technology to discover these drugs in milk samples.
How to improve the odds of developing successful new drugs using Big Data and state-of-the-art analytical tools.


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If you have already registered as a pay telephone provider and need to update address or pay telephone numbers and county locations etc., you must send this information on a cover letter with your company name, PP0 tracking number, and project number.
Submit one original and three copies to:
Public Utility Commission Attention: Central Records P.O. Box 13326 1701 N. Congress Avenue Austin, TX 78711
If you are submitting pay telephone numbers and county locations, it must be submitted on two identical diskettes/CDs - View the format here.
EXAMPLE 512-555-5555 Travis 512-555-5556 Travis 512-555-5557 Travis
Nothing else should be in this file except the 10 digit numbers and name of the county location. Save the file as your Login name - (example) PP010010.txt. USE A ZERO AFTER PP AND NOT THE LETTER O.
How to list county names:
CORRECT - Travis INCORRECT - Travis County
Make sure the name of the county is spelled correctly. View a list of Texas counties.


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A cat's gender and breed do not always predict the individual's temperament. Keep your options open when deciding upon whether or not to adopt a particular breed or gender.
read moreName: Walter
Age: 6 weeks Years
Owner: Wendi
Hometown: Eugene, OR
Likes: People
Dislikes: none
Wendi says:
Cats reach full skeletal development when they are this old:


text: Christopher Lepine, a freelance writer from Delaware. Twenty years ago, a next-door neighbor lent me The Urantia Book. At that time, I had a worldview marred by misconceptions, fears, and an ignorance of life's spiritual essentials. After spending some time with the book, I found that I was not only beginning to see the world differently, but also myself, and thus, was becoming a new person. It gave me a way to remake my life and actually become a bit more alive each day. My real life began based on several core truths I found in the book. When I allowed myself to believe and contemplate them, everything changed and kept changing. To this day, when I actively think and live these truths, I am thrilled and instantly empowered to do anything. The re-creation of my being is profound and unending. Challenges that I once thought impossible to overcome are now met with strength and openness. I am completely on fire with the joy and possibility of life. I still go through ups and downs, but in all of it, I grow stronger daily and become more alive and real. As an eighteen-year-old new to The Urantia Book, I had many issues and yearnings: I felt out of touch with people. I never seemed to fit in. I had little confidence in my abilities. I was always afraid to try, thinking that I just didn't have it in me or that the consequences would be bad. I didn't know what career I wanted to pursue. I had a few close friends, but was basically a lonely person. I wanted to realize my destiny and feel the full joy of relating to people. I had neither a clue nor a source of strength with which to accomplish these things. I had a spiritual outlook, but it was black and white, monotone, flat, conventional, and dim: It lacked the power to set me on fire and change my life. Then I found The Urantia Book and the truths that would release me. So, what did this mysterious, enormous blue book give me – like no other – that made a difference? Well, it gave me the courage to change my life and myself. Very shortly, I was spending more rewarding and quality time with people than I ever had. I was volunteering, dancing, hiking, going to concerts, and enjoying Urantia Book discussion groups. I started to date more women, began to try new projects, and generally believe that I could change myself. Today I am happily married and employed. I live in a great community, rich with family and friends. Over time the key truths in The Urantia Book transformed my mind and improved my ability to make decisions: I started to challenge myself, take more risks, and yearn for adventure. When I had a problem, I began to see it as a growth opportunity. When I was afraid, I sought to change myself with courage. When I failed, I used the truths to show me the real value of learning. When I became mired in introversion and introspection, they helped me to emerge to socialize and serve others. When I didn't know what to do with my life, they reminded me to open up and receive divine guidance. When I wanted to become more than I was, they inspired me and allowed God to fill me. Today I continue to build my life on the foundation of truths in The Urantia Book: I am a child of a perfect and loving Father-God whom I can contact directly in any moment. He loves me with a sublime parental affection that will see me through everything. He wants me to grow, be happy, and know the joy of adventure. He wants me to see myself as He sees me, an eternal being of light, happy and confident with endless potential. He gives me everything I need. He is a loving parent, true friend, and a perfect, eternal, infinite Deity. The Creator of the universe is my Dad. The Designer of all that is, the greatest, unlimited power of all, listens to me each day and offers His kind guidance and gentle divine touch. I know I will surmount every challenge. I know I will grow and exist for eternity. I know there is an unending panorama of breathtaking adventure and discovery in this life and the next. I know that no influence or power in the universe (as Paul has said) can come between me and my God. The Urantia Book has taught me that it is my right to approach God simply through the sincerity of my heart and the effort of my will. I do not need to join any human institution or follow any human being to be close to God. I know that if I truly make an effort to pray and listen, grow and work, forgive and serve, then I will experience the full joy of intimate contact with God. I know through the wonderful example of Jesus as portrayed in The Urantia Book, that I can overcome anything and that, in him, I have a loving, understanding and sympathetic brother by my side. I know that humankind is designed for greatness. I know that every act of good helps me grow and is never lost or forgotten, despite appearances. I know that the Spirit of God lives in me and will always be there to guide me. I know that each day is a new beginning. I know all of this and so much more, all because I know The Urantia Book.


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Via has unveiled a 64-bit, VM-enabled x86-compatible chip architecture for green PCs, home servers, and mobile devices. Chips based on the "Isaiah" architecture promise to outperform Via's current C7/Eden chips two-to-three times, within the same power envelope. I like their mini-itx motherboards aloso i wish they had more market penetration so i could shop the nano-itx or mini-itx from local shops from romania too http://mini-itx.com/
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Friday, January 25, 2008
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text:
Stupid Is Just The Tip Of The Iceberg
Museum | Connecticut, USA | Uncategorized
(I work as an artifacts specialist at an exhibit featuring artifacts from the Titanic wreck. We also have a large "iceberg" to show people how cold the water was the night the ship sank.)
Customer: "So is this the actual iceberg that sank the Titanic?"
Me: "No, it's just a frosted piece of plastic to show how cold the water was."
Customer: "So where in this place is the actual iceberg that sunk the Titanic?"


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Patricia Alwick
1,600pages on
this wiki
Add New Page
this wiki
Minor Character: Las Vegas | |
Name | Patricia Alwick |
Gender | Female |
City | Las Vegas |
Status | Alive |
Portrayed By | Alex Kingston |
First Appearance | Art Imitates Life |
Patricia Alwick was a psychologist portrayed by Alex Kingston in CSI: Crime Scene Investigation in 2008.
She was brought in by Conrad Ecklie to try and help the CSI team deal with the recent death of Warrick Brown. She helps David Hodges and Greg Sanders deal with their grief and manages to console Grissom even after he initially thought he needed no help.
She was also the first person to introduce herself to Riley Adams on her first day as a CSI.


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Math Train - Multiplication Division for Kids
- Publisher: Hetal Shah
- Genre: Education
- Released: 30 Dec, 2009
- Size: 4.1 MB
- Price: $0.99
- App Store Info
Math Train teaches kids to Multiply and Divide VisuallyFeatures
1) Animation rich app which shows how to multiply/divide visually
2) Fun reward system (animals playing and dancing to music) to keep the child motivated and keep progressing to higher levels.
3) Animation shown only if the child asks for it. Once the child gets familiar, the visual clue can be turned off by parents.


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It's been four years since we last saw the characters from Ice Age. The ice age is in full swing and the mixed race herd has settled into their new lives. All seems to be going fine and everyone is happy. But along comes a fast talking lizard crying, "Doomsday!" Of course, after the standard misunderstandings, Manny the mammoth finds the threat to be real. Now, along with Diego the saber tooth tiger and Sid the sloth, they must lead the herd to safety at the far end of the valley.
There you have the story upon which are hung many gags and side stories that comprise the movie that is Ice Age: The Meltdown. I hate to say it, but the story felt very tired and drawn out. I didn't find myself connecting with the characters on any level. I'd be lying if I said I wasn't entertained, I was. However, I wasn't captivated by the story. I didn't really buy into the whole flood thing. Sure, I know it's an animated film targeted primarily at kids, but is it too much to ask to have a story that is at least interesting?
Besides the flood and leading the herd out of danger, which seems to be pushed to the side shortly after the initial move, the main characters get their own side stories. The biggest side story would have to be Manny's. Throughout, he is struggling with the possibility that he is the last of the mammoths; that is, until they meet up with Ellie, a mammoth who thinks she is a possum. This leads to much comedy. There is also a thread concerning Diego and his fear of water, which never really takes off. Finally there is Sid, constantly trying to prove himself a worthy part of the herd. Sid also gets to feel the pressure of being at the head of a herd, a pressure he really doesn't want.
I would be remiss if I did not mention the numerous adventures that Scrat has in his attempts to obtain his precious acorn. Interspersed throughout the movie, he has battles with water, piranhas, and a newly hatched vulture. These are among the best parts of the movie, but they also are so numerous they expose how little story there really is. Almost the same can be said about the possum brothers, Crash and Eddie, whose sole reason for being, other than as Ellie's companions, is to provide comic relief.
Ice Age: The Meltdown feels as if it only had about 40 minutes of story and needed a way to pad out the runtime. This padding takes the form of many of those Scrat interludes, and other things like Sid's adventure with the mini sloths. I just felt as if they were purposely shifting the focus around in hopes that you wouldn't notice that the plot never moved anywhere.
The voice acting was decent. John Leguizamo stood head and shoulders above the rest. Despite not really caring about the story, everything with Leguizamo's Sid was gold. He brought an energy and sense of fun to every line and was one of the saving graces of the film. Denis Leary as Diego was pretty good; just the right amount of surly. That brings us to our two mammoths, Ray Romano and Queen Latifah. They are both adequate, but there really isn't much life to the characters.
Bottomline. In the end, I would have to say that it is an entertaining film, even if unfulfilling and not terribly memorable. Definitely geared towards the younger set. I like the Scrat stuff and everything with Sid, but the rest winds up as so much fluff. But the kids will like it, and that is probably the most important part.
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Oakwood Fencing is a small family run business based in Farnborough in Hampshire, offering the Complete Fencing Service and More.
We offer supply/erect (or both) on fencing. At Oakwood we pride ourselves on the quality of our materials and workmanship.
All timber supplied by Oakwood Fencing comes from a re-newable source and all waste material is recycled or disposed of in an enviromentally friendly manner.
All our work is guaranteed and Oakwood are fully insured.
We accept payment via Bank Transfer and Cheque.
If you would like a free quotation or friendly advice then please contact Amanda, Chris or Maurice using the details on the contact page or fill in the contact enquiry form and Amanda or Chris will contact you.


text:
Donaji & the Magical Poncho
This is the story of a fearless girl and her encounter with the wicked cold wind god
4.31 / 5.00 5,364 ViewsGASP! IT'S HERE THE CASTLE CRASH- .... crappers collab?
Don't forget to recomend it for the Castle Crashers and/or Clock Day 09 collections!! :3
Ok guys here's the story...
I sent this message to all the members of the Castle Crashers Collab, "Hello there, this is a message to all the members of the Castle Crashers Collab. August 14th is the joke date. lol :P Let me explain. August 15th is Clock Day as most of you should know. I'm going to submit a submission called "The Castle Crappers Collab"! haha. It's a joke for clock day. All you have to do is make a crappy submission for it. The funny thing is that on Clock Day it'll pass. But you know don't go overboard and make it utter crap alright. This is suppose to be a funny joke not something to piss everyone off and make them zero bomb us all. So make a crappy submission, but not toooooo crappy. K? lol Anyways the day that Castle Crashers was released was August 27th. So that gives you guys about 10 more days for your REAL part. Sound good? The REAL collab will be submitted on August 27th, so I need your REAL parts by August 25th and your FAKE parts August 14th. lol PM me back with your thoughts and comments if you wish. :)
Co-authors: PM me if you want to be coed. I'm not sure how many of you want to yet. if most of you do then I'll just co the best crappy parts. Or maybe the guys who don't get coed in the REAL collab. idk it'd be to soon I guess. Just tell me if you want to be coed for this. :)
I don't need any games or nothin' for the FAKE collab just flashes.
Now thanks to certain people you may have already seen this coming, but I think it was sucessful anyways. SO DON'T WORRY GUYS!! The real collab is coming to the portal on August 27th! :D
Lol, Darpaladon? "they all died and one of them was g@y" lol you make me laugh, 10/10 5/5.
Um... Dan Paladin is the best Animator, and the C&C is the best flash game... The Behemoth rules!
i cant.... i dont.... i cant..... what!? sure have a ... 10... yeah... makes sense.... i think...


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Special equipment: 24 picket fence cupcake liners (available online or baking supply stores) 4 pastry bags, or resealable plastic bags with 1 corner snipped Large star pastry tip (#885 or similar) 4 tier (23 count) cupcake tree (available online home stores)
Preheat the oven to 350 degrees F. Line 2 (12 cup) muffin tins with white paper liners.
Make the cake mix according to package instructions, substituting the milk for water. Pour the batter into the lined muffin tins and bake until golden and a toothpick inserted in the center comes out clean, about 12 to15 minutes. Remove the tins from the oven and let them cool completely on a wire rack.
In a large bowl, using a hand mixer, beat the frosting with enough confectioners' sugar to create a stiff consistency. Divide the frosting among 4 bowls. Color 1 with blue, 1 with red, and 1 with green, leaving 1 white.
When the cupcakes are cool, drop each into a picket fence liner.
Fit 4 pastry bags with large star tips and fill each with a different color. Pipe a swirl of frosting onto 6 cupcakes with 1 color. Repeat with remaining cupcakes and colors. Arrange them on the cupcake tree, alternating colors and top with nonpareil sprinkles.
Recipe courtesy of Sandra Lee
Celebrate the holiday with fun springtime sweets like this adorable bunny cake.


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Russian troops seize Ukrainian navy base in Sevastopol
Latest update : 2014-03-19
Hundreds of Russian troops and pro-Moscow volunteers seized the Ukrainian navy headquarters in Sevastopol on Wednesday, replacing the Ukrainian flag that used to fly over the base with a Russian tri-colour.
Russian soldiers allied with the so-called "self-defence" units of mainly unarmed Crimean volunteers moved in early in the morning and quickly took control of the Black Sea base without meeting resistance from the Ukrainian servicemen stationed there.
Pro-Russian forces said they had also captured the head of Ukraine's naval forces, but FRANCE 24 could not confirm the reports.
The takeover of the naval base comes a day after Russian President Vladimir Putin signed a treaty to annex Crimea following a Sunday referendum in which Crimean residents overwhelmingly backed joining Russia.
Ukraine to introduce visas for visiting RussiansUkraine's foreign ministry has been given instructions to introduce visas for Russians visiting Ukraine, the country's security chief Andriy Parubiy said on Wednesday.
Parubiy, secretary of the National Security and Defence Council, added that Ukraine's government would appeal to the United Nations to declare Crimea a demilitarised zone and take measures for Russian forces to leave the peninsula.
(FRANCE 24 with REUTERS)
A Ukrainian serviceman and a member of a local pro-Russian self-defence brigade were killed by gunfire in Crimea on Tuesday, sparking fears the incidents could escalate tensions on the Black Sea peninsula.
Russians hailed the moves to annex Crimea while Ukraine's new government described the Russian president as a threat to the "civilised world and international security".
The US and Europe have said the referendum was illegitimate and moved Monday to impose new sanctions on Russia, targeting Russian and Crimean officials with visa bans and asset freezes.
Russian news agencies quoted Valery Zorkin, chairman of the Russian Constitutional Courts, telling reporters on Wednesday that the annexation treaty has been found to be valid. The treaty now only needs to be ratified by the Russian parliament.
Ukraine's months-long political crisis hinged on whether to cast its future with the European Union and the West or with Russia. Mass protests erupted after then president Viktor Yanukovich scrapped a trade deal with the EU in favour of closer ties with Russia, with the unrest eventually leading to his overthrow late last month.
Russia has since refused to recognise the new pro-Western government in Ukraine.
Thousands of Russian troops occupied Crimea in the days following Yanukovich's ouster, seizing Ukrainian military bases, blockading others, and pressuring Ukrainian soldiers to surrender their arms and leave.
Putin has said that the Russian troops were in Crimea under a treaty with Ukraine that allows Russia to have up to 25,000 troops at its Black Sea fleet base in Crimea.
(FRANCE 24 with AP and REUTERS)
Date created : 2014-03-19


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Was going to post this yesterday, when I saw the headlines about the murder of Jo Cox. Horrific. See headline. She seemed such a committed, altruistic person. Anyway. Reread this morning what I'd written, and on balance, it's still where I come out, as it were, on the UK'S EU referendum.
Oh dear. Little Englanders, are you really going to vote out?
Let me start again. In my view, Brexit's consequences for Britain? Perhaps not so drastic. Perhaps. Probably be a bit of a recession at first, followed by a recovery, slow or fast. Britain also has a broader commercial outlook over the seven seas than many countries landlocked in Continental Europe. Plus, I'm not so sure Scotland would then depart the UK as quickly as people are saying, with their biggest trading partner suddenly out of the EU. But look if you ask me, the Brits shouldn't have been in such a rush to join the bloody Common Market in the first place, back in 1972. In those days the sun truly never set on their trade relationships worldwide.
But the UK doesn't exist in a European vacuum of course, and Brexit wouldn't be great for the European Union, possibly creating a domino effect and creating waves of financial chaos, or at least a bad case of the shakes, just when the European economy seems to be pulling out of a nose dive. Brexit could also help stoke the fire under the hard right in Central Europe, something I'm not keen on.
As a betting man however, my ha'penny is on a vote 'out' next week… Continue reading


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Invaluable cannot guarantee the accuracy of translations through Google Translate and disclaims any responsibility for inaccurate translations.
Lot 1039: Chinese bronze seated Guanyin and elephant group
Millea Bros "SELECT" (Day 1 of 3)
by Millea Bros. Ltd.
03 November 2016
Boonton, NJ, USA
Live AuctionDescription: Possibly Ming, nice patina, cast in two parts, unmarked, 13.5"h x 16.5"w x 8"d
Condition Report: Good, shows age, pitting, oxidation, probable repair, dings, losses, rubbing
Provenance: The Estate of Gilbert Ireland, NY - Gilbert Ireland served as the display director at Bergdorf Goodman for over 40 years, where his visual artistry led their iconic window designs. Ireland's exceptional aesthetic manifests in his collection of Asian decorative arts, garnered over several decades with partner Robert Galston. For more information, please visit http://www.nytimes.com/1984/11/19/nyregion/extras-at-the-opera-a-silent-but-dedicated-corps.html


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A faulty mass air flow (MAF) sensor can cause erratic/rough engine operation and fuel economy issues. Since this sensor measures the actual amount of air entering the motor, when it fails, the engine control module (ECM) takes the wrong information and delivers incorrect volumes of fuel to the cylinders.
Problem Description and Possible Solution
1 person reported this problem


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Each day we bring you one stunning little glimpse of history in the form of a historical photograph. Enjoy!
Saturday, November 10, 2012
12 comments:
- AnonymousNovember 10, 2012 at 11:12 AM
Seeing the picture of the building, I wondered if you've ever had a movie theater week. I think it would be great to show off some of the grand old movie houses of yesteryear like the Westmont Theater in New Jersey and others. An off-shoot could be old fashioned drive-ins too.
I don't wear a hat on a daily basis, but I do love to wear my stetson every once and a while! - AnonymousNovember 10, 2012 at 11:39 AM
I like hats, primarily to keep my head warm. I don't particularly like baseball caps (although I own several). I do wear a nice wool tweed hat that I picked up in Ireland, on a daily basis.
Graham in St. John's
PS. I have my fingers crossed for a domestic update tomorrow. Can't wait. - AnonymousNovember 10, 2012 at 12:13 PM
I too like hats. I have some Irish caps that I wear when I'm woodworking and a canvas fedora that I wear when I take my get-a-ways. I sure would like a hat like the fella in the picture but my wife assures me it's not my style. My Dad wore a fedora that was common 50 or 60 years ago with businessmen.
The Queen Anne Style was interesting. It is common to see the horizontally accented lines in brick. Most of the old Queen Anne residences burned down but there are a few left in Denver. I had the chance to help rebuild one of them. It had a sway back like an old horse. We placed large jacks in the basement and raised the entire house about 3 inches in the center. At first there was no progress but suddenly it shot up with a boom. I could hear workers yelling in the basement and running out of the building. They were convinced it was collapsing on them. The finished product was beautiful and it made us proud to have restored her.
Will from Lafayette It's interesting to note that hat wearing, specifically fedoras & other 'business' hats, went out of style in the 60s, when the culture became much more casual in dress. Do we want to return to those days? Or should men start a grassroots campaign to bring those hats (not the backward fifties!) back? Should hats be more than movie props?


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In the city - the big city to see girls wear minimal clothing department has become a common sight. But if a man really - really has been accustomed to seeing the scene?
Not really, the men in town - the big city until now had remained still feel powerless when seeing girl with voluptuous ass bikini minimal.


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A Flight Surgeon serves as the liaison between the medical and aviation commands, and has both clinical and non-clinical duties. The clinical duties involve providing primary medical care to all aviation and support personnel, as well as reviewing medical care provided by others and reviewing its impact on the flight status upon an individual, and performing aeromedical and in-flight evaluations. The non-clinical duties involve providing 24-hour on call service, establishing procedures for grounding of crewmen, monitoring the physical and mental health of all aviation personnel, and participate in Flying Evaluation Board (FEB) to determine if personnel are able to perform aviation duties.
View More Job Search Results


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Surely not?
Is the brain 'massively parallel'? Is the brain
a computer? Is the self an illusion? Some ideas have an appeal that gets them
widely adopted in spite of their inherent unlikeliness. In the
cases below we have a go at some widely-accepted ideas which
we think deserve re-examination. It must be pointed out
that we are in two or more minds about some of these. We may at
some stage, for example, see an entry here which denounces the
widely-held view that the brain isn't a
computer... |


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5 sounds
Distant outdoor recording of children playing. The hum of nearby buildings is in the background.
Several tracks of my voice were superimposed to replicate a whispering group of people.
This is a genuine Non-synthesized heart beat sound. I recorded it on a cheap computer microphone, and digitally enhanced it.
5 sounds


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Cheese Herb Stuffed Chicken Breast
This is an easy Mediterrean type chicken dish.
www.recipezaar.com - Similiar recipes
Chicken Feta Soup
Chicken soup with feta cheese, tomato and spinach. A VERY healthy and tasty soup.
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Chile Rub for Chicken
A great rub to use when grilling skinless chicken breasts. I like to use a mortar and pestle to grind the whole cumin seed, salt, oregano, and garlic together....
www.recipezaar.com - Similiar recipes
Chicken Scarpariello Recipe
Pollo alla Scarpariello ~ This is another Italian-American dish that translates as "shoemaker's" style chicken, and consists of golden brown, pieces of...
oregano, +chicken broth, +flour, +garlic, +lemon, +olive oil, +onions, +rosemary, +salt, +butter, +white wine
www.grouprecipes.com - Similiar recipes
Greek-style Chicken
A simple, but tasty chicken recipe. From "365 Ways to Cook Chicken"
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Braised Chicken With Lemon and Honey
Another great recipe from ABC.net's website and Chef Bill Granger. This chicken recipe will also be included in the Zaar World Tour 2005 swap, Australia.
www.recipezaar.com - Similiar recipes
Chicken Meatballs For Spaghetti and Meatballs
Once you try these, you'll never go back to beef meatballs.(Well, maybe YOU will!) I searched all over the Internet for chicken meatballs, and found these...
www.recipezaar.com - Similiar recipes
Baked Chicken Fingers
This is a recipe I created after trying several baked chicken finger recipes. I like this combination of seasonings, but it's always fun to try different...
oregano, +black pepper, +chicken, +corn flakes, +garlic powder, +breadcrumbs, +buttermilk, +olive oil
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Knowing the procedures for lost baggage will limit your anxiety.
If your checked luggage(s) is missing, please see a Malaysia Airlines representative at the baggage services desk immediately upon arrival at the airport. Once a Property Irregularity Report (PIR) has been completed, tracing of the luggage(s) will commence. You can use the file reference number provided to check the status of your baggage online. During the tracing period, you will also be updated regularly.
In rare cases when the missing luggage(s) is not found within five days, a more detailed tracing process will be conducted. Please provide as many details as possible about the luggage(s) and its contents.
Should your baggage not be returned to you after three days, please download, complete and return the form below to the following address to facilitate a more thorough enquiry.
Missing Baggage Questionnaire Form (English)
Borang Soal Selidik Kehilangan Bagasi (Bahasa Malaysia)
Central Baggage Tracing Office
Malaysia Airlines
Level 3, Main Terminal Building
Kuala Lumpur International Airport
64000 Sepang
Selangor, Malaysia
Tel: +603 8776 3747
Fax: +603 8787 4670
Email: firstname.lastname@example.com
Opening times: (Mon–Fri) 9 am–9 pm, (Sat) 9.30 am–12 pm, (Sun) Closed


text:
Welcome to dickblick
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not null?
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Holbein Standard Drawing Inks are a line of brilliant waterproof inks for drawing lines, illustration, comic design, lettering, and architectural perspective. The transparent inks are dye/shellac-based. Use them with pens, brushes, and airbrushes. 30 ml (1 oz) glass dropper bottles.
Hint — click a thumbnail to enlarge.
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Jan is Senior Counsel with Tonkon Torp's Water Law and Environmental & Natural Resources...
Mar 30, 2017 - Ear to the Ground
A Case Study on the Accuracy of Real Market Values on Tax Statements
Mar 23, 2017 - Ear to the Ground
Is the Real Market Value on Your Tax Statement Accurate?
Mar 16, 2017 - Ear to the Ground
Housecalls Are No Longer a Thing of the Past
Mar 09, 2017 - Ear to the Ground
Gunderson Marine Barge Launch—More than Just a Vessel
Mar 02, 2017 - Ear to the Ground
Portland Loves Coworking
Feb 23, 2017 - Ear to the Ground
It Doesn't Take a Weatherman...
Feb 15, 2017 - Ear to the Ground
Portland General Electric Wants to Electrify Your Commute
Feb 09, 2017 - Ear to the Ground
Downtown Parking Lot Facelift Starts With The Collective
Feb 07, 2017 - Ear to the Ground
Mind Your Tail—A Visit to Banfield Pet Hospital's New Corporate Headquarters
Feb 03, 2017 - Ear to the Ground
Water, Water Everywhere: Coming Soon to a Legislative Chamber Near You
Jan 30, 2017 - Ear to the Ground
Longview Coal Terminal Follows Footsteps of Other Unsuccessful Fossil Fuel Export Proposals
Jan 24, 2017 - Ear to the Ground
Out of Sight, but Not Out of Mind
Jan 19, 2017 - Ear to the Ground
Toxic Air Emissions-Time to Tally
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text:
Study Finds Nevada Vulnerable to Corruption
LAS VEGAS -- Only eight states ranked worse than Nevada in a new study that measured the possibility for political corruption.
The study released today by the nonprofit Center for Public Integrity in Washington, D.C., in partnership with Global Integrity and Public Radio International, assigned Nevada a D-minus grade and a ranking of 42nd among the 50 states.
The state received failing grades for lobbying disclosure, ethics enforcement agencies, internal auditing, pension fund management and insurance commission. A D-minus was assigned to the state's political financing, budget process and civil service management. Nevada also received a D for public access to information, legislative accountability and redistricting, a D-plus for judicial accountability, a C-minus for executive accountability and a B-minus -- its best grade -- for procurement.
"Really poor lobbying disclosure. I think, time and again, you see that a lot in states. That's a problem especially in states where it's a smaller government, so there's this real crossover between people in office and the private interest," said Caitlin Ginley with the Center For Public Integrity.
The eight states that received overall failing grades were: Georgia, Maine, Michigan, North Dakota, South Carolina, South Dakota, Virginia and Wyoming. New Jersey, assigned a B-plus, emerged with the best overall grade.
Joan Whitely, who wrote the Nevada story for the first-of-its-kind State Integrity Investigation study, noted that the state's legislative framework factored heavily into Nevada's poor ranking. This includes part-time citizen lawmakers who face potential conflicts of interest "when proposed laws touch their sources of income," she wrote.
"Lobbyists can operate year round, but their networking and hospitality are tracked for a narrow window of time -- just right before, during and right after legislative sessions," Whitely wrote. "Those who lobby members of the executive or judicial branches do not register at all."
Whitely pointed to flaws involving the Nevada Legislature's Interim Finance Committee, which meets between regular legislative sessions.
"Budget changes occurring between sessions violate, at least in spirit, the principle of representative democracy, as only a handful of legislators serve on the Interim Finance Committee that makes changes," she wrote.
Whitely also wrote that the Legislature has exempted itself from open-meeting laws.
"That exemption, critics say, means the public cannot always readily see what legislators do," Whitely wrote.
Despite having had numerous political corruption cases, New Jersey came out on top because it has since implemented some of nation's toughest ethics and anti-corruption laws, according to the study.
Nevada's Ethics Commission says they are limited to what they can do by laws in place since the 1970's. But they do point to their impeachment of former State Treasurer Kathy Augustine on corruption allegations.
"The Ethics Commission does not on its own motion watch public officers and public employees and call them out and give them a speeding ticket, if you will. Instead, when a member of the public brings up conduct to the attention of the commission, the commission's investigator looks at it from a very, very careful standpoint on behalf of members of the public," said Jenkins.
The report also mentioned how Secretary of State Ross Miller has made recent improvements in campaign finance reporting, making more information available to Nevadans online.
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The Telegraph launches subscription-based iPad app utilising Apple's in-app payments
- 0
The Telegraph has today released a refreshed version of its iPad application, introducing a new subscription-based service that aims to emulate the success of its broadsheet paper in the digital market.
Paidcontent reports that the app, created by the same company that helped produce the The Times' iPad application, is a free download but will require users to purchase "editions" for £1.19 each or £9.99 per month, which are processed within the app using Apple's in-app payment platform.
"This event was off the charts"
Gary Vaynerchuk was so impressed with TNW Conference 2016 he paused mid-talk to applaud us.
The announcement and subsequent release of The Telegraph's updated iPad application suggests the company is readying its subscription policies so it can roll out a new paywalled website that will charge readers to access specific websites and services in The Telegraph's portfolio.
Telegraph Media Group (TMG) has already contacted a number of digital agencies to help adapt the Telegraph website, which currently features content from The Daily Telegraph and The Sunday Telegraph.
Sources believe that TMG will adopt a similar strategy to the Financial Times, where it offers limited free access to content before requiring the reader to subscribe to view any additional content. As it stands, TMG says it has not made the decision to place its content behind a paywall but it has been claimed that limited free access with the option to subscribe would be the best way to combat declining print sales.
The pricing of the Telegraph's iPad app is similar to The Times, costing more than the printed broadsheet paper. The increase in price is expected to compensate for Apple's 30% commission fee, which it takes from each new subscription via the iPad application. However, the £9.99 monthly fee introduces a significant saving, directing users towards taking out monthly subscription.
Print subscribers will be able to access the app for free by entering their subscriber number into the application, a clever touch which will ensure the Group doesn't lose readers that want to switch from print to digital editions.
Read next: Remember The Milk releases its intuitive and powerful tasks app on iPad


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High & Low Winery
in Zinfandel Wineries, Riesling Wineries, Merlot Wineries, Chardonnay Wineries, Cabernet Franc Wineries
High & Low – it's not about class; it's about sass. It's your mood, your attitude. Upscale, down home. High flier, low rider. Walking on air, salt of the earth. Shout it from the mountaintop, keep it on the down low. High jump, how low can you go?
588 Medina Rd
Medina, Ohio
United States
It's Your Winery
in White Zinfandel Wineries, Traminer-Riesling Wineries, Sangiovese Wineries, Riesling Wineries, Pinot Noir Wineries, Pinot Grigio Wineries, Merlot Wineries, Malbec Wineries, Liebfraumilch Wineries, Gewurztraminer Wineries, Chardonnay Wineries, Cabernet Sauvignon Wineries
At It's Your Winery, we offer the wine enthusiast the unique experience of making your own wine! You are invited to experience the best in winemaking with the state of the art equipment.
1484 Medina Road (Rte 18)
Suite 113
Medina, Ohio
United States
Leonard Oakes Estate Winery
in Viognier Wineries, Riesling Wineries, Pinot Noir Wineries, Cabernet Franc Wineries
Forged by 4 generations of Oakes; we pay tribute to our founder, Leonard, and invite you to taste our premium wines of distinction.
10609 Ridge Rd
Medina, New York
United States


text:
American Academy of Otolaryngology—Head and Neck Surgery http://www.entnet.org/
National Library of Medicine http://www.nlm.nih.gov/
Canadian Society of Otolaryngology http://www.entcanada.org/
Health Canada http://www.hc-sc.gc.ca/
Earwax. American Academy of Otolaryngology—Head and Neck Surgery website. Available at: http://www.entnet.org/HealthInformation/earwax.cfm. Accessed June 11, 2012.
Seely DR, Quigley SM, Langman AW. Ear candles: efficacy and safety. Laryngoscope . 1996;106:1226-1229.
2/26/2010 DynaMed's Systematic Literature Surveillance DynaMed's Systematic Literature Surveillance: Ear candles: risk of serious injuries. US Food and Drug Administration website. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201108.htm. Published February 20, 2010. Accessed June 11, 2012.
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Announcing New Fellowship for Incoming Student
Admission Requirements
Applicants to the Doctoral Program in Social Work must meet the following criteria:
- Have an MSW with a grade point average of 3.0 or better from a school accredited by the Council on Social Work Education;
- Have a bachelor's degree with a grade point average of 3.0 or better from an accredited college;
- Have a minimum of two years post MSW experience in social work;
- Have values consistent with the profession of social work
Applicants to the PhD Program will be evaluated based on several criteria, including but not limited to applicant's potential for scholarship, knowledge, research, commitment and promise, conceptual and analytical skills, commitment to diversity and disadvantaged populations, letters of reference, professional experience and potential for success in the program.
PhD Application Deadline
The electronic application and all required documents must be submitted/received by January 15.
The Application Process
UConn School of Social Work uses an online self-managed application process. This process places the responsibility on the applicant for the collection and submission of all documents.
The application requires:
- General Application Information – Personal, Enrollment, Citizenship, Educational Institutions, and Employment Experience.
- Recommendations – Three professional references
- Transcripts
- Personal Statement
- Curriculum Vita
- Writing Sample
- Residence Affidavit
- Test Scores – GRE
International Applicants must also provide:
- Test Scores – TOEFL
- Financial Declaration Form
Please note: Any materials submitted in addition to those listed above will not be reviewed as part of the application.
Please see the How to Apply for PhD and read the Application Instructions before starting the online application. The Application Instructions contain detailed information regarding each of the required application pieces. For additional information, download the PowerPoint from our Application Workshop held October 13, 2016.
Access the Online Application on the How to Apply for PhD page
Questions? If you have questions regarding the application process or have trouble uploading documents, please contact the PhD Program office at 860.570.9323.