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Polycystic kidney diseases (PKDs) comprise a subgroup of ciliopathies characterized by the formation of fluid-filled kidney cysts and progression to end-stage renal disease. A mechanistic understanding of cystogenesis is crucial for the development of viable therapeutic options. Here, we identify CDK5, a kinase active in post mitotic cells, as a new and important mediator of PKD progression. We show that long-lasting attenuation of PKD in the juvenile cystic kidneys ( jck ) mouse model of nephronophthisis by pharmacological inhibition of CDK5 using either R-roscovitine or S-CR8 is accompanied by sustained shortening of cilia and a more normal epithelial phenotype, suggesting this treatment results in a reprogramming of cellular differentiation. Also, a knock down of Cdk5 in jck cells using small interfering RNA results in significant shortening of ciliary length, similar to what we observed with R-roscovitine. Finally, conditional inactivation of Cdk5 in the jck mice significantly attenuates cystic disease progression and is associated with shortening of ciliary length as well as restoration of cellular differentiation. Our results suggest that CDK5 may regulate ciliary length by affecting tubulin dynamics via its substrate collapsin response mediator protein 2. Taken together, our data support therapeutic approaches aimed at restoration of ciliogenesis and cellular differentiation as a promising strategy for the treatment of renal cystic diseases.
The recognition of the role of primary cilia in human disease has led to remarkable advances in our understanding of the function of this organelle in vertebrate development. Among the initial discoveries that compelled these investigations was the discovery that a number of proteins implicated in human polycystic kidney disease (PKD) localized to primary cilia. Since then, primary cilia have been characterized as crucial modulators of developmental signaling pathways including those mediated by Hedgehog, Wnt, Notch and platelet-derived growth factor alpha ( 1 ). Mutations of genes whose products localize to cilia or are required for their formation or function have been implicated in disorders now known collectively as ciliopathies, which are notable for their wide variety of symptoms, including obesity, retinal defects, skeletal defects, brain anomalies and, as noted, PKD ( 2–5 ).
Indeed, PKD is a feature of many of the ciliopathies, as well as the major cause of morbidity and mortality of these disorders. Autosomal dominant PKD (ADPKD) is one of the most common human monogenic diseases with an estimated incidence of 1:400–1:1000. ADPKD affects over 12 million people worldwide and is characterized by the development and progressive enlargement of fluid filled renal cysts leading to end-stage renal disease in 50% of affected individuals by the age of 60 years ( 6–9 ). ADPKD arises from mutations in either the PKD1 or PKD2 genes; their protein products PC1 and PC2 both localize to the ciliary membrane where they form receptor-channel sensory complexes ( 10 ). While ADPKD is primarily an adult disorder, the autosomal recessive PKD syndrome nephronophthisis (NPHP) is the most common genetic disease causing end-stage renal disease in children and adolescents ( 11 , 12 ). NPHP is a genetically heterogeneous disorder with 20 identified genes, most of which have been shown to play a role in cilia function. One of them, NPHP9, is caused by missense mutations in the kinase NEK8, which localizes to the ciliary axoneme ( 13 ). Nek8 was originally characterized as the gene mutated in the mouse mutant juvenile cystic kidneys ( jck ) and the development of PKD in this model of NPHP was described previously ( 14 , 15 ). Interestingly, all the cystogenic Nek8 alleles, including that of the Lewis Polycystic Kidney rat ( 16 ), are missense mutations in its RCC domain, which potentially regulates protein interactions. Null mutations of Nek8 result in developmental defects in mice and humans ( 17 , 18 ) and genetic evidence suggests the jck missense mutation results in a gain-of-function ( 17 ). NEK8 was also identified as a critical component of the DNA damage response that links replication stress with cystic kidney disorders ( 19 ). The first ciliopathy genes described to function within the DNA damage response have been ZNF423, CEP164 and MRE11 ( 20 ). Interestingly, cyclin-dependent kinase (CDK) inhibition by R-roscovitine can cause nuclear translocation of CEP164 and inhibition of CHK1 activation ( 20 ). Of note, cilia lack the capacity for protein synthesis; therefore, all ciliary components are delivered by a specific transport pathway for protein trafficking referred to as intraflagellar transport (IFT). Defects in components of this process are also well-documented causes of PKD ( 21–23 ).
Cystogenesis is accompanied by characteristic changes in tubular epithelial cells including increased proliferation, apoptosis, acquisition of a secretory phenotype, intracellular calcium and cAMP signaling and dysregulation of the cell cycle; the last is the focus of this report. In normal cells, cilium is dynamically regulated by cell cycle transition: cilia assemble after cells exit mitosis and are resorbed during cell cycle re-entry. Reciprocally, the cilia itself is capable of influencing cell cycle as cilia resorption allows the basal body to differentiate into the centrosome, which performs important functions in mitosis as the organizer of the mitotic spindle ( 1 , 24 ). These data support the idea that a dysregulated cell cycle may drive cystogenesis and that therapeutic intervention targeting cell cycle dysregulation could provide therapeutic benefit for PKD. We have shown previously that pharmacological inhibition of cell cycle progression with pan CDK inhibitor, R-roscovitine, effectively attenuates cystogenesis in multiple models of PKD ( 25 , 26 ). Importantly, continuous daily administration of drug was not required to achieve efficacy; pulse treatment provided long-lasting arrest of PKD in jck model of PKD ( 25 ). While mechanistic studies demonstrated that R-roscovitine acted via cell-cycle arrest, transcriptional inhibition and blockade of apoptosis, the mechanism responsible for its long-lasting effect was not known ( 25 ). A recent efficacy study using R-roscovitine and S-CR8, a more potent second-generation analog of R-roscovitine ( 27 , 28 ), has confirmed its effectiveness in an orthologous mouse model with conditionally inactivated Pkd1 genes ( 26 ). Importantly, R-roscovitine and S-CR8 share similar protein kinase selectivity profiles targeting CDK1, CDK2, CDK7, CDK9, as well as CDK5, which is an atypical member of the CDK family ( 27 , 29 ). Unlike mitotic CDKs, CDK5 is regulated by proteins p35 and p39, not by cyclins, and plays an important role in maintaining cellular differentiation in post-mitotic cells ( 30 ).
CDK5 is a multifunctional kinase that plays an important role in regulating diverse cellular functions including differentiation, organization of focal adhesion and cytoskeleton, membrane dynamics, cellular metabolism, cell cycle arrest in post mitotic cells and cell survival, as reviewed in Ref. ( 30 ). Abnormal CDK5 activity has been actively studied in neurodegenerative diseases with hyperactivation of CDK5 with p25, the product of calpain-dependent proteolytic cleavage of p35 ( 31 ). The role of CDK5 in non-neuronal tissue is not well understood. Recent data suggest the possible function of dysregulated CDK5 in a number of kidney diseases, where it may play a pathogenic role by promoting cellular de-differentiation and apoptosis ( 25 , 32–36 ).
In this study, we investigated the specific role of CDK5 in promoting renal cystogenesis. We hypothesized that the long-lasting arrest of cystogenesis observed upon treatment with the pan-CDK inhibitor R-roscovitine is at least partly attributable to the inhibition of CDK5 and the restoration of cellular differentiation. Here, we report that pulse treatment of jck mice with the CDK inhibitors R-roscovitine and S-CR8 results in the reversal of cystic epithelial morphology to that of normal tubular epithelial cells, the normalization of the pattern of expression of markers of renal cell differentiation and the mitigation of the abnormal lengthening of cilia seen in jck kidneys. To directly investigate the role of CDK5 in PKD, we generated and characterized jck mice with a conditionally inactivated Cdk5 gene. We show that loss of CDK5 reduces cystogenesis, improves kidney function, reduces ciliary length and normalizes morphology of cyst-lining kidney epithelial cells. Selective inhibition of CDK5 promotes cellular differentiation and restoration of normal cellular phenotype and therefore represents a viable treatment option for PKD.
Arrest of cystic disease in jck mice with R-roscovitine and S-CR8 is linked to a long-lasting reduction of ciliary length and restoration of renal epithelial phenotype
We and others have shown that cilia of kidney epithelial cells are lengthened in jck mice (8.5 ± 2.5 µm) compared to wild-type controls (2.5 ± 1.5 µm) ( 15 , 37 ). We examined whether the reduction in cystic disease progression conferred by treatment with R-roscovitine ( 25 ) had an effect on the ciliary length in treated kidneys. As shown in Figure 1 , cilia are markedly elongated in kidneys from jck mutant mice and continuous R-roscovitine treatment for 5 weeks mitigates this abnormality ( Fig. 1 B and C). Importantly, this reduction in ciliary length is maintained when kidneys were examined 2 weeks after withdrawal of R-roscovitine treatment ( Fig. 1 B and C). As shown in Figure 1 C, R-roscovitine restores ciliary length to levels comparable to wt controls but does not abrogate cilia formation. Of note, this is not due to persistent exposure to the drug, since pharmacokinetic analysis shows that R-roscovitine is eliminated within 24 h post-administration ( 38 ).
In addition to the reduction in cilia length, we noted that epithelial cells in the treated mice appeared to have a more ordered columnar appearance ( Fig. 1 B). To assess whether this was possibly due to a restoration of cellular differentiation, we assayed the cell state by immunostaining for the mesenchymal markers vimentin and alpha smooth muscle actin (αSMA) and the epithelial marker cytokeratin, which have been shown to be aberrantly expressed in PKD ( 39 , 40 ). We found that kidney epithelial cells are in a de-differentiated state in jck mice, demonstrating increased expression of vimentin and αSMA in the interstitial tissue and cystic epithelial cells and decrease expression of cytokeratin ( Fig. 1 D). In contrast, these markers appeared normally expressed in kidneys from jck mice treated with R-roscovitine, even 2 weeks after treatment withdrawal ( Fig. 1 D).
We similarly investigated the in vivo effect of S-CR8, a more potent and selective second-generation analog of R-roscovitine ( 27 , 41 ). Given the robust efficacy of pulse treatment with R-roscovitine in jck mice, we compared continuous and pulse treatment regimens of S-CR8. For this, we used several schedules of treatment: 24 mg/kg of S-CR8 was administered daily for 5 weeks (schedule 1); or for 3 weeks, followed by 2 weeks without treatment (schedule 2) or for 1 week, followed by 4 weeks without treatment (schedule 3) ( Fig. 2 A). Administration of S-CR8 according to schedules 1 and 2 showed similar reductions of cystogenesis compared to untreated mice, as shown by significant decreases of kidney to body weight ratio (Kidney/BW), cystic volume and blood urea nitrogen (BUN) ( Supplementary Material, Table S1 ). The disease metrics in mice treated using schedule 3 were increased compared to those observed in schedules 1 or 2, suggesting that the therapeutic effect wanes after an extended period (4 weeks) without treatment ( Supplementary Material, Table S1 ).
Next we tested the effect of S-CR8 treatment on cellular phenotypes. S-CR8 administered according to schedules 1 and 2 resulted in a marked reduction of cilia length ( Fig. 2 B and C) similar to that observed with R-roscovitine. We also observed restoration of the normal pattern of vimentin, αSMA and cytokeratin expression ( Fig. 2 D). This normalization of phenotype is less evident in schedule-3-treated mice ( Fig. 2 B–D), again consistent with a reversion to the de-differentiated state with a longer time frame of 4 weeks after treatment.
Specific targeting of CDK5 leads to cilia shortening in vitro
Since both R-roscovitine and S-CR8 inhibit multiple CDKs including CDK1, 2, 5, 7 and 9, it is not clear which CDK is responsible for long-lasting restoration of epithelial differentiation and reduction of cilia length. We asked whether CDK5 plays a pivotal role in regulating these cellular processes. First, we conducted in vitro experiments in a previously described immortalized jck kidney epithelial cell line ( 42 ) using selective inhibition of CDKs with small interfering RNA (siRNA). A shown in Figure 3 , knock down of CDK5 in jck cells resulted in significant shortening of ciliary length, similar to what was observed with R-roscovitine. Knock down of CDK2 did not have this effect ( Fig. 3 ).
Genetic loss of Cdk5 inhibits cystogenesis, reduces cilia length and promotes renal epithelial cell differentiation
To further determine whether CDK5 plays a pathogenic role in PKD progression in vivo , we investigated the effect of genetic reduction of Cdk5 in jck mice. Cdk5 null mutant mice are embryonic lethal ( 43 ); consequently, we crossed jck animals with Cdk5 conditional knock out animals and used the tamoxifen-inducible Gt(ROSA)26Sortm1 allele as a cre-driver ( Supplementary Material, Fig. S1 ). Cdk5 deletion was induced at 4 weeks and kidneys were examined at 9 weeks. Western analysis revealed that CDK5 protein expression was markedly, albeit not completely, reduced ( Fig. 4 A). Comparative analysis of jck mice and jck mice with conditionally inactivated Cdk5 ( jck;Cdk5 cKO ) showed a qualitative mitigation of disease progression after Cdk5 deletion ( Fig. 4 B), as well as quantitative reductions in Kidney/BW, cystic volume and BUN ( Fig. 4 C and Supplementary Material, Table S2 ).
As reported above, the mitigation of PKD progression after R-roscovitine treatment correlates with a normalization of renal epithelial cell phenotypes. We examined whether this is also true in the conditional Cdk5 deletion model. Scanning electron microscopy (SEM) analysis of affected kidneys showed that genetic deletion of Cdk5 in jck mutant mice results in decreased cilia length compared to that observed in jck kidneys ( Fig. 5 A and B). Expression of vimentin and αSMA appears less dysregulated in kidney tissue from jck;Cdk5 cKO mice ( Fig. 5 C). These results show that pharmacologic and genetic attenuation of Cdk5 activity in a cystic kidney model result in similar effects on disease progression and renal cell differentiation.
Inhibition of CDK5 affects kidney expression of its specific substrate, collapsin response mediator protein 2
It has been shown previously that cilium length can be regulated through velocities of IFT machinery ( 44 ). To investigate whether such mechanism can explain the CDK5 mediated regulation of the cilium length, we analyzed IFT transport velocity by using fluorescently labeled IFT88 cells in the presence of R-roscovitine or Cdk5 siRNA. We did not observe any effect on IFT particle velocities in the presence of CDK5 inhibitors ( Supplementary Material, Fig. S2 ).
It is also possible that CDK5 might regulate ciliary length by affecting the dynamics of microtubules. To investigate this possibility, we set out to first identify possible downstream effectors of CDK5 in the kidneys. We compared kidney proteomes of wt, jck mice and jck mice with conditionally inactivated Cdk5 gene ( jck;Cdk5 cKO ) using mass spectrometry and identified 394 proteins that specifically changed as a result of genetic deletion of Cdk5 ( Supplementary Material, Table S3 ). This set was cross-referenced with 40 newly identified brain-specific CDK5 substrates from CDK5 -/- mice ( 45 ). As a result, we identified six possible kidney-specific CDK5 effectors: alpha-adducin ( Add1 ) dihydropyrimidinase-like 2 ( Dpysl2 ), dihydropyrimidinase-related protein 3 ( Dpysl3 ), MARCKS-related protein ( Marcksl 1 ), programmed cell death protein 4 ( Pdcd4 ) and small nuclear ribonucleoprotein 70 (U1) ( Snmp70 ). We have further investigated Dpysl2 , also known as collapsin response mediator protein 2 (CRMP2), because of its known function as a regulator of microtubule dynamics in neurite outgrowth in the brain ( 46 ).
To that end, we evaluated the levels of total CRMP2 and its CDK5-specific phosphorylated form p-CRMP2 (Ser522) in kidneys from jck mice with conditionally inactivated Cdk5 ( Fig. 5 D). Total CRMP2 and p-CRMP2 (Ser522) are elevated in jck kidneys compared to wild type and decreased in jck;Cdk5 cKO kidneys. Next, we examined whether specific depletion of CRMP2 in cultured jck cells leads to cilia shortening. As shown in Figure 5 E and F, knock down of CRMP2 resulted in shortening of cilia similar to that observed previously with Cdk5 knock down ( Fig. 3 ).
These results suggest that CDK5 may play an important role in regulating cilia length in kidney, at least in part, via its direct target CRMP2.
While treatment options for PKD and other ciliopathies are presently very limited, recent advances in characterizing the molecular pathogenesis of these disorders have suggested new therapeutic possibilities ( 47 ). The results presented here reveal the previously unrecognized role of CDK5 dysregulation in renal cystic disease, which affects primary cilia length and tubular epithelial differentiation. Mechanistic studies suggest that CDK5 may act through its downstream target CRMP2 by altering microtubule dynamics and thereby affecting cilia length. Moreover, our findings identify CDK5 as a new and attractive therapeutic target for the treatment of PKD because of its ability to induce sustained epithelial differentiation.
While CDK5 is ubiquitously expressed in all tissues, its role, along with the activator proteins p35 and p39, has been mainly studied in brain, where it is shown to regulate neuronal differentiation, migration and cytoskeletal dynamics ( 30 , 48 ). We have previously shown that R-roscovitine, an inhibitor of CDK1, 2, 5, 7 and 9, arrests cystogenesis in multiple models of PKD via blockade of the cell cycle, induction of apoptosis and transcriptional inhibition ( 25 ). We were particularly intrigued by our observation of a long-lasting therapeutic effect after withdrawal of drug. The specific mechanism of this observation is not known. We have hypothesized that CDK5 plays a role in regulating kidney tubular epithelial differentiation and that this accounts for the mechanism of sustained efficacy with pulse treatment. We have previously shown that CDK5 is, in fact, hyperactivated in cystic kidneys by the conversion of p35 to p25, similar to neurodegenerative diseases ( 25 , 48 ). SEM analysis of kidneys treated with R-roscovitine or its analog S-CR8 either continuously for 5 weeks or treated for only 3 weeks followed by 2 weeks off-drug resulted in dramatic improvement of epithelial morphology. Specifically, we observe a more normal columnar epithelium, as well as reduction of cilia length, which is abnormally elongated in jck kidneys ( 15 ). These data suggested that both R-roscovitine and S-CR8 treatment may restore cellular differentiation. De-differentiation and perturbation of polarized epithelial phenotype represent an important aspect of PKD pathogenesis that is common to disorders caused by different genetic mutations ( 39 , 40 ). Indeed, we have shown restoration of epithelial differentiation by analysis of specific cellular markers. Interestingly, even a short pulse treatment with S-CR8 for only 1 week followed by 4 weeks off-drug showed effective PKD inhibition; however, examination at this time point shows a reversion of epithelial differentiation along with aberrant cilia elongation.
Our data show that pharmacological inhibition of PKD progression is accompanied by a clear effect on ciliary length. This is a particularly interesting finding in view of recent discovery demonstrating that genetic loss of cilia in mouse models of ADPKD actually inhibits cystogenesis ( 49 ). The authors demonstrated a protective effect of the loss of cilia on cystic growth in models with polycystin-1 and polycystin-2 mutations; however, the mechanism for these findings has not been explained. It is tempting to speculate that similar mechanisms can explain our observations. Of note, we and others have previously reported that the Nek8 mutation in jck mice causes aberrant expression and localization of both polycystins-1 and -2 ( 15 , 37 ).
To prove that shortening of cilia and effect on cellular differentiation that we observed with R-roscovitine or S-CR8 treatment is mediated by inhibition of CDK5 specifically, we conducted an in vitro experiment in a jck kidney epithelial cell line with selective inhibition of CDK5 using siRNA. We found that only Cdk5 -specific knock down reduced primary cilia length in jck cells. To further investigate the role of CDK5 in PKD, we generated and characterized jck mice with conditionally inactivated Cdk5 gene. Analysis of these jck;Cdk5 cKO mice at 64 days of age showed significant attenuation of PKD compared to that seen in unmodified jck mice. Most importantly, genetic reduction of Cdk5 in jck mice resulted in the restoration of kidney epithelial cell differentiation, normalized cellular morphology and cilia shortening similar to what we observed with pan-CDK inhibitors, supporting a pivotal role for CDK5 in these cellular processes.
Recent findings suggest that CDK5 is localized to the centrosome in HeLa cells where it may participate in cilia formation ( 50 ). It has also been previously proposed that cilia length can be regulated through the modulation of retrograde and anterograde cargo trafficking along the axoneme ( 44 , 51 ). We have shown that CDK5 inhibition with either R-roscovitine or siRNA did not affect the velocities of the cargo trafficking, suggesting another mechanism must account for shortening of primary cilia length. Because little is known about the role of CDK5 or its substrates in the kidney, we examined the significant body of data describing the role of CDK5 and its substrates in neuronal tissue. Cross referencing brain-specific CDK5 substrates and the proteome of jck;Cdk5 cKO kidney, we identified CRMP2 protein as a possible substrate for CDK5 in the kidney ( 45 ). CRMP2, the product of Dpysl2 gene, is a multifunctional phosphorylated protein that has been widely studied in the brain where it was shown to play an important role in microtubule assembly promoting axon formation, neurite outgrowth and elongation in neuronal cells ( 46 , 52 ). Importantly, recent studies conducted in fibroblasts identified CRMP2 as a protein critically involved in primary cilia formation ( 53 ). Our data suggest a role of CDK5 and its substrate, CRMP2, in maintaining cilia length in the kidney. We showed that total CRMP2 and p-CRMP2 (Ser522) are increased in cystic disease and that the reduction of CDK5 leads to decreased level of both total CRMP2 and p-CRMP2. Interestingly, very recent findings by Maskey et al. described intriguing involvement of CDK5 in regulating the FBW7-NDE1 pathway and its presumptive modulation of cilia length in a cell cycle-dependent manner, at least in vitro ( 54 ). It is possible that CDK5 may act through multiple downstream targets and therefore, its function in kidneys needs to be further investigated in subsequent studies in multiple disease settings.
In conclusion, data presented here identify a critical role of CDK5 in controlling ciliary length and tubular epithelial differentiation. Pharmacological or genetic reduction of CDK5 leads to effective and sustained arrest of PKD. We propose that CDK5 acts on primary cilia, at least in part, by modulating microtubule dynamics. We suggest that new therapeutic approaches aimed at restoration of cellular differentiation are likely to yield effective treatments for cystic kidney diseases.
Materials and Methods
Mouse colony handling, genotyping and treatment
Jck mice (C57BL/6J-Nek8 jck ) were kindly provided by Dr David Beier ( 55 ). Jck mice were bred at Biomedical Research Models "BRM" (Worcester, MA) and treated with R-roscovitine or S-CR8 at Sanofi-Genzyme R&D Center. R-roscovitine (150 mg/kg) and S-CR8 (24 mg/kg) were administered daily intraperitoneally (IP) as previously described ( 26 ).
CDK5 cKO mice (B6.129S4(Cg)-Cdk5 tm1.1Lht /J) and Cre recombinase (B6;129-Gt(ROSA)26Sor tm1(cre/ERT)Nat /J) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and maintained at the McLaughlin Research Institute (Great Falls, MT) ( 56 , 57 ). The breeding scheme is depicted in Supplementary Material, Fig. S1 . Briefly we crossed jck heterozygous male with Cdk5 cKO homozygous females in a first set of mating and Cdk5 cKO homozygous females with Cre recombinase males in a second set of mating. Jck heterozygous/ Cdk5 cKO heterozygous mice were then crossed with Cdk5 cKO heterozygous/ Cre recombinase heterozygous mice. Finally, Jck heterozygous/ Cdk5 cKO homozygous animals were finally crossed with jck heterozygous/ Cdk5 cKO homozygous/ Cre recombinase heterozygous animals to obtain the control animals: jck homozygous/ Cdk5 cKO homozygous (herein called " jck ") and the target animals: jck homozygous/ Cdk5 cKO homozygous/ Cre recombinase heterozygous (herein called " jck;Cdk5 cKO "). Cdk5 recombination was induced upon IP injections of 250 mg/kg of body weight of Tamoxifen in 4-week-old animals. All mice were handled in accordance with McLaughlin Research Institute, BRM and Genzyme respective Institutional Animal Care and Use Committees guidelines. Genotyping was performed by Transnetyx (Cordova, TN) using a proprietary PCR-based assay. S-CR8 was synthesized as previously described ( 58 ). Treatment with S-CR8 was performed by IP injection of 24 mg/kg in 2% Tween 80, 0.3% lactic acid in M/6 sodium lactate once daily from day 26–64 after birth. All animals were euthanized by CO 2 asphyxiation. Tissues harvested for histological analysis were fixed either in Karnovsky's fixative for SEM or 4% paraformaldehyde (Electron Microscopy Science, Hatfield, PA) for histology analyses. BUN levels were measured using a VetACE TM analyzer (Alfa Wasserman, West Coldwell, NJ).
SEM, histology and quantitative analyzes of cystogenesis
For SEM the cilia were imaged at the Schepens Eye Research Institute (MEEI, Boston, MA). Mouse kidneys were fixed for 48 h in 1/2 strength Karnovsky's fixative (2% paraformaldehyde + 2.5% glutaraldehyde in phosphate buffer, pH 7.4). Tissue samples were then rinsed three times in PBS, dehydrated in a graded series of Ethanol baths (35%, 50%, 70%, 95% and 2X 100% for 30 min each) and critical point dried in a Tousimis Samdri-795 Critical Point Dryer (Tousimis, Rockville, MD). Finally, kidney samples were mounted on aluminum stubs and coated with a 150A Chromium layer in a GATAN Ion Beam Coater 610. Cilia were viewed on a JEOL Field Emission Scanning Electron Microscope FESEM 7401F (JEOL, Peabody, MA). Cilia length was quantified with MetaMorph Imaging Series® software (Molecular Devices Corp, Dowington, PA). Cilia length distribution was calculated by measuring cilia in ≥20 random fields per sample. Total number of cilia measured in each group were ≥400. Statistical analysis was performed using GraphPad prism software (GraphPad Software, San Diego, CA). To determine whether these values differed significantly between experimental groups, P values were obtained using an unpaired parametric t -test.
For histological analysis, kidneys were cut 4 μm thick from both sagital and transversal sections and stained with hematoxylin and eosin using a Tissue Tek® 2000 processor (Sakura-Finetek, Torrance, CA). Slides were digitized with a Nanozoomer digital slide scanner (Hamamatsu, Bridgewater, NJ) and processed with the Metamorph Software (Molecular Devices Corp). Cystic volume was measured as percentage of cystic area to a total section area normalized by body weight.
Immunohistochemistry and immunofluorescence
Paraformaldehyde-fixed paraffin-embedded sections were deparaffinized and subjected to antigen retrieval as previously described ( 59 ). Staining for immunohistochemistry was performed using a Leica Vision Biosystems BondMax Immunostainer apparatus using Bond Polymer Refine Detection Kit (Leica Microsystems, Buffalo Grove, IL). Anti-vimentin (Epitomics, Burlingame, CA) or αSMA (Abcam, Cambridge, MA) antibodies were diluted in an antibody dilution reagent (Dako Corporation). Slides were counterstained with hematoxylin prior to mounting and digitized with a Nanozoomer digital slide scanner (Hamamatsu, Bridgewater, NJ).
Staining for immunofluorescence (IF) was performed as described previously using anti cytokeratin 18 antibodies (Sigma-Aldrich) ( 59 ). IF images were acquired on a Leica DM5500B microscope fitted with x40 objectives using Leica Application Suite Advance Fluorescence software (Leica Microsystems).
Cell culture, siRNA transfection and primary cilium staining
Wild type, jck and jck;Cdk5 cKO cell lines were established and maintained as described previously ( 42 , 60 ). Jck cells were cultured on collagen I coated glass slides (BD biosciences, SanJose, CA) and transiently transfected with negative control siRNAs, CDK2, CDK5, CDK7 or CRMP2 siRNA (Life Technologies, Carslbad, CA) using lipofectamine RNAiMAX as recommended by the manufacturer (Life Technologies). After transfection, cells were cultured for 48 h in complete culture medium and for an additional 48 h in serum-free medium. To study the role of R-roscovitine, cells were cultured for 48 h on collagen I-coated glass slides in complete culture medium followed by an additional 48 h in serum-free medium containing 20 μM R-roscovitine. Cells were then fixed with 4% paraformaldehyde followed by IF with anti-acetylated α-tubulin antibodies as previous described ( 15 ). Cilia length measurements and analyses were performed as described earlier.
Sodium dodecylsulfate poly-acrylamide gel electrophoresis and immunoblotting
Kidneys from mice were homogenized with 2.8 mm zirconia beads (Mo Bio Laboratories, Carlsbad, CA) using a Omni Bead Ruptor bead beater (Omni International, Kennesaw, GA) in radio immunoprecipitation assay buffer (Boston Bioproducts, Ashland, MA) complemented with complete protease inhibitors, 240 μg/ml Pefablock (Roche Diagnostics Corp, Indianapolis, IN), 1 mM NaVO 4 and 2 mM NaF (Sigma-Aldrich). Cell debris was pelleted by 10 min centrifugation at 20 000 g at 4ºC, supernatants were harvested and protein concentrations were determined with Pierce BCA protein assay (Pierce/Thermoscientific, Rosckford, IL). Equal protein amounts were resolved by 4–12% gradient sodium dodecylsulfate poly-acrylamide gel electrophoresis and transferred onto nitrocellulose membranes using iBlot device (Life Technologies). Membranes were probed with antibodies against CDK5 (Cell Signaling, Danvers, MA), CRMP2 (Abcam, Cambridge, MA), p-CRMP2 (Ser522) (ECM Biosciences, Versailles, KY) or β-actin (Abcam, Cambridge, MA) overnight at 4 °C as previously described ( 15 ). Membranes were washed in 1x Tris Buffered Saline 0.05% Tween 20 and incubated with anti-mouse or anti-rabbit IgG HRP-conjugated secondary antibodies (Promega, Madison, WI). Immunoreactive proteins were detected using enhanced chemi-luminescence (Amersham/GE, Little Chalfont, Buckinghamshire, England).
Data are expressed as means ± SEM. Comparisons were made by two-tailed t- test and significance was accepted at the 0.05 level of probability ( P < 0.05).
Supplementary material
Supplementary Material is available at HMG online.
The authors would like to thank Ann Tisdale for SEM imagining, Thomas Natoli, Vijay Modur, Katherine Klinger and Seng Cheng for stimulating discussions, Petra Oliva and Yuefeng Lu for critical comments on the manuscript.
Conflict of Interest statement . H.H., S.M., L.A.S., M.A.S., S.R.L., R.J.R, N.O.B., M.L, K.Z. and O.I.-B. are employees of Sanofi-Genzyme R&D Center. L.M. and K.B. are employees of ManRos Therapeutics. All other authors have declared no conflicts of interest.
This work was supported by Sanofi-Genzyme. Funding to pay the Open Access publication charges for this article was provided by Sanofi-Genzyme.


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A&A Heating & Airconditioning
Heating, Gas Heating, Ducted Heating
We can service and supply Reverse Cycle Heat Pump Systems to Ducted Gas Units.
We "think outside the box" with our approach this means innovative designs to meet specialized needs, as there is always a solution for all your heating needs in Canberra.
We can also design zoning systems to provide maximum energy efficiency of your heating or airconditioning systems whether they be a day/night zoning system or singular room control systems.
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Doctor insights on:
Celiac Disease And Acupuncture
Is celiac disease serious?
Can be: Think of the digestive tract as an assembly line where food comes in, is reduced to its parts, then moved into the body where the parts can be re-assembled into usable material.In celiac, the protein allergy injures the gut, reducing the ability to move any parts into the body.If the injury is bad enough you waste away and remain sickly. By avoiding the gluten, the body can heal & the system work ...Read more
Acupuncture (Definition)
Acupuncture is a treatment based on Chinese medicine -- a system of healing that dates back thousands of years. At the core of Chinese medicine is the notion that a type of life force, or energy, known as qi (pronounced "chee") flows through energy pathways (meridians) in the body. Each meridian corresponds to one organ, or group of organs, that governs particular bodily functions. Achieving the proper flow of qi is thought to create health and wellness. Qi maintains the dynamic balance of yin and yang, which are complementary opposites. According to Chinese medicine, everything in nature has both yin and yang. An imbalance of qi (too much, too little, or blocked flow) causes disease. To restore balance to the qi, an acupuncturist inserts needles at points along the meridians. These acupuncture points are places where the energy pathway is close to the ...Read more
How to know it is celiac disease?
A biopsy: There are blood tests that provide some evidence, but they are not totally reliable. A small bowel biopsy is the only absolute diagnostic test. Visit celiac.Org (celiac disease foundation). ...Read more
What is refractory celiac disease?
Hard to treat: "refractory" is a fancy medical term for something that is hard to treat. In other words, the disease is not getting any better using standard treatment. In this case, it's talking about celiac disease, or gluten intolerance. ...Read moreSee 1 more doctor answer
What is refractory celiac disease?
Celiac Disease: It means that the patient is still experiencing symptoms and side effects of the celiac disease despite disease modifying changes in diet (avoidance of gluten), lifestyle and possibly medication. ...Read moreSee 1 more doctor answer
What pp is safe in celiac disease?
PPI: I don't think ppis are contraindicated in celiac disease or any certain ppi that should be avoided. Ppis work on the stomach mucosa whereas celiac disease usually involves duodenum. ...Read more
How to know if I have celiac disease?
Are u symptomatic: Classic symptoms are bloating, gas, abdominal discomfort and/or loose stool. ...Read moreSee 1 more doctor answer
How to tell if you have celiac disease?
Blood test, scope : Screening blood tests can be ordered by your health care provider: tissue transglutaminase IgA and total iga. If positive, consultation with a GI specialist is needed for biopsy of the small intestine obtained through an upper GI endoscopy. It is important not to go on a gluten free diet before diagnosis is made. Labs and biopsy return to normal on gluten free diet (false negative). ...Read moreSee 1 more doctor answer
What are the symptoms of celiac disease?
Grieving gut: Here's their info: http://celiac.org/celiac-disease/symptoms/ Bloating, pain, diarrhea, gas, constipation - general misery around food. Many find avoiding gluten helpful. Best! ...Read moreSee 2 more doctor answers
What are the symptoms of celiac disease?
Usually diarrhea: Celiac disease, among its many manifestations, may result in diarrhea. Simplistically, exposure of intestine to gluten causes inflammation of affected gut lining, with a decrease in absorptive surface of that gut, & resulting malabsorption of food. The best & most enduring fix is to avoid eating gluten. Serum tissue transglutaminase antibody can help determine how successfully gluten is avoided. ...Read more
What are the symptoms to celiac disease?
Diarrhea, bloating: Intestinal symptoms such as diarrhea or constipation, bloating, and gas. Rashes may occur as well. Fatigue is possible. Growth issues in children may occur. ...Read moreSee 1 more doctor answer
Celiac Disease (Definition)
In celiac disease, the body reacts to gluten (in wheat and gluten-like proteins in rye and barley) resulting in damage to the small intestine. This limits the intestine's ability to absorb some nutrients. Typically, people with celiac disease have loose stools, bloating, abdominal pain or discomfort, weight loss, poor weight gain ...Read more
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Petra Bagust
|Petra Bagust
Bagust at the world premiere of The Hobbit - An Unexpected Journey - November 2012 Wellington, New Zealand.
14 April 1972
Christchurch, New Zealand
|Actress, Television presenter
|Years active
|Hamish Wilson (2000-present) 3 children
Petra Bagust is a New Zealand television presenter, perhaps best known for her role as co-presenter of TVNZ's morning show Breakfast.
Bagust grew up in Christchurch and attended University of Canterbury, where she completed a Bachelor of Fine Arts in 1995. She began her television career at local TV station Cry TV, She later co-hosted youth TV series Ice TV, its sequel Ice As, and later a wide range of programming include travel shows, real estate shows, and game shows.[2] She was also a regular host of the annual event Coca-Cola Christmas in the Park.
In 2008 she hosted New Zealand program What's Really In Our Food?, broadcast on TV3. Future seasons of this show would see Bagust nominated for the Qantas Media Award for Best Presenter in 2009 and 2010. At the same time, she hosted a weekly radio programme with Pat Brittenden on Newstalk ZB.[3]
She changed networks in 2011 to present TVNZ's Breakfast alongside Corin Dann.[4] In October 2012 she announced her departure from the show[5] and was replaced the following year by Toni Street.[6]
Personal life[edit]
Bagust married freelance cameraman Hamish Wilson in 2000; the couple have three children. Bagust's departure from morning television was explained as wanting to spend more time with her family.[5]
She is a Christian.[7]
- ^ "Petra Bagust: I've learned my lessons". New Zealand Woman's Weekly. 9 April 2012. Retrieved 20 October 2012.
- ^ "Petra Bagust - presenter extraordinaire". NZ On Screen. Retrieved 16 July 2013..
- ^ "Petra Bagust". LinkedIn. Retrieved 16 July 2013.
- ^ "TVNZ announces new hosts for Breakfast". The Spy Report. Media Spy. 18 December 2010. Retrieved 18 December 2010.
- ^ a b "Why Petra Bagust quit Breakfast on live TV". The New Zealand Herald. 24 October 2012. Retrieved 16 July 2013.
- ^ "New taste for Breakfast". The Diary. The New Zealand Herald. 30 November 2012. Retrieved 16 July 2013.
- ^ Cleave, Louisa (c. 1998). "TV: Petra gets a home life". The New Zealand Herald. Retrieved 24 April 2012.


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Location: Fairplex Expo Halls 4 & 6
Location: Millard Sheets Art Center at...
Location: Expo Hall 9
Location: Fairplex main lot
The world is coming to Fairplex - you'll want to be here too! More Info...
The Learning Centers provides a wide spectrum of innovative and enriching educational experiences that enrich our diverse communities. More info...
Fairplex is committed to support and strengthen the local community by offering educational, social and economic programs throughout the year. More info...
Sign Up to receive discounts, promotions and news
Behind-the-scenes, inner-circle perspective on year-round activities at Fairplex
read on
Fairplex is a private, non-profit 501(c)5, self-funding organization that is not governed by the county or state, and receives no government subsidies for daily business operations. Under the direction of the Los Angeles County Fair Association, we exist to build stronger communities and, through our businesses and The Learning Centers, provide education, entertainment and fun to Southern California.


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Located in one of the South's most charming cities, SpringHill Suites by Marriott Savannah I-95 South is just 12 miles from Savannah's historic downtown area including Paula Deen's Lady and Sons Restaurant, beautiful City Market and River Street featuring local restaurants, shops, galleries and host to many local festivals . Our spacious suites, perfect for short or extended stays, offer many amenities including a pull-out sofa, microwave, refrigerator and large work area. Whether you're in Savannah for work or leisure, enjoy free local call service, high-speed wireless Internet access and HBO. Start your day with our complimentary full hot Breakfast. Keep your fitness program on track by visiting our exercise center and heated indoor swimming pool. Our Southern hospitality makes your stay worthwhile.
Amenities· 24-hour front desk
· Accessible facilities
· Accessible parking
· Barber shop - (In Area)
· Beauty shop/salon - (In Area)
· Boarding pass print-out available
· Bookstore - (In Area)
· Buffet breakfast
· Car rental desk - (In Area)
· Child programs
· Coin operated laundry
· Complimentary breakfast
· Complimentary buffet breakfast
· Complimentary coffee in lobby
· Complimentary in-room coffee or tea
· Complimentary newspaper in lobby
· Direct dial telephone
· Drugstore/pharmacy - (In Area)
· Dry cleaning
· Efolio available to company
· Elevators
· Exercise gym
· Express check-out
· Florist - (In Area)
· Free high speed internet connection
· Free parking
· Front desk
· Full service housekeeping
· Hair dryer
· Health club
· Health club
· High speed internet access
· High speed wireless
· Hot breakfast
· Housekeeping - daily
· Ice machine
· Individual Efolio available
· Indoor pool
· Interior corridors
· Ironing board
· Laundry/Valet service
· Meeting rooms
· Motorcycle parking
· Non-smoking rooms (generic)
· On-Site parking
· Onsite laundry
· Parking
· Pool
· Public area air conditioned
· Safe deposit box
· Security
· Spa - (In Area)
· Tennis court - (In Area)
· Travel agency - (In Area)
· Valet cleaning
· Valet same day dry cleaning
· Wakeup service
· Whirlpool
· Wireless internet connection in public areas
Room InformationThe amenities listed in this description represent a sample of amenities available in some or all guest rooms in this hotel
High speed internet connection, Internet access, Wireless internet connection, High speed wireless, Meal included - breakfast, Non-smoking, Free local calls, Coffee/Tea maker, Wet bar, Alarm clock, Air conditioning, Air conditioning individually controlled in room, Bathtub/shower combination, Private bathroom, Hairdryer, Upgraded bathroom amenities, Separate closet, Closets in room, Iron, Bathroom amenities, Down/feather pillows, Foam pillows, Pillow top mattress, Sofa bed, Cribs, Storage space, Local calls, Free toll free calls, Mini-refrigerator, Microwave, Color television, Cable television, Premium movie channels, List of movie channels available, CNN availaible, HBO available, ESPN available, All news channel, iPod docking station, AM/FM radio, Remote control television, Large desk, Chair provided with desk, Spare electrical outlet available at desk, Electrical current voltage, Telephone, Voice mail, Multi-line phone, Direct dial phone number
Miscellaneous Information
· American Dollars is the native currency.
· Check in time is 3:00 PM
· Check out time is 12:00 PM
· Opened in 2006
· Renovated in 01/01/2014
· 86 rooms.
· 86 suites.
· 3 floors.
Cancellation Policy
Cancel policy may be more restrictive based on rate / room booked, season, special events
Meeting FacilityExecutive Boardroom
Recreation Information
Fitness center on-site
Health club
Tennis court
Bowling alley
Hiking trail
Mountain biking trail
Putt putt golf
Children's program
Indoor pool
Area Attractions- City Market
- Savannah
- Greyhound Bus Lines
- Old Time Trolly
- Grayline Tours
- Savannah Riverboat Cruises
- Dolphin Magic
- Savannah International Trade & Convention Center
- Coastal Empire Fair - 355-7424
- Mighty Eighth Air Force Heritage Museum
- Telfair Museum of Art
- Tybee Island Lighthouse Museum
- Owens Thomas House Museum
- Ships of the Sea Maritime Museum
- The Hurn Museum of Contemporary Folk Art
- Savannah History Museum
- Ralph Mark Gilbert Civil Rights Museum
- Armstrong Atlantic State University
- The Bayou Cafe & Blues Bar
- Savannah Blues Bar
- Wet Willie's
- Sports Bar/The Coach's Corner
- Sports Memorabilla/Coastal Collectibles
- Sports Clubs/Special Olympic Georgia
- Sports Promoters/International Scouting Service
- Sports Medicine/Memorial Health Sports One
- Savannah Sand Gnats Pro Baseball
- Southside of Savannah
- Lucas Theatre For The Arts
- The Savannah Theatre
- Savannah/Hilton Head International Airport
- Armstrong State University
- Bamboo Farm
- Henderson Golf Course
- Historic Downtown
- Keller's Flea Market
- Tybee Beach
- Savannah College of Art & Design
- Savannah Technical College
- Bass Pro Shop
- Flight Safety International
- Gulfstream Aerospace
- Harley Davidson
- Savannah Mall
- St. Joseph's Hospital
- Super Wal-Mart
- Oglethorpe Mall
- River Street - Historic District
- Walmart
- Savannah Festival Factory Stores
- Savannah Tanger Outlet center
- Savannah Tanger Outlet Center
- Surf Lagoon Water Park
- Royal Cinemas IMAX
- Frames and Games
- Pooler fun zone (amusement and sports park)
- Savannah Civic Center and Johnny mercer Theatre
- Wynnsong Movie Theatre
- Get Air Savannah Trampoline park
- Savannah Rock and Roll Marathon
- St Patricks Day Celebration


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THIS time last year, Carl Llewellyn had no expectations of riding one of the favourites in today's Hennessy Cognac Gold Cup. By now, indeed, Llewellyn did not expect to be riding at all. The flow of winners had been drying up, malicious gossipers muttered that age was catching up with him and, as the jockey himself admits: "When you've been going round as long as I have, it's not a lot of fun going racing every day with no chance."
How remarkable, then, that with his 40th birthday looming next July, Llewellyn now feels farther away from retirement than ever.


text:
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Websites are automatically selected for the Tableau based on your browsing history. The set of websites on the Tableau can be changed in edit mode. To get there, open Tableau and select Tableau Settings in the context menu (or click the Set Tableau and background link).
A lock on a widget means the website is pinned to this position on the Tableau. The browser automatically changes the Tableau based on how often you visit various websites. If the lock is closed, the widget will always stay in the same place.
We are aware of this problem and are working on a solution.


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Read More:
Midwife-led continuity models versus other models of care for childbearing women
"In many parts of the world, midwives are the main providers of care for childbearing women. Elsewhere, it may be obstetricians or family physicians that have the main responsibility for care; or the responsibility may be shared."
Home Birth With Midwife As Safe As Hospital Birth: Study
"Having your baby at home with a registered midwife is just as safe as a conventional hospital birth, a new study says."
Outcomes of planned home births with certified professional midwives: large prospective study in North America
"Objective: To evaluate the safety of home births in North America involving direct entry midwives, in jurisdictions where the practice is not well integrated into the healthcare system."
Midwife-led births 'safer', finds major study review
"They found women were also less likely to experience premature birth compared to other types of care, including that led by GPs or consultants."
Listening to Mothers II: Report of the Second National U.S. Survey of Women's Childbearing Experiences
Listening to Mothers III Pregnancy and Birth
"Childbirth Connection's ongoing Listening to MothersSM Initiative is devoted to understanding experiences and perspectives of childbearing women and using this knowledge to improve maternity care policy, practice, education, and research."
Too Many C-Sections: Docs Rethink Induced Labor
"The rise in cesarean-section deliveries in recent years has been characterized by some as a key indication of the overmedicalization of childbirth."
Watch More:
Morning After Pill:
3 Parent Babies:
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To Roy With Love
Robin Hardman | Posted 11.05.2013 | Parents
Read More: Mentors, Roy Nathanson, Teachers, Music, Great Teachers, Back to School, New York City Schools, Institute for Collaborative Education, Music Teachers, Ice, Parents News
I am continually impressed with the dedication, creativity and energy many of my kids' teachers bring to their work. I am frankly amazed at the things my kids know. But if I had to choose the one teacher in my son's life most deserving of a lifetime achievement award, I'd pick Roy Nathanson.


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This Pioneer unit is great value for money, with features that normally only feature on more expensive units.
IPhone, iPod, USB device, MP3 player or CD: enjoy your music collection on the road, how… Read more
These are great entry level speakers that will drop straight into your vehicle's factory locations and improve the sound greatly.
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With speaker cones forged from CURV, a material only found in exclusive audiophile hi-fi products, we've produced a speaker range with industry-leading accuracy and efficient sound reproduction.
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The smaller of the Pioneer mono amps is ideal for driving one subwoofer in your car to sound levels that will satisfy most tastes out there.
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Studies in Modern Diplomacy (3 vols, Portrait of a Diplomatist, Curzon, Peacemaking 1919)
Harold Nicolson; With Illustrations [Illustrator]
Available from more sellers
Three volumes, all with dust wrappers. All three with Square tight binding with clean interiors. Illustrated map end papers to two volumes. Jackets lightly soiled with minor edge wear but in good shape. All three $2.50 original prices intact. Presents handsomely in archival mylar. A beautiful set. Bookseller Inventory # 3777
Bibliographic Details
Title: Studies in Modern Diplomacy (3 vols, ...
Publisher: Houghton Mifflin Company
Publication Date: 1939
Binding: Hardcover
Book Condition: Used: Very Good
Dust Jacket Condition: Good
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Vintage Books and Fine Art
Oxford, MD, U.S.A.
AbeBooks Seller Since March 4, 2013
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Store Description: Vintage Books is a used and collectible books, fine art and local interest store on Maryland's Eastern Shore. We specialize in 18th-century American History, local Fine Art and Eastern Shore memorabilia. We also stock a selection of general used books for readers of any interest. If you can't find it, we'll get it for you.


text: For the past year or so I have had this condition on my right knee. The symptoms of pfs are; pain whilst squatting on the last 30-35 degrees, swimming breaststroke, also a crunching grinding souund on the last 30-35 degrees of extention. Recently I have been getting a shooting pain sometimes while running when my right foot makes contact with the floor. Also I have noticed that when I try to stretch my IT band it feels like the muscle is coming out of the socket (hard to describe.) Also I have definatley realised that my vmo muscle on the right leg is smaller compared to the left leg especially the muscle around the inside of the knee cap. I have been to the physio a few times and she advised me to strengthen the vmo muscles. Is that all that is needed? It seems impossible to do this without causing further irritation to the knee. If there are any other sufferers out there with this condition I would be grateful for any advice you could offer me.


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Here's a close up of them. I think the people (some of whom post in this thread) who expect to get $1800.00 shoes for $400.00 and who examine every shoe using a high powered microscope and a micrometer were the people who sunk the old MTO program.
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Dr. Mandeep Brar MD Patient Reviews
- Endocrinology, Diabetes and Metabolism Glendale, AZ
Overall Rating
1 Patient Reviews
- Easy Appointments
- Promptness
- Friendly Staff
- Fair and Accurate Diagnosis
- Bedside Manner
- Spends Time With Patients
- Appropriate Followup
Showing 1 - 1 review
1.0 of 5
May 2nd, 2014
Dr Brar took over after another endocrinologist retired. After my initial visit, the office called twice changing my appointments. I received a call today stating Dr Brar was no longer with the office. As a diabetic, it has been very frustrating not being able to see Dr Brar on a regular basis. Now I am once again without an endocrinologist. Fortunately, I have a primary doctor that has been there for me when Dr Brar was not available. People with a serious chronic illness must be able to rely on their specialist. Dr Brar is not reliable to her patients.
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Dr. Mandeep Brar, MD is similar to these 3 Doctors near Glendale, AZ.
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Italian grappas are amongst the best in the world, Bepi Tosolini being particulalry well regarded.
Produced using pomace from a selection of grape varieties, this Italian grappa is aged in oak after distillation, to grant the spirit more depth and flavour than the unaged expression. More info
An intense single variety grappa, made solely with chardonnay grapes. As one might expect this produces a particularly intense, powerful and focused grappa. More info
An Italian Grappa, produced using grape pomace, including the skins, pulp, seeds and stems which are left over from winemaking. It's a rather intense spirit, with utterly huge notes of fruity grapes… More info
A single-grape-variety grappa from Bruno Pilzer - this time, the Italian distiller has carefully distilled Yellow Muscat grape pomace using their alembic stills to create this light, delicate spirit. More info
A very impressive 35 year old Grappa from Barile. Grappa with an age statement is pretty darn rare indeed, and ones of this age are few and far between, that's for sure. More info
A fine and consistently high-quality grappa from well-regarded producer Bepi Tosolini. More info
From the maestros of Grappa distillation - Bepi Tosolini - comes an expression produced using the pomace of the Prosecco grape, otherwise known as the Glera grape. A light, markedly sweet Grappa,… More info
This is the first release from the Domus Grappa range - the Ruché 2014. Made with 100% Ruché grape, a little-known variety of red grape grown in Piedmont - you're unlikely to seem many grappas… More info
Italian producers Marolo use the Arneis grape to produce this light, elegant and floral Grappa. Arneis grapes are notoriously tricky to grown, hence their name - in Piedmontese, it means 'little… More info
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A grappa made with the pomace of Merlot grapes from Le Maestrelle Vineyard in Tuscany. More info
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Crisp, tangy aged grappa from Bocchino, this is made exclusively with Moscato d'Asti grapes, which offer a sweet flavour and a rich aroma. More info
Made in Collio and Colli Orientali el Friuli Venezia Giulia, this is an intensely floral Grappa with hints of herbs and apple, made exclusively with the Pomace from Chardonnay grapes. Best served at… More info
A lower strength Agricola grappa from Tosolini distilled within 48 hours of the grapes being crushed and bottled at 40% abv. More info
21 year old Grappa, produced by Barile. A rare and exciting sight for Grappa enthusiasts... More info
A Nebbiolo-grape-based grappa from the Alexander range, made by Bottega in Italy. The Nebbiolo grape is closely associated with the Piedmont region, where Barolo wine is produced. More info
From a series of Grappa produced by Bottega for their Alexander range named after renowned wines, made with the grapes that make said wines. For this one, they use the Corvina and Rondinella… More info
Bortolo Nardini opened his distillery and grapperia, which is still used today, back in 1779. This makes it the oldest operating distillery in Italy! In 1964 a second distillery was opened in… More info
A grappa from the Italian island of Pantelleria (the ancient Cossyra) in the Strait of Sicily - it's 62 miles southwest of Sicily itself and just 37 miles east of Tunisia, from which it can be seen… More info
From the Marolo range comes a fragrant, subtly floral Grappa made with pomace of Sangvoise grapes, used for Di Brunello di Montalcino in Tuscany. Enjoy from a tasting glass to get the full, aromatic… More info
The entry-level grappa from the Alexander range, made from a blend of grape varieties by Italian distillers, Bottega. With a clean, elegant mouth-feel and a flavour profile dominated by fresh white… More info
12 year old Grappa from the Marolo range, which was founded by Paolo Marolo in Alba, Italy. This particular Grappa is produced with Nebbiolo grapes from Barolo and left to mature for a dozen years in… More info
With a herbal infusion of rue, the Nardini Grappa Ruta is an interesting twist on their world famous grappa. A spring of the bitter herb is included in the bottle to ensure the flavours flow through… More info
Just like the 40% and 50% editions that came before it, this Nardini Grappa Riserva was matured in Slavonian oak barrels oak barrels for at least three years before it was bottled. Unlike those two,… More info


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Homestead-Miami Speedway
Shops Filled With Curiosities In Cauley Square
Shnebly Redland's Winery and Brewery
The Tea Room in Cauley Square
Coral Castle
Monkey Jungle
Robert is Here
Downtown Homestead street
Bike riding in Everglades National Park's Shark Valley
Exotic fruits found at Fruit & Spice Park
Biscayne National Park is mostly underwater
A rural green oasis with attractions to match waits just outside the city. Enjoy Homestead's parks and unique attractions.
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This American Orchid Society-judged event is the largest annual orchid show in the U.S., featuring over 50 booths of...
This annual event showcases local agriculture, and tropical fruits. Vendor booths featuring local wines, yummy foods, and rare...


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Celebrity Beauty Studio, conveniently located inside Bella Salon Suites, can help you feel refreshed and revitalized with these high-quality hair and facial treatments:
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Dancing in the Sea
Once the Hijack Was Over
By (author) Catherine Hill
Format: Paperback
Checking availability...
Dancing in the Sea by Catherine Hill
Book DescriptionDancing in the Sea is the beautifully written and moving account of Catherine Hill's horrific experience of a hijack, after which she was left permanently disabled.In 1986, when she was 26, Catherine and her Italian boyfriend Picci went travelling through India. On their journey home, their Pan Am flight from Bombay to Germany was hijacked when it landed in Pakistan to pick up additional passengers. PLO terrorists took over the aircraft and the hostages endured nearly 17 hours of terror. Convinced that Pakistani troops were about to try and rescue the hostages, the terrorists finally forced as many people as possible into the aisles and attempted to massacre them. In the slaughter that followed, 21 people died and more than 100 were injured. Catherine was near-fatally wounded, her left buttock blown off by a grenade. In spite of his own injuries, Picci saved her life by dragging her, bleeding heavily, from the plane. Over the years that followed, Catherine endured a series of over 20 horrendous operations as surgeons attempted to heal her mutilated body. During that time, she also began to fight two major lawsuits, one against Pan Am and another that resulted from medical negligence. She had to call on every resource she had - physical, psychological, emotional and financial - as she attempted to rebuild her life. It was after the conclusion of her legal battles, however, that Catherine found herself facing her greatest challenge so far, as she became engulfed by depression when she slowly realised that nothing would ever be the same agai
Buy Dancing in the Sea book by Catherine Hill from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9781840189971
(198mm x 130mm x 30mm)
Pages: 320
Imprint: Mainstream Publishing
Publisher: Mainstream Publishing
Publish Date: 28-Apr-2005
Country of Publication: United Kingdom
Other Editions...
» Have you read this book? We'd like to know what you think about it - write a review about Dancing in the Sea book by Catherine Hill and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a member - it's free to sign up!)
Author Biography - Catherine Hill
Catherine Hill was born in Watford in 1959. After studying and working in Leeds and London, she travelled to Italy and now lives in Milan, where she works as an English Language teacher in multinational companies.
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To the Editor Dr Powell1 advocated for individualized therapy for the new direct-acting oral anticoagulants (DOACs) based on defined therapeutic target ranges simulated from phase 3 trials.
The idea of therapeutic drug monitoring is derived from the monitoring of vitamin K antagonists (VKAs), which have a narrow therapeutic window. Because of the multiple interactions of VKAs, therapeutic drug monitoring is the only possible way to ensure patient safety.
Kreuzer J, Dugi K. Dosing Recommendations for New Oral Anticoagulants. JAMA. 2015;313(24):2496. doi:10.1001/jama.2015.5739
© 2017


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Location: Italy, Fabriano
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Published:2010-6-9 23:36:30price:5000.00 RMB / m2 Units:2-family homelocation:Jing'an- nearby- transportion:BusRoad-SubwayNumber Size:Select type Description:Layout: 2 bedrooms, 1 living room, 1 bathroom Size: 60sqmPrice:5000rmb/mthDescription:Tongji Garden is located on Yanping Rd. across Kangding Rd. About 8 minutes walking distance to line → Read More
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Dr. Adair is a board certified physiatrist (physical medicine and rehabilitation) who since 2011 has served as the Vice President for Clinical Transformation at Advocate Christ Medical Center—leading the hospital's health outcome, quality and safety efforts. For 4 years in a row, Advocate Christ Medical Center has been recognized as a Truven 100-Top Hospital and a 15-Top Major Teaching Hospital. In 2015, Healthgrades recognized the medical center as a 100-Best Hospital for having performed in the top 2% of the nations' hospitals for 3 successive years.
He has been a leader in post-acute care as a component of population health management, working with the Advocate system in its development of a post-acute network; integrating care across hospitals, acute and day rehabilitation, skilled nursing facilities, home health, and the community.
For the prior 25 years, Dr. Adair was Christ's medical director and chair for rehabilitation medicine services, where he led the creation of tertiary level adult and pediatric rehabilitation programs recognized throughout the Chicagoland area for their excellence in patient outcome.
Dr. Adair is a graduate of the honors program in medical education of the Feinberg School of Medicine, Northwestern University. He completed his medicine internship at Evanston Hospital, and his residency in PM&R at the Rehabilitation Institute of Chicago and Northwestern University Medical School, where he served as chief resident.
Past positions include, graduate medical education medical director and associate medical director at the Rehabilitation Institute of Chicago, as well as medical director at Schwab Rehabilitation Hospital before arriving at Advocate Christ Medical Center.
His heartfelt advocacy for persons with disabilities has impelled him to leadership positions within the Illinois Association of Rehabilitation Facilities, Illinois Hospital Association, American Hospital Association, and the American Academy of Physical Medicine and Rehabilitation.
Dr. Adair and his wife Linda have 3 grown children, and are longtime, active members of their local church, serving in a number of community ministries.


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1 Overview
Children and young people come into care in many different circumstances. For this reason, there are a number of different types of fostering to meet the needs of our children.
Fostering is usually a short-term arrangement while a child's future is planned and agreed. This means that you will look after a child or young person for a few weeks or a few months, while they are unable to live at home.
Sometimes, however, a long-term or permanent fostering arrangement is the most appropriate option for a child. This might be because the child continues to have regular contact with their relatives. Long-term fostering means they will stay with you until they become adults and are ready to live independently.
This can provide the child with an opportunity to develop secure attachments and consistent relationships through being part of a family. It also enables the birth parent(s) to maintain contact with their child, while the foster carer can provide continuous care and feel a sense of achievement as the child progresses.
Before you apply to foster, think about what might suit your family and the skills you have – you may be able to specialise in one of our specialist schemes.
2 Parent and child fostering
Sometimes a parent, or parents, cannot look after their child to the satisfaction of the courts or the County Council.
When this happens both the child and parent(s), are placed with a foster carer. The foster carer helps keep the child safe but also supports the parent(s) with developing their skills to look after the child.
Could you be a parent and child foster carer?
There are a number of things you should consider before you offer a parent and child placement - for example, having some practical childcare experience. If you're flexible, tolerant, patient and a good communicator then this type of fostering could suit your skills. Others include:
- Experience of handling difficult behaviour.
- Good advocacy skills, either on behalf of the parent or their child.
- The ability to keep daily, detailed diary sheets. These will be used to inform the assessment made by the child's social worker.
- An understanding of working in partnership with a range of professionals.
What's involved?
Parent and child placements are usually for 14 weeks, with an additional two week outreach programme offered in some cases with agreement from the carer. Due to the high level of supervision, observations and guidance, you will need to be available at all times.
See the Foster care allowances page for details on payments for parent and child foster carers.
3 Short breaks
Short break foster care involves caring for a child with disabilities. It gives children planned periods of care away from their families or foster carers. This can be for a few hours during the day or overnight stays, such as a weekend every month.
Short breaks help children to spend time away from their birth families and develop their independence. It can help to broaden their horizons and help them integrate with other children, gain confidence and have fun.
This type of fostering also enables the birth family to have a break from the pressures of full-time caring. Many birth parents describe short break foster care as a lifeline for them, allowing them to recharge their batteries and spend quality time with their other children or partner, or do the things that many people take for granted, however small.
Short break foster carers might care for children:
- who have an Autistic Spectrum Disorder
- with physical disabilities that require care in a home with adaptations
- whose behaviour can challenge
- with complex medical needs.
4 Respite foster care
Respite fostering is when you care for a child for short periods of time on a planned and regular basis. This allows the child's parents or usual foster carers to have a break themselves, and supports them in caring for the child longer term.
5 Supported lodgings
Supported lodgings is an accommodation scheme for young people aged 16-21 (or up to 24 if in higher education), who are not yet ready to live on their own. They may need accommodation as they have left care or they may not be able to live with their own family.
The aim of the scheme is to offer young people the opportunity to live in the home of an approved person who will help them develop the necessary life skills to prepare them for independent living.
See the Supported lodgings page for more details on how to get involved in this scheme.
6 Fostering unaccompanied asylum-seeking children
When children find themselves alone in the UK they are taken into the care of the local authority. They could be here because they have:
- been trafficked
- been separated from family on arrival due to an immigration issue
- fled their homeland due to war or fear of persecution.
Foster carers give unaccompanied, asylum-seeking children a safe place to live while their individual case is considered.
The foster carer will be asked to accompany them to immigration meetings and arrange legal support. As well as this they will need to help the young person to access education, make links with local cultural and faith groups and support them in day-to-day living, including helping them to learn the English language.
There are many challenges involved in this type of fostering, however our foster carers tell us that it is also one of the most rewarding.
7 Specialist schemes
Specialist fostering schemes are used to support younger or older children who have had a very difficult start and who may require more therapeutic support. These require very different skills from other kinds of fostering and foster carers receive a higher level of payment.
These schemes can also be used to support children who come into care in an emergency because of a crisis in the family. One example of this is FESP, outlined below.
Fostering Early Support Programme (FESP)
The FESP is a specialist programme to help families resolve their difficulties and prevent young people remaining in care unnecessarily. The scheme accommodates young people who come into care in an emergency because of a crisis in the family. The FESP carer will work closely with the Family Resource Teams in order to return the young person to their family within 3 months.
The foster carer must be available for the duration of the placement in order to respond to any need. To reflect this, FESP foster carers receive a Level 3 allowance - the highest available to foster carers - and also have the potential to receive a retainer's allowance. The foster carer will also have access to regular phone support in the evenings and on weekends and bank holidays through the Family Resource Team.
The focus of FESP is children aged 11-17 years old.


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Left 4 Dead 2 Mac OS X Free One of the giants of CO-OP gaming is now available completely FREE for Mac OS X computers. Download now Left 4 Dead 2 Mac OS X FREE and start your own battle against the hordes of zombies. This game is the sequel to the Left 4 Dead, the first ...[Read More]
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Sniper Elite 4 Mac OS Download Sniper Elite 4 Mac OS Download is now available because this game has been released and we posted it here just for you, all the sniper elite's lovers. Developed by Rebellion, Sniper Elite 4 proceeds the rest of the sniper elite series...[Read More]
Wolfenstein The Old Blood Mac OS X ~ Download Ultimate Version ~ Are you a fan of the FPS genre of games ? Either you searched for this game or you find it by navigating on our website, MacGamesWorld team presents you the Ultimate Version of Wolfenstein The Old Blood Mac...[Read More]


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Courtesy of Chris Cothran
A couple months ago I ordered some LED lights to install on the semi trailer for the high school band. I promised a couple pictures and thought you could use a chuckle. The lights were exactly the right size to do what we wanted...to install in the eyes on the fox logo so they would glow red. We made a simple system with 2 6v lantern batteries in series, added the little voltage regulator on the output side and voila! Wicked red eyes.
The band didn't know we had installed them, so on Saturday we had the first (of 7) competitions...about a 2 hour run up near Clemson. We lit them up about dusk and I have to tell you, the reactions were better than anticipated! The band loved them, and as it grew darker those tiny LED's really glowed. The stadium was on one side of the property and warm up area was on the other. Our trailer was right in the middle so each band had to walk by us on the way to their performance. I wish you could have seen the looks. They all just stared as they walked by, whispered to each other "check THAT out...", that sort of thing. And they were visible for a full quarter mile. No exaggeration. You could see them from a parking lot that distance away...clearly see them. Coolest thing you ever saw!
To make it even better I left them on when I drove the truck back to Columbia down the interstates and cross country. People stared and pointed. Geez those things are BRIGHT!
See the LED Microstars lit at dusk, and then in full darkness. Click images to enlarge. Also shown is the semi so you can see how large the sign is.
Microstars are a very small LED landscaping light available in white, blue, red and amber.
If you'd like to have help with a project like this, contact one of our LED applications specialists for help today.


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Flowering Time ~60 days
Dominance indica
Bio Grows a short bushy plant respmbling a prickly pear cactus in miniature. Smooth and strong like any NL hybrid packing a serious punch without knocking you out! This is an excellent strain and would be best used for pain relief spasms and anxiety.Genetics: Northern Lights x AfghaniFlowering Time: 55-65 Days
Origins indoor
Save money at scores of your favorite industry shops with CANNACoupon by CANNAPAGES!


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Buy a personal copy of Rosalind's new CD
Listen to a sample of La Belle Dame sans Merci
"Even then, the evening was almost stolen by Rosalind Plowright as the old Baroness. It isn't a large part, and she never tried to upstage or outshine anyone - indeed, she often barely moved - but it was impossible to take one's eyes off this great artist." OPERA Magazine - Jan 2017
"This interview from the Daily Telegraph was written a decade ago and rather amusingly I say in the last paragraph that I could go on singing for another decade. Well that decade is now up......what to do?? I am not sure how many of my colleagues feel the same as me but us singers need this like some sort of drug and as long as we still have our voices and are being offered the work we go on until we drop!! Here's to the next decade! http://www.telegraph.co.uk/culture/music/3663172/Singer-on-a-rollercoaster.html"Posted on 11th February 2017 10:15 - Read on Facebook
Copyright © 2013 Rosalind Plowright OBE.
All rights reserved.


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Scene Partner® Casts CoreCommerce in New WebStore Role(March 29, 2012)
Norwalk, CT (PRWEB) March 29, 2012
MyTheaterApps.com announced today that it has chosen CoreCommerce, a leading e-commerce solution from Sum Effect Software, Inc., to host its new Scene Partner® WebStore. The decision sets the stage for MyTheaterApps.com to offer digital e-Scripts from Dramatists Play Service and other theatrical script publishers, via the Scene Partner WebStore.
Scene Partner is a powerful iPhone®, iPad® and iPod Touch® app that helps actors with the age-old problem of how to memorize lines. The new Scene Partner WebStore will make e-Scripts available to actors and theaters for use in learning lines and mounting future theatrical productions.
The CoreCommerce model of Software As A Service (SAAS) is perfect for rapidly growing companies, said MyTheaterApps.com, Owner J. Kevin Smith. As Scene Partner expands over the next 12 18 months to include titles from the worlds premier theatrical publishers, the CoreCommerce solution can expand to meet our needs. The wide array of features offered by CoreCommerce will ensure that Scene Partner customers have a great online experience.
When the new WebStore is launched, theaters can use secure, password protected Theater Libraries to purchase publisher e-Scripts and distribute them to cast members, just as they do with print copies today. The Scene Partner service also provides actors with their own Private Library to purchase, store and download scripts. In addition, the Scene Partner Public Library is available to all Scene Partner customers from the Scene Partner App and contains a growing list of Public Domain scripts including all of William Shakespeares plays.
The Scene Partner WebStore launch is projected for May 2012.
About MyTheaterApps.com:
MyTheaterApps.com is the developer of Scene Partner, an award-winning App for the iPhone, iPad and iPod Touch that helps actors learn their lines. It merges text-to-speech software from the Acapela Group, voice recording and advanced algorithms to provide a unique and innovative tool for actors. Apple listed it as "New and Noteworthy" on the home page of the App Store. It was recently featured in Variety, STAGE Magazine and Stage Directions Magazine. Scene Partner has won awards for design excellence from Graphic Design USA, American Graphic Design & Advertising and the Advertising Club of Westchester. Scene Partner is also the winner of a 2011 Gold CQIA Innovation Prize. In December, MyTheaterApps.com announced a worldwide agreement with Dramatists Play Service to sell digital e-Scripts for use in the Scene Partner App.
Photos available.
Read the full story at http://www.prweb.com/releases/Scene_Partner/how_to_memorize_lines/prweb9343584.htm.
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Card D1: Josh Smith (Atlanta Hawks)
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The Jackie Robinson Foundation, Inc
About us
Founded in 1973 by Rachel Robinson, the Jackie Robinson Foundation (JRF) is a public, not-for-profit national organization, which awards four-year college scholarships to academically gifted minority students, with financial need, to attend the college of their choice. JRF's unique comprehensive support system includes leadership development, mentoring programs and career counseling.
Since 1973, JRF has provided educational and leadership opportunities to economically disadvantaged, academically gifted, young men and women of color with the desire and commitment to pursue a college education. Over the last 34 years, the Foundation has enabled 1,200 talented minority students to follow their own dreams.
Contact information
Government ID number: 13-2896345
Email: Log in to view email addresses.
Phone: (212) 290-8600
Fax: (212) 290-8081
75 Varick Street, 2nd floor, New York, NY, 10013, US