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|Table of Contents
|Vol. 80, No. 1, 2013
Issue release date: August 2013
|Section title: Original Paper
Dominant Form of Congenital Hyperinsulinism Maps to HK1 Region on 10qPinney S.E.a, b · Ganapathy K.a · Bradfield J.c · Stokes D.d · Sasson A.e · Mackiewicz K.f · Boodhansingh K.a · Hughes N.d · Becker S.a · Givler S.a · Macmullen C.a · Monos D.b, f · Ganguly A.g · Hakonarson H.b, c · Stanley C.A.a, b
aDivision of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pa., bDepartment of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa., cCenter for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa., dTranslational Core Facility, Clinical and Translational Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pa., eCenter for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pa., fDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa., and gDepartment of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa., USA Corresponding Author
Charles A. Stanley, MD
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia
3615 Civic Center Boulevard
Philadelphia, PA 19104 (USA)
E-Mail firstname.lastname@example.com
Background/Aims: In a family with congenital hyperinsulinism (HI), first described in the 1950s by McQuarrie, we examined the genetic locus and clinical phenotype of a novel form of dominant HI. Methods: We surveyed 25 affected individuals, 7 of whom participated in tests of insulin dysregulation (24-hour fasting, oral glucose and protein tolerance tests). To identify the disease locus and potential disease-associated mutations we performed linkage analysis, whole transcriptome sequencing, whole genome sequencing, gene capture, and next generation sequencing. Results: Most affecteds were diagnosed with HI before age one and 40% presented with a seizure. All affecteds responded well to diazoxide. Affecteds failed to adequately suppress insulin secretion following oral glucose tolerance test or prolonged fasting; none had protein-sensitive hypoglycemia. Linkage analysis mapped the HI locus to Chr10q21-22, a region containing 48 genes. Three novel noncoding variants were found in hexokinase 1 (HK1) and one missense variant in the coding region of DNA2. Conclusion: Dominant, diazoxide-responsive HI in this family maps to a novel locus on Chr10q21-22. HK1 is the more attractive disease gene candidate since a mutation interfering with the normal suppression of HK1 expression in beta-cells could readily explain the hypoglycemia phenotype of this pedigree.
© 2013 S. Karger AG, Basel
Monogenic disorders of pancreatic beta-cell insulin secretion have become increasingly recognized to be important causes of hypoglycemia in infants and children [1]. Previously, such patients would have been classified as having 'idiopathic hypoglycemia of infancy', a term originated by McQuarrie [2] in 1954. McQuarrie described a brother and sister with onset of hypoglycemia in early infancy, who were treated with pancreatectomy but continued to suffer from hypoglycemia afterwards.
We recently had the opportunity to investigate the family of the affected sibling pair. This pedigree now includes 25 affected individuals, spans four generations and follows an autosomal-dominant inheritance pattern. There are now 8 genetic loci known to be associated with congenital HI and direct sequencing of genomic DNA from our cohort excluded all 8 genes [1,3,4]. Thus, we hypothesized that a novel genetic locus must be responsible for disease in this family. This report describes the clinical phenotype of this novel form of dominantly inherited HI and genetic tests demonstrating linkage of the disorder to an 8.2-Mb region of chromosome 10. Whole genome sequencing and gene capture of a candidate portion of this region identified variants in noncoding regions of hexokinase 1 (HK1) and in the coding sequence of DNA2 as potential candidate loci that may be responsible for this form of congenital HI.
Family members donated saliva samples or blood for DNA isolation and participated in an interview about their hypoglycemic symptoms, treatment, and history. Diagnosis of HI was based on criteria including fasting hypoglycemia accompanied by inadequate suppression of plasma insulin, inappropriately low plasma free fatty acids and plasma β-hydroxybutyrate concentrations, and an inappropriate increase in serum glucose levels after administration of glucagon at the time of hypoglycemia [5,6,7].
Written informed consent was obtained from subjects or their parents for this study. This study was approved by The Children's Hospital of Philadelphia (CHOP) Institutional Review Board.
Fasting adaptation for 20-24 h was evaluated by monitoring plasma concentrations of glucose, β-hydroxybutyrate, free fatty acids, and insulin. Fasts were terminated at 20-24 h or when plasma glucose fell to 2.8 mmol/l [8].
Subjects drank 1.5 g/kg protein (maximum 60 g) in water, 3-4 h after a meal (Resource Instant Beneprotein Powder, Novartis Pharmaceuticals) [9,10]. Blood samples were obtained for plasma glucose and insulin at times 0, 30, 60, 90, 120, 150 and 180 min. A fall in plasma glucose to below 3.9 mmol/l or a delta plasma glucose greater than 0.56 mmol/l was interpreted as abnormal [9,11].
Subjects drank 1.75 g/kg of glucose (maximum 75 g) as Glucola, 3 h after a meal. Blood samples were obtained for plasma glucose and insulin at times 0, 30, 60, 90, 120, 150, 180, 210 and 240 min. Results were compared to published norms for children and adults [12].
Genomic DNA was isolated from saliva samples using the Oragene DNA Self Collection Kit (DNA Genotek; Kanata, Ont., Canada). Genomic DNA from one affected family member was used to sequence the coding regions and intron/exon splice junctions of candidate genes (SIRT1, NEUROG3, PCBD1, HK1, HKDC1)[10]. Resulting chromatograms were analyzed with Sequencher 4.9 (Gene Codes Corp; Ann Arbor, Mich., USA). Novel variants (absent in dbSNPv137 and/or 1,000 genomes project) were sequenced across all family members to confirm tracking with affecteds and obligate carriers. These variants were tested against DNA from 100 healthy control individuals participating in the DNA Polymorphism Discovery Resource (Coriell Cell Depository, Camden, N.J., USA) to exclude rare polymorphisms.
DNA samples were genotyped on the Illumina HumanHap 550v1,v3 and 610v1 arrays at the CHOP Center for Applied Genomics. 24,602 SNPs in linkage equilibrium were included on the arrays and had genetic distances interpolated on the Rutgers second-generation combined linkage-physical map [13]. Thirty-one individuals were used for linkage analysis: 28 affecteds or obligate carriers and 3 unaffected individuals who married into the family. Linkage analysis was performed using Merlin [14], with a parametric rare dominant model in which the disease allele frequency was estimated at 0.0001 and the probability of being affected with 0, 1 and 2 alleles is 0.0001, 1.0 and 1.0, respectively.
Total RNA extracted from lymphocyte cell lines from individuals 2a and 2b (fig. 1) was used to create cDNA libraries followed by high throughput sequencing performed by Illumina Inc. (San Diego, Calif., USA). The data were analyzed by comparing the cDNA sequence to the UCSC genome browser [15] or by direct alignment to the published human genome sequence [16]. Both approaches generated quality analyzable data for 18 of 48 genes in the shared haplotype region. Genetic coordinates listed are based on GRCh37, hg19.
Genomic DNA from individual 2a (fig. 1) was sent to Complete Genomics, Inc. (Mountain View, Calif., USA) for sequencing. Sequence data were analyzed by the CHOP Center for Applied Genomics.
Genomic DNA from individual 3d and a normal control was enriched for region specific extraction encompassing a total of 205 kb (chr10: 70964058-71169635). Enriched samples were amplified with Qiagen Repli-g Midi amplification kit (Valencia, Calif., USA) sent to Illumina for library preparation and sequencing. Please see online supplementary 'Methods' for details (see www.karger.com/doi/10.1159/000351943).
The proband (4d; fig. 1) was the product of an uncomplicated term pregnancy with a birth weight of 3,405 g. Shortly after birth his mother noted that he was a voracious eater and had spells of extreme irritability and inconsolable crying that resolved with feeding, despite being told his plasma glucose was normal in the newborn nursery. At 3 months of age he had a generalized tonic-clonic seizure and during evaluation at Cincinnati Children's Hospital was diagnosed with HI. He was treated with diazoxide, which easily controlled his hypoglycemia and continued on diazoxide until age 10 when it was discontinued at his parents' request. Evaluation off treatment at CHOP demonstrated an ability to maintain plasma glucose concentrations >3.9 mmol/l for over 12 h of fasting. At age 11 years he experienced another generalized tonic-clonic seizure and was restarted on diazoxide.
The proband's father (3d) was never diagnosed with hypoglycemia. He denied having symptoms of hypoglycemia, apart from headaches and jitteriness during athletics, although he has completed marathons. He has two other sons who have no symptoms of hypoglycemia.
As shown in figure 1, the proband is the nephew of the brother and sister (3a and 3b) with 'idiopathic hypoglycemia' described by McQuarrie. Three of their cousins (3i, 3m and 3o) were in McQuarrie's original report and were diagnosed with hypoglycemia after seizures in infancy. Both 3a and 3b underwent pancreatectomy in unsuccessful attempts to control their hypoglycemia. All five original affecteds were treated with ACTH injections, with only partial effectiveness, until the 1960s when diazoxide was found to be effective in some forms of HI [17].
Currently, 25 members of this four-generation pedigree of northern European ancestry have been recognized as clinically affected with HI (fig. 1). In addition, 5 individuals, including the father of our proband have been classified as obligate carriers based on an autosomal dominant inheritance pattern. Obligate carriers did not have recognized symptoms of hypoglycemia, but had children or grandchildren who were diagnosed and treated for HI. The mother of McQuarrie's original proband (2a) was initially classified as an obligate carrier. However, at age 89 after a 10-lb weight loss from adult celiac disease, she suffered a hypoglycemic seizure (plasma glucose 1.7-2.2 mmol/l). She was diagnosed with HI, which improved greatly upon treatment with diazoxide.
Table 1 summarizes the features of 15 affected adults and children in the family. In general their HI disorder was mild: most affecteds failed to show excessive prenatal growth and were not recognized to have hypoglycemia until late in the first year of life. Diazoxide therapy was uniformly effective in the 12 family members for whom it was prescribed and pancreatectomy was only performed in the original two cases. Of the 12 affected adults surveyed, all continued to have symptoms of hypoglycemia, although only case 2a is currently on treatment. Adult diabetes has developed only in the two cases treated with pancreatectomy. Apart from 3a, who suffered permanent brain damage from repeated episodes of hypoglycemia, family members have normal intellectual development; several have advanced degrees.
In order to define the biochemical phenotype of this family's form of congenital HI, 7 of the affected family members participated in tests of fasting and of oral glucose and protein tolerance (table 2). The results showed a pattern of failure to adequately suppress insulin secretion during prolonged fasting and following stimulation with oral glucose. Plasma glucose levels fell to 3.9 mmol/l or below in 5 of the 7 affecteds within 4 h after oral glucose loading; 4 dropped their plasma glucose to approximately 3.1 mmol/l and developed symptoms. The peak glucose and insulin responses to oral glucose were not unusual in most cases; 3 of the adults showed signs of insulin resistance (peak insulin >510 pmol/l), despite having a BMI of 25 or less. Protein sensitive hypoglycemia was not apparent in any of the 5 individuals tested (data not shown). After 20-24 h of fasting, 6 of the 7 affected individuals dropped their plasma glucose to 3.9 mmol/l or below, with little or no activation of ketogenesis; 5 developed symptoms of hypoglycemia. One of the affected children (5b) gradually developed hypoglycemia with inadequate suppression of insulin and delayed and inadequate ketogenesis by the 23rd hour of fasting.
Attempts to identify the genetic defect responsible for dominantly-transmitted HI in this family by direct sequencing of genomic DNA failed to detect a disease-causing mutation in the common genes for congenital HI (ABCC8, KCNJ11, GCK, GLUD1), as well as in the rarer genes (HADH, HNF4α, UCP2) [1,4]. Haplotype analysis excluded the gene for MCT1 (SLC16A1).
We employed positional cloning to map the location of the gene responsible for this novel form of HI by linkage analysis using Illumina SNP arrays. As shown in figure 2a, the only significant LOD score was identified on chromosome 10q21-22, which does not contain any known HI locus. The region of highest LOD score was 6.82 and the shared haplotype was between SNP markers rs10995440 and rs6480513 (genetic distance = 11.1 cM; physical distance = 8.2 Mb).
The region of shared haplotype contains 48 genes (table 3). Several of which are potential candidate genes for HI, including hexokinase 1 (HK1), which encodes a glucose phosphorylating enzyme with greater affinity for glucose than glucokinase, the hexokinase expressed in beta-cells. Direct sequencing of the coding exons and intron/exon boundaries of HK1 and 4 other candidate genes (SIRT1, NEUROG3, PCBD1, HKDC1) did not identify any coding mutations in affected family members. Coding mutations in candidate gene SLC25A16 were excluded by analysis of the whole genome sequencing data.
We next used whole transcriptome sequencing of lymphoblast cDNA to search for exonic mutations among the 48 candidate genes. Good quality sequences were obtained for 18 of the 48 genes, but failed to detect any novel variants and, therefore, excluded these as candidate disease genes (table 3).
Whole genome sequencing (Complete Genomics, Inc., Mountain View, Calif., 94043, USA) was performed on one affected (2a) to search for possible disease variants within the entire shared haplotype region. This analysis detected the presence of 3 novel, non-coding variants in HK1, all of which tracked with all affected individuals and obligate carriers in the family. None of the three were reported in dbSNPv137 or in the 1,000 genomes project (4,362 alleles). As shown in figure 2b, HK1 variants 1 and 2 were found separately at ≤0.5% frequency in 100 healthy controls; however, variant 3 was not present in any healthy controls. The whole genome sequence analysis also detected only one exonic mutation in one of the other 47 genes within the shared haplotype region: a nonsynonymous Q991K missense mutation in DNA2 (Chr10: 70179634 G>T). No intronic, coding or promoter mutations were detected in other candidate genes within the shared haplotype region (NEUROG3, SIRT1 and SLC25A16). The DNA2 variant was present in all of the affecteds and obligate carriers, but was predicted to be tolerated and benign by both SIFT and PolyPhen software programs. It was not found in dbSNPv137 or in 100 healthy controls, but was reported in the ESP database (Exome Sequencing Project-(http://evs.gs.washington.edu/EVS/) [April, 2013]) in 82/11,274 European and African American alleles (75/8,083 European alleles and 7/3,641 African-American alleles) and it was also reported in the 1,000 genomes project in 6/4,362 alleles (4/1,512 European alleles) [18,19]. Therefore, the DNA2 Q991K variant was not considered to be disease causing.
We hypothesized that 1 of the 3 noncoding variants in HK1, identified through whole genome sequencing, or a combination of these variants, could be disease-causing by leading to inappropriate expression of this high affinity hexokinase in beta-cells. In order to confirm the detection of the HK1 sequence variants, genomic DNA was used to capture the entire 205 kb HK1 region, as well as the adjacent HK1 pseudogene, HKDC1 (chr10: 70964058-71169635) for next-generation sequencing. Homozygous variants and variants present in normal controls or reported in dbSNPv137 were eliminated as polymorphisms [18]. Only the same 3 variants detected by whole genome sequencing were detected by gene capture and next generation sequencing. As shown in figure 2b, the three HK1 variants included: (variant 1) chr10: 71046674 C>T, located in intron 1 of the testis specific HK1 isoform; (variant 2) chr10: 71095271 C>G, located in intron 1 of the ubiquitous HK1 isoform, and (variant 3) chr10: 71108666 dup G, located in intron 2 of the ubiquitous HK1 isoform. Analysis of DNA from 100 healthy controls did not identify a single individual that was heterozygous for more than one the three HK1 variants.
The results of these studies show that the hypoglycemia in this family is a form of congenital HI which is autosomal-dominant and diazoxide-responsive. Linkage studies mapped this disorder to a novel locus for congenital HI within an 8.2-Mb region on chromosome 10q21-22. The phenotype of the disorder, including hypoglycemia both with prolonged fasting and 3-4 h following a glucose load, indicates a defect in suppression, rather than in stimulation of insulin secretion; protein sensitive hypoglycemia was not part of the phenotype. Although the hypoglycemia in this family appears to be less severe than several of the other genetic forms of congenital HI, some affecteds suffered profound hypoglycemic brain injury and many of the affecteds continue to suffer episodes of symptomatic hypoglycemia as adults. Genetic analysis of the 10q21-22 region shared by affected family members identified 3 noncoding variants in HK1 and an amino acid substitution in DNA2 as possible candidate disease-causing variants. As described below, HK1 is an attractive candidate disease locus, but DNA2, an endonuclease which functions in mitochondrial DNA replication and repair, has no obvious connection to regulation of insulin secretion [20,21,22,23].
The phenotype of HI in this family indicates that the appropriate suppression of insulin release at low plasma glucose concentrations is impaired, based on responses of affected children and adults to fasting or oral glucose challenge. A lack of protein sensitive hypoglycemia distinguishes this disorder from HI due to mutations of the KATP channel genes or GLUD1 or HADH [1,4]. This suggests that the defect involves the glucose threshold for insulin secretion. Similar to a defect in the beta cell glucose threshold without protein sensitive hypoglycemia a similar, albeit more severe, defect in beta-cell glucose threshold occurs in HI due to glucokinase-activating mutations. The escape of ketogenesis from suppression by insulin observed in patient 5b during fasting (fig. 1; table 2) has also been observed in patients with glucokinase HI, consistent with a lowered glucose threshold for insulin release [24]. Unlike patients with glucokinase HI, birthweight was not increased in our family. This is consistent with the milder course of the disorder in this family compared to that of glucokinase HI in which many patients cannot achieve normoglycemia with diazoxide treatment [1].
The clinical features of this novel form of HI bear some resemblance to those seen in diazoxide-responsive dominant KATP channel HI [10,25,26]. In both conditions, presentation of hypoglycemia is usually within the first year of life, often with the occurrence of a hypoglycemic seizure, sometimes leading to permanent brain injury. In addition, some affected individuals present with severe symptoms at birth while other family members carrying the same mutation have minimal symptoms, never seeking treatment. In some of the other milder forms of dominant HI (e.g. due to mutations in GDH) affected carriers also often escape recognition. Family members of both dominant KATP channel HI and this novel form of HI report that episodes of hypoglycemia seem to become less severe with age and that adults often stop treatment; however, our patient 2a first became symptomatic at age 89, indicating that the dysregulation of insulin secretion persists. In both the diazoxide-responsive forms of dominant KATP HI [1] and this novel form of HI, there does not appear to be an association with the later development of diabetes, with the exceptions of 3a and 3b who had pancreatectomies.
Since it did not appear that a coding region mutation was likely to explain the HI in our family, we extended our search for mutations to noncoding regions of HK1 that might affect its expression in beta-cells. In beta-cells, glucose phosphorylation is normally carried out by glucokinase, a hexokinase whose low affinity for glucose as a substrate is responsible for setting the beta-cell threshold for insulin release at a glucose concentrations of ∼5 mM[27,28,29]. The importance of glucokinase in controlling blood glucose levels is illustrated by the fact that inactivating mutations cause a monogenic form of diabetes (MODY2), while activating mutations of glucokinase lead to HI [1]. In addition, glucose-stimulated insulin release is enhanced by a group of glucokinase activator drugs [30,31,32,33]. In contrast to glucokinase, HK1 has a high affinity for glucose (Km <1 mM) and lacks cooperativity with glucose as substrate [27,28]. Expression of HK1 is normally 'disallowed' in beta-cells, since the presence of this enzyme with high activity at very low levels of glucose would result in hypoglycemia [34]. This has been demonstrated by experiments in which expression of HK1 in MIN6 cells and isolated rat islets leads to elevated basal glycolysis and insulin release and by observations of hypoglycemia in transgenic mice expressing yeast hexokinase in beta-cells [35,36,37]. It is interesting that Henquin et al. [38] recently described increased HK1 immunostaining in islets of 5 of 6 infants with atypical HI defined by a mosaic pattern of hyperfunctional and hypofunctional islets within the pancreas. These authors suggested that the HI in their 5 cases might be related to the apparent increase of HK1 in the abnormal islets, although they did not have sufficient material to confirm this by showing altered levels of HK1 activity or HK1 sequence changes in affected islets. The mechanism(s) for preventing expression of disallowed genes, such as HK1, in beta-cells are not known, but could involve transcription factor regulation, epigenetic mechanisms, or short noncoding RNAs [34,39]. It is noteworthy that recent genome wide association studies have linked the HK1 locus to increased hemoglobin A1C and type 2 diabetes, although specific mutations affecting HK1 expression or activity have not been reported [40,41,42].
Precedent for a genetic form of HI due to aberrant beta-cell expression of a disallowed gene is provided by the exercise-induced HI disorder associated with mutations of SLC16A1, which encodes MCT1, a plasma membrane monocarboxylic acid transporter for pyruvate and lactate. MCT1 is not expressed in beta-cells and, therefore, pyruvate and lactate normally do not stimulate insulin secretion. In patients with exercise-induced HI disorder, Otonkoski et al. [43,44] showed that elevations of plasma pyruvate by anaerobic exercise induced a large release of insulin followed by an episode of hypoglycemia. They also demonstrated that an infusion of pyruvate could provoke an abnormal acute insulin response. The exercise-induced HI disorder patients had no coding sequence mutations of SLC16A1, but mutations were identified in the upstream promoter region, which, presumably, interfered with the process by which MCT1 expression is normally silenced in beta-cells. We propose that a similar mechanism, leading to a failure in the normal silencing of HK1 expression in beta-cells, may be the basis for HI in our family.
Our whole genome sequencing and gene capture experiments identified three HK1 noncoding region variants as potential candidates for causing disease (fig. 2b). Variant 1 was in intron 1 of the testicular isoform of HK1, upstream of the start-site of the ubiquitous form of HK1. Despite the fact that it occurred with a 0.5% frequency in normal control alleles (although it was not in any of the SNP databases), this variant is an attractive disease-causing candidate since it disrupts a consensus sequence for the binding of LBP-1 (fig. 2b) [45]. LBP-1 is a transcription factor known to be a negative regulator of the HIV-1 promoter by preventing binding of the TFII-1 transcriptional activator, while also recruiting histone deacetylases [46,47,48]. The second candidate disease-causing variant was in intron 1 of the ubiquitous isoform of HK1 and also occurred at 0.5% frequency in normal controls, although it was also not listed in any SNP database. This region of intron 1 of the ubiquitous HK1 isoform appears to be enriched for activating histone modifications in cells that express HK1 (UCSC Browser ENCODE data), whereas it shows little enrichment for activating histone modifications in normal islets [49]. The third candidate disease-causing variant was located in intron 2 of the ubiquitous isoform of HK1; it was not found either in normal control alleles or in the SNP databases. Although intron 2 of the ubiquitous HK1 isoform shows histone marks consistent with a role in expression regulation, there do not appear to be marked differences in histone modifications in this region between human islets and tissues which normally express HK1 [15,49]. An examination of the species conservation of the nucleotides at the HK1 variant sites shows that there is conservation among primate species and bovines at all 3 sites; the third HK1 variant site has nucleotide-specific conservation through additional species (fig. 2b).
After an exhaustive search for the specific mutation causing dominant HI in this pedigree, we confidently report that this family represents a novel form of the disease. The previously described HI loci have clearly been excluded and the linkage analysis convincingly points to a novel region on chromosome 10 for this form of HI. The various sequencing experiments narrow the possible genes responsible to HK1 and DNA2 and the potential role that the HK1 variants and possibly the missense mutation found in DNA2 play in disrupting the normal silencing of HK1 in beta-cells remains speculative at present. Direct proof of the functional consequences of the sequence variants in HK1 and DNA2 would require islets from affected patients and, since the disorder is successfully treated with diazoxide, there are no affected islets available for study. In addition, an approach such as using a reporter construct to test the effects of each variant in clonal rodent beta-cells, similar to that taken with MCT1 variants by Otonkoski et al. [43,44], is not feasible due to great distance of the HK1 variants from their promoters (fig. 2b). Study of additional families with this condition would be helpful in determining the causal variant.
In summary, the hypoglycemia disorder in this historically important family represents a novel congenital HI disorder which maps to chromosome 10q21-22. The disorder has an autosomal-dominant inheritance pattern and results in a diazoxide-responsive form of HI. Disease-associated variants were found in non-coding regions of HK1 and exon 18 of DNA2. HK1 appears to be the stronger candidate disease gene since mutations leading to impaired silencing of HK1 expression in beta-cells could lower the glucose threshold for insulin secretion and readily explain the clinical phenotype of this family.
The authors would like to thank Philippe Backeljauw, MD and his colleagues in the Division of Endocrinology at Cincinnati Children's Hospital for referring their patient to the Hyperinsulinism Center at CHOP.
This work was supported in part by CAS: R37 DK056268, R01 DK053012; SEP: K08 DK090302, PES Research Fellowship, K12 HD043245, and P30-DK19525 and UL1RR024134.
The authors have nothing to disclose.
Charles A. Stanley, MD
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia
3615 Civic Center Boulevard
Philadelphia, PA 19104 (USA)
E-Mail firstname.lastname@example.com
Received: February 13, 2013
Accepted: May 10, 2013
Published online: July 12, 2013
Issue release date: August 2013
Number of Print Pages: 10
Number of Figures: 2
Number of Tables: 3
ISSN: 1663-2818 (Print)
eISSN: 1663-2826 (Online)
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Campbellsville University split a Mid-South Conference twinbill at Georgetown on Saturday.
The Lady Tigers (22-3) chalked up a 75-56 triumph as Whitney Ballinger (17), Courtney Danis (16) and Melly Heaton (11) paced coach Ginger Colvin's club.
Georgetown won the men's tilt 73-45 with Zach Allender and Troy Harris scoring 15 and 12 points, respectively, for CU.
Kendra MaKyli Coulter, 2, of Campbellsville competed in the America's Cover Miss USA Pageant on Jan. 31. Coulter received several awards including first runner-up in the 2- to 3-year-olds, best hair, best eyes, most photogenic, most beautiful and best dressed. She will advance to the tri-state pageant in April in Lexington. A win at tri-state would qualify Coulter for nationals in Florida, where she would represent Kentucky. She is the daughter of Jerome and Candace Coulter of Campbellsville. Her grandparents are Rhonda Ray, Ricky and Peggy Ray and Joyce Barnett.
"When he was here, he made rocks, trees and mountains that are high.
He even made valleys that are deep and wide.
He made rivers and lakes and oceans to flow.
He sent sunshine and rain, even stormy winds that blow.
Sometimes in winter he even sends snow.
Can't you see? God did all this for you and me."
—Excerpt from "What God Did," by Ella Mae Edwards
It was announced on Wednesday that 45 new players will be donning a Campbellsville University Tiger uniform in the fall of 2009.
Head Coach Perry Thomas says this class is quite strong and should make an immediate impact.
"We feel really good about the guys we are bringing in," Thomas said. "This class rivals the class we brought in last year. Any time you are building to win a national championship, you have to be able to stack strong recruiting classes back to back and we feel we have done this."
In an average month, the Taylor County Ministerial Food Pantry spends about $5,000 to help nearly 300 needy families keep food on the table. However, while the need is steady, the income is not.
Donations have dropped and the food pantry, now dangerously short of funding, is reaching out to the community.
"We get a big rush at Thanksgiving and Christmas, and then it collapses," said Ted Beam, ministerial association treasurer.
Cheyanne Rose Harmon will be 1 year old on Feb. 28. She is the daughter of David and Jennifer Harmon of Campbellsville. Her grandparents are Larry and Lettie Harmon of Greensburg, Lois Carter of Campbellsville and the late Robert Carter. She also has a special great-uncle, Mike Whitman, who is like a grandfather.
Roca Rice, formerly of Campbellsville, now a resident of Atria Assisted Living in Elizabethtown, displays her quilts during a resident arts and crafts show at Atria.
Jace Legg celebrated his third birthday on Jan. 23. His birthday weekend included a party on the 23rd with his friends at A Child's Workplace, where they decorated monster truck cookies. That night he attended a monster truck show in Lexington, where he was recognized. On Saturday, Jan. 24, he had a Grave Digger monster truck party at his home. Children in attendance included Tyler Gribbins, Bryten Close, Hudsen Close, Madison Hardin, Morgan Hardin, Jillian Hammes, Zack Miles and Caleb Hamilton as well as other friends and family.
Campbellsville Baptist Church will take over the operation of Veterans Memorial Park this spring.
At Tuesday night's regular Fiscal Court meeting, magistrates unanimously approved contracting with the church to provide services at the park for the upcoming sports season from March 1 through Oct. 31.
The future of Veterans Memorial Park has been the topic of several governmental meetings in the past few months and began with a County budget discussion at last October's Fiscal Court meeting.
Southcentral Kentucky residents will have an opportunity to hear Korean folk music and enjoy traditional Korean dance at a concert by the Pai Chai University Choir and Dance Troupe.
The concert will be at 8 p.m. ET Monday, Feb. 9 in V.P. Henry Auditorium. The concert is free and open to the public.
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The Central Kentucky News-Journal is your source for local news, sports, events, and information in Campbellsville, KY and the surrounding area.


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SwimWay teach private swimming lessons in two locations in East Sheen. These classes take place in the comfort of private houses with wonderful pools.
SwimWay is the swimming school that doesn't use buoyancy aids; we don't have to because our instructors are there to give support.
Parent & Baby Swimming Lessons
Wednesday, Thursday and Friday Morning Classes for 6 months old +
Children's Swimming Lessons
Every week day from 1.30pm until 6.30pm for children aged 3–9 years
Term Dates:
Start of Term - WC 3rd January 2017
- 12 Week Term (Tuesdays to Saturdays)
- 11 Week Term (Mondays – bank holiday Monday 2nd January)
Half Term (No Lessons) - WC 13th February 2017
Final Week of Lessons - WC 27th March 2017
If you would like to find out more, visit our website and read about our swimming lessons, locations, prices and availability then email:
Times and prices are subject to change. Contact venue before setting out.
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Eva Sleeveless Deep V-Neck Double Layer Tee
- Top: 100% poly
Lining: 50% cotton , 50% rayon
- Kangaroo pocket
- Drawstring neckline
- Revolve Style No. MGON-WS11
- Manufacturer Style No. L1036
- Modeled in size S.
- Size Guide
- Need size help? Contact our Style Expert!
After introducing us to the leather hoodie, Mike Gonzalez has now set out on a new venture that goes beyond outerwear. His eponymous line of womenswear debuts for fall 2010 with a look that mixes grunge-era inspiration with luxurious elements. Expect street-smart pieces along with elegant draping, soft fabrics, and innovative detailing.
If an item you would like to purchase is out of stock, you can place a Special Order Inquiry. REVOLVE will then check the availability and obtain an approximate arrival date for the item, if available. Typically, it takes up to 3-4 weeks to verify this information.
Placing a Special Order Inquiry is absolutely free and there is no obligation to follow through with a purchase.
- You will be notified by email once we receive the item.
- You may cancel at any time without penalty
- Your card will ONLY be charged when your order is shipped.
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2 Kings 17:15New King James Version (NKJV)
15 And they rejected His statutes and His covenant that He had made with their fathers, and His testimonies which He had testified against them; they followed idols, became idolaters, and went after the nations who were all around them, concerning whom the Lord had charged them that they should not do like them.
New King James Version (NKJV)
Scripture taken from the New King James Version®. Copyright © 1982 by Thomas Nelson. Used by permission. All rights reserved.
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Hotels in Pisa near Pisa (PSA-Galileo Galilei)
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Hotels within 0.5 miles of Pisa (PSA-Galileo Galilei)
- Most bookedBlue Shades Aparthotel
154 people looked at this hotel in the last hour
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"We arrived a lot earlier than expected. We met Isabela during checking in and she was very helpful and friendly. She even had a room ready for us when we arrived. The room was clean, quiet, and very close to the airport. They were celebrating her husband birthday and made us feel like part of..."
A Traveller, Oct 2016, US
- PisalandNo Guest Reviews yet
87 people looked at this hotel in the last hour
- La Casa di MeiNo Guest Reviews yet
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36 people looked at this hotel in the last hour
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"This is a hostel. Which means it is an apartment, close to the airport, in a nice neighborhood, in which you will have a room for yourself. The apartment was nice, clean, and smartly equipped. Which means it had pretty much everything you need, coffee, small breakfast, fridge, kitchen, etc. On t..."
A Traveller, Sep 2015, US
31 people looked at this hotel in the last hour
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"Clean and comfortable stay for 2 nights. Despite one bathroom for 4 rooms it was kept clean and we didn't feel we had to keep waiting to use it. Our room was nice and big for 2 people we had 2 single beds and a double bed! We found it quiet at night (think we were lucky with the other residents)...."
A Traveller, Oct 2016, GB
29 people looked at this hotel in the last hour
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"Staff emailed and were flexible , upgraded our family room to an ensuite & let us leave luggage before and after our overnight stay "
A Traveller, Aug 2016, GB
16 people looked at this hotel in the last hour
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"This hotel was perfectly located right near the airport for an early flight, the receptionist was pleasant and helpful and we had everything we needed. The only disadvantage, not related to the hotel, is there is no set path to the airport, so you have to walk along a main road."
A Traveller, Jul 2016, GB
7 people looked at this hotel in the last hour
Hotels within 1 mile of Pisa (PSA-Galileo Galilei)
17 people looked at this hotel in the last hour
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"Its great place to stay staff is really nice and close to city centre and train station"
A Traveller, Oct 2015, IE
14 people looked at this hotel in the last hour
Hotels in Pisa near Pisa (PSA-Galileo Galilei)
Pisa Airport, or Galileo Galilei airport as it is officially known, is a handy hub for visitors to Tuscany. It is located very close to the center of Pisa, a five-minute taxi ride from the central station. Bus services connect the airport with the city center and with popular Tuscan destinations such as Florence, Lucca, Siena, and Viareggio. Pisa Airport hotels are a convenient option for travelers arriving on a late flight or with an early departure. Online hotel booking specialist Hotels.com offers the best deals on Pisa Airport hotel rooms, regardless of your preferences or budget. Use Hotels.com's interactive maps to locate the major tourist attractions, transport stops, and routes to the terminal.
What's Pisa Airport Like?
Located right by the coast, Pisa is the main airport in Tuscany, receiving well over 4 million passengers annually, with flights to 15 European countries offered by 18 passenger airlines. The terminal offers a variety of amenities for passengers. With the airport so close to the city, it is easy to pop into Pisa after leaving your luggage at the storage area located at the information office. Dining options in the terminal include a bakery, two pizzerias, a modern steakhouse and a self-service restaurant. There are six bars and a sandwich shop. Passengers who don't like to waste their time waiting around for a flight can take advantage of the laundry facilities, a hair stylist, and even a chapel. Pisa Airport may also be the only major transport hub in the world that has its own ballet school. Pisa Airport hotels are within easy reach of the city's attractions, including that Leaning Tower you might have heard about.
Tips for Getting Along with Locals in Pisa
Pisa is a popular tourist destination and English is widely understood in the city, although learning a few courteous Italian phrases will smooth your way in cafes and restaurants. Locals tend to dress stylishly, especially when dining out. Sightseers should note that wearing shorts or sleeveless tops is regarded as disrespectful when visiting churches. Bear in mind that, when climbing the Leaning Tower, you have to leave all bags at the bottom, and are permitted only a camera. In the tourist areas around the Campo deo Miracoli, be vigilant with your valuables, especially in crowds. Make use of Hotels.com's certified guest reviews feature to help you find your perfect option from our selection of Pisa Airport Hotels. Along with our photo galleries and sample room layouts, the reviews give a detailed picture of what to expect from Pisa Airport accommodation.
Pisa travel guides
How Much Does it Cost to Visit the Leaning Tower of Pisa?
Tickets to climb the Leaning Tower of Pisa cost EUR 18. This is one of the major tourist attractions...
A Pisa travel guide – Tuscan cuisine, riverside bars and that famous tower
The Leaning Tower is the iconic image of a Pisa city break. Of course you'll want to climb its centu...


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VTCN1 encodes a protein belonging to the B7 costimulatory protein family. Additionally we are shipping VTCN1 Antibodies (203) and VTCN1 Proteins (27) and many more products for this protein.
Showing 10 out of 22 products:
Human VTCN1 ELISA Kit for Sandwich ELISA - ABIN649160
Geng, Wang, Lu, Li, Xu, Jiang, Wu: Expression of costimulatory molecules B7-H1, B7-H4 and Foxp3+ Tregs in gastric cancer and its clinical significance. in International journal of clinical oncology 2015
Results highlight an importance of VTCN1 stabilization on cell surfaces for the restora (show APCS ELISA Kits)tion of altered balance of immune control during T1D.
Ablation of B7-H3 (show CD276 ELISA Kits) but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer
B7-H4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity.
that B7x can modulate kidney damage in autoimmune diseases including lupus nephritis and anti-glomerular basement membrane disease
B7-H4 can inhibit both antitumor T cells and protumor myeloid-derived suppressor cells (
The endogenous expression of B7-H4 in donor beta cells from transgenic mice prolongs islet allograft survival, confirming the negative role of B7-H4 in regulating alloreactive T-cell responses.
Local overexpression of B7x on pancreatic beta cells is sufficient to abolish CD8 (show CD8A ELISA Kits) T cell-induced diabetes.
B7-H4 expression may influence the outcome of T-cell tumor cell interactions. Tumor-associated macrophage induced membrane-bound B7-H4 on lung cancer cell represents a novel mechanism by which lung cancer cells evade immune recognition and destruction.
Overexpression of B7-H4 was shown in tumor infiltrated dendritic cells.
Tissue-specific expression of B7x protects from CD4 (show CD4 ELISA Kits) T cell-mediated autoimmunity.
study suggest that serum B7-H4 is an independent prognostic indicator for HCC (show FAM126A ELISA Kits) and may be a promising biomarker for early diagnosis as well as disease prognosis of HCC (show FAM126A ELISA Kits).
Data show that disrupted control of costimulation, evidenced by VTCN1 loss in both APCs (show APCS ELISA Kits) and pancreatic islets, ultimately results in altered balance of control of immune responses.
Studied VTCN1 gene polymorphisms in susceptibility to Breast Cancer.
Data indicate that the diagnostic efficiency of V-set domain containing T cell activation inhibitor 1 (sB7-H4) combined carcinoembryonic antigen (CEA (show CEACAM5 ELISA Kits)) was superior to either sB7-H4 or CEA (show CEACAM5 ELISA Kits).
In human amniotic fluid stem cells, the negative co-stimulatory molecule B7H4 regulates low immunogenicity, which can provide a modest inflammatory reaction microenvironment for wound repair.
Low expression of VTCN1 inhibits the viability and metastasis of ovarian carcinoma.
B7-H4 expressed is elevated in colorectal cancer tissues than in the adjacent normal tissues. B7-H4 siRNA effectively inhibited the proliferation at 24 h and 48 h, arrested cell cycle at G0/G1, and suppressed cell invasion and migration.
our data suggest that the evaluation of B7-H4 expression in tissues and blood is a useful tool for predicting the progression of osteosarcoma and prognosis
B7-H4 levels in hepatocellular carcinoma patients were significantly higher than that in healthy controls. High B7-H4 levels were correlated with tumor size, tumor invasion, tumor differentiation and tumor-node metastasis stage.
This gene encodes a protein belonging to the B7 costimulatory protein family. Proteins in this family are present on the surface of antigen-presenting cells and interact with ligand bound to receptors on the surface of T cells. Studies have shown that high levels of the encoded protein has been correlated with tumor progression. A pseudogene of this gene is located on chromosome 20. Multiple transcript variants encoding different isoforms have been found for this gene.
V-set domain-containing T-cell activation inhibitor 1
, V-set domain containing T cell activation inhibitor 1
, V-set domain containing T-cell activation inhibitor 1
, immune costimulatory protein B7-H4
, t cell costimulatory molecule B7x
, B7 family member, H4
, B7 superfamily member 1
, T cell costimulatory molecule B7x
, T-cell costimulatory molecule B7x


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My favorite Corvette commercial - Banned
My favorite Corvette commercial - Banned. The censors thought it would encourage kids to drive so they yanked it.
1965 Chevrolet TV Commercial
1965 Chevrolet TV Commercial
Corvette Mako Shark TV Commercial
It Takes A Chevy
This spot opens on a cowboy, who is clearly frustrated about something, though immediately, we're not sure what. We soon see that he's in a rural setting and leaning against a 2012 Centennial Edition Corvette, Chevrolet's newest, fastest and most sophisticated Corvette ever. Why is the cowboy frustrated about that? Has it broken down? Has he had a flat? No, there's nothing wrong with the car. The payoff is that he's been stopped by a typical southern sheriff, who's busily writing a citation. We're not sure why, but the pay-off shot comes when we see what the sheriff is driving and hear the tag line: 'It Takes A Chevy...To Catch A Chevy'. Produced by Michael Brown Productions, Inc. (www.mbpvideo.com), the production firm which earlier released 'The Quest', a documentary on the Corvettes that first raced at Le Mans in 1960.


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Top Definition
Born in Mona Vale Sydney NSW Australia this word is used to describe the act of expelling feces from you bowels into your hand and in a sexual act smearing it in you partners face to reveille a clown smile.
I was having sex with my girlfriend and i scat clowned her.
Look at becky shes such a scat clown.
Look at becky shes such a scat clown.
by JayN October 31, 2007
The Urban Dictionary Mug
One side has the word, one side has the definition. Microwave and dishwasher safe. Lotsa space for your liquids.Buy the mug
The Urban Dictionary T-Shirt
Smooth, soft, slim fit American Apparel shirt. Custom printed. 100% fine jersey cotton, except for heather grey (90% cotton).Buy the t-shirt


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Amphitheater at Oak Point Park
Amphitheater at Oak Point Park
The Amphitheater at Oak Point Park is a beautiful outdoor venue incorporating all the natural elements that make the Oak Point Nature Preserve so special. The Amphitheater can accommodate 1,500 guests on its grass-covered landings. Lawn chairs, blankets, and picnic baskets are welcomed and encouraged. Please note that alcohol will only be allowed inside the venue for certain events. Please inquire if you are unsure.
This venue is the perfect place for concerts, festivals, benefits and more. Situated within the Oak Point Nature Preserve, the Amphitheater is also a great starting point for 5K's, as the trails and distances have already been pre-measured throughout the nature preserve. In coordination with Special Events, the grassy areas outside the gates are also available to be utilized.
The Amphitheater is a seasonal venue that closes throughout the winter months. Capacities for each event will be determined based on a number of parameters. Contact Plano Stages for more information about booking this beautiful venue.
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Read about 6ft Superking Divan Beds
The Super Kingsize divan bed is 6ft wide and will look fantastic in the bedroom. It is very important to ensure that the bedroom is wide enough to accommodate it. The whole effect could be spoilt if the bed is too wide and not allow any space either side of the bed. The super kingsize bed is the perfect choice for couples who like to stretch out in bed without disturbing their partner.


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Distinctive Flair Salon
We know you are gorgeous, but Distinctive Flair Salon Hair Stylist services provided by bridal beauty specialists can make you absolutely stunning!
Alicia White at Legacy Salons and D...
Make all your guests marvel at your beauty with Hair Stylist services by the talented beauty experts at Alicia White at Legacy Salons and Day Spa in Roanoke.
Splurge Salon
Relax on your special day with the talented Splurge Salon wedding professionals that are devoted to handling everything Makeup Artist related.
Strandz Hair Design
Looking for a change? Strandz Hair Design's experienced glamour professionals offer Hair Stylist services and many more services in Roanoke.
Samantha Mastropolo
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Hazel Eyes Makeup Artistry
This business knows exactly what to do to make sure you and the bridal party look absolutely stunning in Roanoke.
meHD Skincare and Makeup Studio
Want to do something special for your party? The glamour makeover professionals at meHD Skincare and Makeup Studio offer Facials services you'll love.
Every bride deserves a relaxing Massage experience on their day, and the experts at CTM in Roanoke love to help!
The Hair Artisan
Show off your amazing style with help from the makeover experts at The Hair Artisan and their range of Hair Stylist services.
Hair by Gayle
At Hair by Gayle our skilled wedding beauty experts have established our reputation for providing the most superior Makeup Artist services available.
All Dolled Up Makeup and Hair Studi...
You deserve only the best Makeup Artist services, and the sensational Visuelle Artistry Makeup Studio freelance beauty professionals know how to deliver outstanding results.
DDR Salon Elegance
The beauty professionals at DDR Salon Elegance will make sure you achieve the look you want with Makeup Artist services.
Glamorous Lash
At Glamorous Lash in Roanoke, we know exactly how to create any look you want with imaginative and professional Day Spa Package services.
Get exceptional Tanning results with the freelance beauty experts at THE BEAUTY CLINIC, which are only available to those in Roanoke.
Memorable Occasions and Hair Design
Perfect hair and/or makeup is an art, and the bridal artists at Memorable Occasions and Hair Design offer Day Spa Package services that are canvas-worthy!
Mary Kay Independent Beauty Consult...
Picture yourself with a perfectly gorgeous look; the wedding beauty experts at Mary Kay Independent Beauty Consultant offer Facials services with perfect results.
Hair Designs by Shelli
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For my: Holiday Party
Taking place on: May 05
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SAP global
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Connecting Families to Senior Living
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We value your privacy. By clicking you agree to the terms and conditions of our privacy policy. You also consent that we can reach out to you using a phone system that can auto-dial numbers (we miss rotary telephones, too!). Your consent is not required to use our service.
You know your family, A Place For Mom knows Assisted Living. Our dedicated local Edgar, WI advisors have helped 15 families make the right choice for their needs. Get full details, pricing and read 31 reviews of our hand-picked communities. Typically prices range from $2750.00 to $7699.00 per month.
Finding the best options for assisted living in Edgar can be a challenge. With so many choices for seniors, making the right one for your family can seem overwhelming. Working together, we can help you gain peace of mind. Our free service includes a local Senior Living Advisor dedicated to matching you with
a tailored list of hand-picked communities that meet your needs. We provide you with full details and pricing, scheduling property tours and move in support. There's no cost to you.
PROVIDING THE NEXT BEST THING TO HOME The Wellington Place Homes are single-story assisted living residences with seniors in mind. When living at home is no longer a safe or practical option, we offer an affordable, home-like atmosphere along with the assistance sometimes needed in our later adult...
14 miles from Edgar, WI
Provides: Assisted Living in Wausau, WI
Mountain Terrace Senior Living offers everything you need for a vibrant life and assurance for the future. We're conveniently located in Wausau, WI with a beautiful view of Rib Mountain. The senior lifestyle at Mountain Terrace includes an abundance of services, where you can enjoy maintenance-free...
The goal at Our House Assisted Living is to create an environment that nourishes the intellectual, emotional, and physical needs of each resident. Our House provides secruity and care to seniors in their hometowns and are designed to support seniors who can no longer live alone. Respect, dignity and...
17 miles from Edgar, WI
Surround yourself with convenience and compassion at The Waterford at Colby. Our Assisted Living community in the charming city of Colby, Wisconsin offers a relaxed atmosphere of warmth and caring that promotes companionship among residents and staff. Enjoy an array of unique amenities, including...
Provides: Assisted Living in Colby, WI
Basic Services for our residents include a Private suite, Health Status Monitoring, Three Home Cooked Meals Daily, Snacks Upon Request, Routine Housekeeping and Laundry Services, 24-hour Security and Staff Availability, Emergency Call System in Each Unit, Health Promotion and Exercise Programs, Self...
PROVIDING THE NEXT BEST THING TO HOME The Cedar Ridge Homes are single-story assisted living residences with seniors in mind. When living at home is no longer a safe or practical option, we offer an affordable, home-like atmosphere along with the assistance sometimes needed in our later adult years...
18 miles from Edgar, WI
Provides: Assisted Living in Schofield, WI
We see in each individual their grand potential to live a life of self-respect and integrity. We also strive to lessen your worry as we provide compassionate skilled care that brings a spirit of independence into the life of your loved one. Our priority is to provide the highest level of care &...
Care Partners Assisted Living in Weston (5905 Delikowski Street) is a 20 bed assisted living facility that offers a secure and home-like environment for our residents. It is located near medical facilities, as well as numerous shopping, dining and recreational facilities. The facility provides our...
19 miles from Edgar, WI
Provides: Assisted Living in Weston, WI
There's something for everyone at Deerview Meadows. A Senior Living community that offers the comforts of home with the security and enriching activities of a group home. We work hard to make Deerview Meadows the kind of place where we would want our own mothers and fathers to live. Deerview...
Provides: Assisted Living in Marshfield, WI
Tenants of the Aster Assisted Living of Marshfield enjoy a lifestyle that connects contemporary elegance, tradition and the historic spirit of Marshfield! Consisting of 53 assisted living suites, the Aster of Marshfield provides a comfortable neighborhood setting, accented by manicured flower beds,...
21 miles from Edgar, WI
*15 private rooms offering dignity, privacy, and peaceful living in a small, homelike setting *Three home-cooked meals and snacks every day *Medication supervision and management ensuring doctors orders are followed accurately *Health monitoring and regular assessments of physical and mental health...
22 miles from Edgar, WI
Provides: Assisted Living in Merrill, WI
24 miles from Edgar, WI
Provides: Assisted Living in Medford, WI
25 miles from Edgar, WI
10 miles from Edgar, WI
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15 miles from Edgar, WI
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Provides: Assisted Living in Abbotsford, WI
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Hotfrog SouthAfrica provides information regarding Wimpy in Gauteng. Wimpy is located at The Rivonia Centre, Shop A5, Rivonia Blvd, Gauteng and provides social services. Contact them on 011 803 6467 or by visiting them on their website http://www.wimpy.co.za/.
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Inklings (noun):
1. A slight knowledge or suspicion; a hint
2. A literary discussion group in the 1930s and 40s, associated with University of Oxford. Members met weekly for readings, criticisms, and conversations around their literary work. The group famously included members such as C.S. Lewis, J.R.R. Tolkien, and Charles Williams.
3. A literary magazine and workshop group at Colby College
See the Aims and Scope for a complete coverage of the journal.
Current Issue: Volume 2, Issue 2 (2016) Spring 2016
A Note From the Editor
Jessica Greenwald
Canyonlands National Park
Eenie Bernard
To the Sky, the Stars, and All They Teach Us
Ellie Geoghegan
You and Me: An Explanation
Katie Monteleone
Caleb's Rules
Jessica Greenwald
Would You Smash Pt. 1
Emery Lawrence
Of a Nemesis
Jay Huskins
Quercus Robur
Fini Just
Night Dawns
Tonayo Crow
Tell Me When
Katie Monteleone
The World on Foot
Sarah Neal
Would You Smash Pt. 2
Emery Lawrence
A Conversation in the Blue
Jay Huskins
Canyonlands National Park
Jessica Greenwald


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1. You might think you feel like this…
2. But actually, not doing things is seriously overrated.
3. After a few days at home…
4. …vacation boredom leaves you vulnerable to pathetic downward spirals.
8. And it could get worse…
9. Much worse.
10. God forbid.
11. You lose appreciation for well-drawn characters and meticulous pacing.
12. Plus, who wants to sit at home when you could get adorable notes like this at school?
Via imgur.com
13. Sure, a stocked fridge may be nice if you've been toughing it out on your own…
16. But avoiding these horrible incidents is much nicer…
tfl.nu / Via textsfromlastnight.com
18. And when you're lazing around the house, parental manipulation can really be a drag.
19. But at school, there are precious moments of relaxation…
Via blog.lib.umn.edu
20. …that are yours, and yours alone.
Via funnyjunk.com
21. Unless you are James Franco, for whom lecture snoozes become TMZ phenomena.
22. Sure, Mom may make pancakes on holiday mornings, but you can't get away with this at home.
imgur.com / Via reddit.com
23. And bunsen burners in chem lab? Sexy.
Via gifstumblr.com
24. School is where it's at, people.
25. And if you study hard enough, one day this could be you.
imgur.com / Via reddit.com
University of Nebraska classics professor, Tom Winter, is beloved for traversing campus by skateboard.
26. So get excited!
27. Because starting fresh just feels soooo good.
28. And let's be real. Deep down, we all want to go back to school.
29. Especially this lady.
Via knowyourmeme.com
98 year-old Nola Ochs, the oldest person to earn a Master's Degree.
30. So hey there, second semester.
This post was created by a user and has not been vetted or endorsed by BuzzFeed's editorial staff. BuzzFeed Community is a place where anyone can post awesome lists and creations. Learn more or post your buzz!
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In The News Today
- A newly unearthed Homeland Security report contradicts Donald Trump's travel ban, saying country of origin is not a reliable indicator of terrorism.
- A draft of an Obamacare repeal plan was released that would strip many benefits and taxes from the healthcare law, while blocking federal funds from Planned Parenthood.
- Time to change your passwords: Uber and Fitbit are among the millions of websites that may have been compromised 🔐
- A billboard in North Carolina that claims "Real men provide. Real women appreciate it," has sparked controversy across the country 👀
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Long Beach ATTRACTIONS See all
Naples is a great neighborhood for exploring Long Beach's restaurant scene, as it's filled with delicious options for local and ethnic dining. While Russo's Neighborhood Ristorante & Bar serves up hearty Italian, Sushi of Naples can satiate your Japanese craving. And at the Naples Rib Company, you'll savor fall-off-the-bone ribs, juicy sausage and tender chicken.
When visiting Naples, La Bella Fontana Di Napoli is a fountain in the center of the neighborhood that's also a popular attraction. The structure was erected in 1971 and sits in a peaceful park that many say makes them feel as though they're in Naples, Italy.
If you're visiting during the holidays, Naples is well-known for its Naples Island Christmas Boat Parade. This annual tradition features small and large boats adorned in holiday decorations floating on the water.
Tours & Tickets
Platinum Naples Island and Waterfront Segway Tour
Enjoy a 2.5 hour segway tour of Naples Island and the beach-side of Long Beach. Naples Island is famous for being the "Dreamland of Southern ... Read more
Location: Long Beach, California
Duration: 2 hours 30 minutes (approx.)


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The Unexpected and Fictional Career Change of Jim Kearns
€ 13,99
Lieferbar innert 2 Wochen
September 2005
BeschreibungJim Kearns, a career manual labourer, struggles to overcome stifling cynicism brought on by missed opportunities and mid-life discord - then he loses his job for punching out a Hollywood action star in a bizarre job-site confrontation. In an effort to salvage not only Jim's sanity but also their unravelling family, his wife, Maddy, assigns him a series of life-affirming tasks to complete while he suffers through unemployment and his fifteen minutes of fame. Through the pages of his journal, we get an often humorous and sometimes touching view of one man's life journey. At once compelling and hilarious, "The Unexpected and Fictional Career Change of Jim Kearns" is the most refreshing novel of the 2005.
PortraitDavid Munroe is the author of the critically acclaimed short story collection "Mahoney in Control." He has won the "Toronto Star" Short Story Contest for his story Marathon Man. He currently lives in East Toronto with his wife, Anita, his son, Sam, and their dog, Peach.
Pressestimmen"an enjoyable, light read." -- Mid-Town Crier (Toronto, ON), 20060401
Verlag: Dundurn Group Ltd
Erscheinungsdatum: September 2005
Seitenanzahl: 328 Seiten
Format: kartoniert
Alle Preise inkl. MwSt., ggf. zzgl. Versandkosten


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Air Jordan 11 (XI) Retro Bred
|Air Jordan
|Air Jordan 11 (XI)
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Master of Arts Media and Creative Enterprise
Entry Requirements
Candidates should have a First or Second Class degree and two references and/or, appropriate professional experience, other qualifications or achievements, as judged by the MA Media and Creative Enterprise team.
Our close links with business and the professions mean that our courses are always relevant, up-to-date and meet the exact needs of the current marketplace. Wherever possible, we involve employers in planning the curriculum, while many of our lecturers come from and maintain their links with industry, ensuring they are up to speed with the latest developments. Employability will be an integral outcome of your studies. We have a strong research culture inviting postgraduate students to see themselves as part of the research community and encouraging further academic studies.
Employment Opportunities: Completing this course will provide graduates with an in-depth understanding of the practical and theoretical frameworks in creative entrepreneurship. This is a highly flexible course, which emphasises individuals' personal and professional development, they will also have developed an awareness about how creative businesses operate . After completing this course students have developed their careers in further academic studies, festivals, creative industry consultancy, social enterprise and starting their own creative business.
Placements: Full-time students have the opportunity to undertake placements during the postgraduate Diploma phase of the course.
Further Studies: For anyone interested in taking their research onto an MPhil or PhD speak to the course director in your particular area.
Course Structure
The course involves high-level practice and theory, including student-led activities and live projects. Understanding of the cultural, economical and technological frameworks of the creative and cultural industries is applied to enhance creative and business opportunities. In the Postgraduate Certificate phase you gain a critical overview of how media, social and creative policies. You can develop your entrepreneurial skills developing innovative solutions in creative, media and social enterprise. In the Postgraduate Diploma phase there is the option of working on live briefs or working on a research project. You will critically explore cultural entrepreneurship through the study of cultural work, new developments in entrepreneurship studies and case studies of cultural organisations. The Masters phase focuses on a student-led project linked to your personal research or practice interests .
Each taught module consists of 10 class sessions, in which students will be introduced to topics through lectures, seminar discussions and workshop activities. There will often be guest lectures from leading practitioners in the field and we place a strong emphasis on lecturer and peer review of student presentations and work-in-progress. These sessions are supported by structured material available on the university's Moodle online system. Each week, students are set independent study tasks, often based upon production activities, and there are two further weeks of directed study.
Many modules make significant use of new social media, and students will be asked frequently to contribute to fora, write blogs, or produce podcasts to chart personal and professional development. They will also examine and comment on the work of their peers.
Modules: Creative Industries and Cultural Policy (30 credits), Enterprise (30 credits), Cultural Enterprise (30 credits), Production Lab or Research Methods (30 credits) , MA by Practice or MA by Dissertation (60 credits).
Assessments usually emphasise scholarly or professional practice through which the key learning objectives are tested. Three weeks are set aside for assessment work.
This school offers programs in:
- English
Last updated February 13, 2017


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From Wikimedia Commons, the free media repository
Hasdrubal, son of Hamilcar Barca, (d. 207 BC, short form Hasdrubal) was Hamilcar's second son and a Carthaginian general in the Second Punic War. He was a younger brother of Hannibal, son of Hamilcar Barca.
This category has the following 3 subcategories, out of 3 total.
- ► Battle of the Metaurus (11 F)
- ► Sophonisba (1 C, 40 F)
Media in category "Hasdrubal"
The following 10 files are in this category, out of 10 total.
- Hasdrubal coin.jpg 47 KB
- Second Punic War full-de.svg 480 KB
- Second Punic War full-en.svg 770 KB
- Second Punic War full-es.svg 982 KB
- Second Punic War full-fr.svg 1.1 MB
- Second Punic War full-nl.svg 1.02 MB
- Second Punic War full-pt.svg 689 KB


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Donald J. Zelazny, DDS and the entire team at Z Dental invite you and your family to come visit our Franklin, MI dental office to see how we can help with your dental care. We proudly serve the people of Franklin, West Bloomfield, Beverly Hills, Farmington Hills, Southfield, and Birmingham. But even if you live as far out as Detroit, we are happy to make an appointment for you.
Because we are a family dentist in Franklin, we offer many different dental treatments. Of course, we offer general dentistry procedures like cleanings, exams, and fluoride treatments. But we also can help improve the look of your smile with cosmetic treatments like teeth whitening, tooth bonding, and dental veneers. Our restorative treatments, such as dental crowns and fillings, can return the proper function to your teeth. We have orthodontics such as braces, Six Month Smiles clear braces, and Red, White & Blue clear plastic aligners so your teeth can get to where they belong. We even offer free mouthguards for participants in school sports for patients of record.
We take a holistic approach here at Z Dental, so we work with more than just your teeth. Our sleep apnea treatment can help end the horrible snoring that happens every night, leaving you exhausted and moody. If you have pain in your jaw, a TMJ treatment can help. Many people grind their teeth unconsciously, so we offer special mouthguard-like devices that will protect your teeth from harm and eliminate pain. We can also check for and treat gum disease to stop your gums from bleeding or your teeth from falling out.
Dr. Zelazny (many people call him "Dr. Z") has been practicing dentistry in Oakland County for more than 25 years, giving him a depth of experience that's hard to find. But he has kept up with new advances in dentistry, recently becoming a Fellow of the Academy of General Dentistry (FAGD). He and his team know how dental anxiety can be tough to get past, which is part of why they are so friendly, welcoming, and warm. What's the other part? They're just nice people!
With our commitment to dental care, a mix of experience and modern training, and staff that knows how to treat you like a real person, we are the dental office for your family. If you are ready to schedule a new appointment for you or a member of your family, or if you have any questions about how we can improve your dental health, call us today at 248‑785‑3426 or use our convenient online form.
All new patients scheduling an appointment with us will receive a FREE Family 4-Pack of tickets to see our new local baseball team! Enter your information to claim your offer!


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News By Tag
Industry News
News By Place
Industry News
Concord Extra Discussion Event: What needs to be done to improve the skills of our youth?
Concord Extra organised a discussion event on 12 June on topic "What needs to be done to improve the skills of our youth?" This was done on Facebook platform.
Here are discussions on different ideas:
Idea #1: An idea? company's should be encouraged to join together to do job promotion days for the young to come along and see what there companies do and how they can achieve the qualifications to get into the specific workplace if more companies encouraged mentoring programmes to help the young focus on what they could achieve in timescales it would help
Lisa Auty I think its a great idea, if you have an idea of what you want to achieve n then go n visit the place n you find its not what you want to do then at least you haven't wasted years in college n end up doing something you hate but on the other hand if you still want to do it, it gives you experience n knowledge
12 June at 13:31 • Unlike • 1
Nicola D Seary I agree there should be more work based experience as part of the curriculum for Year 9 and upwards, small taster like sessions for says once a week for a month.
Idea #2: Kids need teachers that they look up to, teachers that have enthusiasm for the job. They also need as much "real life" experience as possible. For example work based training. Some children are not "academic" this does not and should not mean that they should be written off. Also as I am finding quiet, children that achieve well but make no "noise" and keep there heads down seem to be overlooked. Learning should be fun but not necessarily "easy". Respect seems to be a key element those todays youth are lacking-this comes from a mum of 5 children.
Lisa Auty yup, quiet people do get overlooked, esp. when there are boisterous kids in the same class, the teachers make sure the boisterous n noisy ones are the ones that get their full attention which isn't fair at all on the quiet ones who do want to learn. i agree with work based training, my school had 2 weeks work experience, i loved it!
Nicola D Seary I did 2 weeks work experience but where we live now this has been made optional and only available if parents can arrange it themselves.
Idea #3: My son's school does a great thing which is called skills for work its 2 periods a week and they do a little taster of all different jobs plumbing electrician painting and decorating etc they do this for 2 years I think it is a great idea.
Lisa Auty yup, another great idea :)
Nicola D Seary This is exactly what I think all schools should be offering to pupils. How can a child/young adult know what they want to do with their life when they are 16? I wanted to be a Nanny, looking after children-am now a mum of 5, lol.Similar vein I suppose. As many opportunities should be made available for young adults to sample the types of skills required for the real world. Financial education is also a huge must.
Lisa says - I think more needs to be done on getting experience whilst at school as most employers wont give you a job or give you any opportunity unless you've had experience in a particular field, going to college doesn't help all the time coz its just a qualification and most employers want actual work experience, just find it unfair that you cant get a job due to lack of experience but then you cant get the experience because no one gives you that chance!
Nicola D Seary I agree. I also feel there should be more FREE extra help available to ALL children that are struggling with their school work.CV's should be something taught from an early age too.
Lisa Auty yup I agree with that swell, to enable young adults to get jobs, it needs to be done quite soon after leaving school or in school so they have the motivation to carry on with it, and you get knock back after knock back n it gets to the point when you just kind of give up
Nicola D Seary Many teenagers these days seem to lack drive and inspiration, they don't want to learn or get out and work-they want a free and easy ride. I do agree that more should be done to enable the government to offer more work experience to teenagers either at school or soon after they leave. People often forget about the voluntary sector and I am aware that this is now being offered as an option by jobcentres to gain experience, however there is still a long way to go.
12 June at 13:57 • Like
Lisa Auty thing is most kids don't want to do voluntary work once they've left school, there's also the careers centre who pay you about 3 quid a week and you do a full weeks work but for a third of what everyone is getting paid, that's what is kind of bad about it as you are doing the same as everyone else for nothing really
12 June at 13:59 • Like
Nicola D Seary but surely it's better than kids wasting time playing on consoles etc or getting drunk or stoned. I don't like to generalise but that is what an awful lot of lads between 18-25 do.
Nicola D Seary Inspiration to achieve something with their lives is what they need not JSA active they want JSA they should earn it by doing voluntary work-not full time necessarily but make some sort of contribution to society.
Lisa Auty yeah I do agree with that, JSA is given out too easily to people nowadays they give people who do want a hard time whereas the people who don't want to work gets it easy, they don't have to prove they have been looking for work, its just given out to them on a plate
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Fish Baked In An Herb Crust
|Catfish fillets
|6 Ounce
|Olive oil
|2 Teaspoon
|Sweet red pepper
|1 , chopped
|Defatted chicken stock
|1 1⁄2 Cup (24 tbs)
|Plum tomatoes
|1 Cup (16 tbs), chopped
|Loosely packed fresh basil
|2 Cup (32 tbs)
|Dry bread crumbs
|1 Cup (16 tbs)
1) With 1 teaspoon oil, rub the fish all over.
2) Allow to marinate for 5 minutes.
3) Preheat oven to temperature of 400 degrees.
4) In a large non-stick frying pan, put 1 teaspoon of oil and add the peppers. Saute over moderate-high heat for about 5 minutes.
5) Add the tomatoes and stock and cover the pan. Gently simmer for about 10 minutes, or till the vegetables are soft.
6) Put the sautéed mixture in a food processor or blender and puree. The mixture should be thick enough to lightly coat a spoon's back. In case the mixture is too thin, put it back in the pan and cook till the desired level of thickness has been achieved.
7) Keep the puree warm.
8) Coarsely chop the basil and put it in the food processor. Add the breadcrumbs and process till finely chopped and thoroughly mixed with on/off turns. Ensure that a paste is not formed.
9) Put the mixture in a large plate or on a sheet of wax pepper.
10) In the crumb mixture, dredge the marinated fish and coat both the sides properly.
11) Use non-stick spray to coat a large non-stick frying pan.
12) Sear the fish over moderate-high heat for about 3 minutes on each side.
13) Put the fish on a baking sheet and bake in preheated oven for 4 minutes per side, till the fish is firm to touch and crispy.
14) Serve hot with the tomato mixture.
Recipe Summary
Rate It
Nutrition Rank
Nutrition Facts
Serving size
Calories 145 Calories from Fat 50
% Daily Value*
Total Fat 5 g8.3%
Saturated Fat 1.1 g5.4%
Trans Fat 0 g
Cholesterol 16.9 mg5.6%
Sodium 295.6 mg12.3%
Total Carbohydrates 14 g4.7%
Dietary Fiber 2.1 g8.4%
Sugars 2.1 g
Protein 10 g20.7%
Vitamin A 41% Vitamin C 80.5%
Calcium 8.3% Iron 10.3%
*Based on a 2000 Calorie diet


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Our Events team host a range of different events from small seminars to large scale award ceremonies, drinks receptions and International events.
We are a highly professional team who plan and deliver every event ensuring that all details are taken care of no matter how small – perfection is our aim.
For more information on our planned events or to make a booking, please view our current events.
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Hllywd's Event Journal
Sunday June 9, 2013 / 7:00pmAlison Whittaker's Vital Signs: The Pulse of an American Nurse
1 ticket
General Admission Complimentary
How was your experience?
I enjoyed this performance. She was very honest about her experiences. I think all of the nurses in the audience could certainly relate more and enjoyed it more than us "non-nurses". Some sad and funny moments. Certainly worth seeing.


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Aden Hall
Aden Hall is located centrally on campus and is part of the Quadrangle Community. It houses approximately 116 students. Participation in the Engineering Living & Learning Community is mandatory for students who request and are assigned to Aden Hall.
Who Lives Here
Primarily freshmen majoring in engineering and applied sciences.


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Maui Whitening at Indy Health & Fitness
|8660 Guion Rd
|Indianapolis, In 46268
|(317) 550-4999
- Monday: 1:00pm – 6:00pm
- Tuesday: 7:30am – 12:30pm
- Wednesday: 1:00pm – 6:00pm
- Thrusday: 7:30am – 12:30pm
- Friday: 9:30am – 12:30pm
Indy Health and Fitness now has a permanent Maui Whitening salon location located inside this 10,000 ft wellness facility. No appointment is necessary for teeth whitening services. Simply walk-in or check-in online to be serviced right away, 5 days a week! Results are fast and professional, and at a fraction of the cost compared to other clinics. Our whitening associates are Maui Whitening Certified and trained. We use Made in USA fresh, professional-grade gels only. Our gels and lights are both registered with the FDA to provide you with a safe, effective experience! You can expect a professional, fast teth whitening experience in an hour or less. This Maui Whitening salon location is located at 8660 Guion Rd., just west of Michigan Rd. off 86th Street.


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Coast International Inn Anchorage3 star hotel
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- 4360 Spenard Road, Anchorage, AK, United States, 99517 , Map
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Home Suites By Hilton Anchorage/Midtown3 star hotel
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