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The episodic long-term memory system supports remembering of events. It is considered to be the most age-sensitive system, with an average onset of decline around 60 years of age. However, there is marked interindividual variability, such that some individuals show faster than average change and others show no or very little change. This variability may be related to the risk of developing dementia, with elevated risk for individuals with accelerated episodic memory decline. Brain imaging with functional magnetic resonance imaging (MRI) of blood oxygen level-dependent (BOLD) signalling or positron emission tomography (PET) has been used to reveal the brain bases of declining episodic memory in ageing. Several studies have demonstrated a link between age-related episodic memory decline and the hippocampus during active mnemonic processing, which is further supported by studies of hippocampal functional connectivity in the resting state. The hippocampus interacts with anterior and posterior neocortical regions to support episodic memory, and alterations in hippocampus–neocortex connectivity have been shown to contribute to impaired episodic memory. Multimodal MRI studies and more recently hybrid MRI/PET studies allow consideration of various factors that can influence the association between the hippocampal BOLD signal and memory performance. These include neurovascular factors, grey and white matter structural alterations, dopaminergic neurotransmission, amyloid-Β and glucose metabolism. Knowledge about the brain bases of episodic memory decline can guide interventions to strengthen memory in older adults, particularly in those with an elevated risk of developing dementia, with promising results for combinations of cognitive and physical stimulation.
Click here to view the Letter to the Editor by Dr. Vuorio et al.]]>
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The long-term consequences of autoimmune diabetes in adults (AIDA) are largely unexplored.
To investigate the risk of myocardial infarction (MI) in AIDA compared to type 2 diabetes, taking into consideration the effects of socio-economic and lifestyle factors, the metabolic syndrome and glycaemic control.
A total of 62 995 participants including 207 individuals with AIDA (onset ≥35 years and anti-GAD positive) and 2322 individuals with type 2 diabetes (onset ≥35 years and anti-GAD negative), from the population-based Norwegian HUNT study, were followed for a first MI during the period 1995–2008. We identified 2614 MIs by hospital records or the National Cause of Death Registry. Cox proportional hazard models were used to estimate the risk of MI by diabetes subgroups after adjustment for age and socio-economic and lifestyle factors.
AIDA amongst women was associated with a nearly fourfold increased risk of MI [hazard ratio (HR) 3.63, 95% confidence interval (CI) 2.21–5.96) compared to nondiabetic participants, whereas no excess risk was found in men with AIDA (HR 1.30, 95% CI 0.70–2.52). By contrast, type 2 diabetes was associated with an increased MI risk in both men (HR 1.92, 95% CI 1.62–2.26) and women (HR 2.39, 95% CI 1.98–2.89). The metabolic profile was more favourable in patients with AIDA than in those with type 2 diabetes, but glycaemic control was worse. Multivariable models and sensitivity analyses suggest that these results were robust.
Women with AIDA were more likely to develop MI, compared to men with AIDA and both men and women with type 2 diabetes. Further investigations are warranted to confirm this gender difference.
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Click here to view the Letter to the Editor by Dr. Lindqvist et al.]]>
Neuroendocrine tumour of the small intestine (SI-NET), formerly known as midgut carcinoid tumour, is the most common small intestinal malignancy. The incidence is rising, with recent reports of 0.67 per 100 000 in the USA and 1.12 per 100 000 in Sweden. SI-NETs often present a challenge in terms of diagnosis and treatment, as patients often have widespread disease and are beyond cure by surgery. Somatostatin analogues provide the mainstay of medical treatment to control hormonal excess and increase the time to progression. Despite overall favourable prognosis (5-year overall survival of 65%), there is a need to find markers to identify both patients with worse outcome and new targets for therapy. Loss on chromosome 18 has been reported in 60–90% of SI-NETs, but mutated genes on this chromosome have failed detection. Recently, a putative tumour suppressor role has been suggested for TCEB3C occurring at 18q21 (encoding elongin A3), which may undergo epigenetic repression. CDKN1B has recently been revealed as the only recurrently mutated gene in SI-NETs but, with a frequency as low as 8%, its role as a driver in SI-NET development may be questioned. Integrated genomewide analysis including exome and whole-genome sequencing, gene expression, DNA methylation and copy number analysis has identified three novel molecular subtypes of SI-NET with differing clinical outcome. DNA methylation analysis has demonstrated that SI-NETs have significant epigenetic dysregulation in 70–80% of tumours. In this review, we focus on understanding of the genetic, epigenetic and molecular events that lead to development and progression of SI-NETs.
Primary hyperparathyroidism (PHPT), due to parathyroid tumours, may occur as part of a complex syndrome or as an isolated (nonsyndromic) disorder, and both forms can occur as familial (i.e. hereditary) or nonfamilial (i.e. sporadic) disease. Syndromic PHPT includes multiple endocrine neoplasia (MEN) types 1 to 4 (MEN1 to MEN4) and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome. Syndromic and hereditary PHPT are often associated with multiple parathyroid tumours, in contrast to sporadic PHPT, in which single parathyroid adenomas are more common. In addition, parathyroid carcinomas may occur in ~15% of patients with the HPT-JT syndrome. MEN1 is caused by abnormalities of the MEN1 gene which encodes a tumour suppressor; MEN2 and MEN3 are due to mutations of the rearranged during transfection (RET) proto-oncogene, which encodes a tyrosine kinase receptor; MEN4 is due to mutations of a cyclin-dependent kinase inhibitor (CDNK1B); and HPT-JT is due to mutations of cell division cycle 73 (CDC73), which encodes parafibromin. Nonsyndromic PHPT, which may be hereditary and referred to as familial isolated hyperparathyroidism, may also be due to MEN1, CDC73 or calcium-sensing receptor (CASR) mutations. In addition, ~10% of patients presenting below the age of 45 years with nonsyndromic, sporadic PHPT may have MEN1, CDC73 or CASR mutations, and overall more than 10% of patients with PHPT will have a mutation in one of 11 genes. Genetic testing is available and of value in the clinical setting, as it helps in making the correct diagnosis and planning the management of these complex disorders associated with parathyroid tumours.
G protein-coupled receptors (GPCRs) are the most abundant receptor family encoded by the human genome and are the targets of a high percentage of drugs currently in use or in clinical trials for the treatment of diseases such as diabetes and its associated complications. Thus, orphan GPCRs, for which the ligand is unknown, represent an important untapped source of therapeutic potential for the treatment of many diseases. We have identified the previously orphan GPCR, GPR146, as the putative receptor of proinsulin C-peptide, which may prove to be an effective treatment for diabetes-associated complications. For example, we have found a potential role of C-peptide and GPR146 in regulating the function of the retinal pigment epithelium, a monolayer of cells in the retina that serves as part of the blood–retinal barrier and is disrupted in diabetic macular oedema. However, C-peptide signalling in this cell type appears to depend at least in part on extracellular glucose concentration and its interaction with insulin. In this review, we discuss the therapeutic potential of orphan GPCRs with a special focus on C-peptide and GPR146, including past and current strategies used to 'deorphanize' this diverse family of receptors, past successes and the inherent difficulties of this process.
Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.
The success of antiretroviral therapy in treating HIV infection has greatly prolonged life expectancy in affected individuals, transforming the disease into a chronic condition. A number of HIV-associated non-AIDS comorbidities have emerged in the ageing HIV-infected population, including osteoporosis and increased risk of fracture. The pathogenesis of fracture is multifactorial with contributions from both traditional and HIV-specific risk factors. Significant bone loss occurs on initiation of antiretroviral therapy but stabilizes on long-term therapy. Fracture risk assessment should be performed in HIV-infected individuals and bone mineral density measured when indicated. Lifestyle measures to optimize bone health should be advised and, in individuals at high risk of fracture, treatment with bisphosphonates considered.
In this review, we present findings that support autocrine cell protection by C-peptide in the context of clinical studies of type 1 diabetes (T1D), which universally measure C-peptide serum levels as a surrogate for β cell functional mass. Over the last decade, evidence has accumulated that supports models in which C-peptide, cosecreted with insulin by pancreatic β cells, acts on peripheral targets including the vascular endothelium to reduce oxidative stress and apoptosis subsequent to exposure to diabetic insults. In parallel, as assays have become more sensitive, C-peptide has been detected in the circulation of most subjects with T1D where higher C-peptide levels are associated with fewer and slower development of diabetic microvascular complications, consistent with antioxidant protection by C-peptide. Clinical trials investigating C-peptide-replacement therapy effects have demonstrated amelioration of T1D nephropathy and neuropathy. Recently, the antioxidant action of C-peptide was extended to the β cells secreting it, that is an autocrine mechanism. Autocrine protection has major implications for the treatment of diabetes because the more C-peptide secreted, the more protection provided to the same β cells resulting in a slower decay in β cell functional mass over the time course of disease. Why β cells evolved to cosecrete an antioxidant C-peptide hormone together with the glycaemia-lowering insulin hormone is explored in the context of proposed evolutionary advantages of physiologically transient oxidative stress and insulin resistance as an adaptation for survival through times of fuel scarcity. The importance of recognizing autocrine C-peptide protection of functional β cell mass in observational clinical studies, and its therapeutic implications in interventional C-peptide-replacement studies, will be discussed.
Studies have shown that lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, is causally related to calcific aortic valve stenosis (CAVS). Recently, we found that Lp(a) mediates the development of CAVS through autotaxin (ATX).
To determine the predictive value of circulating ATX mass and activity for CAVS.
We performed a case-control study in 300 patients with coronary artery disease (CAD). Patients with CAVS plus CAD (cases, n = 150) were age- and gender-matched (1 : 1) to patients with CAD without aortic valve disease (controls, n = 150). ATX mass and enzymatic activity and levels of Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) were determined in fasting plasma samples.
Compared to patients with CAD alone, ATX mass (P < 0.0001), ATX activity (P = 0.05), Lp(a) (P = 0.003) and OxPL-apoB (P < 0.0001) levels were elevated in those with CAVS. After adjustment, we found that ATX mass (OR 1.06, 95% CI 1.03–1.10 per 10 ng mL−1, P = 0.001) and ATX activity (OR 1.57, 95% CI 1.14–2.17 per 10 RFU min−1, P = 0.005) were independently associated with CAVS. ATX activity interacted with Lp(a) (P = 0.004) and OxPL-apoB (P = 0.001) on CAVS risk. After adjustment, compared to patients with low ATX activity (dichotomized at the median value) and low Lp(a) (<50 mg dL−1) or OxPL-apoB (<2.02 nmol L−1, median) levels (referent), patients with both higher ATX activity (≥84 RFU min−1) and Lp(a) (≥50 mg dL−1) (OR 3.46, 95% CI 1.40–8.58, P = 0.007) or OxPL-apoB (≥2.02 nmol L−1, median) (OR 5.48, 95% CI 2.45–12.27, P < 0.0001) had an elevated risk of CAVS.
Autotaxin is a novel and independent predictor of CAVS in patients with CAD.
Bone loss at peripheral sites in the elderly is mainly cortical and involves increased cortical porosity. However, an association between bone loss at these sites and 25-hydroxyvitamin D has not been reported.
To investigate the association between serum levels of 25-hydroxyvitamin D, bone microstructure and areal bone mineral density (BMD) in elderly men.
A population-based cohort of 444 elderly men (mean ± SD age 80.2 ± 3.5 years) was investigated. Bone microstructure was measured by high-resolution peripheral quantitative computed tomography, areal BMD by dual-energy X-ray absorptiometry and serum 25-hydroxyvitamin D and parathyroid hormone levels by immunoassay.
Mean cortical porosity at the distal tibia was 14.7% higher (12.5 ± 4.3% vs. 10.9 ± 4.1%, P < 0.05) whilst cortical volumetric BMD, area, trabecular bone volume fraction and femoral neck areal BMD were lower in men in the lowest quartile of vitamin D levels compared to the highest. In men with vitamin D deficiency (<25 nmol L−1) or insufficiency [25–49 nmol L−1, in combination with an elevated serum level of parathyroid hormone (>6.8 pmol L−1)], cortical porosity was 17.2% higher than in vitamin D-sufficient men (P < 0.01). A linear regression model including age, weight, height, daily calcium intake, physical activity, smoking vitamin D supplementation and parathyroid hormone showed that 25-hydroxyvitamin D independently predicted cortical porosity (standardized β = −0.110, R2 = 1.1%, P = 0.024), area (β = 0.123, R2 = 1.4%, P = 0.007) and cortical volumetric BMD (β = 0.125, R2 = 1.4%, P = 0.007) of the tibia as well as areal BMD of the femoral neck (β = 0.102, R2 = 0.9%, P = 0.04).
Serum vitamin D is associated with cortical porosity, area and density, indicating that bone fragility as a result of low vitamin D could be due to changes in cortical bone microstructure and geometry.
Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.
Patients with diabetes have an increased risk of stroke with a poor prognosis. Moreover, diabetic patients are at increased risk of depression and therefore likely to use selective serotonin reuptake inhibitors (SSRIs). We examined whether preadmission SSRI use was associated with increased mortality in diabetic patients hospitalized due to stroke.
Population-based medical databases were used to identify all first-time stroke-related hospitalizations and subsequent mortality in diabetic patients in Denmark between 2004 and 2012 (n = 12 620). Based on redeemed prescriptions, SSRI use was categorized as current (new or long term), former or nonuse, and absolute 30-day mortality and mortality rate ratios (MRRs) were computed using Cox regression controlling for confounding factors.
Amongst SSRI nonusers, 30-day stroke mortality was 15.8% (10.4% for ischaemic stroke, 41.8% for intracerebral haemorrhage and 27.3% for subarachnoid haemorrhage). Amongst current SSRI users, 30-day stroke mortality was 23.3% (17.1% for ischaemic stroke, 50.7% for intracerebral haemorrhage and 28.6% for subarachnoid haemorrhage). Current SSRI use was associated with increased 30-day stroke mortality compared with nonuse [adjusted MRR 1.3, 95% confidence interval (CI) 1.1–1.5], with the highest risk observed amongst new users (MRR 1.5, 95% CI 1.2–1.8). Overall stroke mortality was driven by increased mortality due to ischaemic stroke, with adjusted MRRs of 1.3 (95% CI 1.1–1.7) for current users and 1.7 (95% CI 1.2–2.4) for new users. Propensity score-matched results were similar and robust across subgroups.
In patients with diabetes, preadmission SSRI use was associated with increased mortality following ischaemic stroke, compared with nonuse.
Haploid cells contain one set of chromosomes and are amenable for genetic analyses. In mammals, haploidy exists only in gametes. An intriguing question is whether haploid cells can be derived from gametes. Recently, by application of haploid cell enrichment using fluorescence-activated cell sorting, stable haploid embryonic stem cells (haESCs) have been successfully derived from oocyte-derived parthenogenetic and sperm-derived androgenetic embryos from several species. Whilst both parthenogenetic and androgenetic (AG)-haESCs enable whole-genome genetic screening at the cellular level, such as screening of drug resistance or disease-related genes, AG-haESCs, after intracytoplasmic injection into oocytes, can also be used to produce alive semi-cloned mice. Nevertheless, one major drawback associated with wild-type AG-haESCs is the very low birth rate of healthy semi-cloned mice. Of interest, after inhibiting the expression of two paternally imprinted genes (H19 and Gtl2) in AG-haESCs by removal of their differentially DNA methylated regions, double-knockout AG-haESCs can efficiently and stably support the generation of healthy semi-cloned pups. Importantly, double-knockout AG-haESCs are feasible for multiple genetic manipulations, followed by efficient generation of semi-cloned mice carrying multiple genetic traits; thus they could be used to validate candidate loci that have been identified in genome-wide association studies of multigenic diseases by generation of mouse models carrying multiple alterations. Of note, by combining a CRISPR-Cas9 library and double-knockout AG-haESCs, semi-cloned mice carrying different mutant genes can be efficiently generated in one step, enabling functional mutagenic screening in mice. HaESCs, therefore, provide a powerful tool for genetic analyses in mammals at both the cellular and organismal levels.
Nonhuman primates (NHPs) are superior than rodents to be animal models for the study of human diseases, due to their similarities in terms of genetics, physiology, developmental biology, social behaviour and cognition. Transgenic animals have become a key tool in functional genomics to generate models for human diseases and validate new drugs. However, until now, progress in the field of transgenic NHPs has been slow because of technological limitations. Many human diseases, including neurodegenerative disorders, are caused by mutations in endogenous genes. Fortunately, recent developments in precision gene editing have led to the generation of NHP models for human diseases. Since 2014, there have been several reports of the generation of monkey models using transcription activator-like endonucleases (TALENs) or clustered regularly interspaced short palindromic repeats (CRISPR/Cas9); some of these NHP models showed symptoms that were much closer to those of human diseases than have been seen previously in mouse models. No off-targeting was observed in the NHP models, and multiple gene knockout and biallelic mutants were feasible with low efficiency. These findings suggest that there are many possibilities to establish NHP models for human diseases that can mimic human diseases more faithfully than rodent models.
The cornea is the transparent front part of the eye that transmits light to the back of the eye to generate vision. Loss of corneal transparency, if irreversible, leads to severe vision loss or blindness. For decades, corneal transplantation using human donor corneas has been the only option for treating corneal blindness. Despite recent improvement in surgical techniques, donor cornea transplantation remains plagued by risks of suboptimal optical results and visual acuity, immune rejection and eventually graft failure. Furthermore, the demand for suitable donor corneas is increasing faster than the number of donors, leaving thousands of curable patients untreated worldwide. Here, we critically review the state of the art of biomaterials for corneal regeneration. However, the lessons learned from the use of the cornea as a disease model will allow for extension of the biomaterials and techniques for regeneration of more complex organs such as the heart.
Primary hyperparathyroidism (pHPT) is a common endocrine disease characterized by excessive secretion of parathyroid hormone and an increased level of serum calcium. Overall, 80–85% of pHPT cases are due to a benign, single parathyroid adenoma (PA), and 15% to multiglandular disease (multiple adenomas/hyperplasia). Parathyroid carcinoma (PC) is rare, accounting for <0.5–1% of pHPT cases. Secondary hyperparathyroidism (sHPT) is a complication of renal failure, with the development of parathyroid tumours and hypercalcaemia. Recurrent mutations in the MEN1 gene have been confirmed by the whole-exome sequencing in 35% of PAs, suggesting that non-protein-coding genes, regulatory elements or epigenetic derangements may also have roles in the majority of PAs. DNA translocations with cyclin D1 overexpression occur in PAs (8%). In PCs, mutations in CDC73/HRPT2 are common. Activation of the WNT/β-catenin signalling pathway (accumulation of nonphosphorylated β-catenin) by an aberrantly truncated LRP5 receptor has been seen for the majority of investigated PAs and sHPT tumours, and possibly by APC inactivation through promoter methylation in PCs. Promoter methylation of several other genes and repressive histone H3 lysine 27 trimethylation by EZH2 of the HIC1 gene may also contribute to parathyroid tumorigenesis. It is possible that a common pathway exists for parathyroid tumour development. CCND1 (cyclin D1) and EZH2 overexpression, accumulation of nonphosphorylated β-catenin and repression of HIC1 have all been observed to occur in PAs, PCs and sHPT tumours. In addition, hypermethylation has been observed for the same genes in PAs and PCs (e.g. SFRP1, CDKN2A and WT1). Whether β-catenin represents a 'hub' in parathyroid tumour development will be discussed.
The human gut microbiota has been studied for more than a century. However, of nonculture-based techniques exploiting next-generation sequencing for analysing the microbiota, development has renewed research within the field during the past decade. The observation that the gut microbiota, as an environmental factor, contributes to adiposity has further increased interest in the field. The human microbiota is affected by the diet, and macronutrients serve as substrates for many microbially produced metabolites, such as short-chain fatty acids and bile acids, that may modulate host metabolism. Obesity predisposes towards type 2 diabetes and cardiovascular disease. Recently, it has been established that levels of butyrate-producing bacteria are reduced in patients with type 2 diabetes, whereas levels of Lactobacillus sp. are increased. Recent data suggest that the reduced levels of butyrate-producing bacteria might be causally linked to type 2 diabetes. Bariatric surgery, which promotes long-term weight loss and diabetes remission, alters the gut microbiota in both mice and humans. Furthermore, by transferring the microbiota from postbariatric surgery patients to mice, it has been demonstrated that an altered microbiota may contribute to the improved metabolic phenotype following this intervention. Thus, greater understanding of alterations of the gut microbiota, in combination with dietary patterns, may provide insights into how the gut microbiota contributes to disease progression and whether it can be exploited as a novel diagnostic, prognostic and therapeutic target.
Early human development is a dynamic, heterogeneous, complex and multidimensional process. During the first week, the single-cell zygote undergoes eight to nine rounds of cell division generating the multicellular blastocyst, which consists of hundreds of cells forming spatially organized embryonic and extra-embryonic tissues. At the level of transcription, degradation of maternal RNA commences at around the two-cell stage, coinciding with embryonic genome activation. Although numerous efforts have recently focused on delineating this process in humans, many questions still remain as thorough investigation has been limited by ethical issues, scarce availability of human embryos and the presence of minute amounts of DNA and RNA. In vitro cultures of embryonic stem cells provide some insight into early human development, but such studies have been confounded by analysis on a population level failing to appreciate cellular heterogeneity. Recent technical developments in single-cell RNA sequencing have provided a novel and powerful tool to explore the early human embryo in a systematic manner. In this review, we will discuss the advantages and disadvantages of the techniques utilized to specifically investigate human development and consider how the technology has yielded new insights into pre-implantation development, embryonic stem cells and the establishment of the germ line.
To delineate the association of weight with cardiovascular health throughout adulthood.
We conducted a population-based prospective cohort study of 26 097 community-dwelling individuals who were followed for 11.4 years with measurements of cardiovascular risk factors and common chronic disorders. Body weight and height were directly measured at baseline in 1995–1997 as they had been 10 and 30 years prior to baseline. From these measurements, we estimated average body mass index (BMI) over time and calculated weight change.
The association of average BMI with acute myocardial infarction (AMI) became weaker with adjustment for the most recent BMI measurement, whilst this adjustment had a more limited effect on associations with heart failure (HF) risk. For example, the multi-adjusted hazard ratios for AMI in a comparison of individuals with average BMI until baseline ≥35 kg m−2 and between 18.5 and 22.4 kg m−2 decreased from 1.75 [95% confidence interval (CI) 1.04–2.95] to 1.32 (0.73–2.40). The corresponding numbers for HF were 3.12 (1.85–5.27) and 2.95 (1.53–5.71), respectively. The associations between weight change and risk of AMI and HF were U-shaped, with stable weight showing the lowest risk.
Sustained overweight or obesity over time is associated with increased risk of HF, even after adjustment for the most recent BMI. For AMI risk, the most recent BMI appears to be the most important. Weight change also increases risks for both outcomes beyond the effects of BMI. Our results suggest that a global epidemic of obesity is likely to increase the incidence of HF, even if BMI in middle age can be controlled.
The relationship between vitamin D insufficiency and cognitive impairment remains equivocal in Asians. We examined the association between circulating 25-hydroxyvitamin D (25OHD) concentration and cognitive performance in a large multi-ethnic Singaporean population-based study. We also conducted a meta-analysis of 25OHD concentrations amongst cognitively impaired older adults in Asia.
Our population-based cross-sectional study included 2273 persons ≥60 years of age from the Singapore Epidemiology of Eye Diseases (SEED) study (mean ± SD age 70.4 ± 6.2 years; 44.7% female), who were categorized according to 25OHD concentration (i.e. ≤10, 10.1–20 and >20 ng mL−1). The 25OHD concentration was measured and adjusted to reflect a deseasonalized value. Cognition was assessed using the total and domain scores of the Abbreviated Mental Test (AMT). Global cognitive impairment was defined as AMT score of ≤6 if 0–6 years of education and AMT score of ≤8 if >7 years of education. Fully adjusted multivariate models were used. We included seven studies in a meta-analysis of 25OHD and cognition in Asia (6068 participants; 1179 cognitively impaired cases).
Participants with 25OHD levels >20 ng mL−1 (n = 1302) had higher AMT total scores (mean ± SD 8.5 ± 1.9) and were less likely to have cognitive impairment (14.1%) than participants with lower 25OHD levels (overall P < 0.001, P-trend < 0.001). Deseasonalized 25OHD concentration was associated with AMT score (β = 0.10 per 10 ng mL−1, P = 0.035). Vitamin D insufficiency (25OHD ≤20 ng mL−1) was associated with global cognitive impairment (OR 1.56, P = 0.028). Specifically, 25OHD concentration correlated with semantic memory (r = 0.08, P = 0.009) and orientation in time (r = 0.09, P = 0.003). In the meta-analysis, the pooled mean 25OHD difference was −6.83 ng mL−1 (95% confidence interval −11.36; −2.30), indicating lower 25OHD concentrations amongst cognitively impaired compared to cognitively healthy participants in Asia.
Vitamin D insufficiency is associated with a greater likelihood of and more severe cognitive impairment in Asian populations.
It has been suggested that osteoblasts are involved in the regulation of haematopoietic stem cells. Whether osteocalcin, which is derived from osteoblasts and is metabolically active, influences blood haemoglobin (Hb) levels is not known.
To determine whether plasma osteocalcin is a determinant of Hb in elderly men.
A total of 993 men (mean age 75.3 ± 3.2 years) participated in the population-based MrOS (osteoporotic fractures in men) study. Plasma osteocalcin concentration was evaluated in relation to Hb and adjustments were made for potential confounders (i.e. age, body mass index, erythropoietin, total oestradiol, fasting insulin, adiponectin, ferritin and cystatin C).
Hb correlated (age adjusted) negatively with osteocalcin in the total study group (r = −0.12, P < 0.001) as well as in the subgroup of nondiabetic men (r = −0.16, P < 0.001). In nondiabetic men with higher osteocalcin levels, it was more likely that Hb would be in the lowest quartile (odds ratio per SD decrease in osteocalcin 1.32, 95% confidence interval 1.13–1.53). Quartiles of Hb were negatively associated (age adjusted) with osteocalcin (P < 0.001). Anaemic men (47/812) (Hb <130 g L−1) had significantly higher mean osteocalcin levels than nonanaemic men (33.9 vs. 27.1 μg L−1, P < 0.001). In multiple stepwise linear regression analyses (adjusted for age, body mass index, total oestradiol, adiponectin, erythropoietin, fasting insulin, cystatin C, leptin, ferritin and holotranscobalamin), osteocalcin was an independent predictor of Hb concentration in nondiabetic men (P < 0.05).
These data add further support to the evidence indicating that the bone-specific protein osteocalcin has several endocrine functions targeting the pancreas, testes, adipocytes, brain. An additional novel finding is that osteocalcin may also have a paracrine function as a regulator of haematopoiesis.
Very low-carbohydrate, high-fat (LC) diets are used for type 2 diabetes (T2DM) management, but their effects on psychological health remain largely unknown. This study examined the long-term effects of an LC diet on psychological health.
One hundred and fifteen obese adults [age: 58.5 ± 7.1 years; body mass index: 34.6 ± 4.3 kg m−2; HbA1c: 7.3 ± 1.1%] with T2DM were randomized to consume either an energy-restricted (~6 to 7 MJ), planned isocaloric LC or high-carbohydrate, low-fat (HC) diet, combined with a supervised exercise programme (3 days week−1) for 1 year. Body weight, psychological mood state and well-being [Profile of Mood States (POMS), Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SAI)] and diabetes-specific emotional distress [Problem Areas in Diabetes (PAID) Questionnaire] and quality of life [QoL Diabetes-39 (D-39)] were assessed.
Overall weight loss was 9.5 ± 0.5 kg (mean ± SE), with no difference between groups (P = 0.91 time × diet). Significant improvements occurred in BDI, POMS (total mood disturbance and the six subscales of anger-hostility, confusion-bewilderment, depression-dejection, fatigue-inertia, vigour-activity and tension-anxiety), PAID (total score) and the D-39 dimensions of diabetes control, anxiety and worry, sexual functioning and energy and mobility, P < 0.05 time. SAI and the D-39 dimension of social burden remained unchanged (P ≥ 0.08 time). Diet composition had no effect on the responses for the outcomes assessed (P ≥ 0.22 time × diet).
In obese adults with T2DM, both diets achieved substantial weight loss and comparable improvements in QoL, mood state and affect. These results suggest that either an LC or HC diet within a lifestyle modification programme that includes exercise training improves psychological well-being.
Women with active sunlight exposure habits experience a lower mortality rate than women who avoid sun exposure; however, they are at an increased risk of skin cancer. We aimed to explore the differences in main causes of death according to sun exposure.
We assessed the differences in sun exposure as a risk factor for all-cause mortality in a competing risk scenario for 29 518 Swedish women in a prospective 20-year follow-up of the Melanoma in Southern Sweden (MISS) cohort. Women were recruited from 1990 to 1992 (aged 25–64 years at the start of the study). We obtained detailed information at baseline on sun exposure habits and potential confounders. The data were analysed using modern survival statistics.
Women with active sun exposure habits were mainly at a lower risk of cardiovascular disease (CVD) and noncancer/non-CVD death as compared to those who avoided sun exposure. As a result of their increased survival, the relative contribution of cancer death increased in these women. Nonsmokers who avoided sun exposure had a life expectancy similar to smokers in the highest sun exposure group, indicating that avoidance of sun exposure is a risk factor for death of a similar magnitude as smoking. Compared to the highest sun exposure group, life expectancy of avoiders of sun exposure was reduced by 0.6–2.1 years.
The longer life expectancy amongst women with active sun exposure habits was related to a decrease in CVD and noncancer/non-CVD mortality, causing the relative contribution of death due to cancer to increase.
There is growing awareness of the coexistence of Alzheimer's disease and cerebrovascular disease (AD+CVD), however, due to lack of well-defined criteria and treatment guidelines AD+CVD may be underdiagnosed in Asia.
Sixteen dementia specialists from nine Asia Pacific countries completed a survey in September 2014 and met in November 2014 to review the epidemiology, diagnosis and treatment of AD+CVD in Asia. A consensus was reached by discussion, with evidence provided by published studies when available.
AD accounts for up to 60% and AD+CVD accounts for 10-20% of all dementia cases in Asia. The reasons for underdiagnosis of AD+CVD include lack of awareness as a result of a lack of diagnostic criteria, misdiagnosis as vascular dementia or AD, lack of diagnostic facilities, resource constraints and cost of investigations. There is variability in the tools used to diagnose AD+CVD in clinical practice. Diagnosis of AD+CVD should be performed in a stepwise manner of clinical evaluation followed by neuroimaging. Dementia patients should be assessed for cognition, behavioural and psychological symptoms, functional staging and instrumental activities of daily living. Neuroimaging should be performed using computed tomography or magnetic resonance imaging. The treatment goals are to stabilize or slow progression as well as to reduce behavioural and psychological symptoms, improve quality of life and reduce disease burden. First-line therapy is usually an acetylcholinesterase inhibitor such as donepezil.
AD+CVD is likely to be under-recognised in Asia. Further research is needed to establish the true prevalence of this treatable and potentially preventable disease.
The vasculature is essential for proper organ function. Many pathologies are directly and indirectly related to vascular dysfunction, which causes significant morbidity and mortality. A common pathophysiological feature of diseased vessels is extracellular matrix (ECM) remodelling. Analysing the protein composition of the ECM by conventional antibody-based techniques is challenging; alternative splicing or post-translational modifications, such as glycosylation, can mask epitopes required for antibody recognition. By contrast, proteomic analysis by mass spectrometry enables the study of proteins without the constraints of antibodies. Recent advances in proteomic techniques make it feasible to characterize the composition of the vascular ECM and its remodelling in disease. These developments may lead to the discovery of novel prognostic and diagnostic markers. Thus, proteomics holds potential for identifying ECM signatures to monitor vascular disease processes. Furthermore, a better understanding of the ECM remodelling processes in the vasculature might make ECM-associated proteins more attractive targets for drug discovery efforts. In this review, we will summarize the role of the ECM in the vasculature. Then, we will describe the challenges associated with studying the intricate network of ECM proteins and the current proteomic strategies to analyse the vascular ECM in metabolic and cardiovascular diseases.
JIM Podcast – A conversation and discussion between Bengt Winblad and Jan Johansson about the current Amyloid research, and what was discussed at the conference in Stockholm, with focus on Key messages and Future visions.]]>
Content List – Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.]]>
Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area.
There are around 30 human diseases associated with protein misfolding and amyloid formation, each one caused by a certain protein or peptide. Many of these diseases are lethal and together they pose an enormous burden to society. The prion protein has attracted particular interest as being shown to be the pathogenic agent in transmissible diseases such as kuru, Creutzfeldt–Jakob disease and bovine spongiform encephalopathy. Whether similar transmission could occur also in other amyloidoses such as Alzheimer's disease, Parkinson's disease and serum amyloid A amyloidosis is a matter of intense research and debate. Furthermore, it has been suggested that novel biomaterials such as artificial spider silk are potentially amyloidogenic. Here, we provide a brief introduction to amyloid, prions and other proteins involved in amyloid disease and review recent evidence for their potential transmission. We discuss the similarities and differences between amyloid and silk, as well as the potential hazards associated with protein-based biomaterials.
Amyloid diseases are characterized by the accumulation of insoluble, β-strand-rich aggregates. The underlying structural conversions are closely associated with cellular toxicity, but can also drive the formation of functional protein assemblies. In recent years, studies in the field of structural studies have revealed astonishing insights into the origins, mechanisms and implications of amyloid formation. Notably, high-resolution crystal structures of peptides in amyloid-like fibrils and prefibrillar oligomers have become available despite their challenging chemical nature. Nuclear magnetic resonance spectroscopy has revealed that dynamic local polymorphisms in the benign form of the prion protein affect the transformation into amyloid fibrils and the transmissibility of prion diseases. Studies of the structures and interactions of chaperone proteins help us to understand how the cellular proteostasis network is able to recognize different stages of aberrant protein folding and prevent aggregation. In this review, we will focus on recent developments that connect the different aspects of amyloid biology and discuss how understanding the process of amyloid formation and the associated defence mechanisms can reveal targets for pharmacological intervention that may become the first steps towards clinically viable treatment strategies.
There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.
Obesity, which affects 600 million adults worldwide, is a major risk factor for type 2 diabetes (T2D) and insulin resistance. Current therapies for these metabolic disorders include weight management by lifestyle intervention or bariatric surgery and pharmacological treatment with the aim of regulating blood glucose. Probably because of their short-term effectiveness, these therapies have not been able to stop the rapidly rising prevalence of T2D over the past decades, highlighting an urgent need to develop new therapeutic strategies. The role of immune cells, such as macrophages, in insulin resistance has been extensively studied. Major advances have been made to elucidate the role of adipose tissue macrophages in these pathogeneses. Recently, anti-inflammatory drugs have been suggested as an alternative treatment for T2D, and clinical trials of these agents are currently ongoing. In addition, results of previous clinical trials using antibodies against inflammatory cytokines, which showed modest effects, are now being rigorously re-evaluated. However, it is still unclear how liver macrophages [termed Kupffer cells (KCs)], which constitute the major source of macrophages in the body, contribute to the development of insulin resistance. In this review, we will discuss the present understanding of the role of liver immune cells in the development of insulin resistance. We will particularly focus on KCs, which could represent an attractive target for the treatment of metabolic diseases.
The effects of saturated fat on atherosclerotic vascular disease are currently debated.
In the Oslo cardiovascular study initiated in 1972/1973, a 5-year randomized intervention was conducted in healthy middle-aged men at high risk of coronary heart disease to compare the effects on coronary heart disease incidence of diet and antismoking advice versus control (no intervention). A significant reduction (47%) in first myocardial infarction incidence was observed. We have followed mortality up to 40 years to establish whether a lifelong benefit on mortality risk of myocardial infarction could be observed.
In the present study, a total of 16 203 men (63% of those invited), aged 40–49 years, participated in a screening examination. Overall, 1232 men with total serum cholesterol levels of 6.9–8.9 mmol L−1 (80% smokers) were included in the study. The dietary intervention consisted of mainly decreasing the intake of saturated fats and increasing fish and vegetable products, as well as weight reduction in overweight subjects. Smokers were advised to stop smoking. Cox regression analysis was used for statistical analyses.
The intervention group showed a sustained reduced risk of death at first myocardial infarction (hazard ratio 0.71, 95% confidence interval 0.51–1.00; P = 0.049), compared to control subjects up to 40 years. During follow-up, the beneficial effect developed gradually but proportionally up to about 15 years after randomization. Later, the curves were parallel. All-cause mortality decreased in the period 8–20 years after randomization, but not thereafter.
Receiving advice about a healthy lifestyle led to a long-term reduced risk of coronary mortality during the following 40 years. Our results suggest that systematically providing effective counselling for a healthy lifestyle for 5 years can lead to lifelong benefits.


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Dear Mr.Westerfeld, Following an enthusiastic recommendation from Lou of The Book Pushers, I picked up your Leviathan Trilogy, a YA steampunk series, to read with my husband. The series is set in a fun, detailed and engaging if not 100% believable world where World War I is a clash between ... more >
NB: This review from AJH is the fourth in his series of "I'm getting to know the romance genre." His introduction is here. You can buy the book with these links. The Iron Duke takes place in an alt-history steampunk England, some nine years after the revolution which evicted the ... more >
Paris, 1923 The daughter of a scandalous mother, Delilah Drummond is already notorious, even amongst Paris society. But her latest scandal is big enough to make even her oft-married mother blanch. Delilah is exiled to Kenya and her favorite stepfather's savannah manor house until gossip subsides. Fairlight is the crumbling, ... more >
Dear Ms. Raby: I love a good enemies-to-lovers story. What also helped pique my interest in this book was the gorgeous cover of a strong woman NOT in a bizarre contorted supposed-to-be sexy pose. On its face, this is the story of a super-assassin who falls in love with her ... more >
Lottie just knows that her boyfriend is going to propose during lunch at one of London's fanciest restaurants. But when his big question involves a trip abroad, not a trip down the aisle, she's completely crushed. So when Ben, an old flame, calls her out of the blue and ... more >
Dear Ms. McMaster: Your first gaslight fantasy/steampunk novel took my pleasantly by surprise and I was excited to read the follow up, Heart of Iron, which paired Lena and Will. Will is a wuthvern in Britian where shapeshifting is outlawed. The English wiped out the Scottlish clans in the battle ... more >
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SOURCE: The Daily Beast
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Pope Lands in Israel -- denounces HolocaustBreaking News
Under heavy scrutiny after a scandal over the reinstatement of four Holocaust denier priests, Pope Benedict struck a conciliatory tone in his first speech in Israel, emphasizing the importance of memorializing the Jewish people's suffering. "Tragically, the Jewish people have experienced the terrible circumstances of ideologies that deny the fundamental dignity of every human person," the Pope said after arriving in Israel. "I will have the opportunity to honor the memory of the six million Jewish victims of the Shoah and to pray that humanity will never again witness a crime of such magnitude." He also addressed the Israeli-Palestinian conflict, where he said he hoped for a "climate of greater trust" between the parties that could allow for peace negotiations to take root.
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- Diane Ravitch: The Common Core Costs Billions and Hurts Students
- Israel Historian on King David Hotel Bombing: 'It Was an Act of Terror'
- Daniel Pipes: "Why I Just Quit the Republican Party"
- Jill Lepore attended the GOP convention
- Ramsay Cook died in Toronto on July 14, after a brief battle with pancreatic cancer


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STARmeterSEE RANK
Up 54,265 this week
Rory Mallinson (1913–1976)
Rory Mallinson was born on October 27, 1913 in Atlanta, Georgia, USA as Charles Joseph Mallinson. He was an actor, known for Dark Passage (1947), Possessed (1947) and Pride of the Marines (1945). He was married to Eileen D. McNulty and Helen Mallinson. He died on March 26, 1976 in Los Angeles, California, USA. See full bio »
Born:in Atlanta, Georgia, USA
Died:(age 62) in Los Angeles, California, USA
4 photos | 3 videos | 1 news article »


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St. Francis Pet Tag
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Throughout his life and travels, St. Francis of Assisi spoke of God's great love and care for his companions. Today, St. Francis is considered to be the patron saint of animals, especially on his Feast Day of October 4th. Our pet tag honors St. Francis, and is a constant prayer of protection for your pet.
- Zinc alloy and enamel
- Nickel-free
- Smooth back for engraving
- Blue, Purple, and Pink tags: 0.75" diameter (1.9 cm)
White tag: 1" diameter (2.5 cm)
- Imported
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- July 28, 2016
These tags are the best!!!! My cat goes outside on a leash & always has his St. Francis metal on! Still looks like new.....Love it!!!
- June 1, 2016
great pet tag i love it you are doing great things for our pets thank you Inge Addario
- March 17, 2016
Love it
- February 7, 2016
I love these. I have one for my dogs and ordered one for two more people. I got the white one. Gorgeous! Well made, sturdy, and lettering does not wear off after months of use. Highly recommend.
- February 1, 2016
What's to say-my baby is protected!
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Associated Press
LOS ANGELES — As Hollywood's major movie studios try to trim costs every way they can — including layoffs, mergers and slashed expense accounts and producer deals — there's one budget item that heads ever upward: the movies themselves.
This year's summer movie season — which kicks off May 4 with the superhero team-up film "The Avengers" and continues with 16 more "event" films through August — is the industry's most expensive ever. Five of the top titles cost more than $200 million each, a once-unthinkable ceiling that's being broken with increasing regularity.
In total, the studios spent more than $2.7 billion to make this summer season's big movies, an increase of 29 percent from just two years ago. The ever escalating costs show that the only thing Hollywood executives may fear more than spending too much is not spending enough to impress audiences around the world.
That's particularly true during the summer season, when theaters are packed and more than 40 percent of the year's box-office dollars are spent.
"In the current business climate you want to be as cost-efficient as possible, but there's no avoiding the fact that to produce a summer tent-pole on the scale necessary to succeed globally, you've got to spend to be competitive," said Amy Pascal, co-chairman of Sony Pictures.
The summer's costliest films are all sequels or adaptations packed with special effects — most digital, some physical — and action sequences meant to blow audiences' minds. The five that cost more than $200 million are Warner Bros.' next Batman film, "The Dark Knight Rises"; Sony Pictures' science-fiction sequel "Men in Black 3"; Sony's superhero reboot "The Amazing Spider-Man"; Walt Disney Studios' and Marvel's superhero mash-up "The Avengers"; and Universal Pictures' board-game-meets-alien-invasion film "Battleship."
Studios are traditionally coy about discussing movie budgets. So there is some dispute about which title cost the most. One person familiar with the "Dark Knight" budget but not authorized to speak publicly said the film cost between $250 million and $300 million. Another said it was closer to $225 million. "Men in Black 3," meanwhile, cost about $250 million, people knowledgeable about that picture said.
The tab for those five movies alone is more than $1.1 billion. And that's just to produce them. Television, online and print advertisements, along with the thousands of film reels shipped to theaters worldwide, can add $150 million per picture.
Last summer's five most expensive movies — "Pirates of the Caribbean: On Stranger Tides," "Transformers: Dark of the Moon," "Green Lantern," "Harry Potter and the Deathly Hallows: Part 2" and "Fast Five" — cost closer to $1 billion to produce.
The skyrocketing production budgets come at a time when studios have clamped down hard on all costs, particularly actors' salaries. With few exceptions, including "Men in Black" headliner Will Smith, there are no stars left on Hollywood's A-list whose worldwide luster justifies more than $20 million per performance.
The star now is the spectacle. Studios can spend more than $100 million just on the special effects necessary to make Spider-Man swing through New York in 3-D or Iron Man and the Hulk plow through an enemy army.
Although executives say they're trying to control special effects costs by having multiple vendors bid on each project and often outsourcing the work to other countries, the greater pressure is to give audiences something they've never seen before. During a crowded summer season, when big-budget, high-stakes films open nearly every Friday, it's crucial to stand out from the crowd.
And with many movies completed mere weeks before they are scheduled to hit theaters, studios are often more concerned with hitting their promised release date than saving a few million dollars.
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sr financial analyst jobs
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Sr. Financial Analyst
Wabash National Corporation - Lafayette, IN
Support development of Strategic Plan financial model. Develop financial models and analysis for new business initiatives....
Senior Financial Analyst
AP Staffing - Boston, MA
The Senior Financial Analyst will be responsible for budgeting and forecasting, business line financial reporting, business line profitability, executive...
Sr. Financial Operations Analyst
Fidelity & Guaranty Life - Baltimore, MD
Oracle Financials and Financial Applications Management (50%). Financial Operations:. This position willmanage the Oracle EBS Financials application(s) and...
Senior Administrative Analyst TCTC
County of Tuolumne - Sonora, CA
Senior Administrative Analyst is the lead and/or specialist class within the Administrative Analyst series. Primary responsibilities are normally in the areas...
Supervisor - Alternative Investment Funds/Hedge Funds/Private Equity Fund Accounting
SEI - Oaks, PA
Review daily work performed by Accounting Analysts. SEIC) is a leading global provider of investment processing, fund processing, and investment management...
Sr. Financial Analyst
Community Health Group - Chula Vista, CA
Knowledge of budgeting processes/principles, financial analysis and reporting principles. Minimum of five (5) years financial or accounting analytics experience...
Senior Financial Analyst - FP&A
Lowe's - Mooresville, NC
Additionally, the Sr. To accomplish this, the Sr. Analyst must have solid knowledge of finance and business analytics....
Sr. Treasury Analyst
IEWC Corp. - New Berlin, WI
Treasury Analyst will take action under the direct supervision of the Chief Financial Officer. Advanced excel and financial modeling skills....
Financial Controller
Penobscot Indian Nation Enterprises - Old Town, ME
Overseeing the accounting staff, and the financial analysts. Corresponds with the senior management regarding any financial decisions that are made....
Sr. Health Economics Analyst
UPMC - Pittsburgh, PA
Health Economics Analyst must be highly professional and understand the causes of financial & clinical trends and anomalies....


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Crazy Substitute Teachers
Enjoy, NG4.03 / 5.00 2,323 Views
Vacuum Salesman
This dude and his Megazord vacuum cleaner4.00 / 5.00 2,672 Views
Markiplier Animated | Mark Of The Survey Corps
This took far too long to make...3.97 / 5.00 5,998 Views
Rika Suzuki
Love 'er. Giver her my regaurds,
Reikooo nice sound
well well Bad reiko she is but i never expected that to happend lol Nice Superb Perfect !
this is my favorite!!!
i absolutely love reiko anyways, but none of the other ones made me laugh like that!
Absolutely amazing!
Cool. Glad you enjoyed it.
Getting better! :-)
Sweet! :-) The little thing at the end as Reiko looked on (which I shall refrain from identifying d/t spoilerage) was a cute touch. Very "Pet Semetary-ish", if you recall the little boy's death early in the movie.
I saw Pet Sematary once many years ago but I can't remember anything except that Herman Munster was in it. Oh well. Glad you enjoyed the cartoon!
Um... gross
This one was my least favorite of the series. First off, a child would notice if another one is standing there with a bunch of land mines. Secondly, in the other ones she would torture kids who messed with her. I thought that was more clever than her torturing innocent children. Plus, the other ones were a tad more realistic and easier to believe. This one left out the great tac the other ones had. I hope the next one of these is more crude humor and less deranged nasty.
How can you tell who is "innocent"? If that is your complaint I wonder why you liked "Double Dutch". Oh well, can't please everyone all of the time.


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Saradha Scam: CBI Arrests East Bengal Club Official
CBI today arrested an official of East Bengal football club Debabrata Sarkar in connection with Saradha chit fund scam in which deposits of thousands of investors were allegedly swindled by ponzi companies.
CBI sources said Sarkar was allegedly the middleman between the Saradha group and regulatory bodies like SEBI. He was arrested in Kolkata, they said. The CBI had earlier taken into custody six people in connection with the scam.
The sources said Sarkar is accused of conspiring with Saradha top brass in the alleged misappropriation of funds of the company.
The agency had recently carried out searches at his residence from where it recovered incriminating documents and Fixed Deposit Receipts worth Rs 25 lakh, the sources said.
There are four FIRs against Saradha Group in which it is alleged that thousands of investors were allegedly duped by the company officials and their associates who swindled their deposits. Besides, there are 44 FIRs in Odisha against ponzi companies.
The Supreme court had handed over the Saradha chit fund scam probe to CBI and asked the state governments to provide all logistical help to the CBI team investigating the matter.
CBI has formed a Special Investigating Team (SIT) headed by Joint Director Rajeev Singh to also probe the role of Securities Exchange Board of India (SEBI) and RBI.
"Investigation conducted so far puts a question mark on the role of regulatory authorities like SEBI, Registrar of Companies and officials of RBI within whose respective jurisdictions and areas of operation the scam not only took birth but flourished unhindered," an apex court bench headed by Justice T S Thakur had said in its order.
FROM OUTLOOKbusiness: stockmarketsSEBI is getting active in its role as regulator. Is it doing right?...more from outlook>>>
FROM THE WEBOpinionWithin weeks of the Satyam founder and former CEOmore from WEB>>>
FROM WIRESSrinagar, Jul 29 (PTI) Seven ultras, including a Nmore from WIRES>>>
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vet jobs near Tampa, FL
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Budget-Financial Analyst
St. Michael's Inc. - Tampa, FL
This is an outstanding opportunity for those with demonstrated experience and knowledge related to the areas of Planning, Programming, Budgeting, and
Inside Sales Representative
Verizon - Tampa, FL
Responsibilities Looking for a challenging career with unlimited potential for growth? Then its time to consider Verizon Wireless. We believe in peak
Arabic / English Interpreter
Booz Allen Hamilton - Tampa, FL
Job Number: 01214233 Key Role: Provide professional expertise through onsite consulting assistance stationed overseas. Demonstrate excellent client delivery
Quality Control Lab Technician - Tampa, FL (90394)
Preferred Materials - Asphalt - Tampa, FL
EOE / M / F / Vet / Disability. Preferred Materials – Asphalt Division, part of Oldcastle Materials Southeast Division of Companies, is the leader in production...
Production Supervisor - UniFirst
UniFirst - Tampa, FL
Job Description: Where will a UniFirst Career take you? As an industry leader in the rental, lease and sale of uniforms and facility services products,
Royal Pets Veterinary Center Technicians and Assistants Wanted
Royal Pets Market & Resort - Palm Harbor, FL
Generous Employee Discount on merchandise, salon services, Vet and Hotel/Daycare services. \*Assistants are an important member of our Vet team, mentored by...
Outside Sales Representative - UniFirst
UniFirst - Tampa, FL
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Relating to special abilities given by good for the edification of the church and described in the NT, such as prophecy, healing, speaking in tongues, teaching, and service.
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Are there any authors that who believe Eph. 4:11 is not describing titles but general characteristics of how God created the church to work together?
Ephesians 4:11ff reads: And He gave some as apostles, and some as prophets, and some as evangelists, and some as pastors and teachers, for the equipping of the saints for the work of service, to ...


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- File Size: 1484 KB
- Print Length: 313 pages
- Simultaneous Device Usage: Unlimited
- Publisher: Sweet River Romance (November 11, 2013)
- Publication Date: November 11, 2013
- Sold by: Amazon Digital Services LLC
- Language: English
- Text-to-Speech: Enabled
- Word Wise: Enabled
- Lending: Enabled
Amazon Best Sellers Rank:
#2,043,519 Paid in Kindle Store (See Top 100 Paid in Kindle Store)
- #2925 in Kindle Store > Kindle eBooks > Romance > Paranormal > Angels
- #4357 in Kindle Store > Kindle eBooks > Teen & Young Adult > Romance > Paranormal & Fantasy
- #4593 in Books > Teens > Romance > Paranormal
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Top Customer Reviews
The Wind Whisperer is a story of love, family, drama and growing up. Anaii is a one of a kind girl called a wind whisperer. She can communicate with the wind for information to help her tribe. Elan is her childhood friend. He has always loved and protected Anaii.
One day, Anaii meets Jayttin who seems to take her by surprise. Jayttin comes from the rival tribe. He is an enemy. She is challenged mentally and physically by him. She is left to admire him as he comes from a different tribe. He is different in so many ways.
As a wind whisperer, her father, the head of the tribe confides in her for her knowledge of gathering information to keep them all safe.
Elan makes his feelings clear towards Anaii while Jayttin does the same. Anaii is torn between two different men. She realizes she is breaking their spirits by prolonging her decision as to who she chooses.
I sympathize with both men and how they react, whether it is with joy, anger and annoyance towards Anaii. I also sympathize with her having to decide. Bith men treat her so well and incredibly kind and protective over her.
If you enjoy romance, drama and adventure you will love The Wind Whisperer.
Elan has been close to Anaii since they were babies. They played together and plotted together, and now he wants them to have a future together. But she's only ever seen him as a best friend, practically a brother, and his none-too-subtle suggestions that they become more are straining their relationship. But other men in the tribe have their eyes on her as well, and it's only a matter of time before one of them wins her hand, even if he can't win her heart.
Anaii's position in the tribe is a tenuous one. She is favored for her abilities, but not adored as a daughter or friend (except by Elan), and those who don't rely on her for information make no secret of their dislike for her. She's not required to work as the other women are, and she's allowed within the council, a place reserved only for male elders of some importance. On the surface, her life seems rather charmed, but she's left with few friends and no freedom. The importance of her gift makes her indispensable, and when danger looms outside, the village becomes a virtual prison.
But then Anaii comes upon Jayttin in the meadow, and for possibly the first time, she sees a man she can truly imagine marriage with. Only their tribes are at war, their fathers sworn enemies, and if simply knowing Jayttin is treason, running off to marry him would be the highest crime.Read more ›
Amazing story! I loved every minute of this book! Even then intense parts, and there are a lot! I enjoyed this so much that I kept having to tell myself not to skip ahead to find out what was going to happen, although, I really, really wanted to!
First of all, the plot in this is fantastic. At first it seems like a Native American Twilight with maybe some Romeo and Juliet thrown in. But honestly the paranormal aspect and the plot itself really makes this story something of its own. Not only is it different and mesmerizing but it's fun.
The characters also really make this story. I love all of them. There's a bit of a love triangle that starts a little before half way through and oh boy… I was thinking that this wasn't going to be good. But instead it totally made sense. The characters really stood out and wanted each of their stories told and the love triangle just happened to be a part of those stories. Even though I'm not a lover of love triangles, I really think this one helped Anaii to grow. Actually, it helped each of the characters involved grow. And I think I liked them even more because of the love triangle.
And this isn't just about the love triangle. That is only a part of Anaii's story. There's so much more about her powers and how she comes to find out even more about her powers and herself and trying to save those she loves. AND there are some twists in this baby! I mean seriously… I didn't see quite a few things coming but I find myself yelling at the book, and the characters, multiple times!
And there's a part 2 coming in the fall! I cannot wait!
Enjoy paranormal romance? Don't miss this one!
Received by author for an honest review. 5/5
I was surprised that The Wind Whisperer ended up almost being a typical YA Paranormal Romance complete with the BFF versus the forbidden boy love triangle. Elan and Anaii have been friends since childhood and he's one of the few members of their tribe who treat her like a normal person. Jayttin is slightly older and the son of the enemy chief. However, unlike Elan, Jayttin is not a warrior and wishes for peace between the two tribes. There's also another player in this romance: Koko, an esteemed warrior who believes Anaii should be his. He's essentially the Kocoum to Anaii's Pocahontas. Jayttin is John Smith, and Elan is Flick, since he's far too serious to be Meeko. This love triangle didn't end up how I was expecting. There's a very nice twist at the end, which luckily didn't feel like a cop out.
Although, Koko isn't a real contender. Anaii despises him, but he is the final straw which makes her leave her village.Read more ›
Most Recent Customer Reviews
The Wind Whisperer by Krista Holle was an incredible story of first love, second love, growing up, and responsibility. Read morePublished on March 14, 2014 by What's Beyond Forks?
Don't laugh but I keep thinking of Pocahontas when I read this book. I mean not really, but I love the Disney cartoon and some things fit. Read morePublished on January 26, 2014 by Maghon Thomas
Anaii is the daughter of the chief, but she is more important than just that. She has been given a gift from the gods, a gift to be able to hear the wind spirits and gather... Read morePublished on January 23, 2014 by Cheree Smith
I really enjoyed reading this book. I loved the love triangle, it really kept my interest. I was torn between the two men in the first half of the story and then by the middle of... Read morePublished on January 17, 2014 by alice
It has been some time since I have read a Young Adult Paranormal romance that has captured my attention as much as The Wind Whisperer did. Read morePublished on January 13, 2014 by Edwards
I'm conflicted over whether to like Anaii or to hate her for her scheming ways. I know hate is a powerful and negative word but the way she treated the men in her life, I just felt... Read morePublished on January 7, 2014 by Live Outside
I received this book from the author in exchange for an honest review.
A YA book that is definitely worth reading whether you are into Native American tales or not. Read more
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Dr. Timothy C. A. Brown, MD, FACOG, MS
Book an Appointment
Qualifications and Experience
- Medical School - University of Colorado, Doctor of Medicine
- Saint Vincent Catholic Medical Centers, Internship in Obstetrics and Gynecology
- Saint Vincent Catholic Medical Centers, Residency in Obstetrics and Gynecology
- Northwestern University (Master's)
Hospital Affiliations
- Huntington Hospital
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Languages Spoken
- English
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- American Board of Obstetrics and Gynecology
Professional Memberships
- American Congress of Obstetricians and Gynecologists
- American Medical Association
- Medical Society of the State of New York
- Nassau County Medical Society
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Professional Statement
Medicine always appealed to me because I saw it as the perfect way to use my intellectual abilities to help others. In medical school obstetrics and gynecology seemed the perfect combination of medicine and surgery. From resolving the unique health problems women face to sharing in the amazing time of pregnancy and childbirth, women's health care is especially fulfilling. I try to give each patient the time they need, to listen, and be a sounding board. That allows us to create a partnership that the patient can rely on, no matter what life brings their way – and it's the standard of care they deserve.
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Is very pleasant. Thank you.
Everything is always running smoothly in the office. Dr. Brown is very attentive and takes his time.
Good doctor but just was waiting in the wait room for like a hr
He took his time with me and was very knowledgable!!!
So spectacular. I was obscenely nervous (first obgyn visit ever!) and he was more than kind and efficient. Even the girls at the desk were super nice! I wanted to stay and talk with them!


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1. Reeemiiix!
2. #SelfieSunday every day.
3. It's 106 miles to Chicago, we got a full tank of gas, half a pack of cigarettes, it's dark… and we're wearing sunglasses.
4. Play saxophone? Oh, it's easy.
5. Don't worry, I'll never do Arsenio.
6. Brothers don't shake hands…
7. …brothers gotta hug.
8. TWINS 2: New Jersey Ballers
9. Nope, didn't need it.
10. Nailed it.
11. Killed it.
12. Dug it.
13. Lost it. #TheFleece
14. Rebuilt it.
15. Slow Jammed it.
16. Alright, what else you got?
18. Favorite football team?
19. Our thoughts exactly.
20. What did 2013 REALLY teach us?
21. Amen, GOV. Amen.
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- The Democratic National Committee on Monday apologized for remarks sent over email criticizing the Bernie Sanders campaign 🇺🇸
- At least 19 people died and dozens others were injured in a knife attack at a facility for the disabled near Tokyo, Japan.
- The Solar Impulse 2 completed its first round-the-world flight after landing in Abu Dhabi ☀


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Next-gen MacBook shipments begin ahead of 'sharp ramp'The first shipments of Apple's next-generation 13-inch MacBooks have left China ahead of a large-scale manufacturing ramp scheduled for later this month, according to investment bank Citigroup.
In a "Company Flash" bulletin issued to clients on Monday, analyst Rich Gardner said he expects the Cupertino-based Mac maker to introduce its fall line of notebooks "within weeks."
"Field checks confirm that shipments of new MacBooks have begun, with a sharp production ramp planned for September and an introduction planned for early October," he wrote. "The most distinctive features of the new MacBook appear to be a very thin aluminum casing, an LED-backlit display and an aggressive entry-level price point."
Gardner also used the bulletin to reiterate his Buy rating on Apple's badly-beaten shares, which tacked onto Friday's losses by falling another $6.44, or 4.32 percent, to $142.50 in afternoon trading.
Following his checks in Asia, the analyst said he remains comfortable with his above-consensus September quarter earnings estimates of $1.20 per share on sales of $8.3 billion.
Surprisingly robust iPod shipments combined with sharp declines in NAND flash memory, flat panel displays and DRAM pricing should allow the company to beat its gross margin guidance despite recent iPod price cuts and the just-ended back-to-school promotion, Gardner said.
"New products, iPhone geographic expansion and sharp declines in key component prices also bode well for upside [next quarter]," he added.
Gardner's MacBook predictions fall in line with earlier reports from AppleInsider, as well as a recent report which pinned an introduction for mid-October.
On Topic: Future Hardware
- Apple patent filing shows future potential of Touch ID not tied to a button
- Apple bolsters 'Project Titan' self-driving software team with former QNX CEO
- Rumor: Apple to adopt USB Type-C in another upcoming MacBook, whether it's Pro or Air
- Apple shakes up electric vehicle team, places Bob Mansfield in charge of 'Project Titan' - report
- Intel's 7th-gen 'Kaby Lake' processors delivered to manufacturers


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2015 WSIAT Annual Report Now Available NEW
June 29, 2016
Caseload update, January 1 to March 31, 2016, Now Available
April 25, 2016
Practice Directions 2014
July 2, 2014
The Tribunal recently completed a project to review and revise its Practice Directions, which were last published in 2007. More on Practice Directions 2014...
Highlights of Noteworthy Decisions
Review of benefits after final review based on significant deterioration that results in a determination of permanent impairment under s. 44(2.1)(d) of the WSIA, and that is likely to result in a redetermination of the degree of permanent impairment under s. 44(2.1)(e).
Consideration of entitlement for maintenance chiropractic treatment after retirement.
Referral of a claim back to the Board pursuant to s. 15.2(5) of the WSIA.
Retroactivity of an employer reclassification.
Whether an exception applied to allow review of a worker's LOE benefits after the final 72-month review.
Consideration of entitlement in a case of serious and wilful misconduct.
Whether a worker was entitled to a NEL assessment for a physical loss.
Whether a plaintiff's right of action against the employer was taken away regarding claims related to matters other than the workplace accident.
Determination of the earnings basis of a dependent contractor.
Acceptance of a settlement in a case concerning a construction employer's re-employment obligations, and determination of the penalty.
View more recent noteworthy decisions...


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Home :: Wedding Bands :: Gold Wedding Bands :: Designer Two Tone Bands :: Two Tone Gold
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Tri-color Braided Wedding Band
For sad reasons, I needed to replace my wedding band, which had been hand made 13 years ago. I searched for quite a while before I decided to order from...
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A Lot Of Love....
For Jonathon and everyone at Joshua's. We love our bands. I could not have asked for a better group of fine individuals to work with. You have given us a...
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Crazy Substitute Teachers
Enjoy, NG4.04 / 5.00 1,421 Views
Vacuum Salesman
This dude and his Megazord vacuum cleaner3.98 / 5.00 2,396 Views
Markiplier Animated | Mark Of The Survey Corps
This took far too long to make...3.94 / 5.00 3,711 Views
Inspiring. You are a legend Adam Phillips.
This is one of the pieces that got me into wanting to become an animator.
Thank you!
great story, great job. Nothing else to say
Prove that sometimes there is more outstanding animation skill than in professional animation studios, this is priceless.
What is there to say? The piece speaks for itself!
I love it, but why doesn't he just throw it all up?


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|Nelly Thompson was a happy housewife who did not care much about anything but keeping her house and raising the kids. But there was one thought which deprived her of her sleep. She had once seen Terry, her son, in the shower, and his sizeable cock was her obsession. One evening she could not keep in her lust anymore and simply pulled Terry's pants off! At first she was anxious whether Terry would like her mature body, but the boy was so passionate:
Mary's father, lives with Mary, while their mother moved to another town after
divorce. Bob has many friends, and Mary, a shy pretty girl,
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|Anthony Kowalski, a divorced teacher, loved his cute blonde daughter Amanda more than anyone in the world. Since her very childhood he enjoyed taking photos and filming her on camera. When she grew into a very beautiful teen girl, Anthony's shootings acquired a different taste. Sometimes he thought that it would have been great to film her naked, and one day he talked her into some naked posing, which led them to a totally hardcore incest scene:
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Nightlife near Ability
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Summer Streets
Shopping | Until 31st July 2016
Regent Street 14 minutes walk from Ability
Every Sunday in July Regent Street is banning traffic for the popular Summer Streets series. The month-long event will see ...More
Royal Academy Of Arts: Summer Exhibition 2016
Exhibitions | Until 21st August 2016
Royal Academy of Arts 15 minutes walk from Ability
Works in a variety of media and genres by emerging and established contemporary artists. Curator Richard Wilson RA explores the ...More
David Hockney RA: 79 Portraits and 2 Still Lifes
Exhibitions | Until 2nd October 2016
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Exhibitions | Until 21st August 2016
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Yayoi Kusama
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Yayoi Kusama
Exhibitions | Until 30th July 2016
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text: I would use an $18,000 mini just to move 5 yards of topsoil. Screw humping that with wheel barrels, even with my own guys. Been there done that, tired of it. The only thing that is keeping me from getting a mini is that I have to buy a new enclosed trailer to haul it.


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Denver, COUSA
December 27, 2011
I love to run. I've recently caught the marathon and half marathon bug and getting out with fellow runners helps keep me motivated!
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Mashups using the same API (3)
A free information and entertainment community built by and for dog people. Adopt a new dog. Get answers, recommendations, and more. Dogster has integrated the Userplane APIs as part of their social...
Join groups to talk to moms with similar interests and issues. Start a journal to ask for advice, share stories, or just vent. Meet other moms and stay in touch with friends.
Find Professionals - get your job done. Find Web & programming professionals, writing, translation, design, sales, marketing, finance, management, legal, engineering professionals, and more.
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