The nature of malnutrition in children with end-stage liver disease awaiting orthotopic liver transplantation

To evaluate malnutrition in chronic liver disease, and its relationship to nutrient deficiencies and hepatic dysfunction. 27 children with end-stage liver disease were studied. Mean protein-energy intakes were 70% of recommended daily intakes. The patients were underweight and stunted with reduced mean triceps and subscapular skinfold thicknesses and midupper arm circumference. Mean total body potassium was only 63 ± 18% of that expected for age and sex. Deficiency of essential fatty acids (32%), and low concentrations of fat-soluble vitamins (A, 92%; E, 32%), iron (32%), zinc (42%), and selenium (13%) were common. Serum ammonia concentrations were raised in all patients, and increased methionine, tyrosine, and glutamic acid, and reduced glutamine concentrations were noted. There was no correlation between the degree of malnutrition and the degree of liver synthetic function, the degree of cholestasis, or the degree of liver injury. We suggest that potentially correctable factors in addition to liver failure (eg, inadequate absorbed intake) were important determinants of malnutrition in these patients.

The hemodynamic effects of in-tandem carotid artery stenosis: Implications for carotid endarterectomy

Objectives: It remains controversial whether patients with severe disease of the internal carotid artery and a coexisting stenotic lesion downstream would benefit from a carotid endarterectomy (CEA) of the proximal lesion. The aim of this study was to simulate the hemodynamic and wall shear effects of in-tandem internal carotid artery stenosis using a computational fluid dynamic (CFD) idealized model to give insight into the possible consequences of CEA on these lesions. Methods: A CFD model of steady viscous flow in a rigid tube with two asymmetric stenoses was introduced to simulate blood flow in arteries with multiple constrictions. The effect of varying the distance between the two stenoses, and the severity of the upstream stenosis on the pressure and wall shear stress (WSS) distributions on the second plaque, was investigated. The influence of the relative positions of the two stenoses was also assessed. Results: The distance between the plaques was found to have minimal influence on the overall hemodynamic effect except for the presence of a zone of low WSS (range -20 to 30 dyne/cm2) adjacent to both lesions when the two stenoses were sufficiently close (<4 times the arterial diameter). The upstream stenosis was protective if it was larger than the downstream stenosis. The relative positions of the stenoses were found to influence the WSS but not the pressure distribution. Conclusions: The geometry and positions of the lesions need to be considered when considering the hemodynamic effects of an in-tandem stenosis. Low WSS is thought to cause endothelial dysfunction and initiate atheroma formation. The fact that there was a flow recirculation zone with low WSS in between the two stenoses may demonstrate how two closely positioned plaques may merge into one larger lesion. Decision making for CEA may need to take into account the hemodynamic situation when an in-tandem stenosis is found. CFD may aid in the risk stratification of patients with this problem.

Nuclear power and Japan's collective future: Understanding beliefs about how nuclear policies will affect society

Despite ongoing controversies regarding possible directions for the nuclear plants program throughout Japan since the Fukushima disaster, little has been researched about people's belief structure about future society and what may affect their attitudes toward different policy options. Beyond policy debates, the present study focused on how people see a future society according to the assumptions of different policy options. A total of 125 students at Japanese universities were asked to compare a future society with society today in which one of alternative policies was adopted (i.e., shutdown or expansion of nuclear reactors) in terms of characteristics of individuals and society in general. While perceived dangerousness of nuclear power predicted attitudes and behavioural intentions to make personal sacrifices for nuclear power policies, beliefs about the social consequences of the policies, especially on economic development and dysfunction, appeared to play stronger roles in predicting those measures. The importance of sociological dimensions in understanding how people perceive the future of society regarding alternative nuclear power policies, and the subtle discrepancies between attitudes and behavioural intentions, are discussed.

A Phenomic Scan of the Norfolk Island Genetic Isolate Identifies a Major Pleiotropic Effect Locus Associated with Metabolic and Renal Disorder Markers

Multiphenotype genome-wide association studies (GWAS) may reveal pleiotropic genes, which would remain undetected using single phenotype analyses. Analysis of large pedigrees offers the added advantage of more accurately assessing trait heritability, which can help prioritise genetically influenced phenotypes for GWAS analysis. In this study we performed a principal component analysis (PCA), heritability (h2) estimation and pedigree-based GWAS of 37 cardiovascular disease -related phenotypes in 330 related individuals forming a large pedigree from the Norfolk Island genetic isolate. PCA revealed 13 components explaining >75% of the total variance. Nine components yielded statistically significant h2 values ranging from 0.22 to 0.54 (P<0.05). The most heritable component was loaded with 7 phenotypic measures reflecting metabolic and renal dysfunction. A GWAS of this composite phenotype revealed statistically significant associations for 3 adjacent SNPs on chromosome 1p22.2 (P<1x10-8). These SNPs form a 42kb haplotype block and explain 11% of the genetic variance for this renal function phenotype. Replication analysis of the tagging SNP (rs1396315) in an independent US cohort supports the association (P = 0.000011). Blood transcript analysis showed 35 genes were associated with rs1396315 (P<0.05). Gene set enrichment analysis of these genes revealed the most enriched pathway was purine metabolism (P = 0.0015). Overall, our findings provide convincing evidence for a major pleiotropic effect locus on chromosome 1p22.2 influencing risk of renal dysfunction via purine metabolism pathways in the Norfolk Island population. Further studies are now warranted to interrogate the functional relevance of this locus in terms of renal pathology and cardiovascular disease risk.

Age-related alterations in immunoreactive pancreatic lipase and cationic trypsinogen in young children with cystic fibrosis

Serum immunoreactive pancreatic lipase and cationic trypsinogen are elevated in young infants with cystic fibrosis (CF) and may be useful neonatal screening tests for CF. We compared lipase measured by a recently developed ELISA immunoassay with trypsinogen measured by radioimmunoassay in 70 children (ages 0.1 to 9.9 years) with CF who had various degrees of pancreatic dysfunction and in 79 similarly aged children without CF (controls). In the control children, lipase activity increased with advancing age, whereas trypsinogen showed no age-related trend. Lipase and trypsinogen were significantly elevated in the infants with CF who were younger than 1 year, irrespective of pancreatic function (trypsinogen, P<0.001; lipase, P<0.05). Sensitivities in detecting CF were 76% and 90% for lipase and trypsinogen, respectively. After the first year of life, lipase and trypsinogen values declined toward normal, the rate of decline of lipase being greater than that of trypsinogen; 67% of lipase values were within or below the normal range by 3 years, whereas 67% of trypsinogen values continued to be elevated. We conclude that trypsinogen is an excellent screening test for CF in young infants regardless of pancreatic function, and that the addition of a serum pancreatic lipase determination does not improve the accuracy of trypsinogen as a screening test for cystic fibrosis.

Prolonged hyperinsulinemia affects metabolic signal transduction markers in a tissue specific manner

Insulin dysregulation is common in horses although the mechanisms of metabolic dysfunction are poorly understood. We hypothesized that insulin signaling in striated (cardiac and skeletal) muscle and lamellae may be mediated through different receptors as a result of receptor content, and that transcriptional regulation of downstream signal transduction and glucose transport may also differ between tissues sites during hyperinsulinemia. Archived samples from horses treated with a prolonged insulin infusion or a balanced electrolyte solution were used. All treated horses developed marked hyperinsulinemia and clinical laminitis. Protein expression was compared across tissues for the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) by immunoblotting. Gene expression of metabolic insulin-signaling markers (insulin receptor substrate 1, Akt2, and glycogen synthase kinase 3 beta [GSK-3β]) and glucose transport (basal glucose transporter 1 and insulin-sensitive glucose transporter 4) was evaluated using real-time reverse transcription polymerase chain reaction. Lamellar tissue contained significantly more IGF-1R protein than skeletal muscle, indicating the potential significance of IGF-1R signaling for this tissue. Gene expression of the selected markers of insulin signaling and glucose transport in skeletal muscle and lamellar tissues was unaffected by prolonged hyperinsulinemia. In contrast, the significant upregulation of Akt2, GSK-3β, GLUT1, and GLUT4 gene expression in cardiac tissue suggested that the prolonged hyperinsulinemia induced an increase in insulin sensitivity and a transcriptional activation of glucose transport. Responses to insulin are tissue-specific, and extrapolation of data across tissue sites is inappropriate.

Genetic analysis for a shared biological basis between migraine and coronary artery disease

Objective: To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD). Methods: Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci. Results: We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP). Conclusions: The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 x 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-kappaB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-)(9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-)(1)(1) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-)(5), permuted threshold for genome-wide significance 7.7 x 10(-)(5). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Towards (dis)Satisfaction

Hosted at Blindside Artist-Run Initiative (Melbourne) the exhibition Towards (dis)Satisfaction (2015) was a re-staging of earlier sculptural works from the exhibitions Means are the Ends: The Command Issue and Crude Tools (2014), Feeble Actions (2013). The forms humorously interrogated representations of gender and sexuality via strategies of sculptural intervention. A stripper’s pole oozes grease from its stainless surface, fluted with holes. A dildo vibrates on a glass tabletop; propped up by simulated testicles, the intensity of the dildo’s vibrations makes the form spin. With its continual circling, the phallus drags Vaseline over the table, performing a drawing and redrawing of a smeared circle. In Towards (dis)Satisfaction fetish is used as an instrumental strategy, employed as a mode to work across different theoretical and material discourses. In the works the play between explicit and implicit depiction creates an ambiguity that has suggestive potency, where fragmentation and dysfunction initiate diverse readings. These material dialogues make apparent the anxiety and desire inherent in the viewer and question how the visual conventions of erotica and art history are mutually informative.

The dopamine-mediation of perception hypothesis and the implications for schizophrenia

- Background Following Kapur’s hypothesis [1] that schizophrenia is the intensification of phenomenological experience caused by the upregulation of dopamine, a survey of observed dopamine responses to phenomenal information was conducted. - Method An integrative study. - Results When considered in the light of the ecological theory of perception (ETP) [2] and global workspace theory (GBT) [3] Kapur’s hypothesis makes sense: Both the ETP and the GBT require an agent to attribute salience to perceptual information in order to filter an infinite array of available information and usefully sort information by importance. Dopamine may be the primary agent for this purpose. Thus perception itself is suspected as being a dopamine-mediated, and the symptoms and signs of schizophrenia may therefore be the result of dopamine dysfunction. - Conclusions The application of both ETP and GBT to the dopamine hypothesis gives the hypothesis a much-needed causal mechanism and the confl uence of these theories also provides ETP with a neurological perceptual fi lter. This paper provides a compelling model for schizophrenia; a hypothesis that ties perceptual theory to Kapur ’ s concept of dopamine-mediated salience.

Which patients with chronic kidney disease have the greatest symptom burden? A comparative study of advanced CKD stage and dialysis modality

Background Chronic kidney disease (CKD) leads to a range of symptoms, which are often under-recognised and little is known about the multidimensional symptom experience in advanced CKD. Objectives To examine (1) symptom burden at CKD stages 4 and 5, and dialysis modalities, and (2) demographic and renal history correlates of symptom burden. Methods Using a cross-sectional design, a convenience sample of 436 people with CKD was recruited from three hospitals. The CKD Symptom Burden Index (CKD-SBI) was used to measure the prevalence, severity, distress and frequency of 32 symptoms. Demographic and renal history data were also collected. Results Of the sample, 75.5 % were receiving dialysis (haemodialysis, n = 287; peritoneal dialysis, n = 42) and 24.5 % were not undergoing dialysis (stage 4, n = 69; stage 5, n = 38). Participants reported an average of 13.01 ± 7.67 symptoms. Fatigue and pain were common and burdensome across all symptom dimensions. While approximately one-third experienced sexual symptoms, when reported these symptoms were frequent, severe and distressing. Haemodialysis, older age and being female were independently associated with greater symptom burden. Conclusions In CKD, symptom burden is better understood when capturing the multidimensional aspects of a range of physical and psychological symptoms. Fatigue, pain and sexual dysfunction are key contributors to symptom burden, and these symptoms are often under-recognised and warrant routine assessment. The CKD-SBI offers a valuable tool for renal clinicians to assess symptom burden, leading to the commencement of timely and appropriate interventions.

Measuring the multidimensions of symptoms in people with advanced stages of chronic kidney disease

Chronic kidney disease (CKD) is increasing globally and in Saudi Arabia it affects approximately 8% annual increment of dialysis population. It is associated with a high symptom burden. Previous studies have largely reported on the prevalence of symptoms only in the haemodialysis population. This study examined symptom burden across disease stages and treatment groups in advanced CKD, and their correlation with demographic and clinical factors. Using a cross-sectional design, a convenience sample of 436 patients with CKD was recruited from three hospitals in Saudi Arabia. The CKD Symptom Burden Index (CKD-SBI) was used to measure 32 CKD symptoms. Demographic and clinical data were also collected. Of the sample 75.5% were receiving dialysis (haemodialysis, n = 287; peritoneal dialysis, n = 42) and 24.5% were non-dialysis (CKD stage 4, n = 69; CKD stage 5, n = 38). Average symptom reported was 13.01 ± 7.67. Fatigue and pain were common and burdensome across all symptom dimensions.Approximately one-third of participants experienced sexual symptoms. Dialysis patients reported greater symptom burden, especially patients on haemodialysis. Haemodialysis treatment, older age and being female were independently associated with greater total symptom burden. In conclusion, symptom burden is high among advanced stages of CKD, particularly among those receiving dialysis. Although fatigue, pain and sexual dysfunction are key contributors to symptom burden in CKD, these symptoms are often under-recognised and warrant routine assessment. The CKD-SBI offers a valuable tool to assess symptom burden, leading to the commencement of timely and appropriate interventions.

Genetics of ankylosing spondylitis - Insights into pathogenesis

Ankylosing spondylitis (AS), an immune-mediated arthritis, is the prototypic member of a group of conditions known as spondyloarthropathies that also includes reactive arthritis, psoriatic arthritis and enteropathic arthritis. Patients with these conditions share a clinical predisposition for spinal and pelvic joint dysfunction, as well as genetic associations, notably with HLA-B*27. Spondyloarthropathies are characterized by histopathological inflammation in entheses (regions of high mechanical stress where tendons and ligaments insert into bone) and in the subchondral bone marrow, and by abnormal osteoproliferation at involved sites. The association of AS with HLA-B*27, first described >40 years ago, led to hope that the cause of the disease would be rapidly established. However, even though many theories have been advanced to explain how HLA-B*27 is involved in AS, no consensus about the answers to this question has been reached, and no successful treatments have yet been developed that target HLA-B27 or its functional pathways. Over the past decade, rapid progress has been made in discovering further genetic associations with AS that have shed new light on the aetiopathogenesis of the disease. Some of these discoveries have driven translational ideas, such as the repurposing of therapeutics targeting the cytokines IL-12 and IL-23 and other factors downstream of this pathway. AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies.