Good for the environment good for health

“First do no harm”. This phrase, attributed to the 19th century surgeon, Thomas Inman, 1 reflects an equivalent phrase found in Epidemics, Book I of the Hippocratic School, “Practise two things in your dealings with disease: either help or do not harm the patient”. Pharmacists have played, and continue to play, an important role in reducing patient harm from medication misadventures. Now, they have a new role to play. The delivery of pharmaceutical care contributes to climate change (e.g. through the embedded carbon in the manufacture and distribution of medicines, disposal of waste, and energy and water use),2 which in turn has a negative impact on health. 3,4 This paradox argues a moral and ethical obligation by pharmacists, to deliver pharmaceutical care more sustainably – do no harm. Sustainability “…. is concerned, on one hand, with resources and how we can preserve them, and, on the other hand, with waste products and how we can best reduce or dispose of them.” 5(p.37) It is about preserving and nurturing Earth’s resources and systems for this generation and future generations to enjoy. Pharmacists play an important role in preventative health strategies such as smoking cessation, promotion of healthier lifestyles and vaccination/immunisation programmes and have the potential to also play a significant role in delivering pharmaceutical care more sustainably. Sustainable pharmaceutical care may be considered a virtuous cycle - what is good for the environment is also good for our health. 5 The good news for community pharmacy owners and managers is that implementing sustainability initiatives in the pharmacy can also have significant financial co-benefits.

Commentary on the article by Swanenburg et al. ‘Validity and reliability of a German version of the Neck Disability Index (NDI-G)’

We commend Swanenburg et al. (2013) on translation, development, and clinimetric analysis of the NDI-G. However, the dual-factor structure with factor analysis and the high level of internal consistency (IC) highlighted in their discussion were not emphasized in the abstract or conclusion. These points may imply some inconsistencies with the final conclusions since determination of stable point estimates with the study's small sample are exceedingly difficult.

Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects

Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson's disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 706) and the Queensland Twin Imaging Study (QTIM; N = 639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (PMA = 4. 79 × 10-8). This commonly-carried genetic variant accounted for 2. 68 % and 0. 84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster's involvement in lentiform nucleus volume differences in human populations.

Bivariate genome-wide association study of genetically correlated neuroimaging phenotypes from DTI and MRI through a seemingly unrelated regression model

Large multisite efforts (e.g., the ENIGMA Consortium), have shown that neuroimaging traits including tract integrity (from DTI fractional anisotropy, FA) and subcortical volumes (from T1-weighted scans) are highly heritable and promising phenotypes for discovering genetic variants associated with brain structure. However, genetic correlations (rg) among measures from these different modalities for mapping the human genome to the brain remain unknown. Discovering these correlations can help map genetic and neuroanatomical pathways implicated in development and inherited risk for disease. We use structural equation models and a twin design to find rg between pairs of phenotypes extracted from DTI and MRI scans. When controlling for intracranial volume, the caudate as well as related measures from the limbic system - hippocampal volume - showed high rg with the cingulum FA. Using an unrelated sample and a Seemingly Unrelated Regression model for bivariate analysis of this connection, we show that a multivariate GWAS approach may be more promising for genetic discovery than a univariate approach applied to each trait separately.

Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, highangular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Discovery and replication of gene influences on brain structure using LASSO regression

We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2.We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8±2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain.

Identification of common variants associated with human hippocampal and intracranial volumes

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10 -16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10 -12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10 -7).

The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Hydraulic conductivity increases in a sodic clay soil in response to gypsum applications impacts of bulk density and cation exchange

Amelioration of sodic soils is commonly achieved by applying gypsum, which increases soil hydraulic conductivity by altering soil chemistry. The magnitude of hydraulic conductivity increases expected in response to gypsum applications depends on soil properties including clay content, clay mineralogy, and bulk density. The soil analyzed in this study was a kaolinite rich sodic clay soil from an irrigated area of the Lower Burdekin coastal floodplain in tropical North Queensland, Australia. The impact of gypsum amelioration was investigated by continuously leaching soil columns with a saturated gypsum solution, until the hydraulic conductivity and leachate chemistry stabilized. Extended leaching enabled the full impacts of electrolyte effects and cation exchange to be determined. For the columns packed to 1.4 g/cm3, exchangeable sodium concentrations were reduced from 5.0 ± 0.5 mEq/100 g to 0.41 ± 0.06 mEq/100 g, exchangeable magnesium concentrations were reduced from 13.9 ± 0.3 mEq/100 g to 4.3 ± 2.12 mEq/100 g, and hydraulic conductivity increased to 0.15 ± 0.04 cm/d. For the columns packed to 1.3 g/cm3, exchangeable sodium concentrations were reduced from 5.0 ± 0.5 mEq/100 g to 0.51 ± 0.03 mEq/100 g, exchangeable magnesium concentrations were reduced from 13.9 ± 0.3 mEq/100 g to 0.55 ± 0.36 mEq/100 g, and hydraulic conductivity increased to 0.96 ± 0.53 cm/d. The results of this study highlight that both sodium and magnesium need to be taken into account when determining the suitability of water quality for irrigation of sodic soils and that soil bulk density plays a major role in controlling the extent of reclamation that can be achieved using gypsum applications.

The Value of Financial Planning Advice: Process and Outcome Effects on Consumer Well-being [Time 1 and 2 Survey Summary Results]

While anecdotal evidence indicates financial advice affects consumers’ financial well-being, this research project is motivated by the absence of empirically-grounded research relating to the extent to which, and, importantly, how, financial planning advice contributes to broader client well-being. Accordingly, the aim of this project is to establish how the quality of financial planning advice can be optimised to add value, not only to clients’ financial situation, but also to broader aspects of their well-being. This broader construct of well-being captures a range of process and outcome factors that map to concepts of security, control, choice, mastery, and life satisfaction (Irving, 2012; Gallery, Gallery, Irving & Newton, 2011; Irving, Gallery, and Gallery, 2009). Financial planning is commonly purported to confer not only tangible benefits, but also intangible benefits, such as increased security and peace of mind that are considered as important, if not more important, than material outcomes. Such claims are intuitively appealing; however, little empirical evidence exists for the notion that engaging with a financial planner or adviser promotes peace of mind, feelings of security, and expands choices and possibilities. Nor is there evidence signalling what mechanisms might underpin such client benefits. In addressing this issue, we examine the financial planning advice (including financial product advice) provided to retail clients, and consider the short- and longer-term impacts on clients’ financial satisfaction and broader well-being. To this end, we examine both process (e.g., how financial planning advice is given) and outcome (e.g., financial situation) effects.

A taxonomic assessment of the Australian Dusky Antechinus Complex: A new species, the Tasman Peninsula Dusky Antechinus (Antechinus vandycki sp. nov.) and an elevation to species of the Mainland Dusky Antechinus (Antechinus swainsonii mimetes (Thomas))

In 2014, the northern outlying population of carnivorous marsupial Dusky Antechinus (Antechinus swainsonii) was nominated a new species, A. arktos. Here, we describe a further new species in the dasyurid A. swainsonii complex, which now contains five taxa. We recognise two distinct species from Tasmania, formerly represented by A. swainsonii swainsonii (Waterhouse); one species (and 2 subspecies) from mainland south-eastern Australia, formerly known as A. swainsonii mimetes (Thomas) and A. swainsonii insulanus Davison; and one species from the Tweed Caldera in mid-eastern Australia, formerly known as A. s. mimetes but recently described as A. arktos Baker, Mutton, Hines and Van Dyck. Primacy of discovery dictates the Tasmanian Dusky Antechinus A. swainsonii (Waterhouse) is nominate; the Mainland Dusky Antechinus taxa, one raised from subspecies within A. swainsonii mimetes (Thomas) is elevated to species (now A. mimetes mimetes) and the other, A. swainsonii insulanus Davison is transferred as a subspecies of A. mimetes (now A. mimetes insulanus); a species from Tasmania, the Tasman Peninsula Dusky Antechinus, is named A. vandycki sp. nov. These taxa are strongly differentiated: geographically (in allopatry), morphologically (in coat colour and craniodental features) and genetically (in mtDNA, 7.5-12.5% between species pairs).

N-ethyl-N-nitrosourea (ENU) induced mutations within the Klotho gene lead to ectopic calcification and reduced lifespan in mouse models

Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established. © 2015 Esapa et al.

A mouse with an N-ethyl-N-nitrosourea (ENU) induced Trp589Arg Galnt3 mutation represents a model for hyperphosphataemic familial tumoural calcinosis

Mutations of UDP-N-acetyl-alpha-D-galactosamine polypeptide N-acetyl galactosaminyl transferase 3 (GALNT3) result in familial tumoural calcinosis (FTC) and the hyperostosis-hyperphosphataemia syndrome (HHS), which are autosomal recessive disorders characterised by soft-tissue calcification and hyperphosphataemia. To facilitate in vivo studies of these heritable disorders of phosphate homeostasis, we embarked on establishing a mouse model by assessing progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU), and identified a mutant mouse, TCAL, with autosomal recessive inheritance of ectopic calcification, which involved multiple tissues, and hyperphosphataemia; the phenotype was designated TCAL and the locus, Tcal. TCAL males were infertile with loss of Sertoli cells and spermatozoa, and increased testicular apoptosis. Genetic mapping localized Tcal to chromosome 2 (62.64-71.11 Mb) which contained the Galnt3. DNA sequence analysis identified a Galnt3 missense mutation (Trp589Arg) in TCAL mice. Transient transfection of wild-type and mutant Galnt3-enhanced green fluorescent protein (EGFP) constructs in COS-7 cells revealed endoplasmic reticulum retention of the Trp589Arg mutant and Western blot analysis of kidney homogenates demonstrated defective glycosylation of Galnt3 in Tcal/Tcal mice. Tcal/Tcal mice had normal plasma calcium and parathyroid hormone concentrations; decreased alkaline phosphatase activity and intact Fgf23 concentrations; and elevation of circulating 1,25-dihydroxyvitamin D. Quantitative reverse transcriptase-PCR (qRT-PCR) revealed that Tcal/Tcal mice had increased expression of Galnt3 and Fgf23 in bone, but that renal expression of Klotho, 25-hydroxyvitamin D-1α-hydroxylase (Cyp27b1), and the sodium-phosphate co-transporters type-IIa and -IIc was similar to that in wild-type mice. Thus, TCAL mice have the phenotypic features of FTC and HHS, and provide a model for these disorders of phosphate metabolism. © 2012 Esapa et al.

A Mouse Model of Early-Onset Renal Failure Due to a Xanthine Dehydrogenase Nonsense Mutation

Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid. © 2012 Piret et al.

Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese

Objectives: Recent association studies by the Australo-Anglo-American Spondyloarthritis Consortium (TASC) in Caucasian European populations from Australia, North America and the UK have identified a number of genes as being associated with ankylosing spondylitis (AS). A candidate gene study in a Han Chinese population was performed based on these findings to identify associated genes in this population. Methods: A case-control study was performed in a Han Chinese population of patients with AS (n=775) and controls (n=1587) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The cases and controls were genotyped for 115 single nucleotide polymorphisms (SNPs) tagging IL23R, ERAP1, STAT3, JAK2, TNFRSF1A and TRADD, as well as other confirmation SNPs from the TASC study, using the Sequenom iPlex and the ABI OpenArray platforms. Statistical analysis of genotyped SNPs was performed using the Cochran - Armitage test for trend and meta-analysis was performed using METAL. SNPs in AS-associated genes in this study were then imputed using MaCH, and association with AS tested by logistic regression. Results: SNPs in TNFRSF1A (rs4149577, p=8.2×10-4), STAT3 (rs2293152, p=0.0015; rs1053005, p=0.017) and ERAP1 (rs27038, p=0.0091; rs27037, p=0.0092) were significantly associated with AS in Han Chinese. Association was also observed between AS and the intergenic region 2p15 (rs10865331, p=0.023). The lack of association between AS and IL23R in Han Chinese was confirmed (all SNPs p>0.1). Conclusions: The study results demonstrate for the first time that genetic polymorphisms in STAT3, TNFRSF1A and 2p15 are associated with AS in Han Chinese, suggesting common pathogenic mechanisms for the disease in Chinese and Caucasian European populations. Furthermore, previous findings demonstrating that ERAP1, but not IL23R, is associated with AS in Chinese patients were confirmed.