Journals
2012 EN
André Pascal Kengne · S. Limen · Eugène Sobngwi
+2 more
Background Available definition criteria for metabolic syndrome (MS) have similarities and inconsistencies. The aim of this study was to determine the prevalence of MS in a group of Cameroonians with type 2 diabetes, according to the International Diabetes Federation (IDF) and the National Cholesterol Education Programme Adult Treatment Panel III (NCEP-ATP III) criteria, and to assess the concordance between both criteria, and the implications of combining them. Methods We collected clinical and biochemical data for 308 patients with type 2 diabetes (men 157) at the National Obesity Center of the Yaounde Central Hospital, Cameroon. Concordance was assessed with the use of the Kappa statistic. Results Mean age (standard deviation) was 55.8 (10.5) years and the median duration of diagnosed diabetes (25 th –75 th percentiles) was 3 years (0.5–5.0), similarly among men and women. The prevalence of MS was 71.7% according to the IDF criteria and 60.4% according to NCEP-ATP III criteria. The prevalence was significantly higher in women than in men independently of the criteria used (both p < 0.001). Overall concordance between both definitions was low to average 0.51 (95% confidence interval: 0.41–0.61). Combining the two sets of criteria marginally improved the yield beyond that provided by the IDF criteria alone in men, but not in the overall population and in women. Conclusions The IDF and NCEP-ATP III criteria do not always diagnose the same group of diabetic individuals with MS and combining them merely increases the yield beyond that provided by the IDF definition alone. This study highlights the importance of having a single unifying definition for MS in our setting.
Journals
2012 EN
Florence F. Roussotte · Lindsay Soderberg · Tamara D. Warner
+5 more
Background Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure. Methods We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants. Results The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant ( P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls. Conclusions Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.
Journals
2012 EN
Phillip J Whiley · Lary C. Walker · Miguel de la Hoya
+28 more
Classification of intronic and predicted missense changes in the breast cancer susceptibility genes BRCA1 and BRCA2 remains a significant challenge for management of patients carrying these variants. Defective mRNA splicing is established as a pathway to disease, and mRNA analysis of unclassified variants has been shown to assist in classification and genetic counselling. However the interpretation of splicing assay results can be difficult, particularly for those variants that give rise to aberrations in a background of naturally occurring isoforms. The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium was set up to facilitate research and improve research methods used to classify rare variants in the BRCA1 and BRCA2 (and potentially other) breast cancer predisposition genes. ENIGMA has established a Splicing Working Group, with stated purpose to pool the expertise of different active research groups to conduct large-scale studies that improve the clinical classification of likely spliceogenic variants. An initial project of the Splicing Working Group is to assess the consistency of protocols and results obtained across the multiple participating laboratories from Australia, Europe, UK and the USA. A comparison of mRNA assay protocols in use across 21 labs has identified differences in source material for RNA assays (cultured and uncultured lymphocytes, lymphoblastoid cell lines (LCLs) or constructs), differential use of nonsense-mediated decay inhibitors, and numerous differences in mRNA extraction, DNase treatment and cDNA synthesis methods. A second phase of the project is now underway to determine the impact of the splicing assay methods routinely used by these laboratories on assay data and clinical interpretation of a panel of variants. LCLs were selected from the kConFab repository from carriers of a variant associated with single major aberrant mRNA transcript absent in controls (n=4); carriers of a variant associated with a complicated aberrant mRNA splicing profile involving multiple transcripts including naturally occurring isoforms (n=5); female cancer-free controls (n=11). LCLs have already been distributed to 15 of 20 participating sites, and mRNA assays are underway. Preliminary results indicate that major aberrations associated with several variants mirror results previously observed for mRNA from uncultured lymphocytes. In addition, there is evidence for notable differences in expression of some isoforms compared to results previously observed for RNA from uncultured lymphocytes . This collaborative effort will provide information to inform optimal standardised mRNA splicing assay methodology, and to improve guidelines for clinical interpretation of assay results.
Journals
2012 EN
Ruth McGovern · Graeme Wilson · Catherine Wray
+8 more
Health outcomes are key to patients and clinicians, but trials of alcohol brief intervention (BI) tend to focus on behavioral outcomes, while those finding positive effects on physical- or mental-health outcomes generally lack power to show robust effects. To test the feasibility of a randomized controlled trial of BI for either hypertensive or depressed primary-care patients who drink alcohol above recommended levels, records at 25 English primary-care practices were searched for adult patients with risky drinking and comorbid hypertension or depression. Eligible patients were randomized to either a hypertension or depression arm, then to a control or intervention condition. They were screened for at-risk drinking using the Alcohol Use Disorders Identification Test (AUDIT). Consenting respondents scoring >7 on the AUDIT completed the Patient Health Questionnaire-9 (PHQ-9) (depression arm) or blood pressure measurement (hypertension arm) and received either BI or standard advice. At six-month follow-up, participants are again screened for alcohol use and comorbid condition. Seventeen practices (median adult patients, 7181; quartile 1, 5195, quartile 3, 8050) searched their databases. Fourteen percent of adult patients (median; quartile 1, 8.4%, quartile 3, 16.5%) drank above guidelines. Twenty percent of adult patients (median; quartile 1, 18.5%, quartile 3, 23.2%) were hypertensive, of which 5% (median; quartile 1, 3.9%, quartile 3, 5.3%) also drank heavily. Fourteen percent of adult patients had mild to moderate depression (median; quartile 1, 8.9%, quartile 3, 16.9%), of which 2% (median; quartile 1, 1.9%, quartile 3, 2.9%) also drank heavily. Of 2590 eligible patients, 633 (24%) completed the AUDIT. Thirty-five percent scored positively on the AUDIT in the hypertension arm, and 50% scored positively in the depression arm. Eighty patients were recruited to the hypertension arm, and recruitment to the depression arm is ongoing. Patients eligible for an RCT of BI for comorbid heavy drinking and hypertension or mild/moderate depression are identifiable in primary care records, though with variation among practices. Almost a quarter of these patients can be screened by mail for current alcohol use; more screen positively in the depression arm than in the hypertension arm. A trial in the hypertension arm seems most feasible.
Journals
2012 EN
Lambertus Klei · Stephan Sanders · Michael T. Murtha
+22 more
Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.
Journals
2012 EN
Catherine Lee · Nobuaki Kikyo
Long noncoding RNAs (lncRNAs) have been detected in nearly every cell type and found to be fundamentally involved in many biological processes. The characterization of lncRNAs has immense potential to advance our comprehensive understanding of cellular processes and gene regulation, along with implications for the treatment of human disease. The recent ENCODE (Encyclopedia of DNA Elements) study reported 9,640 lncRNA loci in the human genome, which corresponds to around half the number of protein-coding genes. Because of this sheer number and their functional diversity, it is crucial to identify a pool of potentially relevant lncRNAs early on in a given study. In this review, we evaluate the methods for isolating lncRNAs by immunoprecipitation and review the advantages, disadvantages, and applications of three widely used approaches – microarray, tiling array, and RNA-seq – for identifying lncRNAs involved in gene regulation. We also look at ways in which data from publicly available databases such as ENCODE can support the study of lncRNAs.
Journals
2012 EN
Elodie Vandenhaute · Maxime Culot · Fabien Gosselet
+7 more
Background The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB) function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS) is the only confirmed, homologous model of malignant hyperthermia (MH) in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome. Methods In the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n) mutant ryr1/hal alleles, respectively), and tested in vitro for their influence on the permeability of BBB endothelial monolayers. Results Enlarged perivascular spaces were observed in ryr1 -mutant samples , corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro . Our results indicated that pericytes from the three genotypes of pigs had differing influences on the BBB. Unlike pericytes from NN pigs, pericytes from Nn and nn pigs were not able to maintain low BBB permeability. Conclusions Electron microscopy observations demonstrated brain capillary modifications in PSS condition, but no change in pericyte morphology. Results from in vitro experiments suggest that brain pericytes from ryr1 mutated pigs, even if they are not affected by this condition at the ultrastructural level, are not able to maintain BBB integrity in comparison with pericytes from wild-type animals.
Journals
2012 EN
Catherine Chiu · Miles C. Miller · Ilias N Caralopoulos
+5 more
Background Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aβ) accumulation in the aging rat brain. Methods Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aβ40 and Aβ42 concentrations in the cortex and hippocampus were measured by ELISA. Results There was a significant linear increase in total cranial CSF volume with age: 3-20 months ( p < 0.01); 3-30 months ( p < 0.001). CSF production rate increased from 3-12 months ( p < 0.01) and decreased from 12-30 months ( p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day -1 ) to 12 months (11.30 day -1 ) and then a decrease to 20 months (10.23 day -1 ) and 30 months (6.62 day -1 ). Aβ40 and Aβ42 concentrations in brain increased from 3-30 months ( p < 0.001). Both Aβ42 and Aβ40 concentrations approached a steady state level by 30 months. Conclusions In young rats there is no correlation between CSF turnover and Aβ brain concentrations. After 12 months, CSF turnover decreases as brain Aβ continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.
Journals
2012 EN
Daniel P. S. Osborn · Catherine Boucher · Patricia D. Wilson
+4 more
Polycystin-1 (PKD1) forms a mechanosensitive cation channel complex with polycystin-2 (PKD2) in the primary cilium. Functional defects in this complex caused by mutation of PKD1 and PKD2 result in autosomal dominant polycystic kidney disease (ADPKD). The mechanisms by which this complex regulates normal cell physiology remain elusive. In particular the proteins that interact directly with polycystin-1 remain poorly characterised. A Y-2H screen using the C-terminus of polycystin-1 as bait identified a novel binding partner that we have called PIP9 (polycystin interacting protein 9). PIP9 is evolutionary conserved, ubiquitously expressed, and predicted to be a 9KDa phosphoprotein containing a single coiled-coil domain that interacts with the coiled-coil domain of PC-1. Specific anti-PIP9 antisera confirmed the widespread and developmentally regulated expression of PIP9 and identified phosphorylated isoforms. PIP9 co-localised to the renal primary cilium with PC1 and immuno-EM studies revealed localisation to IFT particles. Knockdown of zPip9, using morpholino oligonucleotides, resulted in developmental defects in gastrulation movements. In addition, evidence of cell detachment was observed, common to the phenotype described for double bbs4;bbs10 morphant zebrafish which suggests pip9 may act in the same genetic pathway. zpip9 morphants also displayed variable head and eye degeneration, including coloboma and hydrocephalus, pronephric cysts and shortening of the body axis. Loss of Pip9 function in mice is lethal before embryonic day E11.5. This preliminary analysis suggests that PIP9 plays a central role in mediating polycystin-1 dependant signalling.
Springer Science+Business Media
Journals
2012 EN
RB Paisey · Catherine Carey · Richard J. Seymour
+8 more
Alstrom syndrome (OMIM 203800) is an autosomal recessive condition caused by pathological mutations in the ALMS1 gene of worldwide distribution prevalence. 200 subjects and longitudinal in depth studies of the UK cohort of 100 subjects have highlighted the extreme variation not only in the rate of visual and hearing loss but also in extent and progression of cardiac, renal, hepatic and endocrine dysfunction. The range in age at which visual acuity declines to <6/36 and/or when neuronal deafness is diagnosed is from 5 to 40 years. Life threatening cardiomyopathy occurs in 30% of neonates and can recur or arise de novo in 25% of all young adults from 12 to 25 years of age with sporadic cases later than this. Renal failure (CKD stage 5) occurs from 16 to 50 years in 25% of cases and hepatic cirrhosis in 10% between 10 and 40 years. Underlying this trend is some degree of cardiac and renal fibrosis and fatty liver in all, and severe insulin resistance. Progression from insulin resistance to type 2 diabetes and its severity and from fatty liver to fibrosis, then cirrhosis may be halted in early stages by lifestyle improvement especially in the second and third decades. Variation in deafness, renal and cardiac fibrosis differs within families but shows ethnic clustering suggestive that modifier genes contribute.
Springer Science+Business Media