And Her Mother Came Too!

https://digitalcommons.library.umaine.edu/mmb-vp/5725/thumbnail.jp

The use of next generation sequencing in rare disease

Introduction: High throughput next generation sequencing (NGS) strategies such as whole exome sequencing (WES) are frequently used in medical research to identify the molecular cause of Mendelian genetic disease. WES, or clinical exome sequencing strategies are now being adopted into clinical genetics practice. This study focuses on the application of WES for genetic diagnosis in a group of mainly consanguineous families with rare phenotypes for which an autosomal recessively inherited disease was suspected but the molecular basis was unknown. Materials and methods: Families were recruited retrospectively from a previous research cohort (the National Autozygosity Mapping study) and prospectively from the Birmingham Women’s and Children’s NHS Foundation Trust. WES was subsequently performed. Results: 35 families with rare genetic disorders were studied by WES (in 9 families a single individual underwent sequencing). After bioinformatics analysis of WES data and detailed reassessment of the phenotype a molecular genetic diagnosis was reached in 15 families (42.9%). Conclusion: WES is an effective strategy for identifying the molecular basis of recessively inherited disorders in consanguineous families. The combination of WES with detailed phenotyping significantly improved variant interpretation and diagnostic yield over WES alone

Splanchnic metabolism of nutrients and hormones in steers fed alfalfa under conditions of increased absorption of ammonia and L-arginine supply across the portal-drained viscera

Effects of increased ammonia and/or arginine absorption on net splanchnic (portal-drained viscera [PDV] plus liver) metabolism of nonnitrogenous nutrients and hormones in cattle were examined. Six Hereford × Angus steers (501 ± 1 kg BW) prepared with vascular catheters for measurements of net flux across the splanchnic bed were fed a 75% alfalfa:25% (as-fed basis) corn and soybean meal diet (0.523 MJ of ME/[kg BW0.75.d]) every 2 h without (27.0 g of N/kg of DM) and with 20 g of urea/kg of DM (35.7 g of N/kg of DM) in a split-plot design. Net flux measurements were made immediately before and after a 72-h mesenteric vein infusion of L-arginine (15 mmol/h). There were no treatment effects onPDVor hepaticO2 consumption. Dietary urea had no effect on splanchnic metabolism of glucose or L-lactate, but arginine infusion decreased net hepatic removal of L-lactate when urea was fed (P < 0.01). Net PDV appearance of n-butyrate was increased by arginine infusion (P < 0.07), and both dietary urea (P < 0.09) and arginine infusion (P < 0.05) increased net hepatic removal of n-butyrate. Dietary urea also increased total splanchnic acetate output (P < 0.06), tended to increase arterial glucagon concentration (P < 0.11), and decreased arterial ST concentration (P < 0.03). Arginine infusion increased arterial concentration (P < 0.07) and net PDV release (P < 0.10) and tended to increase hepatic removal (P < 0.11) of insulin, as well as arterial concentration (P < 0.01) and total splanchnic output (P < 0.01) of glucagon. Despite changes in splanchnic N metabolism, increased ammonia and arginine absorption had little measurable effect on splanchnic metabolism of glucose and other nonnitrogenous components of splanchnic energy metabolism

Cambridge Cognitive Examination and Hachinski Ischemic Score as predictors of MRI confirmed pathology in dementia: a cross-sectional study

AIMS AND BACKGROUND: Dementia is diagnosed through a combination of clinical assessment, cognitive assessment tools and neuroimaging. The aim of this retrospective, naturalistic study was to explore the association between the clinical assessment tools used in a memory clinic and the findings of Magnetic Resonance Imaging (MRI) scans in patients with dementia. METHODS: Data were collected through routine clinical practice for all patients assessed at a memory assessment clinic in East Sussex, UK. Included patients had an MRI scan and received a formal diagnosis of dementia. Multinomial logistic regression was used to investigate the associations between atrophy on MRI with age, gender, Cambridge Cognitive Examination (CAMCOG) and Hachinski Ischemic Score (HIS). Ordinal logistic regression was used to study the associations between vascular findings on MRI with age, gender, CAMCOG and HIS. Because of the distribution of HIS scores a cut-off of 1 or greater was used in the regression analysis. RESULTS: Male gender was associated with an increased likelihood of moderate atrophy (relative risk ratio (RRR) = 1.99, 95% confidence interval (CI) = 1.04-3.82), severe atrophy (RRR = 3.04, 95% CI = 1.38-6.68) and regional atrophy (RRR = 2.25, 95% CI = 1.26-4.00) on MRI. An increase of one point on the CAMCOG was associated with a decreased risk of regional atrophy (RRR = 0.98, 95% CI = 0.96-1.00) on MRI. There were no significant associations between age, or HIS, and atrophy on MRI. An increase in age of one year was associated with an increase in severity of vascular pathology reported on MRI (OR = 1.08, 95% CI = 1.05-1.12). Male gender was associated with reduced severity of vascular pathology reported on MRI (OR = 0.53, 95% CI = 0.36-0.78). There were no associations between CAMCOG, or HIS, and vascular pathology on MRI. DISCUSSION: Our data show that CAMCOG was associated with MRI findings of regional atrophy and vascular pathology was greater in older patients. We highlight the importance of using a multi-modal approach to dementia diagnosis