PediDraw: A web-based tool for drawing a pedigree in genetic counseling

<p>Abstract</p> <p>Background</p> <p>Drawing a pedigree is a prerequisite in genetic counseling. In medical records, a pedigree is useful to document the family history of the patient. Drawing a pedigree is also necessary in collecting genetic resources for medical research such as positional cloning. Currently, most pedigrees are drawn by hand or by drawing software. Due to the special requirements in a standardized pedigree, generating a pedigree by these methods is usually time-consuming and requires professionals. This limits the usage of a pedigree as demanded in remote diagnosis or online counseling from the counselees to send an electronic pedigree.</p> <p>Results</p> <p>We developed an online pedigree drawing tool, PediDraw, which enables users to generate pedigrees after inputting the family information step-by-step on web. It outputs a pedigree or table to present a family history to the counselors.</p> <p>Conclusion</p> <p>PediDraw is a user-friendly web-based drawing tool. It is accessible via Internet.</p

Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy

Introduction: Lymphedema is a frequent consequence of lymph node excision during breast cancer surgery. Current treatment options are limited mainly to external compression therapies to limit edema development. We investigated previously, postsurgical lymphedema in a sheep model following the removal of a single lymph node and determined that autologous lymph node transplantation has the potential to reduce or prevent edema development. In this report, we examine the potential of lymphangiogenic therapy to restore lymphatic function and reduce postsurgical lymphedema. Methods: Lymphangiogenic growth factors (vascular endothelial growth factor C (VEGF-C)) and angiopoietin-2 (ANG-2) were loaded into a gel-based drug delivery system (HAMC; a blend of hyaluronan and methylcellulose). Drug release rates and lymphangiogenic signaling in target endothelial cells were assessed in vitro and vascular permeability biocompatibility tests were examined in vivo. Following, the removal of a single popliteal lymph node, HAMC with the growth factors was injected into the excision site. Six weeks later, lymphatic functionality was assessed by injecting 125Iodine radiolabeled bovine serum albumin (125I-BSA) into prenodal vessels and measuring its recovery in plasma. Circumferential leg measurements were plotted over time and areas under the curves used to quantify edema formation. Results: The growth factors were released over a two-week period in vitro by diffusion from HAMC, with 50% being released in the first 24 hr. The system induced lymphangiogenic signaling in target endothelial cells, while inducing only a minimal inflammatory response in sheep. Removal of the node significantly reduced lymphatic functionality (nodectomy 1.9 ± 0.9, HAMC alone 1.7 ± 0.8) compared with intact groups (3.2 ± 0.7). In contrast, there was no significant difference between the growth factor treatment group (2.3 ± 0.73) and the intact group indicating improved function with the molecular factors. An increase in the number of regenerated lymphatic vessels at treatment sites was observed with fluoroscopy. Groups receiving HAMC plus growth factors displayed significantly reduced edema (107.4 ± 51.3) compared with nontreated groups (nodectomy 219.8 ± 118.7 and HAMC alone 162.6 ± 141). Conclusions: Growth factor therapy has the potential to increase lymphatic function and reduce edema magnitude in an animal model of lymphedema. The application of this concept to lymphedema patients warrants further examination

Quantitative Metabolomics by 1H-NMR and LC-MS/MS Confirms Altered Metabolic Pathways in Diabetes

Insulin is as a major postprandial hormone with profound effects on carbohydrate, fat, and protein metabolism. In the absence of exogenous insulin, patients with type 1 diabetes exhibit a variety of metabolic abnormalities including hyperglycemia, glycosurea, accelerated ketogenesis, and muscle wasting due to increased proteolysis. We analyzed plasma from type 1 diabetic (T1D) humans during insulin treatment (I+) and acute insulin deprivation (I-) and non-diabetic participants (ND) by 1H nuclear magnetic resonance spectroscopy and liquid chromatography-tandem mass spectrometry. The aim was to determine if this combination of analytical methods could provide information on metabolic pathways known to be altered by insulin deficiency. Multivariate statistics differentiated proton spectra from I- and I+ based on several derived plasma metabolites that were elevated during insulin deprivation (lactate, acetate, allantoin, ketones). Mass spectrometry revealed significant perturbations in levels of plasma amino acids and amino acid metabolites during insulin deprivation. Further analysis of metabolite levels measured by the two analytical techniques indicates several known metabolic pathways that are perturbed in T1D (I-) (protein synthesis and breakdown, gluconeogenesis, ketogenesis, amino acid oxidation, mitochondrial bioenergetics, and oxidative stress). This work demonstrates the promise of combining multiple analytical methods with advanced statistical methods in quantitative metabolomics research, which we have applied to the clinical situation of acute insulin deprivation in T1D to reflect the numerous metabolic pathways known to be affected by insulin deficiency

Insulin Sensitivity Is Reflected by Characteristic Metabolic Fingerprints - A Fourier Transform Mass Spectrometric Non-Targeted Metabolomics Approach

BACKGROUND: A decline in body insulin sensitivity in apparently healthy individuals indicates a high risk to develop type 2 diabetes. Investigating the metabolic fingerprints of individuals with different whole body insulin sensitivity according to the formula of Matsuda, et al. (ISI(Matsuda)) by a non-targeted metabolomics approach we aimed a) to figure out an unsuspicious and altered metabolic pattern, b) to estimate a threshold related to these changes based on the ISI, and c) to identify the metabolic pathways responsible for the discrimination of the two patterns. METHODOLOGY AND PRINCIPAL FINDINGS: By applying infusion ion cyclotron resonance Fourier transform mass spectrometry, we analyzed plasma of 46 non-diabetic subjects exhibiting high to low insulin sensitivities. The orthogonal partial least square model revealed a cluster of 28 individuals with alterations in their metabolic fingerprints associated with a decline in insulin sensitivity. This group could be separated from 18 subjects with an unsuspicious metabolite pattern. The orthogonal signal correction score scatter plot suggests a threshold of an ISI(Matsuda) of 15 for the discrimination of these two groups. Of note, a potential subgroup represented by eight individuals (ISI(Matsuda) value between 8.5 and 15) was identified in different models. This subgroup may indicate a metabolic transition state, since it is already located within the cluster of individuals with declined insulin sensitivity but the metabolic fingerprints still show some similarities with unaffected individuals (ISI >15). Moreover, the highest number of metabolite intensity differences between unsuspicious and altered metabolic fingerprints was detected in lipid metabolic pathways (arachidonic acid metabolism, metabolism of essential fatty acids and biosynthesis of unsaturated fatty acids), steroid hormone biosyntheses and bile acid metabolism, based on data evaluation using the metabolic annotation interface MassTRIX. CONCLUSIONS: Our results suggest that altered metabolite patterns that reflect changes in insulin sensitivity respectively the ISI(Matsuda) are dominated by lipid-related pathways. Furthermore, a metabolic transition state reflected by heterogeneous metabolite fingerprints may precede severe alterations of metabolism. Our findings offer future prospects for novel insights in the pathogenesis of the pre-diabetic phase

Spatial and Genetic Epidemiology of Hookworm in a Rural Community in Uganda

There are remarkably few contemporary, population-based studies of intestinal nematode infection for sub-Saharan Africa. This paper presents a comprehensive epidemiological analysis of hookworm infection intensity in a rural Ugandan community. Demographic, kinship, socioeconomic and environmental data were collected for 1,803 individuals aged six months to 85 years in 341 households in a cross-sectional community survey. Hookworm infection was assessed by faecal egg count. Spatial variation in the intensity of infection was assessed using a Bayesian negative binomial spatial regression model and the proportion of variation explained by host additive genetics (heritability) and common domestic environment was estimated using genetic variance component analysis. Overall, the prevalence of hookworm was 39.3%, with the majority of infections (87.7%) of light intensity (≤1000 eggs per gram faeces). Intensity was higher among older individuals and was associated with treatment history with anthelmintics, walking barefoot outside the home, living in a household with a mud floor and education level of the household head. Infection intensity also exhibited significant household and spatial clustering: the range of spatial correlation was estimated to be 82 m and was reduced by a half over a distance of 19 m. Heritability of hookworm egg count was 11.2%, whilst the percentage of variance explained by unidentified domestic effects was 17.8%. In conclusion, we suggest that host genetic relatedness is not a major determinant of infection intensity in this community, with exposure-related factors playing a greater role

Metabolic Profiling Reveals Distinct Variations Linked to Nicotine Consumption in Humans — First Results from the KORA Study

Exposure to nicotine during smoking causes a multitude of metabolic changes that are poorly understood. We quantified and analyzed 198 metabolites in 283 serum samples from the human cohort KORA (Cooperative Health Research in the Region of Augsburg). Multivariate analysis of metabolic profiles revealed that the group of smokers could be clearly differentiated from the groups of former smokers and non-smokers. Moreover, 23 lipid metabolites were identified as nicotine-dependent biomarkers. The levels of these biomarkers are all up-regulated in smokers compared to those in former and non-smokers, except for three acyl-alkyl-phosphatidylcholines (e.g. plasmalogens). Consistently significant results were further found for the ratios of plasmalogens to diacyl-phosphatidylcolines, which are reduced in smokers and regulated by the enzyme alkylglycerone phosphate synthase (alkyl-DHAP) in both ether lipid and glycerophospholipid pathways. Notably, our metabolite profiles are consistent with the strong down-regulation of the gene for alkyl-DHAP (AGPS) in smokers that has been found in a study analyzing gene expression in human lung tissues. Our data suggest that smoking is associated with plasmalogen-deficiency disorders, caused by reduced or lack of activity of the peroxisomal enzyme alkyl-DHAP. Our findings provide new insight into the pathophysiology of smoking addiction. Activation of the enzyme alkyl-DHAP by small molecules may provide novel routes for therapy

Metabonomic fingerprints of fasting plasma and spot urine reveal human pre-diabetic metabolic traits

Impaired glucose tolerance (IGT) which precedes overt type 2 diabetes (T2DM) for decades is associated with multiple metabolic alterations in insulin sensitive tissues. In an UPLC-qTOF-mass spectrometry-driven non-targeted metabonomics approach we investigated plasma as well as spot urine of 51 non-diabetic, overnight fasted individuals aiming to separate subjects with IGT from controls thereby identify pathways affected by the pre-diabetic metabolic state. We could clearly demonstrate that normal glucose tolerant (NGT) and IGT subjects clustered in two distinct groups independent of the investigated metabonome. These findings reflect considerable differences in individual metabolite fingerprints, both in plasma and urine. Pre-diabetes associated alterations in fatty acid-, tryptophan-, uric acid-, bile acid-, and lysophosphatidylcholine-metabolism, as well as the TCA cycle were identified. Of note, individuals with IGT also showed decreased levels of gut flora-associated metabolites namely hippuric acid, methylxanthine, methyluric acid, and 3-hydroxyhippuric acid. The findings of our non-targeted UPLC-qTOF-MS metabonomics analysis in plasma and spot urine of individuals with IGT vs NGT offers novel insights into the metabolic alterations occurring in the long, asymptomatic period preceding the manifestation of T2DM thereby giving prospects for new intervention targets

Rediscovering the value of families for psychiatric genetics research

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the “Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders” consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.This research was supported by National Institute of Mental Health grants U01 MH105630 (DCG), U01 MH105634 (REG), U01 MH105632 (JB), R01 MH078143 (DCG), R01 MH083824 (DCG & JB), R01 MH078111 (JB), R01 MH061622 (LA), R01 MH042191 (REG), and R01 MH063480 (VLN).UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí