Sucrose Acceptance and Different Forms of Associative Learning of the Honey Bee (Apis Mellifera L.) in the Field and Laboratory

The experiments analyze different forms of learning and 24-h retention in the field and in the laboratory in bees that accept sucrose with either low (≤3%) or high (≥30% or ≥50%) concentrations. In the field we studied color learning at a food site and at the hive entrance. In the laboratory olfactory conditioning of the proboscis extension response (PER) was examined. In the color learning protocol at a feeder, bees with low sucrose acceptance thresholds (≤3%) show significantly faster and better acquisition than bees with high thresholds (≥50%). Retention after 24 h is significantly different between the two groups of bees and the choice reactions converge. Bees with low and high acceptance thresholds in the field show no differences in the sucrose sensitivity PER tests in the laboratory. Acceptance thresholds in the field are thus a more sensitive behavioral measure than PER responsiveness in the laboratory. Bees with low acceptance thresholds show significantly better acquisition and 24-h retention in olfactory learning in the laboratory compared to bees with high thresholds. In the learning protocol at the hive entrance bees learn without sucrose reward that a color cue signals an open entrance. In this experiment, bees with high sucrose acceptance thresholds showed significantly better learning and reversal learning than bees with low thresholds. These results demonstrate that sucrose acceptance thresholds affect only those forms of learning in which sucrose serves as the reward. The results also show that foraging behavior in the field is a good predictor for learning behavior in the field and in the laboratory

Morbidity and Quality of Life in Bladder Cancer Patients following Cystectomy and Urinary Diversion: A Single-Institution Comparison of Ileal Conduit versus Orthotopic Neobladder

Objective. To evaluate and compare noncontinent and continent urinary diversion after radical cystectomy in patients with bladder cancer. Methods. A total of 301 patients submitted to radical cystectomy at the Charité-University Hospital Berlin from 1993 to 2007 including 146 with an ileal conduit and 115 with an ileal neobladder. Clinical and pathological data as well as oncological outcome were retrospectively analyzed and compared. Quality of life was analyzed using the EORTC QLQ-C30 and BLM30 questionnaires. Results. 69.1% and 69.6% of all patients who received an ileal conduit and ileal neobladder, respectively, developed early complications. The two groups differed significantly concerning the occurrence of postoperative ileus (P = 0.02) favoring patients who received an ileal conduit but not with regard to any other early-onset complication evaluated. Patients with ileal neobladder had a significantly better global health status and quality of life (P = 0.02), better physical functioning (P = 0.02), but also a higher rate of diarrhoea (P = 0.004). Conclusion. Cystectomy with any type of diversion remains a complication-prone surgery. Even if the patient groups are not homogeneous in all respects, there are many arguments in favor of the ileal neobladder as the urinary diversion of choice

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Phenotypic Characterization of <i>EIF2AK4</i> Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of &lt;1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation. </jats:sec

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype

Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Retrospective analysis of operative results and quality of life in patients with bladder cancer after radical cystectomy and urinary diversion at Charité Universitätsmedizin Berlin between 1993 and 2007

Die Zielsetzung der vorliegenden Arbeit ist es, die Auswirkungen, die Komplikationen und die Lebensqualität nach radikaler Zystektomie und der anschließenden Harnableitung retrospektiv zu analysieren. Hierzu wurde ein Vergleich zwischen den Harnableitungsformen Ileumneoblase und Ileumkonduit durchgeführt. Im Kollektiv Ileumneoblase wurden die Ergebnisse des primär intraperitonealen und des primär extraperitonealen Verfahrens miteinander verglichen. Im ausgewerteten Zeitraum von 1993 bis 2007 wurden 301 radikale Zystektomien in der urologischen Klinik der Charité-Universitätsmedizin Berlin am Standort Campus Benjamin Franklin durchgeführt. Aus diesem Kollektiv wurden die Patienten mit Anlage eines Ileumkonduits (n=146) und einer Ileumneoblase (n=115) für die Auswertung ausgewählt. Die beiden Kollektive unterschieden sich signifikant in der Altersverteilung, im Komorbiditätsgrad, in der Verteilung auf die Prognosegruppen und in der Liegezeit voneinander. Bei den Frühkomplikationen traten eine metabolische Azidose und ein postoperativer Ileus bei Patienten mit Ileumneoblase signifikant häufiger auf. Patienten mit einer Ileumneoblase zeigten eine signifikant höhere Überlebenswahrscheinlichkeit als Patienten mit einem Ileumkonduit. Bei den Todesursachen unterschieden sich die beiden Kollektive nicht signifikant voneinander. Unter der Verwendung der EORTC QLQ-C30 und QLQ-BLM30 Fragebögen ergaben sich signifikante Unterschiede zwischen den beiden Kollektiven Ileumneoblase (n=34) und Ileumkonduit (n=23). Der allgemeine Gesundheitszustand und die Lebensqualität wurden von Patienten mit einer Ileumneoblase signifikant höher eingeschätzt; sie bewältigten physische Alltagsfunktionen signifikant besser und zeigten eine signifikant höhere sexuelle Aktivität. Patienten mit einem Ileumkonduit zeigten ein hochsignifikant geringeres Auftreten des Symptoms Diarrhoe. 66 Patienten mit primär extraperitonealer und 48 Patienten mit primär intraperitonealer radikaler Zystektomie und Anlage einer Ileumneoblase wurden verglichen. Die Patienten mit primär extraperitonealem Verfahren waren geringfügig jünger und zeigten eine signifikant kürzere Liegezeit auf der Intensiv- und Wachstation. Eine Lymphozele trat bei Patienten mit primär extraperitonealem Verfahren signifikant häufiger auf, während ein Ileus bei Patienten mit primär intraperitonealem Verfahren häufiger war. Beim primär intraperitonealen Verfahren trat ein Rezidiv signifikant häufiger auf (ca. 37%) als bei Patienten mit primär extraperitonealem Verfahren (ca. 16%). Bei der Auswertung der Überlebensverteilungen wurden keine signifikanten Unterschiede zwischen beiden Verfahren nachgewiesen. Bei der Auswertung der EORTC QLQ-C30 und QLQ- BLM30 Fragebögen traten die Symptome Obstipation und abdominale Probleme signifikant häufiger beim primär intraperitionealen Verfahren auf. Der allgemeine Gesundheitszustand und die Lebensqualität wurden in beiden Kollektiven gleich bewertet.To evaluate the advantages and disadvantages of noncontinent (ileal conduit) and continent (ileal neobladder) urinary diversion after radical cystectomy in patients with bladder cancer, a retrospective analysis was performed. In addition, data for the primary extraperitoneal approach of radical cystectomy and extraperitonealization of neobladder were compared with those for the primary intraperitoneal approach. 301 radical cystectomies were performed in the Department of Urology at Charité Campus Benjamin Franklin Berlin between 1993 and 2007. From this collective, 146 patients with an ileal conduit and 115 with an ileal neobladder were selected for the analysis. Significant differences between the two groups were found for the age distributions, the degrees of comorbidity, the distributions into prognosis groups, and the hospitalization time. Among the early complications metabolic acidose and postoperative ileus were significantly more frequent in patients with ileal neobladder. The probability of overall survival was significantly higher in patients with ileal neobladder. The causes of death were not different between the two groups. Using the EORTC QLQ-C30 and QLQ-BLM30 questionnaires, significant differences between patients with ileal neobladder (n=34) and ileal conduit (n=23) were found. The general health status and the quality of life were significantly higher in patients with ileal neobladder. They managed physical functions significantly better and had significantly better sexual functions. Patients with ileal conduit showed significantly less diarrhea. 66 patients with primary extraperitoneal and 48 patients with primary intraperitoneal cystectomy and neobladder were compared. Patients with primary extrapertioneal approach were slightly younger and had significantly shorter time of hospitalization in the intensive care unit than patients with primary intraperitoneal approach. A lymphocele was significantly more frequent for patients with primary extraperitoneal approach, while an ileus was more frequent in patients with intraperitoneal approach. The relapse rate was significantly higher in patients with primary intraperitoneal approach (approximately 37%) compared to patients with primary extraperitoneal approach (approximately 16%). The overall survival rate did not differ significantly between both groups. Analysis of the QLQ-C30 and QLQ-BLM30 questionnaires demonstrated significantly more obstipation and abdominal problems in patients with primary intraperitoneal approach. The general health status and the quality of life did not differ between the two groups