Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS

Evidences for a quasi 60-year North Atlantic Oscillation since 1700 and its meaning for global climate change

The North Atlantic Oscillation (NAO) obtained using instrumental and documentary proxy predictors from Eurasia is found to be characterized by a quasi 60-year dominant oscillation since 1650. This pattern emerges clearly once the NAO record is time integrated to stress its comparison with the temperature record. The integrated NAO (INAO) is found to well correlate with the length of the day (since 1650) and the global surface sea temperature record HadSST2 and HadSST3 (since 1850). These findings suggest that INAO can be used as a good proxy for global climate change, and that a 60-year cycle exists in the global climate since at least 1700. Finally, the INAO ~60-year oscillation well correlates with the ~60- year oscillations found in the historical European aurora record since 1700, which suggests that this 60-year dominant climatic cycle has a solar-astronomical origin

Primary right atrium angiosarcoma mimicking pericarditis

<p>Abstract</p> <p>Background</p> <p>Primary cardiac neoplasms occur rarely and most of them are benign. Malignant tumors including angiosarcoma are extremely rare and have a non specific clinical presentation and a poor prognosis.</p> <p>Case presentation</p> <p>We present a case of a young male who was transferred to our hospital because of shock and multiple organ failure after a complicated pericardial biopsy. During the previous seven months he presented with recurrent episodes of pericardial effusions and tamponade. Chest computed tomography revealed a mass in the right atrium, infiltrating the myocardium and pericardium. During emergency surgery that followed, the patient died because of uncontrolled hemorrhage. Autopsy revealed the mass of the right atrium, which was identified on histological examination as primary cardiac angiosarcoma.</p> <p>Conclusion</p> <p>This case highlights the difficulties both in early diagnosis and in the management of patients with cardiac angiosarcoma.</p

Different genes interact with particulate matter and tobacco smoke exposure in affecting lung function decline in the general population

BACKGROUND: Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. OBJECTIVES: We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. METHODS: For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV(1)), FEV(1) over forced vital capacity (FEV(1)/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF(25-75)) was regressed on interval exposure to particulate matter >10 microm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction)>0.05). Replication was attempted for SNPs with MAF<10% in 3320 SAPALDIA participants without GWAS. RESULTS: On the SNP-level, rs2035268 in gene SNCA accelerated FEV(1)/FVC decline by 3.8% (p(interaction) = 2.5x10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction) = 9.7x10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction) = 3.0x10(-4)) on FEV(1)/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. CONCLUSIONS: Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobac smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challengin

Social marketing and healthy eating : Findings from young people in Greece

This document is the Accepted Manuscript version. The final publication is available at Springer via http://dx.doi.org/10.1007/s12208-013-0112-xGreece has high rates of obesity and non-communicable diseases owing to poor dietary choices. This research provides lessons for social marketing to tackle the severe nutrition-related problems in this country by obtaining insight into the eating behaviour of young adults aged 18–23. Also, the main behavioural theories used to inform the research are critically discussed. The research was conducted in Athens. Nine focus groups with young adults from eight educational institutions were conducted and fifty-nine participants’ views towards eating habits, healthy eating and the factors that affect their food choices were explored. The study found that the participants adopted unhealthier nutritional habits after enrolment. Motivations for healthy eating were good health, appearance and psychological consequences, while barriers included lack of time, fast-food availability and taste, peer pressure, lack of knowledge and lack of family support. Participants reported lack of supportive environments when deciding on food choices. Based on the findings, recommendations about the development of the basic 4Ps of the marketing mix, as well as of a fifth P, for Policy are proposedPeer reviewe

Measuring Anxiety in Youth with Learning Disabilities: Reliability and Validity of the Multidimensional Anxiety Scale for Children (MASC)

Youth with learning disabilities (LD) are at an increased risk for anxiety disorders and valid measures of anxiety are necessary for assessing this population. We investigated the psychometric properties of the Multidimensional Anxiety Scale for Children (MASC; March in Multidimensional anxiety scale for children. Multi-Health Systems, North Tonawanda, 1998) in 41 adolescents (ages 11– 17 years) with LD. Youth and parents completed the MASC and were administered the semi-structured Anxiety Disorders Interview Schedule: Child and Parent Versions (ADIS: C/P; Silverman and Albano in The Anxiety Disorders Interview Schedule for DSM-IV-Child and Parent Versions. Psychological Corporation, San Antonio, 1996). Results found that child and parent reports of Social Anxiety on the MASC closely corresponded with ADIS-generated social phobia diagnoses, and parent total scores discriminated well among youth with and without any anxiety disorder. A multi-method multi-trait matrix provided evidence of the construct validity of the MASC total score for both parent and child reports. Our findings provide empirical evidence that parent and child versions of the MASC are useful for assessing anxiety in youth with LD

The IgG1/G2 subclass shift – a sensitive, tissue non-specific marker for malignancy. Diagnostic performance with squamous cell carcinoma of the head and neck

A significant decrease in %IgG1 accompanied by an increase in %IgG2 in total serum IgG has been previously reported as a highly sensitive marker for detecting early stages of carcinomas of various localizations. Here we investigated the question as to whether this phenomenon is also observed in sera of patients with squamous cell carcinoma of the head–neck region (SCC-HN), and to evaluate its diagnostic performance in the post-operative monitoring. Using quantitative affinity chromatography, serum concentrations of IgG1, IgG2 and total IgG were determined in 81 patients with different stages of primary and untreated SCC-HN, in 51 SCC-HN patients in post-therapeutical follow up, and in 33 patients with organ matched benign diseases. The data were compared with a total of 174 healthy controls. It was found that (i) 105 SCC-HN patients exhibited a mean value of 56.0 ± 0.7% IgG1, which likewise differed from healthy controls (63.2 ± 0.5) and benign diseases (61.5 ± 1.0) with P < 0.0005, (ii) sensitivities and specificities for discriminating primary malignancies from healthy controls were 70 and 74% respectively, and from benign diseases 65 and 76%, (iii) highest sensitivities and specificities were observed with post-therapeutic cases suffering from tumour recurrence (88% and 75%) or patients with distant metastases (87% and 86%), (iv) apparently tumour-free post-therapeutic patients showed a mean %IgG1 not different from the normal value. The decrease in %IgG1 accompanied by increased %IgG2 is an efficient, sensitive and early marker of SCC-HN, which appears particularly useful for the post-therapeutic monitoring. © 1999 Cancer Research Campaig

Resection of thoracic malignancies infiltrating cardiac structures with use of cardiopulmonary bypass

Background: Only few reports exist on malignant thoracic neoplasms that require cardiopulmonary bypass during resection. We aimed to investigate the early and late clinical outcome of these patients. Methods: Patients with thoracic malignancies that underwent surgery between 2002 and 2014 were analyzed. All patients had cardiopulomonary bypass support during resection. Clinical and perioperative data was retrospectively reviewed for outcome and overall survival. Results: Fifteen patients (12 female, mean age of 55 ± 15 years, range 24 to 80 years) were identified. Eleven (8 female) were diagnosed with primary thoracic malignomas and four with metastases. Three patients died early postoperatively. Patients diagnosed with sarcoma had a significantly worse outcome than non-sarcoma patients (83.3 ± 15.2 % after 1 year, 31.3 ± 24.5 % after 5 years vs. 83.3 ± 15.2 % after 1 year, 0 ± 0 % after 5 years, p = 0.005). Conclusions: Malignancies with extension into cardiac structures or infiltration of great vessels can be resected with cardiopulmonary bypass support and tolerable risk. Carefully selected patients can undergo advanced operative procedures with an acceptable 1-year-survival, but only few patients achieved good long-term outcome

Development of a web-based insulin decision aid for the elderly: usability barriers and guidelines

In recent years, researchers have attempted to shift patient decision aids (PDAs) from paper-based to web-based to increase its accessibility. Insulin decision aids help diabetes patients, most of whom are elderly to make an informed decision to start insulin. However, the lack of usability guidelines applicable for such target group causes developers to struggle to answer the challenging question ‘How can such web service be made usable, and, ultimately, acceptable and accessible for elderly patients?’. Hence, the purpose of this study is to identify the common usability requirements that may facilitate good practices to empower elderly diabetes patients in utilizing a web-based insulin decision aid for their benefit. We set out an approach to use prototyping and retrospective think-aloud techniques to explore web usability barriers that elderly patients may encounter when using an insulin decision aid web site and use the feedback for improving the prototype. Usability requirements were captured iteratively through scoping, brainstorming, prototype, testing and evaluating. The study suggests that the insights from experts and users are equally important to assure the validity of the identified usability guidelines; they reflect the accessibility needs of the aging community while complementing the key requirements of an insulin decision aid. The study contributes to recommend web usability guidelines backed by a series of expert and user evaluations which could be a proactive resource to improve usability, acceptability and accessibility of online insulin decision aids for elderly with diabetes