Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder

<p>Abstract</p> <p>Background</p> <p>Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients.</p> <p>Methods</p> <p>We screened the 15q11-13 and 22q11.2 chromosomal regions for genomic imbalances in 236 patients with OCD using multiplex ligation-dependent probe amplification (MLPA).</p> <p>Results</p> <p>No deletions or duplications involving 15q11-13 or 22q11.2 were identified in our patients.</p> <p>Conclusions</p> <p>Our results suggest that deletions/duplications of chromosomes 15q11-13 and 22q11.2 are rare in OCD. Despite the negative findings in these two regions, the search for copy number variants in OCD using genome-wide array-based methods is a highly promising approach to identify genes of etiologic importance in the development of OCD.</p

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly

<p>Abstract</p> <p>Background</p> <p>Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the <it>NSD1 </it>gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that <it>NSD1 </it>could be involved in other cases of autism and macrocephaly.</p> <p>Methods</p> <p>We screened the <it>NSD1 </it>gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of <it>NSD1 </it>was carried out using multiplex ligation-dependent probe amplification.</p> <p>Results</p> <p>We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed.</p> <p>Conclusion</p> <p>Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for <it>NSD1 </it>mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.</p

Patients&rsquo; and physicians&rsquo; preferences for type 2 diabetes mellitus treatments in Spain and Portugal: a&nbsp;discrete choice experiment

Carlos Morillas,1 Rosa Feliciano,2 Pablo Fern&aacute;ndez Catalina,3 Carla Ponte,4 Marta Botella,5 Jo&atilde;o Rodrigues,6 Enric Esmatjes,7 Javier Lafita,8 Luis Liz&aacute;n,9 Ignacio Llorente,10 Crist&oacute;bal Morales,11 Jorge Navarro-P&eacute;rez,12 Domingo Orozco-Beltran,13 Silvia Paz,9 Antonio Ramirez de Arellano,14 Cristina Cardoso,15 Maribel Tribaldos Causadias9 1Hospital Universitario Dr Peset, Valencia, Spain; 2USF S&atilde;o Domingos, Santar&eacute;m, Portugal; 3Hospital Montecelo de Pontevedra, Galicia, Spain; 4USF Porta do Sol, Matosinhos, Portugal; 5Hospital Universitario Principe de Asturias, Madrid, Spain; 6USF Serra da Lous&atilde;, Lous&atilde;, Portugal; 7Hospital Clinic, Barcelona, Spain; 8Hospital de Navarra, Navarra, Spain; 9Outcomes&rsquo;10, Universidad Jaume I, Castell&oacute;n, Spain; 10Hospital Universitario Nuestra Se&ntilde;ora de la Candelaria, Canarias, Spain; 11Hospital Universitario Virgen de la Macarena, Sevilla, Spain; 12INCLIVA, CIBERESP, Universidad de Valencia, Valencia, Spain; 13Sociedad Espa&ntilde;ola de Medicina Familiar y Comunitaria, Valencia, Spain; 14Novo Nordisk EU-HEOR Europe, Madrid, Spain; 15Novo Nordisk, Lisbon, Portugal Objective: To assess Spanish and Portuguese patients&rsquo; and physicians&rsquo; preferences regarding type 2 diabetes mellitus (T2DM) treatments and the monthly willingness to pay (WTP) to gain benefits or avoid side effects.Methods: An observational, multicenter, exploratory study focused on routine clinical practice in Spain and Portugal. Physicians were recruited from multiple hospitals and outpatient clinics, while patients were recruited from eleven centers operating in the public health care system in different autonomous communities in Spain and Portugal. Preferences were measured via a discrete choice experiment by rating multiple T2DM medication attributes. Data were analyzed using the conditional logit model.Results: Three-hundred and thirty (n=330) patients (49.7% female; mean age 62.4 [SD: 10.3] years, mean T2DM duration 13.9 [8.2] years, mean body mass index 32.5 [6.8] kg/m2, 41.8% received oral&nbsp;+ injected medication, 40.3% received oral, and 17.6% injected treatments) and 221 physicians from Spain and Portugal (62% female; mean age 41.9 [SD: 10.5] years, 33.5% endocrinologists, 66.5% primary-care doctors) participated. Patients valued avoiding a gain in bodyweight of 3 kg/6 months (WTP: &euro;68.14 [95% confidence interval: 54.55&ndash;85.08]) the most, followed by avoiding one hypoglycemic event/month (WTP: &euro;54.80 [23.29&ndash;82.26]). Physicians valued avoiding one hypoglycemia/week (WTP: &euro;287.18 [95% confidence interval: 160.31&ndash;1,387.21]) the most, followed by avoiding a 3 kg/6 months gain in bodyweight and decreasing cardiovascular risk (WTP: &euro;166.87 [88.63&ndash;843.09] and &euro;154.30 [98.13&ndash;434.19], respectively). Physicians and patients were willing to pay &euro;125.92 (73.30&ndash;622.75) and &euro;24.28 (18.41&ndash;30.31), respectively, to avoid a 1% increase in glycated hemoglobin, and &euro;143.30 (73.39&ndash;543.62) and &euro;42.74 (23.89&ndash;61.77) to avoid nausea.Conclusion: Both patients and physicians in Spain and Portugal are willing to pay for the health benefits associated with improved diabetes treatment, the most important being to avoid hypoglycemia and gaining weight. Decreased cardiovascular risk and weight reduction became the third most valued attributes for physicians and patients, respectively. Keywords: diabetes, discrete choice model, preferences, willingness to pay, hypoglycemia, weight, cardiovascular risk, HbA1

Role of Bacterial Surface Structures on the Interaction of <i>Klebsiella pneumoniae</i> with Phagocytes

Phagocytosis is a key process of the immune system. The human pathogen Klebsiella pneumoniae is a well known example of a pathogen highly resistant to phagocytosis. A wealth of evidence demonstrates that the capsule polysaccharide (CPS) plays a crucial role in resistance to phagocytosis. The amoeba Dictyostelium discoideum shares with mammalian macrophages the ability to phagocytose and kill bacteria. The fact that K. pneumoniae is ubiquitous in nature and, therefore, should avoid predation by amoebae, poses the question whether K. pneumoniae employs similar means to counteract amoebae and mammalian phagocytes. Here we developed an assay to evaluate K. pneumoniae-D. discoideum interaction. The richness of the growth medium affected the threshold at which the cps mutant was permissive for Dictyostelium and only at lower nutrient concentrations the cps mutant was susceptible to predation by amoebae. Given the critical role of bacterial surface elements on host-pathogen interactions, we explored the possible contribution of the lipopolysaccharide (LPS) and outer membrane proteins (OMPs) to combat phagoyctosis by D. discoideum. We uncover that, in addition to the CPS, the LPS O-polysaccharide and the first core sugar participate in Klebsiella resistance to predation by D. discoideum. K. pneumoniae LPS lipid A decorations are also necessary to avoid predation by amoebae although PagP-dependent palmitoylation plays a more important role than the lipid A modification with aminoarabinose. Mutants lacking OMPs OmpA or OmpK36 were also permissive for D. discoideium growth. Except the LPS O-polysaccharide mutants, all mutants were more susceptible to phagocytosis by mouse alveolar macrophages. Finally, we found a correlation between virulence, using the pneumonia mouse model, and resistance to phagocytosis. Altogether, this work reveals novel K. pneumoniae determinants involved in resistance to phagocytosis and supports the notion that Dictyostelium amoebae might be useful as host model to measure K. pneumoniae virulence and not only phagocytosis

12 Grand Challenges in Single-Cell Data Science

Laehnemann D, Köster J, Szczurek E, et al. 12 Grand Challenges in Single-Cell Data Science. PeerJ. 2019.The recent upswing of microfluidics and combinatorial indexing strategies, further enhanced by very low sequencing costs, have turned single cell sequencing into an empowering technology; analyzing thousands—or even millions—of cells per experimental run is becoming a routine assignment in laboratories worldwide. As a consequence, we are witnessing a data revolution in single cell biology. Although some issues are similar in spirit to those experienced in bulk sequencing, many of the emerging data science problems are unique to single cell analysis; together, they give rise to the new realm of 'Single-Cell Data Science'. Here, we outline twelve challenges that will be central in bringing this new field forward. For each challenge, the current state of the art in terms of prior work is reviewed, and open problems are formulated, with an emphasis on the research goals that motivate them. This compendium is meant to serve as a guideline for established researchers, newcomers and students alike, highlighting interesting and rewarding problems in 'Single-Cell Data Science' for the coming years.</jats:p