Endemic Acinetobacter baumannii in a New York Hospital

Acinetobacter baumannii is an increasingly multidrug-resistant (MDR) cause of hospital-acquired infections, often associated with limited therapeutic options. We investigated A. baumannii isolates at a New York hospital to characterize genetic relatedness.Thirty A. baumannii isolates from geographically-dispersed nursing units within the hospital were studied. Isolate relatedness was assessed by repetitive sequence polymerase chain reaction (rep-PCR). The presence and characteristics of integrons were assessed by PCR. Metabolomic profiles of a subset of a prevalent strain isolates and sporadic isolates were characterized and compared.We detected a hospital-wide group of closely related carbapenem resistant MDR A. baumannii isolates. Compared with sporadic isolates, the prevalent strain isolates were more likely to be MDR (p = 0.001). Isolates from the prevalent strain carried a novel Class I integron sequence. Metabolomic profiles of selected prevalent strain isolates and sporadic isolates were similar.The A. baumannii population at our hospital represents a prevalent strain of related MDR isolates that contain a novel integron cassette. Prevalent strain and sporadic isolates did not segregate by metabolomic profiles. Further study of environmental, host, and bacterial factors associated with the persistence of prevalent endemic A. baumannii strains is needed to develop effective prevention strategies

Association of ultra-rare coding variants with genetic generalized epilepsy: A case\u2013control whole exome sequencing study

Objective: We aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE. Methods: We performed a case\u2013control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18 834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19 genes encoding \u3b3-aminobutyric acid type A [GABAA] receptors, 113 genes representing the GABAergic pathway). Results: GABRG2 was associated with GGE (p = 1.8  7 10 125), approaching study-wide significance in familial GGE (p = 3.0  7 10 126), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.9\u20137.8, false discovery rate [FDR]-adjusted p =.0024), whereas their association with sporadic GGE had marginally lower odds (OR = 3.1, 95% CI = 1.3\u20136.7, FDR-adjusted p =.022). URVs in GABAergic pathway genes were associated with familial GGE (OR = 1.8, 95% CI = 1.3\u20132.5, FDR-adjusted p =.0024) but not with sporadic GGE (OR = 1.3, 95% CI =.9\u20131.9, FDR-adjusted p =.19). Significance: URVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

Pain acceptance and personal control in pain relief in two maternity care models: a cross-national comparison of Belgium and the Netherlands

<p>Abstract</p> <p>Background</p> <p>A cross-national comparison of Belgian and Dutch childbearing women allows us to gain insight into the relative importance of pain acceptance and personal control in pain relief in 2 maternity care models. Although Belgium and the Netherlands are neighbouring countries sharing the same language, political system and geography, they are characterised by a different organisation of health care, particularly in maternity care. In Belgium the medical risks of childbirth are emphasised but neutralised by a strong belief in the merits of the medical model. Labour pain is perceived as a needless inconvenience easily resolved by means of pain medication. In the Netherlands the midwifery model of care defines childbirth as a normal physiological process and family event. Labour pain is perceived as an ally in the birth process.</p> <p>Methods</p> <p>Women were invited to participate in the study by independent midwives and obstetricians during antenatal visits in 2004-2005. Two questionnaires were filled out by 611 women, one at 30 weeks of pregnancy and one within the first 2 weeks after childbirth either at home or in a hospital. However, only women having a hospital birth without obstetric intervention (N = 327) were included in this analysis. A logistic regression analysis has been performed.</p> <p>Results</p> <p>Labour pain acceptance and personal control in pain relief render pain medication use during labour less likely, especially if they occur together. Apart from this general result, we also find large country differences. Dutch women with a normal hospital birth are six times less likely to use pain medication during labour, compared to their Belgian counterparts. This country difference cannot be explained by labour pain acceptance, since - in contrast to our working hypothesis - Dutch and Belgian women giving birth in a hospital setting are characterised by a similar labour pain acceptance. Our findings suggest that personal control in pain relief can partially explain the country differences in coping with labour pain. For Dutch women we find that the use of pain medication is lowest if women experience control over the reception of pain medication and have a positive attitude towards labour pain. In Belgium however, not personal control over the use of pain relief predicts the use of pain medication, but negative attitudes towards labour.</p> <p>Conclusions</p> <p>Apart from individual level determinants, such as length of labour or pain acceptance, our findings suggest that the maternity care context is of major importance in the study of the management of labour pain. The pain medication use in Belgian hospital maternity care is high and is very sensitive to negative attitudes towards labour pain. In the Netherlands, on the contrary, pain medication use is already low. This can partially be explained by a low degree of personal control in pain relief, especially when co-occurring with positive pain attitudes.</p

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox–Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient–parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population

MAPK-Activated Protein Kinase 2 Is Required for Mouse Meiotic Spindle Assembly and Kinetochore-Microtubule Attachment

MAPK-activated protein kinase 2 (MK2), a direct substrate of p38 MAPK, plays key roles in multiple physiological functions in mitosis. Here, we show for the first time the unique distribution pattern of MK2 in meiosis. Phospho-MK2 was localized on bipolar spindle minus ends and along the interstitial axes of homologous chromosomes extending over centromere regions and arm regions at metaphase of first meiosis (MI stage) in mouse oocytes. At metaphase of second meiosis (MII stage), p-MK2 was localized on the bipolar spindle minus ends and at the inner centromere region of sister chromatids as dots. Knockdown or inhibition of MK2 resulted in spindle defects. Spindles were surrounded by irregular nondisjunction chromosomes, which were arranged in an amphitelic or syntelic/monotelic manner, or chromosomes detached from the spindles. Kinetochore–microtubule attachments were impaired in MK2-deficient oocytes because spindle microtubules became unstable in response to cold treatment. In addition, homologous chromosome segregation and meiosis progression were inhibited in these oocytes. Our data suggest that MK2 may be essential for functional meiotic bipolar spindle formation, chromosome segregation and proper kinetochore–microtubule attachments

Tubulin isoform composition tunes microtubule dynamics

Microtubules polymerize and depolymerize stochastically, a behavior essential for cell division, motility and differentiation. While many studies advanced our understanding of how microtubule-associated proteins tune microtubule dynamics in trans, we have yet to understand how tubulin genetic diversity regulates microtubule functions. The majority of in vitro dynamics studies are performed with tubulin purified from brain tissue. This preparation is not representative of tubulin found in many cell types. Here we report the 4.2Å cryo-EM structure and in vitro dynamics parameters of α1B/βI+βIVb microtubules assembled from tubulin purified from a human embryonic kidney cell line with isoform composition characteristic of fibroblasts and many immortalized cell lines. We find that these microtubules grow faster and transition to depolymerization less frequently compared to brain microtubules. Cryo-EM reveals that the dynamic ends of α1B/βI+βIVb microtubules are less tapered and that these tubulin heterodimers display lower curvatures. Interestingly, analysis of EB1 distributions at dynamic ends suggests no differences in GTP cap sizes. Lastly, we show that the addition of recombinant α1A/βIII tubulin, a neuronal isotype overexpressed in many tumors, proportionally tunes the dynamics of α1B/βI+βIVb microtubules. Our study is an important step towards understanding how tubulin isoform composition tunes microtubule dynamics

Redes epóxi/amina alifáticas com perspectivas para aplicações cardiovasculares. Propriedades biológicas in vitro

Este trabalho descreve as propriedades biológicas in vitro de três redes epoxídicas à base do éter diglicidílico do glicerol (DGEG) curadas com poli(oxipropileno) diamina (D230), isoforona diamina (IPD) e 4,4'-diamino-3,3'-dimetil-diciclohexilmetano (3DCM). As interações biológicas entre os polímeros e o sangue foram estudadas por ensaios biológicos in vitro. Estudos de adsorção de proteínas, adesão de plaquetas, atividade do lactato desidrogenase (LDH) e propriedades de tromboresistência estão apresentados. Os ensaios de adsorção de proteínas na superfície dos polímeros mostrou que as redes epoxídicas adsorvem mais albumina do que fibrinogênio. Os resultados relacionados à adesão de plaquetas, atividade do lactato hidrogenase e propriedades de tromboresistência indicaram que as redes DGEG/IPD e DGEG/3DCM exibem comportamento hemocompatível. Desta maneira, assumimos que estes polímeros epoxídicos são materiais compatíveis com o sangue