Pulmonary apoptotic and oxidative damaging effects of Triclosan alone or in combination with Fluoride in Sprague Dawley rats.
This study aimed to assess the potential apoptotic and oxidative damaging impacts of Triclosan (TCS) and Sodium Fluoride (NaF) administered separately or in combination, in rats for thirty days. For this purpose, forty immature female Sprague-Dawley rats were equally allocated into five groups. TCS group administered 185mg TCS/kg Bw dissolved in distilled water (DW), while its control group received only DW. NaF group was given 50mg/kg NaF in corn oil BW and its respective control had corn oil alone. The co-treated group was administered TCS and NaF. The oxidative stress biomarkers were evaluated in lung tissue homogenate and apoptotic proteins (BcL-2 and Caspase-3) expression were quantified in lung tissues. The results of TCS or NaF treated groups revealed a prominent depletion of super oxide dismutase (SOD), Catalase (CAT) and Glutathione (GSH) in lung tissue homogenate. On contrary, a marked increase in the tissue levels of Malondialdehyde (MDA) and lactate dehydrogenase (LDH) enzymatic assay levels. The co-exposed group evoked less severity in the oxidative stress biomarkers concentration than individually exposed groups. The apoptotic genes protein expression was significantly higher in TCS or NaF treated rats when compared to the control with intense to moderate immunolabeling of the bronchiolar lining epithelium and surrounding mononuclear inflammatory cells. On the contrary, no significant differences were detected in the expression of the investigated apoptotic biomarkers between the control and the combined exposed group. We concluded that the exposure to either TCS or NaF resulted in significant perturbations in lung tissue after short term oral administration at variable instances but the co-exposure resulted in less severe toxicological consequences.


Phylogeny by a polyphasic approach of the order Caulobacterales, proposal of Caulobacter mirabilis sp. nov., Phenylobacterium haematophilum sp. nov. and Phenylobacterium conjunctum sp. nov., and emendation of the genus Phenylobacterium.
Three strains of Gram-negative, rod-shaped, non-spore-forming bacteria were isolated from fresh water and human blood. As determined by analyses of 16S rRNA gene sequences, the prosthecate strain FWC 38T was affiliated to the alphaproteobacterial genus Caulobacter, with Caulobacter henricii (96.8 %) and Caulobacter fusiformis (96.8 %) as its closest relatives. The non-prosthecate strain LMG 11050T and the prosthecate strain FWC 21T both belonged to the genus Phenylobacterium with Phenylobacterium koreense (96.9 %) and Phenylobacterium immobile (96.3 %) as the closest relatives. This affiliation was supported by chemotaxonomic data (polar lipids and cellular fatty acids). Physiological and biochemical tests allowed genotypic and phenotypic differentiation of the novel strains from all hitherto recognized species of the genera Caulobacter and Phenylobacterium. The strains therefore represent novel species, for which the names Caulobacter mirabilis sp. nov. (type strain FWC 38T=LMG 24261T=CCUG 55073T), Phenylobacterium conjunctum (type strain FWC 21T=LMG 24262T=CCUG 55074T), the first described prosthecate Phenylobacterium species, and Phenylobacterium haematophilum sp. nov. (type strain LMG 11050T=CCUG 26751T) are proposed. Marker nucleotides within the 16S rRNA genes were determined for the genera Asticcacaulis, Brevundimonas, Caulobacter and Phenylobacterium and the description of the genus Phenylobacterium is emended.


[Uncertainty, agency relationships and miscommunication].
This author finds it curious that for a long time, whenever I have tried to explain what an agent relationship is, everyone understands the concept with ease. "It's common sense," they usually respond. Nonetheless, it is curious to note to what point agent relationships are ignored by those persons having managerial responsibilities in the majority of businesses in any industrial or service field. We use this statement by the author to introduce the fundamental purpose of this article. Probably, once having read it, any professional would have a clearer idea about such important concepts (in order to realize how costs function and how they are generated inside a health organization) as uncertainty, agent relationships or asymmetrical information. Using a British Airways flight as a comparison, it will be difficult not to understand these terms in their practical applications to the health field.


The Unprepared Caregiver.
Years of studying health care financing and delivery does not prepare you for the actuality of dealing with a serious health event. The practical challenges of our extremely fragmented and complex health care system make it difficult to navigate this world-even when someone is there to help the patient. And, being a caregiver is a far cry from being a health care analyst. There are many lessons to be learned for improving our system: the need for skilled co-ordination support, the need for simplifying and re-orienting the various silos of postacute care, the importance of generating ways to support caregivers, and not least, promoting simple lessons in civility for providers of services.


Out-of-pocket health spending among Medicare beneficiaries: Which chronic diseases are most costly?
Little is known about the impact of different types of chronic diseases on older adults' out-of-pocket healthcare spending and whether certain diseases trigger higher spending needs than others. We use data from the 2014 Health and Retirement Study representing a weighted population of 35,939,270 Medicare beneficiaries aged 65+. Generalized linear models are applied to estimate the effect of different chronic diseases on total out-of-pocket expenditure, adjusted for demographics, socio-economic status, physical health, and other factors. We also decompose total spending by expenditure categories (inpatient, non-inpatient, and prescription drug spending). Sensitivity analysis is performed using a younger sample of older adults aged 50-64. Cardiovascular disease, diabetes, hypertension and cancer, induce significantly higher adjusted out-of-pocket spending among older adults than other conditions. These results hold regardless how the spending differences are assessed (absolute or percentage terms). For Medicare beneficiaries, cardiovascular disease is associated with an excess out-of-pocket spending of $317 per year, followed by diabetes ($237), hypertension ($150), and cancer ($144). Prescription drug spending is singularly the most important driver of additional expenses for cardiovascular disease, diabetes and hypertension, while non-inpatient services spending accounts for the bulk of increased spending among those with cancer. Our finding that major noncommunicable diseases impact individuals' out-of-pocket medical spending differentially-and that service drivers of increased spending may be heterogeneous across disease types-suggest that health professionals and policymakers should recognize that certain chronic diseases exert greater financial toll on the elderly. Interventions to promote more cost efficient healthcare services and consumer choices can help older adults better cope with these expensive long-lasting conditions and reduce the overall burden of noncommunicable diseases.


Leifsonia bigeumensis sp. nov., isolated from soil on Bigeum Island, Korea.
A Gram-positive, motile, mesophilic bacterium that formed yellowish-white, circular, convex, glistening colonies, strain MSL-27T, was isolated from a soil sample from Bigeum Island, Korea, and its taxonomic position was investigated by a polyphasic approach. Cells of strain MSL-27T are non-spore-forming, irregular rods, usually fragmenting into shorter rods or coccoid elements. The growth temperature and pH ranges are 20-37 degrees C and pH 6.0-12.0, with optimum growth at 28 degrees C and pH 8.0. MK-11 is the major menaquinone and dl-2,4-diaminobutyric acid is found in the cell-wall peptidoglycan. The major fatty acids are i-C16:0 (39 %), ai-C15:0 (36 %), ai-C17:0 (18 %) and i-C15:0 (2 %). The G+C content is 69.0 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain MSL-27T should be placed in the genus Leifsonia. Levels of similarity between the 16S rRNA gene sequence of strain MSL-27T and those of the type strains of the other members of the genus Leifsonia ranged from 95.8 to 96.7 %. Based on phenotypic characteristics, biochemical properties and chemotaxonomic features, strain MSL-27T (=KCTC 19268T =DSM 19322T) represents the type strain of a novel species of Leifsonia, for which the name Leifsonia bigeumensis sp. nov. is proposed.


Extracellular YB-1 blockade in experimental nephritis upregulates Notch-3 receptor expression and signaling.
Notch receptors are involved in kidney development and pathogenesis of inflammatory glomerular diseases. Given the secretion of Y-box (YB) protein-1 following cytokine stimulation and subsequent extracellular association with membrane receptor Notch-3 in vitro, we elucidated functional effects of YB-1 targeting on the Notch-3 signaling pathway. Rat mesangial cells were challenged with a monoclonal anti-YB-1 antibody (YB-1-mAb) and analyzed for YB-1 and Notch-3 expression. Notch-3 expression in mice with a targeted disruption of one YB-1 allele (YB-1(+/d)) was compared with their wild-type littermates. Furthermore, YB-1-mAb was applied during mesangioproliferative anti-Thy1.1 nephritis, and glomerular Notch-3, Notch target genes and YB-1 expression were analyzed by immunohistochemistry, quantitative real-time PCR and immunoblotting. Upon challenge with YB-1-mAb, rat mesangial cells showed an increased expression of YB-1 and Notch-3 protein. Concordantly, we found a significant upregulation of Notch-3 expression in renal cells of YB-1(+/d) mice. YB-1-mAb treatment in anti-Thy1.1 nephritis resulted in enhanced mesangial Notch-3 expression and differential Notch target gene activation (HES2/Hey-2). Notably, YB-1 mRNA content did not differ between groups; however, glomerular YB-1 protein was significantly increased, suggesting a posttranslational mechanism. Extracellular targeting of YB-1 potently induces glomerular Notch-3 receptor expression, Notch signaling and YB-1 stabilization, most likely via an autoregulatory feedback mechanism.


A comparative study on feature selection and classification methods using gene expression profiles and proteomic patterns.
Feature selection plays an important role in classification. We present a comparative study on six feature selection heuristics by applying them to two sets of data. The first set of data are gene expression profiles from Acute Lymphoblastic Leukemia (ALL) patients. The second set of data are proteomic patterns from ovarian cancer patients. Based on features chosen by these methods, error rates of several classification algorithms were obtained for analysis. Our results demonstrate the importance of feature selection in accurately classifying new samples.


The association between migration and smoke-free families: how do migrants from different world regions compare?
Studies on adolescent secondhand smoke exposure within the family often dichotomously operationalize migration background without paying attention to social and cultural diversity within migrant populations. As a result, little is known about variation within migrant groups in smoke-free family environments (SFFEs). This study analyses the association between SFFEs and parental migration from different world regions. Data from 14- to 16-year-old adolescents (N = 17 144) on SFFEs and parental migration were obtained from cross-sectional repeated SILNE-R surveys. A multivariable multinomial regression was applied, presenting relative risks (RRs) with 95% confidence intervals (CIs) for maternal or paternal tobacco smoking and home smoking bans. Variation in migration background was measured according to parental sex and place of birth. Approximately 18% of adolescents are exposed to maternal smoking, and 25% are exposed to paternal smoking. Almost half of the respondents do not live in SFFEs but are subject to permissive (5%) or partial (39%) smoking bans at home. We found that adolescents of Eastern European descent are at a higher risk of being exposed to both paternal and maternal smoking. A sex difference in parental smoking was found among Arabic/Islamic migrants, where mothers are less likely to be smokers. Maternal and paternal African origins are associated with prohibitive smoking bans at home. Eastern European mothers show higher odds of permissiveness and freely allowing smoking at home. Notable within-differences according to parental sex and place of birth were found for SFFEs and should be taken into account when implementing equity-sensitive tobacco prevention programs.


The relationship between peer conflict resolution knowledge and peer victimization in school-age children across the language continuum.
Peer victimization, or bullying, has been identified as a significant child health priority and children with language impairment (LI) are among those who are vulnerable. Given the mandate of educators to provide support for all students who are bullied regardless of language status, research is needed that integrates the study of risk factors for peer victimization among children who are developing typically and children who have LI. Accordingly, this preliminary study explored the degree to which one potential risk factor, peer conflict resolution knowledge, was related to peer victimization in children across the language continuum, and considered whether or not individual differences in language ability influenced that relationship. Participants included 17 girls and 15 boys aged 9-12 years with a wide range of language abilities, six meeting criteria for LI. Participants completed a hypothetical peer conflict resolution task and a measure of peer victimization. Correlational analyses revealed very different patterns of relationships for boys and girls. Whereas boys' reports of peer victimization were meaningfully related to how they responded to hypothetical peer conflicts, girls' reports were most strongly associated with language ability. These preliminary findings suggest that it is important to consider gender when conceptualizing how factors such as peer conflict resolution knowledge might influence children's risk of being bullied. Readers will be able to: (1) provide a definition of peer victimization and give examples of different forms of peer victimization; (2) recognize that inadequate peer conflict resolution knowledge may be a risk factor for peer victimization; (3) describe the relationships between peer conflict resolution knowledge, language ability, and peer victimization in this study, and explain how these relationships differed for boys and girls; and (4) identify at least three opportunities for future research that would help to clarify risk factors for peer victimization in boys and girls.


Development of an operational substrate for ZapA, a metalloprotease secreted by the bacterium Proteus mirabilis.
The protease ZapA, secreted by Proteus mirabilis, has been considered to be a virulence factor of this opportunistic bacterium. The control of its expression requires the use of an appropriate methodology, which until now has not been developed. The present study focused on the replacement of azocasein with fluorogenic substrates, and on the definition of enzyme specificity. Eight fluorogenic substrates were tested, and the peptide Abz-Ala-Phe-Arg-Ser-Ala-Ala-Gln-EDDnp was found to be the most convenient for use as an operational substrate for ZapA. A single peptide bond (Arg-Ser) was cleaved with a Km of 4.6 microM, a k cat of 1.73 s-1, and a catalytic efficiency of 376 (mM s)-1. Another good substrate for ZapA was peptide 6 (Abz-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-Gln-EDDnp) which was cleaved at a single bond (Phe-Ser) with a Km of 13.6 microM, a k cat of 3.96 s-1 and a catalytic efficiency of 291 (mM s)-1. The properties of the amino acids flanking the scissile bonds were also evaluated, and no clear requirement for the amino acid residue at P1 was found, although the enzyme seems to have a preference for a hydrophobic residue at P2.


Upstream regulatory regions required to stabilize binding to the TATA sequence in an adenovirus early promoter.
Of the five early adenovirus promoters, the early region 3 (E3) promoter is one of the most strongly induced by the E1A protein. To identify cellular proteins involved in both the basal and E1A-induced transcriptional regulation of the E3 promoter, DNase I footprinting using partially purified Hela cell extracts was performed. Four regions of the E3 promoter serve as binding domains for cellular proteins. These regions are found between -156 to -179 (site IV), -83 to -103 (site III), -47 to -67 (site II), and -16 to -37 (site I), relative to the start of transcription. Examination of the DNA sequences in each binding domain suggests that site III likely serves as a binding site for activator protein 1 (AP-1), site II for the cyclic AMP regulatory element binding protein (CREB), and site I for a TATA binding factor. The factors binding to either site II or III were sufficient to stabilize binding to the TATA sequence (site I). Mutagenesis studies indicated that both sites II and III, in addition to site I, are needed for complete basal and E1A-induced transcription. These results suggest that multiple cellular factors are involved in both the basal and E1A-induced transcriptional regulation of the E3 promoter, and that either of two upstream regions are capable of stabilizing factor binding to the TATA sequence.


Vochysia rufa Stem Bark Extract Protects Endothelial Cells against High Glucose Damage.
Background: Increased oxidative stress by persistent hyperglycemia is a widely accepted factor in vascular damage responsible for type 2 diabetes complications. The plant Vochysia rufa (Vr) has been used in folk medicine in Brazil for the treatment of diabetes. Thus; the protective effect of a Vr stem bark extract against a challenge by a high glucose concentration on EA.hy926 (EA) endothelial cells is evaluated. Methods: Vegetal material is extracted with distilled water by maceration and evaporated until dryness under vacuum. Then; it is isolated by capillary electrophoresis-tandem mass spectrometry. Cell viability is evaluated on EA cells treated with 0.5-100 µg/mL of the Vr extract for 24 h. The extract is diluted at concentrations of 5, 10 and 25 µg/mL and maintained for 24 h along with 30 mM of glucose to evaluate its protective effect on reduced glutathione (GSH); glutathione peroxidase (GPx) and reductase (GR) and protein carbonyl groups. Results:V. rufa stem bark is composed mainly of sugars; such as inositol; galactose; glucose; mannose; sacarose; arabinose and ribose. Treatment with Vr up to 100 µg/mL for 24 h did not affect cell viability. Treatment of EA cells with 30 mM of glucose for 24 h significantly increased the cell damage. EA cells treated with 30 mM of glucose showed a decrease of GSH concentration and increased Radical Oxygen Species (ROS) and activity of antioxidant enzymes and protein carbonyl levels; compared to control. Co-treatment of EA with 30 mM glucose plus 1-10 μg/mL Vr significantly reduced cell damage while 5-25 μg/mL Vr evoked a significant protection against the glucose insult; recovering ROS; GSH; antioxidant enzymes and carbonyls to baseline levels. Conclusion:V. rufa extract protects endothelial cells against oxidative damage by modulating ROS; GSH concentration; antioxidant enzyme activity and protein carbonyl levels.


Generation of single or double parallel breathing soliton pairs, bound breathing solitons, moving breathing solitons, and diverse composite breathing solitons in optical fibers.
Interactions of two truncated Airy pulses with arbitrarily initial relative phases, initial pulse intervals, and different soliton order are numerically investigated in optical fibers. When the soliton order is 1, depending on different initial pulse intervals, the initial in-phase Airy pulses may evolve to single breathing solitons, bound breathing solitons, and single parallel breathing solitons. While the out-of-phase Airy pulses may evolve to parallel or repulsive soliton pairs with breathing or weak breathing, after radiating away some dispersive waves. When the initial relative phases take arbitrary values except 0 and π, moving single breathing solitons and repulsive or parallel soliton pairs will form. Moreover, the whole temporal profiles may become asymmetric. The repulsive soliton pairs consist of two moving breathing solitons with different intensities, moving velocities, and breathing periods. The most interestingly is that, when the soliton order is larger than one, we observe double bound breathing solitons, double parallel breathing soliton pairs, and diverse composite breathing solitons which consist of two or more different breathing solitons. one can effectively manipulate and select the soliton expected and its evolution dynamics by adjusting the soliton order, initial pulse intervals, and initial relative phases.


Experimental study on the treatment of AMD by SRB immobilized particles containing "active iron" system.
The inhibition and toxicity of high acidity and heavy metals on sulfate-reducing bacteria in acid mine drainage (AMD) were targeted. Highly active SRB immobilized particles were prepared using SRB, warm sticker wastes (iron powders), corncobs, and Maifan stones as the main matrix materials, employing microbial immobilization technology. The repair ability and reusability of highly active immobilized particles for AMD were explored. The results indicate that the adaptability of immobilized particles to AMD varied under different initial conditions, such as pH, Mn2+, and SO42-. The adsorption process of immobilized particles on Mn2+ follows the quasi-second-order kinetic model, suggesting that it involves both physical and chemical adsorption. The maximum adsorption capacity of immobilized particles for Mn2+ is 3.878 mg/g at a concentration of 2.0 mg/L and pH 6. On the other hand, the reduction process of immobilized particles on SO42- adheres to the first-order reaction kinetics, indicating that the reduction of SO42- is primarily driven by the dissimilation reduction of SRB. The maximum reduction rate of SO42- by immobilized particles is 94.23% at a concentration of 800 mg/L and pH 6. A layered structure with a flocculent appearance formed on the surface of the immobilized particles. The structure's characteristics were found to be consistent with sulfate green rust (FeII4FeIII2(OH)12SO4·8H2O). The chemisorption, ion exchange, dissimilation reduction, and surface complexation occurring between the matrices in the immobilized particles can enhance the alkalinity of AMD and decrease the concentration of heavy metals and sulfates. These results are expected to offer novel insights and materials for the treatment of AMD using biological immobilization technology, as well as improve our understanding of the mechanisms behind biological and abiotic enhanced synergistic decontamination.


Red blood cell storage and in-hospital mortality: a secondary analysis of the INFORM randomised controlled trial.
No randomised trials have addressed whether exposure to red blood cells (RBCs) stored longer than 35 days is associated with harm in patients. We aimed to assess the risk of in-hospital mortality associated with transfusing blood stored longer than 35 days. We did a secondary analysis of the INforming Fresh versus Old Red cell Management (INFORM) trial, a pragmatic, multicentre, randomised controlled trial of patients (≥18 years) admitted to one of six hospitals in Australia, Canada, Israel, and the USA and expected to need RBC transfusions. Patients were randomly assigned (2:1) to receive blood in inventory stored for the longest time (standard care) or the shortest time, using a random allocation schedule and stratified by centre and patient ABO blood group. The primary objective of the INFORM trial was to assess all-cause in-hospital mortality in patients with blood group A and O who were transfused. For our exploratory secondary analysis, we classified individuals into one of three mutually exclusive exposure categories on the basis of the maximum storage duration of any blood unit patients had received on each day in hospital: exclusively exposed to RBCs stored no longer than 7 days, exposed to at least one unit of RBCs stored 8-35 days, and exposed to least one unit of RBCs stored longer than 35 days. Our primary objective was to determine the effect on risk of in-hospital death of time-dependent exposure to RBCs stored longer than 35 days compared with exclusive exposure to RBCs stored no longer than 7 days, both in patients of blood groups A and O and all patients. The INFORM trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN08118744. Between April 2, 2012, and Oct 21, 2015, 31 497 patients were recruited, and 24 736 patients were eligible for inclusion in this analysis. We excluded nine patients for whom information about the storage duration of transfused blood was missing and one patient whose sex was unknown. 4480 (18%) patients were exposed to RBCs with longest storage, 1392 (6%) patients were exposed exclusively to RBCs with shortest storage, and 18 854 (76%) patients were exposed to RBCs stored 8-35 days. Median follow-up was 11 days (IQR 6-20). Exposure to RBCs stored longer than 35 days was not associated with increased risk of in-hospital death compared with exclusive exposure to the freshest RBC units after adjusting for demographic variables, diagnosis category, and blood product use history (in patients with blood group A or O: hazard ratio 0·94, 95% CI 0·73-1·20, p=0·60; in all patients: 0·91, 0·72-1·14, p=0·40). The risk of in-hospital death also did not differ between patients exposed to blood stored 8-35 days and patients exposed to blood stored 7 days or less (in patients with blood group A or O: 0·92, 0·74-1·15, p=0·48; in all patients: 0·90, 0·73-1·10, p=0·29). These data provide evidence that transfusion of blood stored for longer than 35 days has no effect on in-hospital mortality, which suggests that current approaches to blood storage and inventory management are reasonable. Canadian Institutes for Health Research, Canadian Blood Services, and Health Canada.


Methods for quantifying T cell receptor binding affinities and thermodynamics.
αβ T cell receptors (TCRs) recognize peptide antigens bound and presented by class I or class II major histocompatibility complex (MHC) proteins. Recognition of a peptide/MHC complex is required for initiation and propagation of a cellular immune response, as well as the development and maintenance of the T cell repertoire. Here, we discuss methods to quantify the affinities and thermodynamics of interactions between soluble ectodomains of TCRs and their peptide/MHC ligands, focusing on titration calorimetry, surface plasmon resonance, and fluorescence anisotropy. As TCRs typically bind ligand with weak-to-moderate affinities, we focus the discussion on means to enhance the accuracy and precision of low-affinity measurements. In addition to further elucidating the biology of the T cell mediated immune response, more reliable low-affinity measurements will aid with more probing studies with mutants or altered peptides that can help illuminate the physical underpinnings of how TCRs achieve their remarkable recognition properties.


G-quadruplex in the TMV Genome Regulates Viral Proliferation and Acts as Antiviral Target of Photodynamic Therapy.
Plant viruses seriously disrupt crop growth and development, and classic protein-targeted antiviral drugs could not provide complete protection against them. It is urgent to develop antiviral compounds with novel targets. Photodynamic therapy shows potential in controlling agricultural pests, but nonselective damage from reactive oxygen species (ROS) unexpectedly affects healthy tissues. A G-quadruplex (G4)-forming sequence in the tobacco mosaic virus (TMV) genome was identified to interfere the RNA replication in vitro, and affect the proliferation of TMV in tobacco. N-methyl mesoporphyrin IX stabilizing the G4 structure exhibited inhibition against viral proliferation, which was comparable to the inhibition effect of ribavirin. This indicated that G4 could work as an antiviral target. The large conjugate planes shared by G4 ligands and photosensitizers (PSs) remind us that the PSs could work as antiviral agents by targeting G4 in the genome of TMV. Chlorin e6 (Ce6) was identified to stabilize the G4 structure in the dark and selectively cleave the G4 sequence by producing ROS upon LED-light irradiation, leading to 92.2% inhibition against TMV in vivo, which is higher than that of commercial ningnanmycin. The inhibition of Ce6 was lost against the mutant variants lacking the G4-forming sequence. These findings indicated that the G-quadruplex in the TMV genome worked as an important structural element regulating viral proliferation, and could act as the antiviral target of photodynamic therapy.


Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial.
Randomized trials have indicated that well-managed anticoagulation with warfarin could prevent more than half of the strokes related to atrial fibrillation. However, many patients with atrial fibrillation who are eligible for this therapy either do not receive it or are not maintained within an optimal prothrombin time-international normalized ratio (INR) range. We sought to determine whether an anticoagulation service within a managed care organization would be a feasible alternative for providing anticoagulation care. We performed a multi-site randomized trial in six large managed care organizations in the United States. Subjects were aged 65 years or older and had nonvalvular atrial fibrillation. At each site, physician practices were divided into two geographically defined practice clusters; each site was randomly assigned to have one intervention and one control cluster. The intervention cluster received an anticoagulation service that satisfied specifications for high-quality anticoagulation care and was coordinated through the managed care organization. Control clusters continued with their usual provider-based care. We measured the proportion of time that warfarin-treated patients in each of the clusters (intervention and control) were in the target range for the INR at baseline, and again during a follow-up period. Five of the six selected sites succeeded at developing an anticoagulation service. Patients in the intervention and control clusters had similar demographic characteristics, contraindications to warfarin, and risk factors for stroke. Among patients (n = 144 in the intervention clusters; n = 118 in the control clusters) for whom data were available during the baseline and follow-up periods, the changes in percentages of time in the target range were similar for those in the intervention clusters (baseline: 47.7%; follow-up: 55.6%) and in the control clusters (baseline: 49.1%; follow-up: 52.3%; intervention effect: 5%; 95% confidence interval: -5% to 14%; P = 0.32). Although it was feasible in a managed care organization to implement anticoagulation services that were tailored to local circumstances, provision of this service did not improve anticoagulation care compared with usual care. The effect of the anticoagulation service was limited by the utilization of the service, the degree to which the referring physician supports strict adherence to recommended target ranges for the INR, and the ability of the anticoagulation service to identify and to respond to out-of-range values promptly.


Uncommon Manifestations of Intervertebral Disk Pathologic Conditions.
Beyond the familiar disk herniations with typical clinical features, intervertebral disk pathologic conditions can have a wide spectrum of imaging and clinical manifestations. The goal of this review is to illustrate and discuss unusual manifestations of intervertebral disk pathologic conditions that radiologists may encounter, including disk herniations in unusual locations, those with atypical imaging features, and those with uncommon pathophysiologic findings. Examples of atypical disk herniations presented include dorsal epidural, intradural, symptomatic thoracic (including giant calcified), extreme lateral (retroperitoneal), fluorine 18 fluorodeoxyglucose-avid, acute intravertebral (Schmorl node), and massive lumbar disk herniations. Examples of atypical pathophysiologic conditions covered are discal cysts, fibrocartilaginous emboli to the spinal cord, tiny calcified disks or disk-level spiculated osteophytes causing spinal cerebrospinal fluid (CSF) leak and intracranial hypotension, and pediatric acute calcific discitis. This broad gamut of disease includes a variety of sizes of disk pathologic conditions, from the tiny (eg, the minuscule calcified disks causing high-flow CSF leaks) to the extremely large (eg, giant calcified thoracic intradural disk herniations causing myelopathy). A spectrum of clinical acuity is represented, from hyperacute fibrocartilaginous emboli causing spinal cord infarct, to acute Schmorl nodes, to chronic intradural herniations. The entities included are characterized by a range of clinical courses, from the typically devastating cord infarct caused by fibrocartilaginous emboli, to the usually spontaneously resolving pediatric acute calcific discitis. Several conditions have important differential diagnostic considerations, and others have relatively diagnostic imaging findings. The pathophysiologic findings are well understood for some of these entities and poorly defined for others. Radiologists' knowledge of this broad scope of unusual disk disease is critical for accurate radiologic diagnoses. Online supplemental material is available for this article. (©)RSNA, 2016.


Risk factors for renal function decline in adults with normal kidney function: a 7-year cohort study.
We aimed to examine the risk factors for renal function decline (RFD) in a community-based cohort of a rural Chinese population with normal kidney function (estimated glomerular filtration rate, eGFR ≥60 mL/min/1.73 m(2)), both for the population as a whole and stratified by sex. 2518 participants were included in the current analysis. RFD was defined as follows: a drop in the eGFR category accompanied by a 25% or greater drop in eGFR from baseline; or a sustained decline in eGFR of more than 5 mL/min/1.73 m(2)/year. The incidence rate of RFD was 8.7% (women 7.4% and men 9.8%). In the multivariable logistic regression model, the ORs (95% CI) of developing RFD was 1.60 (1.01 to 2.54) for men versus women, and 1.51 (1.09 to 2.08) for participants with obesity or abdominal obesity versus none (1.35 (0.85 to 2.14) for men, and 1.65 (1.04 to 2.64) for women). However, prehypertension (OR=1.64; 95% CI 1.02 to 2.63) or hypertension (2.05; 1.21 to 3.47), higher mean blood pressure (≥90 vs <80 mm Hg, 2.63; 1.11 to 6.20), higher pulse pressure (≥50 vs <40 mm Hg, 2.00; 1.26 to 3.18), lower high-density lipoprotein cholesterol (<0.9 vs ≥0.9 mmol/L, 2.65; 1.08 to 6.50) and low physical activity levels (vs high, 3.11; 1.59 to 6.10) were major risk factors for RFD in men. Current smoking (3.22; 1.22 to 2.64) and worse self-reported health (vs better, 2.57; 1.20 to 5.50) were major risk factors for RFD in women. Our findings suggested that sex-specific risk factors should be considered in prevention of RFD in the Chinese rural population with normal kidney function.


Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors.
The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead. A similarity-based screening of small molecule libraries, followed by docking calculations and experimental studies, allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting its binding to both heparan sulfate proteoglycans and FGFR-1. The compounds inhibit FGF2 activity in in vitro and ex vivo models of angiogenesis, with improved potency over SM27. Comparative analysis of the selected hits, complemented by NMR and biochemical analysis of 4 newly synthesized functionalized phenylamino-substituted naphthalenes, allowed identifying the minimal stereochemical requirements to improve the design of naphthalene sulfonates as FGF2 inhibitors.


Postoperative outcomes of arthroscopic subacromial decompression for rotator cuff tear with shoulder stiffness.
Some patients with rotator cuff tear have shoulder stiffness preoperatively. Concomitant preoperative shoulder stiffness may affect postoperative outcomes of arthroscopic subacromial decompression (ASD) for rotator cuff tear. The purpose of this study was to compare postoperative outcomes for ASD between rotator cuff tear patients with and without preoperative shoulder stiffness and to analyze the serial change in functional scores, range of motion (ROM), and pain intensity of the 2 groups after operation. 60 shoulders of 58 patients who underwent ASD for rotator cuff tear were studied. Arthroscopic release was performed for the stiffness group. The results were assessed before surgery and 1, 3, 6, 12 and 24 months after surgery, and the results in the stiffness group and non-stiffness group were compared. No differences in serial changes for postoperative outcomes of ASD were seen in terms of the Japanese Orthopaedic Association shoulder scoring system (JOA scores) and the visual analog scale (VAS scores) for pain at night and pain during motion between the stiffness group and non-stiffness group. However, compared to the non-stiffness group, forward flexion and abduction angles were significantly smaller for the stiffness group at 1 and 3 months after surgery. External rotation and internal rotation angles were significantly smaller at 1 month after surgery for the stiffness group than for the non-stiffness group. Preoperative shoulder stiffness does not affect improvement of postoperative JOA scores and VAS scores of ASD. When measured 6 months after surgery, ROM in the stiffness group and the non-stiffness group was similar.


Interaction of the E1A oncoprotein with Yak1p, a novel regulator of yeast pseudohyphal differentiation, and related mammalian kinases.
The C-terminal portion of adenovirus E1A suppresses ras-induced metastasis and tumorigenicity in mammalian cells; however, little is known about the mechanisms by which this occurs. In the simple eukaryote Saccharomyces cerevisiae, Ras2p, the homolog of mammalian h-ras, regulates mitogen-activated protein kinase (MAPK) and cyclic AMP-dependent protein kinase A (cAMP/PKA) signaling pathways to control differentiation from the yeast form to the pseudohyphal form. When expressed in yeast, the C-terminal region of E1A induced pseudohyphal differentiation, and this was independent of both the MAPK and cAMP/PKA signaling pathways. Using the yeast two-hybrid system, we identified an interaction between the C-terminal region of E1A and Yak1p, a yeast dual-specificity serine/threonine protein kinase that functions as a negative regulator of growth. E1A also physically interacts with Dyrk1A and Dyrk1B, two mammalian homologs of Yak1p, and stimulates their kinase activity in vitro. We further demonstrate that Yak1p is required in yeast to mediate pseudohyphal differentiation induced by Ras2p-regulated signaling pathways. However, pseudohyphal differentiation induced by the C-terminal region of E1A is largely independent of Yak1p. These data suggest that mammalian Yak1p-related kinases may be targeted by the E1A oncogene to modulate cell growth.


First-time treatment with steroids in bronchial asthma: comparison of the effects of inhaled beclomethasone and of oral prednisone on airway function, bronchial reactivity and hypothalamic-pituitary-adrenal axis.
In a double-blind cross-over study of 12 asthmatic patients the effects of 1,000 micrograms.day-1 beclomethasone dipropionate (BDP) on airway function, bronchial reactivity and hypothalamic-pituitary-adrenal (HPA) axis have been compared to those of 15 mg.day-1 oral prednisone (PRD). None of the patients had ever received corticosteroids before. Fourteen days treatment with either of both steroids improved airway function, both subjectively and objectively. Both steroids slightly reduced the responsiveness to histamine. PRD suppressed the corticotrophin-releasing factor (CRF) stimulated cortisol release more than BDP did, whereas there was no significant change in adrenocorticotrophic hormone (ACTH) release. The results indicate that short-term treatment with 1,000 micrograms.day-1 BDP reduces bronchial hyperreactivity (BHR) in asthmatic patients, whilst having subtle effects on HPA axis.


Associations and propositions: the case for a dual-process account of learning in humans.
We review evidence that supports the conclusion that people can and do learn in two distinct ways - one associative, the other propositional. No one disputes that we solve problems by testing hypotheses and inducing underlying rules, so the issue amounts to deciding whether there is evidence that we (and other animals) also rely on a simpler, associative system, that detects the frequency of occurrence of different events in our environment and the contingencies between them. There is neuroscientific evidence that associative learning occurs in at least some animals (e.g., Aplysia californica), so it must be the case that associative learning has evolved. Since both associative and propositional theories can in principle account for many instances of successful learning, the problem is then to show that there are at least some cases where the two classes of theory predict different outcomes. We offer a demonstration of cue competition effects in humans under incidental conditions as evidence against the argument that all such effects are based on cognitive inference. The latter supposition would imply that if the necessary information is unavailable to inference then no cue competition should occur. We then discuss the case of unblocking by reinforcer omission, where associative theory predicts an irrational solution to the problem, and consider the phenomenon of the Perruchet effect, in which conscious expectancy and conditioned response dissociate. Further discussion makes use of evidence that people will sometimes provide one solution to a problem when it is presented to them in summary form, and another when they are presented in rapid succession with trial-by trial information. We also demonstrate that people trained on a discrimination may show a peak shift (predicted by associative theory), but given the time and opportunity to detect the relationships between S+ and S-, show rule-based behavior instead. Finally, we conclude by presenting evidence that research on individual differences suggests that variation in intelligence and explicit problem solving ability are quite unrelated to variation in implicit (associative) learning, and briefly consider the computational implications of our argument, by asking how both associative and propositional processes can be accommodated within a single framework for cognition.


Evaluation of clinical trials by Ethics Committees in Germany--results and a comparison of two surveys performed among members of the German Association of Research-Based Pharmaceutical Companies (vfa).
The objective of this project was to evaluate the quality and quantity of initial applications for a clinical trial according to § 7 of the German Good Clinical Practice (GCP) ordinance (German: GCP-Verordnung, GCP-V), the quality of evaluations of those applications by Ethics Committees (ECs)/Investigational Review Boards (IRBs) in Germany as well as the pattern of EC objections in their reasoned opinions (vote). In order to identify a change over time, the results of the present survey were also compared with a survey performed in 2008. Based on reasoned opinions issued by the respective EC in charge of the coordinating principle investigator (coordinating EC) in 2011, a written survey among members of the German Association of Research-Based Pharmaceutical Companies (vfa) was conducted in 2012. The answers to the questionnaire were analyzed descriptively. Since the data set collected in 2011 was structurally identical with the data set gained in 2007 both surveys were compared. Of the 24 companies represented on the vfa Clinical Research/Quality Assurance Subcommittee, 75% (18) took part in the survey. Survey evaluation was based on a total of 251 applications of these 18 companies submitted to 43 ECs. These account for about 21% of 1,214 applications for authorization of commercial and non-commercial phase I-IV clinical trials submitted to the regulatory authorities (BfArM and PEI) in 2011. In comparison to 2007, a lower amount of applications (n=251 in 2011 vs. n=288 in 2007) was submitted to a slightly higher number of ECs (43 in 2011 vs. 40 in 2007). The amount of objections increased by 21% from 1,299 (2007) to 1,574 (2011) resulting in an average of 4.5 (2007) vs. 6.3 (2011) objections per application. Overall, the analysis of both formal and content related objections revealed almost the same pattern as in the previous survey. In total, the most frequent objections applied to the patient information and consent form followed in descending order by trial protocol content, miscellaneous, other application documents pursuant to § 7 (2) and (3) GCP-V, formal deficiencies pursuant to § 8 (1) GCP-V, and investigator and site qualifications. A trend towards a slightly increased rate of objections concerning patient information and consent form (+4%) and a minimal decrease in objections concerning investigator and site qualifications (-2%) was observed. As in 2007, about 1 in 6 applications was still incomplete with formal objections. Whilst the proportion of study applications with objections related to the patient information and consent form (+7.2%), the trial protocol content (+11.6%), and documents according to § 7 (2) and (3) GCP-V (+11.8%) increased in 2011 compared to 2007, the amount of study applications with objections related to the investigator and site qualifications decreased by 6.3%. The majority of findings with respect to quantity, quality and main focus of objections reported in the first survey in 2008 were also found in 2012, indicating a shared understanding of applicable measures and criteria by sponsors and ECs on how to ensure patient rights and well-being, data integrity, and high quality documentation in clinical trials.


TLR adaptor MyD88 is essential for pathogen control during oral toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite.
TLR adaptor MyD88 activation is important in host resistance to Toxoplasma gondii during i.p. infection, but the function of this signaling pathway during oral infection, in which mucosal immunity assumes a predominant role, has not been examined. In this study, we show that MyD88(-/-) mice fail to control the parasite and succumb within 2 wk of oral infection. Early during infection, T cell IFN-gamma production, recruitment of neutrophils and induction of p47 GTPase IGTP (Irgm3) in the intestinal mucosa were dependent upon functional MyD88. Unexpectedly, these responses were MyD88-independent later during acute infection. In particular, CD4(+) T cell IFN-gamma reached normal levels independently of MyD88, despite continued absence of IL-12 in these animals. The i.p. vaccination of MyD88(-/-) mice with an avirulent T. gondii uracil auxotroph elicited robust IFN-gamma responses and protective immunity to challenge with a high virulence T. gondii strain. Our results demonstrate that MyD88 is required to control Toxoplasma infection, but that the parasite can trigger adaptive immunity without the need for this TLR adaptor molecule.


Asymmetric sampling in human auditory cortex reveals spectral processing hierarchy.
Speech perception is mediated by both left and right auditory cortices but with differential sensitivity to specific acoustic information contained in the speech signal. A detailed description of this functional asymmetry is missing, and the underlying models are widely debated. We analyzed cortical responses from 96 epilepsy patients with electrode implantation in left or right primary, secondary, and/or association auditory cortex (AAC). We presented short acoustic transients to noninvasively estimate the dynamical properties of multiple functional regions along the auditory cortical hierarchy. We show remarkably similar bimodal spectral response profiles in left and right primary and secondary regions, with evoked activity composed of dynamics in the theta (around 4-8 Hz) and beta-gamma (around 15-40 Hz) ranges. Beyond these first cortical levels of auditory processing, a hemispheric asymmetry emerged, with delta and beta band (3/15 Hz) responsivity prevailing in the right hemisphere and theta and gamma band (6/40 Hz) activity prevailing in the left. This asymmetry is also present during syllables presentation, but the evoked responses in AAC are more heterogeneous, with the co-occurrence of alpha (around 10 Hz) and gamma (>25 Hz) activity bilaterally. These intracranial data provide a more fine-grained and nuanced characterization of cortical auditory processing in the 2 hemispheres, shedding light on the neural dynamics that potentially shape auditory and speech processing at different levels of the cortical hierarchy.


Direct venous reconstruction.
Direct reconstruction of veins is being applied to patients with chronic venous stasis. Crosspubic bypass and saphenopopliteal bypass have proven satisfactory, and valve reconstruction by valvuloplasty, segment transfer and autotransplantation is being explored. These procedures add to the surgeon's armamentarium in dealing with chronic venous stasis. The results of their application are summarized.


Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1-infected long-term survivors.
HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.


Emotional Prototypicality Ratings for 636 Chinese Words: A Database of Chinese Words with Affective Information.
Exemplars of concepts vary in their degree of prototypicality. This is also true for emotion concepts. This study presents prototypicality ratings for a large set of Chinese words. The database contains 636 potential Chinese emotion words (i.e., words that directly express particular emotions, like " happy" and " sad"), from different grammatical categories. Native Chinese speakers rated the words in terms of emotional prototypicality. The database also contains values for valence, arousal, and emotionality. The analyses of the ratings revealed that 502 out of 636 words had a high prototypicality value (value equal to or above three on a 1-to-5 scale), the most prototypical words being negative and high-arousal words. The analyses also indicated that the emotional prototypicality of a word was positively related to both arousal and emotionality, and negatively related to valence. Among these variables, arousal was the most important contributor. Similar results have been found in studies conducted in other languages. This will be a useful resource for researchers interested in studying emotion words in the Chinese language and for those interested in cross-linguistic comparisons.


Vaginoplasty for disorders of sex development.
One of the most common problem found in patients with Disorders of Sexual Developments is the absence or extreme hypoplasia of the vagina. The type of patients presenting this anomaly may belong to completely different groups: (1) Patients with a urogenital sinus with urethra and vagina fusing together to form a common channel. (2) Patients with absent Müllerian structures and different degrees of external virilization. (3) Complex malformations. Treatment options: treatment of these patients is under discussion and may consist, basically, in non-operative dilation methods or surgical creation of a neovagina. Consensus is far to be reached among the various surgical subspecialties regarding the optimal method of vaginal replacement. Adequate number of long-term follow up patients are still non-available so that most conclusions are based on small number series. The authors describe the different treatment options in detail.


Ultrafast polarization response of an optically trapped single ferroelectric nanowire.
One-dimensional potassium niobate nanowires are of interest as building blocks in integrated piezoelectric devices, exhibiting large nonlinear optical and piezoelectric responses. Here we present femtosecond measurements of light-induced polarization dynamics within an optically trapped ferroelectric nanowire, using the second-order nonlinear susceptibility as a real-time structural probe. Large amplitude, reversible modulations of the nonlinear susceptibility are observed within single nanowires at megahertz repetition rates, developing on few-picosecond time-scales, associated with anomalous coupling of light into the nanowire.


Improved Survival of Stage I Non-Small Cell Lung Cancer: A VA Central Cancer Registry Analysis.
The combined impact of advances in diagnosis and treatment of stage I NSCLC has not been assessed comprehensively. To define the survival impact of modern staging and treatment techniques for clinical stage I NSCLC, the Veterans Administration Central Cancer Registry, a database of U.S. veterans in whom the disease was diagnosed in the Veteran's Health Administration, was queried. From this database, patients who had stage I NSCLC diagnosed from 2001 to 2010 and were treated with either surgery or radiation were identified. Overall survival (OS) and lung cancer-specific survival were determined. Propensity score matching and Cox multivariate analysis were used to adjust for baseline patient characteristics. A total of 11,997 patients were identified. The 4-year OS rate increased from 38.9% to 53.2% from 2001 to 2010 for all patients. Positron emission tomography and endobronchial ultrasound did not improve OS. Survival of radiated patients improved from 12.7% to 28.5%. The introduction of stereotactic body radiation therapy (SBRT) significantly improved OS (hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.54-0.68) and lung cancer-specific survival (HR = 0.39, 95% CI: 0.32-0.46) compared with conventionally fractionated radiation. The 4-year OS rate also improved after surgery (from 51.5% to 66.5%). This increase was associated with use of adjuvant chemotherapy, increased use of video-assisted thoracoscopic surgical procedures, and decreased pneumonectomy rates, with similar survival between open and video-assisted thoracoscopic surgical procedures. OS after lobectomy was superior to that after sublobar resection (HR = 0.82, 95% CI: 0.75-0.89). In the era of available SBRT (2008-2010), 4-year OS was not significantly different after sublobar resection or lobectomy for medically unfit patients (Charlson comorbidity index = 2) (55.4% and 58.1%, respectively; p = 0.69) but was significantly worse for fit patients (Charlson comorbidity index = 0-1) undergoing sublobar resection (55.5% and 68.0%, respectively; p < 0.001). OS (HR = 0.36, 95% CI: 0.35-0.38) and lung cancer-specific survival (HR = 0.31, 95% CI: 0.29-0.33) were improved after surgery as compared with after radiation, with the improvement maintained on matched comparison of lobectomy and SBRT. OS increased in veterans with a diagnosis of stage I NSCLC from 2001 to 2010; the increase was coincident with improved radiation and surgical techniques.


Auditory processing in individuals with mild aphasia: a study of resource allocation.
This study examined the effects of lesion location (frontal vs. posterior) and nature of distraction (nonverbal vs. verbal secondary, competing task) on mildly aphasic individuals' performances of listening tasks that required semantic judgments and lexical decisions under isolation, focused attention, and divided attention conditions. Despite comparable accuracy among all groups during isolation conditions, the aphasic groups responded less accurately and more slowly than the normal control group during focused and divided attention conditions. Generally, the two aphasic groups performed similarly, quantitatively and qualitatively. Demographic characteristics such as time post stroke did not correlate with performance decrements. Independent of group, all individuals showed greater disruption of auditory processing skills when the secondary task was verbal rather than nonverbal. Within a limited-capacity model of attention, the results suggest that aphasic individuals display impairments of attention and resource allocation and that these impairments negatively interact with their auditory processing abilities.


Gestation and COVID-19: clinical and microbiological observational study (Gesta-COVID19).
The Coronavirus Disease 2019 (COVID-19) is a novel disease which has been having a worldwide affect since December 2019. Evidence regarding the effects of SARS-CoV-2 during pregnancy is conflicting. The presence of SARS-CoV-2 has been demonstrated in biological samples during pregnancy (placenta, umbilical cord or amniotic fluid); however, maternal and fetal effects of the virus are not well known. Descriptive, multicentre, longitudinal, observational study in eight tertiary care hospitals throughout Spain, that are referral centres for pregnant women with COVID-19. All pregnant women with positive SARS-CoV-2 real-time reverse transcriptase polymerase chain reaction during their pregnancy or 14 days preconception and newborns born to mothers infected with SARS-CoV-2 will be included. They will continue to be followed up until 4 weeks after delivery. The aim of the study is to investigate both the effect of COVID-19 on the pregnancy, and the effect of the pregnancy status with the evolution of the SARS-CoV-2 disease. Other samples (faeces, urine, serum, amniotic fluid, cord and peripheral blood, placenta and breastmilk) will be collected in order to analyse whether or not there is a risk of vertical transmission and to describe the behaviour of the virus in other fluids. Neonates will be followed until 6 months after delivery to establish the rate of neonatal transmission. We aim to include 150 pregnant women and their babies. Ethics approval will be obtained from all the participating centres. There is little information known about COVID-19 and its unknown effects on pregnancy. This study will collect a large number of samples in pregnant women which will allow us to demonstrate the behaviour of the virus in pregnancy and postpartum in a representative cohort of the Spanish population.


Identification and validation of the optimal reference genes for standardizing the gene expression profiling diagnostic panel of Ph-like B-lineage acute lymphoblastic leukemia.
Gene expression profiling is the criterion standard for recognizing Ph-like ALL signatures among B-ALLs. The prerequisite of GEP is the accurate normalization of target genes with stable expression of housekeeping genes in a quantitative PCR. HKGs exhibit differential expression in the different experimental conditions and affect the target genes' expression, leading to imprecise qPCR results. The selection of stable HKGs is crucial in GEP experiments, especially in identifying high-risk Ph-like ALL cases. We have evaluated the expression stability of nine HKGs (GAPDH, ACTB, GUSB, RNA18S, EEF2, PGK1, B2M, TBP and ABL1) in identified Ph-like ALLs and Ph-negative (n = 23 each) using six algorithms, 4 traditional softwares; geNorm, BestKeeper, NormFinder, Delta Cq value method, and two algorithms, RefFinderTM and ComprFinder. Further, we have validated the expression of 8 overexpressed normalized genes in Ph-like ALL cases (JCHAIN, CA6, MUC4, SPATS2L, BMPR1B, CRLF2, ADGRF1 and NRXN3). GeNorm, BestKeeper, NormFinder, Delta Cq value method, RefFinderTM and ComprFinder algorithm analysis revealed that EEF2, GAPDH, and PGK1 form the best representative HKGs in Ph-like ALL cases, while RNA18s, ß-actin, and ABL1 in Ph-negative ALLs. Lastly, we performed a correlation analysis and found that the combination of EEF2, GAPDH, and PGK1 represents the best combination with a very high correlation in Ph-like ALL cases. This is the first report that shows EEF2, GAPDH, and PGK1 are the best HKG genes and can be used in the diagnostic panel of Ph-like ALL cases using qPCR at baseline diagnosis.


Data sharing, management, use, and reuse: Practices and perceptions of scientists worldwide.
With data becoming a centerpiece of modern scientific discovery, data sharing by scientists is now a crucial element of scientific progress. This article aims to provide an in-depth examination of the practices and perceptions of data management, including data storage, data sharing, and data use and reuse by scientists around the world. The Usability and Assessment Working Group of DataONE, an NSF-funded environmental cyberinfrastructure project, distributed a survey to a multinational and multidisciplinary sample of scientific researchers in a two-waves approach in 2017-2018. We focused our analysis on examining the differences across age groups, sub-disciplines of science, and sectors of employment. Most respondents displayed what we describe as high and mediocre risk data practices by storing their data on their personal computer, departmental servers or USB drives. Respondents appeared to be satisfied with short-term storage solutions; however, only half of them are satisfied with available mechanisms for storing data beyond the life of the process. Data sharing and data reuse were viewed positively: over 85% of respondents admitted they would be willing to share their data with others and said they would use data collected by others if it could be easily accessed. A vast majority of respondents felt that the lack of access to data generated by other researchers or institutions was a major impediment to progress in science at large, yet only about a half thought that it restricted their own ability to answer scientific questions. Although attitudes towards data sharing and data use and reuse are mostly positive, practice does not always support data storage, sharing, and future reuse. Assistance through data managers or data librarians, readily available data repositories for both long-term and short-term storage, and educational programs for both awareness and to help engender good data practices are clearly needed.


Accelerating image registration of MRI by GPU-based parallel computation.
Automatic image registration for MRI applications generally requires many iteration loops and is, therefore, a time-consuming task. This drawback prolongs data analysis and delays the workflow of clinical routines. Recent advances in the massively parallel computation of graphic processing units (GPUs) may be a solution to this problem. This study proposes a method to accelerate registration calculations, especially for the popular statistical parametric mapping (SPM) system. This study reimplemented the image registration of SPM system to achieve an approximately 14-fold increase in speed in registering single-modality intrasubject data sets. The proposed program is fully compatible with SPM, allowing the user to simply replace the original image registration library of SPM to gain the benefit of the computation power provided by commodity graphic processors. In conclusion, the GPU computation method is a practical way to accelerate automatic image registration. This technology promises a broader scope of application in the field of image registration.


Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation.
Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin β-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin β-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients' magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype-phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable.


Detection of malignant cells in cerebrospinal fluid using fluorescence in situ hybridization.
Cytologic examination of cerebrospinal fluid (CSF) is the diagnostic gold standard for leptomeningeal metastasis (LMM). However, this technique is only moderately sensitive when routine staining procedures are applied. The use of fluorescence in situ hybridization (FISH) to identify malignant cells may have an additional value in diagnosing LMM, since numerical chromosomal aberrations (NCA) can be detected at the single cell level. We tested the feasibility of FISH to detect tumor cells in CSF by analyzing 22 samples with proven LMM with a probe for chromosome 1 (1q12) to detect NCA in the cells. A control group consisted of samples from 10 patients with inflammatory neurologic disease. In 7 LMM samples no cells or only lysed cells were found, due to time delay before fixation. Of the other 15 LMM samples analyzed, 13 showed NCA (87%), while no NCA were found in the control group. Our results indicate that FISH may be a useful additional diagnostic tool to the cytodiagnosis of CSF in cases of LMM. We expect that FISH can become an additional marker for malignancy at the single cell level in patients with LMM, which may also be of use to determine the effect of therapy for LMM.


Emergency and successful management for a case of inferior vena cava perforation caused by cannulation of venovenous extracorporeal membrane oxygenation: A case report.
Vascular complications associated with extracorporeal membrane oxygenation (ECMO) increase the in-hospital mortality. Perforation of the inferior vena cava (IVC) during venovenous extracorporeal membrane oxygenation (V-V ECMO) cannulation and subsequent emergency management prior to vascular surgery has rarely been reported. A 72-year-old female was diagnosed with IVC perforation caused by venovenous extracorporeal membrane oxygenation cannulation. Abdominal computed tomography venography with 3D reconstruction confirmed that the cannula tip had perforated the abdominal cavity from the conjunction of the iliac vein and IVC. As a result, the patient was diagnosed with inferior vena cava perforation. Attempts to reposition the dislocated cannula using digital subtraction angiography were unsuccessful. However, we found that ECMO could maintain a stable blood flow; therefore, we decided to keep ECMO running, and to minimize blood loss from the puncture site, we ensured adequate blood transfusion while operating V-V ECMO. Subsequently, emergency laparotomy was performed to fix the vascular lesion, and we established a new V-V ECMO circuit through cannulation of the bilateral internal jugular veins. In the case of confirmed V-V ECMO-related vascular perforation of the IVC, it is crucial to continue ECMO device operation to maintain negative pressure in the IVC and position the dislocated catheter to block the perforation site, effectively controlling bleeding. Therefore, emergency laparotomy should be promptly performed for vascular repair. Fortunately, the patient recovered successfully and was subsequently discharged. This case highlights several important lessons: When advancing a cannula, in this case, it is essential to first identify the guidewire placement to ensure proper guidance; In the event of a confirmed V-V ECMO-related vascular perforation of the IVC, maintaining negative pressure in the IVC through continued ECMO device operation and positioning the dislocated catheter to block the perforation site are crucial steps to control bleeding prior to emergency open vascular repair; After undergoing vascular repair, if ECMO support is still necessary, it is advisable to opt for a catheterization strategy that avoids previously repaired blood vessels.


Exercise hormone irisin is a critical regulator of cognitive function.
Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.


Retrotransposition of gene transcripts leads to structural variation in mammalian genomes.
Retroposed processed gene transcripts are an important source of material for new gene formation on evolutionary timescales. Most prior work on gene retrocopy discovery compared copies in reference genome assemblies to their source genes. Here, we explore gene retrocopy insertion polymorphisms (GRIPs) that are present in the germlines of individual humans, mice, and chimpanzees, and we identify novel gene retrocopy insertions in cancerous somatic tissues that are absent from patient-matched non-cancer genomes. Through analysis of whole-genome sequence data, we found evidence for 48 GRIPs in the genomes of one or more humans sequenced as part of the 1,000 Genomes Project and The Cancer Genome Atlas, but which were not in the human reference assembly. Similarly, we found evidence for 755 GRIPs at distinct locations in one or more of 17 inbred mouse strains but which were not in the mouse reference assembly, and 19 GRIPs across a cohort of 10 chimpanzee genomes, which were not in the chimpanzee reference genome assembly. Many of these insertions are new members of existing gene families whose source genes are highly and widely expressed, and the majority have detectable hallmarks of processed gene retrocopy formation. We estimate the rate of novel gene retrocopy insertions in humans and chimps at roughly one new gene retrocopy insertion for every 6,000 individuals. We find that gene retrocopy polymorphisms are a widespread phenomenon, present a multi-species analysis of these events, and provide a method for their ascertainment.


Prostate Specific Antigen Nadir of 0.1 or Less Is a Predictor of Treatment Success in Men Undergoing Salvage Whole Prostate Gland Cryoablation.
To assess factors that affect prostate biopsy results following salvage whole gland cryoablation. One hundred seventy-four patients underwent prostate biopsy following salvage whole gland cryoablation of the prostate in the Cryo-OnLine Database registry. Wilcoxon rank-sum and χ2 tests and logistic regression analysis were used to assess predictors of positive biopsy. Prostate specific antigen (PSA) nadir was divided into a statistical tertile for comparisons between different nadir PSA cut points. Fifty-two of 174 (29.9%) of this highly select group of men who underwent biopsy had a posttreatment biopsy demonstrating malignant cancer. Men who had positive biopsy following salvage therapy had significantly higher median nadir PSA, shorter median time to prostate biopsy, and shorter median time to biochemical failure. Compared to the lowest tertile (PSA nadir defined as ≤0.1 ng/mL), PSA in the second tertile (0.11-0.8 ng/mL) and third tertile (>0.8 ng/mL) demonstrated increased odds ratio (OR) for positive biopsy, 4.34 (95% confidence interval [CI] 1.66, 11.4, p = 0.003) and 2.81 (95% CI 1.14, 7.00, p = 0.02), respectively, in adjusted models. In addition, men with a presalvage PSA >20 (OR 7.65; 95% CI 2.03, 28.9; p = 0.003) and Gleason score ≥8 (OR 2.26; 95% CI 0.93, 5.47; p = 0.07) had a higher OR of positive biopsy. Nadir PSA of 0.1 ng/mL or less following salvage cryotherapy is predictive of treatment success. Routine biopsy should be reserved for men with nadir PSA >0.1 ng/mL and patients with high risk features of prostate cancer before salvage cryoablation.


Be a Lighthouse for Your Medical Students: How to Help Them Navigate During Changing Times to a Successful Match.
The transition between medical school and residency is a complex, multifaceted process that is commonly a time of stress and uncertainty for medical students. Occupying most of a student's final year of medical school, the residency application includes a primary Electronic Residency Application Service application, a variable number of program-specific secondary applications, and interviews. The application process culminates with The Match. Orthopaedic surgery is among the more competitive specialties; thus, it is critical that all involved parties understand the complexity of the process and the numerous variables that play into such a critical decision point in the career trajectory of a future physician. It is important to provide a mentor with an overview of the residency application process, specifically with respect to orthopaedic surgery, so that they may be best prepared to guide their medical student mentee through the process and help them find success.


Activity of cefiderocol against high-risk clones of multidrug-resistant Enterobacterales, Acinetobacter baumannii, Pseudomonas aeruginosa and Stenotrophomonas maltophilia.
Cefiderocol is a novel siderophore cephalosporin, developed for activity against MDR Gram-negative bacilli (MDR-GNB). To assess the in vitro antibacterial activity of cefiderocol against a collection of MDR-GNB clinical isolates from hospitals in southern Spain. Two hundred and thirty-one isolates of successful clones were tested: 125 Enterobacterales (121 ESBL- and/or carbapenemase-producing Klebsiella pneumoniae and 4 carbapenemase-producing Enterobacter cloacae), 80 Acinetobacter baumannii, 6 Pseudomonas aeruginosa and 20 Stenotrophomonas maltophilia. Ceftolozane/tazobactam, ceftazidime, ceftazidime/avibactam, cefepime, aztreonam, meropenem, amikacin, ciprofloxacin, colistin and tigecycline were used as comparators against Enterobacterales, P. aeruginosa and A. baumannii. Minocycline, levofloxacin and trimethoprim/sulfamethoxazole were studied against S. maltophilia instead of aztreonam, ciprofloxacin and cefepime. MICs were determined by broth microdilution according to CLSI guidelines. MIC determination was performed in CAMHB for all antimicrobials except cefiderocol, where iron-depleted CAMHB was used. Cefiderocol showed potent in vitro activity against the isolates analysed. MIC50 and MIC90 values were in the ranges 0.125-8 mg/L and 0.5-8 mg/L, respectively, and 98% of isolates were inhibited at ≤4 mg/L. Only five isolates showed cefiderocol MICs of >4 mg/L: three ST2/OXA-24/40-producing A. baumannii, one ST114/VIM-1-producing E. cloacae and one ST114/VIM-1 + OXA-48-producing E. cloacae. All KPC-3-producing K. pneumoniae were susceptible to cefiderocol, even those resistant to ceftazidime/avibactam. P. aeruginosa isolates showed cefiderocol MICs of <4 mg/L, including those resistant to ceftolozane/tazobactam. S. maltophilia isolates displayed cefiderocol MICs of <4 mg/L, including those resistant to levofloxacin and/or trimethoprim/sulfamethoxazole. Cefiderocol showed excellent activity against MDR-GNB, including carbapenem-resistant isolates, and was the most active antimicrobial tested against this collection.


Active and passive adsorption of 47 trace atmospheric volatile organic compounds onto carbon nanotubes.
Carbon nanotubes (CNTs) of varying sizes and CNTs functionalised with carboxylic acids were examined by thermal desorption gas chromatography mass spectrometry (TD-GCMS) to determine the degree of surface contamination of atmospheric volatile organic compounds (VOCs). The CNTs could be purged of physisorbed VOCs by heating to 380 °C under a stream of purified nitrogen gas. As soon as the cleaned CNTs were exposed to atmospheric air they spontaneously adsorbed trace VOCs. As well as passive adsorption of VOCs, active sampling was carried out by pumping atmospheric air through the CNTs and comparing the results with the standard multisorbent materials Carbopack X and Tenax that are used widely for VOC trapping and analysis. The CNTs were found to trap many VOCs at a comparable level to the standard sorbent materials. Therefore, to maintain the CNTs in a pristine condition, it is recommended that they are first heated under vacuum to remove residual physisorbed VOCs, and then stored under vacuum or in a purified inert gas atmosphere.


Quantitative GC-TCD Measurements of Major Flatus Components: A Preliminary Analysis of the Diet Effect.
The impact of diet and digestive disorders in flatus composition remains largely unexplored. This is partially due to the lack of standardized sampling collection methods, and the easy atmospheric contamination. This paper describes a method to quantitatively determine the major gases in flatus and their application in a nutritional intervention. We describe how to direct sample flatus into Tedlar bags, and simultaneous analysis by gas chromatography-thermal conductivity detection (GC-TCD). Results are analyzed by univariate hypothesis testing and by multilevel principal component analysis. The reported methodology allows simultaneous determination of the five major gases with root mean measurement errors of 0.8% for oxygen (O2), 0.9% for nitrogen (N2), 0.14% for carbon dioxide (CO2), 0.11% for methane (CH4), and 0.26% for hydrogen (H2). The atmospheric contamination was limited to 0.86 (95% CI: [0.7-1.0])% for oxygen and 3.4 (95% CI: [1.4-5.3])% for nitrogen. As an illustration, the method has been successfully applied to measure the response to a nutritional intervention in a reduced crossover study in healthy subjects.


Sagittal plane translations of the knee in anterior cruciate deficient subjects and controls.
Static anterior-posterior (AP) laxity is one of the commonly used criteria in selecting patients for cruciate ligament reconstructions, but in reality dynamic AP laxity plays a more important role. The aim of this in vivo study was to compare the sagittal translation of the knee during active and passive motion, signifying dynamic AP laxity, with static AP laxity in healthy subjects (controls) and patients with anterior cruciate ligament deficiency. The sagittal plane knee translations were recorded and compared in both knees of nine healthy subjects (Controls) and seven patients with confirmed unilateral ACL deficiency during dynamic and static situations with an electrogoniometer system. In all groups during the ascents the tibia moved anteriorly in relation to the femur, whereas during the descents it moved posteriorly. The static anterior-posterior translation was significantly smaller in the control knee than in both healthy and injured knees of the ACL deficient group (P < 0.05). The injured knee showed the same laxity (92%) as the uninjured knee during dynamic activities, but it was 46% of static laxity. Also in the injured knees, the dynamic active laxity was larger during descents than ascents (P < 0.05). The results indicate that there is also a change in mechanics of the noninjured knee following injury to the contralateral knee and that this population of patients with ACL deficiency had good control over their abnormal anterior-posterior laxity.


Inequalities in access to treatment in Argentina: Differences in management of CLL and multiple myeloma?
Health equity is today an important objective to evenly reach the population among different health care systems. This article will focus on diagnosis and treatment access inequalities in Argentina. Although different aspects must be optimized to overcome access barriers worldwide, access inequalities in some regions of Argentina may depend basically on the type of health coverage or insurance. Health care in Argentina is divided into Public, Social security and Private care systems. Access to diagnosis and disease monitoring will vary according whether the patient is under each of these systems. Reducing inequalities may help target some important aspects not covered today and that may directly impact patients' outcome. Disparities in health cancer care were analyzed according to Public, Social security and Private sectors. A disadvantage in resource access, inadequate funding and limited medical infrastructures are common characteristics of the public health care systems. In our country the disparity between the public and private sectors in terms of timely diagnosis, stage of disease at diagnosis, accuracy of diagnosis, access to novel agents and transplantation is notorious, with the public sector lagging behind in access to diagnostic and treatment resources. While the Private sector has treatment outcomes comparable to those of high-income countries, challenges remain in the Public sector for patients who rely on early and accurate diagnosis and timely access to treatment. There is an urgent need to provide equitable care for multiple myeloma and CLL patients and reduce the emotional and financial consequences of the disease for the patient. A survey about diagnosis and therapeutic resources was conducted between April and May 2023 among large centers in the Public, Social security and Private systems. A total of 49 hematologists from 31 institutions from five provinces of Argentina participated in the survey. We observed differences between the different systems with more access for the Private system on genetic diagnosis (FISH-IGVH access). More CLL patients in the public and social security systems were treated with CIT reflecting the inaccessibility in these sectors of more expensive targeted therapies rather than a gap in information since the Public centers surveyed were large hospitals with knowledgeable physicians. Access to different treatments both in first-line and relapsed settings was more equitable in the treatment of multiple myeloma for the different systems with the exception of access to daratumumab in first-line that was extremely infrequent in the public coverage. With increasing cost and treatment complexity as the introduction of CARTs and BITEs for CLL and MM, the gap will probably deepen more if the problem is not treated comprehensively by all the actors of the health sector: government, physicians, patients' organizations and pharmaceutical companies.


Secondary measles vaccine failures identified by measurement of IgG avidity: high occurrence among teenagers vaccinated at a young age.
Failure to seroconvert (primary vaccine failure) is believed to be the principal reason (approx. > 95%) why some vaccinees remain susceptible to measles and is often attributed to the persistence of maternal antibodies in children vaccinated at a young age. Avidity testing is able to separate primary from secondary vaccine failures (waning and/or incomplete immunity), but has not been utilized in measles epidemiology. Low-avidity (LA) and high-avidity (HA) virus-specific IgG antibodies indicate primary and secondary failure, respectively. Measles vaccine failures (n = 142; mean age 10.1 years, range 2-22 years) from an outbreak in 1988-9 in Finland were tested for measles-virus IgG avidity using a protein denaturating EIA. Severity of measles was recorded in 89 failures and 169 non-vaccinees (mean age 16.2 years, range 2-22 years). The patients with HA antibodies (n = 28) tended to have clinically mild measles and rapid IgG response. Among failures vaccinated at < 12, 12-15 and > 15 months of age with single doses of Schwarz-strain vaccine in the 1970s, 50 (95% CI 1-99), 36 (CI 16-56) and 25% (CI 8-42) had HA antibodies, respectively. When a single measles, mumps and rubella (MMR) vaccine had been given after 1982 at 15 months of age, only 7% (CI 0-14) showed HA antibodies. Omitting re-vaccinees and those vaccinated at < 15 months, Schwarz-strain recipients had 3.6 (CI 1.1-11.5) higher occurrence of HA responses compared to MMR recipients. Apart from one municipality, where even re-vaccinees had high risk of primary infection, 89% (CI 69 to approximately 100) of the infected re-vaccinees had an HA response. Secondary measles-vaccine failures are more common than was more previously thought, particularly among individuals vaccinated in early life, long ago, and among re-vaccinees. Waning immunity even among individuals vaccinated after 15 months of age, without the boosting effect of natural infections should be considered a relevant possibility in future planning of vaccination against measles.


Weighting of neural prediction error by rhythmic complexity: A predictive coding account using mismatch negativity.
The human brain's ability to extract and encode temporal regularities and to predict the timing of upcoming events is critical for music and speech perception. This work addresses how these mechanisms deal with different levels of temporal complexity, here the number of distinct durations in rhythmic patterns. We use electroencephalography (EEG) to relate the mismatch negativity (MMN), a proxy of neural prediction error, to a measure of information content of rhythmic sequences, the Shannon entropy. Within each of three conditions, participants listened to repeatedly presented standard rhythms of five tones (four inter-onset intervals) and of a given level of entropy: zero (isochronous), medium entropy (two distinct interval durations), or high entropy (four distinct interval durations). Occasionally, the fourth tone was moved forward in time that is it occurred 100 ms (small deviation) or 300 ms early (large deviation). According to the predictive coding framework, high-entropy stimuli are more difficult to model for the brain, resulting in less confident predictions and yielding smaller prediction errors for deviant sounds. Our results support this hypothesis, showing a gradual decrease in MMN amplitude as a function of entropy, but only for small timing deviants. For large timing deviants, in contrast, a modulation of activity in the opposite direction was observed for the earlier N1 component, known to also be sensitive to sudden changes in directed attention. Our results suggest the existence of a fine-grained neural mechanism that weights neural prediction error to the complexity of rhythms and that mostly manifests in the absence of directed attention.


Synthesis and bioconjugation of 2 and 3 nm-diameter gold nanoparticles.
By adjustment of solvent conditions for synthesis, virtually monodisperse 4-mercaptobenzoic acid (p-MBA) monolayer-protected gold nanoparticles, 2 and 3 nm in diameter, were obtained. Large single crystals of the 2 nm particles could be grown from the reaction mixture. Uniformity was also demonstrated by the formation of two-dimensional arrays and by quantitative high-angle annular dark-field scanning transmission electron microscopy. The 2 and 3 nm particles were spontaneously reactive for conjugation with proteins and DNA, and further reaction could be prevented by repassivation with glutathione. Conjugates with antibody Fc fragment could be used to identify TAP-tagged proteins of interest in electron micrographs, through the binding of a pair of particles to the pair of protein A domains in the TAP tag.


Investigations of AGEs' inhibitory and nephroprotective potential of ursolic acid towards reduction of diabetic complications.
In diabetes, interactions between AGEs (advanced glycation end products) and RAGEs (receptors of AGEs) are responsible for chronic complications and the current work reports the potential of ursolic acid as a RAGE inhibitor. The three-dimensional crystal structure of RAGE was first docked with target molecules by 'AutodockVina' using GROMOS 96 4381 parameters. Druggability and pharmacokinetic properties were calculated from the SwissADME server. In vitro bovine serum albumin (BSA)-glucose fluorescence and BSA-methylglyoxal fluorescence assays were also performed. Finally, alloxan-induced diabetic mice were administered ursolic acid and metformin standards (at 1, 50, 100 mg/kg) for 50 days. Blood glucose levels, several blood parameters, blood lipid profiles, supernatants of homogenized kidney and plasma of mice were examined. In the computational study, ursolic acid showed greater binding affinity (-7.5 kcal/mol) for RAGE with an ADMET profiles and lead-likeness compared to metformin as a standard antidiabetic. In the in vitro fluorescence assays, the IC50 value for ursolic acid was much less than that of metformin standard. During the in vivo study, significant reduction in the levels of blood glucose, HbA1C (glycated hemoglobin), creatinine, uric acid, BUN (blood urea nitrogen), AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase) were observed in the ursolic acid and metformin-treated mice. Substantial inhibition of AGEs' formation in the plasma and kidney were also detected. Finally, the histopathological examinations of the kidney revealed reversal of cellular necrosis. Hence, ursolic acid is proved to be a potent AGE inhibitory agent in managing the diabetic complications.


DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis.
Neurogenesis in the developing neocortex relies on the ability of radial glial progenitor cells (RGCs) to switch from proliferative to differentiative neuron-generating divisions, but the molecular mechanisms that control this switch in a correct temporal manner are not well understood. Here, we show that DOCK7, a member of the DOCK180 family of proteins, regulates RGC proliferation versus differentiation. Silencing of DOCK7 in RGCs of developing mouse embryos impedes neuronal differentiation and maintains cells as cycling progenitors. In contrast, DOCK7 overexpression promotes RGC differentiation to basal progenitors and neurons. We further present evidence that DOCK7 influences neurogenesis by controlling apically directed interkinetic nuclear migration of RGCs. DOCK7 exerts its effects by antagonizing the microtubule growth-promoting function of the centrosome-associated protein TACC3. Thus, DOCK7 interaction with TACC3 controls interkinetic nuclear migration and the genesis of neurons from RGCs during cortical development.


A dissimilatory sirohaem-sulfite-reductase-type protein from the hyperthermophilic archaeon Pyrobaculum islandicum.
A sulfite-reductase-type protein was purified from the hyperthermophilic crenarchaeote Pyrobaculum islandicum grown chemoorganoheterotrophically with thiosulfate as terminal electron acceptor. In common with dissimilatory sulfite reductases the protein has an alpha 2 beta 2 structure and contains high-spin sirohaem, non-haem iron and acid-labile sulfide. The oxidized protein exhibits absorption maxima at 280, 392, 578 and 710 nm with shoulders at 430 and 610 nm. The isoelectric point of pH 8.4 sets the protein apart from all dissimilatory sulfite reductases characterized thus far. The genes for the alpha- and beta-subunits (dsrA and dsrB) are contiguous in the order dsrAdsrB and most probably comprise an operon with the directly following dsrG and dsrC genes. dsrG and dsrC encode products which are homologous to eukaryotic glutathione S-transferases and the proposed gamma-subunit of Desulfovibrio vulgaris sulfite reductase, respectively. dsrA and dsrB encode 44.2 kDa and 41.2 kDa peptides which show significant similarity to the two homologous subunits DsrA and DsrB of dissimilatory sulfite reductases. Phylogenetic analyses indicate a common protogenotic origin of the P. islandicum protein and the dissimilatory sulfite reductases from sulfate-reducing and sulfide-oxidizing prokaryotes. However, the protein from P. islandicum and the sulfite reductases from sulfate-reducers and from sulfur-oxidizers most probably evolved into three independent lineages prior to divergence of archaea and bacteria.


Preparation and in vivo toxicity study of solid lipid microparticles as carrier for pulmonary administration.
The purpose of this research was to investigate the effects of processing conditions on the characteristics of solid lipid microparticles (SLM) with a potential application as carriers for pulmonary administration. Compritol (5.0% wt/wt) SLM dispersions were prepared by rotor-stator homogenization, at different surfactant concentrations and emulsification times. The SLM were characterized, in terms of morphology and size, after lyophilization and sterilization by autoclaving process. In vivo assessment was carried out in rats by intratracheal instillation of either placebo or SLM dispersion, and by bronchoalveolar lavage for cytological analysis. Mean particle size of 4 to 5 microm was achieved using 0.3% and 0.4% (wt/wt) of emulsifier (Poloxamer 188) and emulsification times of 2 and 5 minutes. The particles showed spherical shape and smooth surface. The morphology of microparticles, the size, and the size distribution were not substantially modified after lyophilization and sterilization. Total cell counts showed no significant differences between placebo and SLM 0.5% or 2.5% groups. Regarding cytology, percentage of polymorphonuclear neutrophils and macrophages did not significantly differ between groups. These results suggest that a single intratracheal administration of the SLMs does not induce a significant inflammatory airway response in rats and that the SLMs might be a potential carrier for encapsulated drug via the pulmonary route.