Memory and coping with stress: the relationship between cognitive-emotional distinctiveness, memory valence, and distress.
Cognitive-emotional distinctiveness (CED), the extent to which an individual separates emotions from an event in the cognitive representation of the event, was explored in four studies. CED was measured using a modified multidimensional scaling procedure. The first study found that lower levels of CED in memories of the September 11 terrorist attacks predicted greater frequency of intrusive thoughts about the attacks. The second study revealed that CED levels are higher in negative events, in comparison to positive events and that low CED levels in emotionally intense negative events are associated with a pattern of greater event-related distress. The third study replicated the findings from the previous study when examining CED levels in participants' memories of the 2004 Presidential election. The fourth study revealed that low CED in emotionally intense negative events is associated with worse mental health. We argue that CED is an adaptive and healthy coping feature of stressful memories.


Macro-B12 masking B12 deficiency.
In clinical practice, the finding of an elevated serum B12 concentration is often the consequence of supplementation with B12 in either oral form or injections. Also, elevated serum B12 may be associated with underlying disorders, like liver diseases or a (haematologic) malignancy. Only a few studies have shown that it may also be the consequence of complex formation of B12-vitamin binding proteins with immunoglobulins, the so-called macro-B12 We describe a young woman who previously was diagnosed with B12 deficiency, and in whom, after cessation of B12 injection treatment, neurologic symptoms re-appeared, and despite this, repeatedly elevated serum B12 concentrations above the upper limit of the assay were found. We demonstrated that this was caused by the presence of macro-B12, which not only resulted in erroneous and longstanding elevated serum B12, but also masked her underlying B12 deficiency.


Black Petrels (Procellaria parkinsoni) patrol the ocean shelf-break: GPS tracking of a vulnerable procellariiform seabird.
Determining the foraging movements of pelagic seabirds is fundamental for their conservation. However, the vulnerability and elusive lifestyles of these animals have made them notoriously difficult to study. Recent developments in satellite telemetry have enabled tracking of smaller seabirds during foraging excursions. Here, we report the first successful precision tracking of a c. 700 g seabird, the vulnerable Black Petrel, Procellaria parkinsoni, foraging at sea during the breeding season, using miniature GPS-logging technology. Employing a combination of high-resolution fixes and low-power duty-cycles, we present data from nine individual foraging excursions tracked during the chick-rearing period in February 2006. We provide a snapshot of the species' foraging range and behaviour in relation to detailed underlying bathymetry off the coast of New Zealand, finding a significant relationship between foraging movements and regions of the shelf-break. We also highlight the potential of more sophisticated analyses to identify behavioural phenomena from position data alone.


Host immune response against Scedosporium species.
Scedosporium apiospermum and Scedosporium prolificans cause therapy-refractory infections in immunocompromised and immunocompetent hosts. While innate immune response is believed to be critical for the host defense against these fungi, its role has only recently been elucidated. Undefined pathogen-associated molecular patterns on the surface of conidia and hyphae are recognized by pattern-recognition receptors (PRRs) on the membrane of phagocytes, and the signal is transmitted intracellularly. PRRs that are important in the recognition of both fungal species are human Toll-like receptors (or Toll receptors in Drosophila melanogaster) and dectin-1. These induce signals responsible for the activation of genes leading to an effective host defense, especially those encoding pro-inflammatory cytokines. Both species are efficiently phagocytosed and elicit an oxidative burst by neutrophils and monocytes. While cytokines, such as interleukin-15, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interferon-gamma, have been found in vitro to variably modulate antifungal activity of human phagocytes, cytokines in vivo activities are less well documented. Certain antifungal agents exert immunopharmacological effects on phagocytes against S. apiospermum and S. prolificans. Translation of these in vitro findings to appropriate in vivo systems and into clinical trials may lead to improved strategies for augmenting innate host defenses in patients infected with these emerging pathogens.


Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases.
MicroRNAs (miRNAs) are the smallest class of noncoding RNAs, which widely exist in animals and plants. They can inhibit translation or overexpression by combining with mRNA and participate in posttranscriptional regulation of genes, resulting in reduced expression of target proteins, affecting the development, growth, aging, metabolism, and other physiological and pathological processes of animals and plants. It is a powerful negative regulator of gene expression. It mediates the information exchange between different cellular pathways in cellular homeostasis and stress response and regulates the differentiation, plasticity, and neurotransmission of neurons. In neurodegenerative diseases, in addition to the complex interactions between genetic susceptibility and environmental factors, miRNAs can serve as a promising diagnostic tool for diseases. They can also increase or reduce neuronal damage by regulating the body's signaling pathways, immune system, stem cells, gut microbiota, etc. They can not only affect the occurrence of diseases and exacerbate disease progression but also promote neuronal repair and reduce apoptosis, to prevent and slow down the development of diseases. This article reviews the research progress of miRNAs on the mechanism and treatment of neurodegenerative diseases in the nervous system. This trial is registered with NCT01819545, NCT02129452, NCT04120493, NCT04840823, NCT02253732, NCT02045056, NCT03388242, NCT01992029, NCT04961450, NCT03088839, NCT04137926, NCT02283073, NCT04509271, NCT02859428, and NCT05243017.


Multiple breakpoints within the BCL-1 locus in B-cell lymphoma: rearrangements of the cyclin D1 gene.
Centrocytic lymphoma (CC) and intermediately differentiated lymphocytic lymphoma (IDL) are B-cell non-Hodgkin's lymphomas composed of lymphocytes presumably derived from follicle mantle cells. In these lymphomas, a specific chromosomal translocation, t(11;14)(q13;q32), has been described. Previous studies suggested an association between t(11;14) chromosomal translocations and BCL-1 rearrangements. To evaluate the association between BCL-1 rearrangements and CC/IDL, Southern blot analysis was performed on a panel of 20 cases of CC/IDL, 22 cases of morphologically similar non-Hodgkin's lymphomas, 11 cases of chronic B-cell leukemias, and 2 cases of myelomas. We used various probes covering a considerable proportion of the 120-kilobase BCL-1 locus, and rearrangements in 50% of CC/IDL (10 of 20) were detected. In CC, all 4 breakpoints were located at the major translocation cluster (MTC). In contrast, in IDL, rearrangements were detected in 3 different cluster regions: 2 cases in the MTC, 2 cases with a breakpoint 24 kilobases outside the MTC, and 2 additional cases with breakpoints found 3 kilobases 5' of the first exon of the PRAD1/CCND1 gene, which is located 120 kilobases outside the MTC. In addition, one leukemia showed a breakpoint 63 kilobases outside the MTC. In all cases, there was comigration of the rearranged 11q13 fragment and the immunoglobulin heavy chain-joining gene complex, indicating a t(11;14)(q13;q32) chromosomal rearrangement. Our results show that Southern blot analysis is helpful to identify CC/IDL, but multiple breakpoints are present over a large region, and therefore, many probes are necessary to cover all breakpoints.


Leucine-rich repeat kinase 2 phosphorylation on synapsin I regulates glutamate release at pre-synaptic sites.
Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain scaffolding protein with kinase and GTPase activities involved in synaptic vesicle (SV) dynamics. While its role in Parkinson's disease has been largely investigated, little is known about LRRK2 physiological role and until now few proteins have been described as substrates. We have previously demonstrated that LRRK2 through its WD40 domain interacts with synapsin I, an important SV-associated phosphoprotein involved in neuronal development and in the regulation of neurotransmitter release. To test whether synapsin I is substrate for LRRK2 and characterize the properties of its phosphorylation, we used in vitro kinase and binding assays as well as cellular model and site-direct mutagenesis. Using synaptosomes in superfusion, patch-clamp recordings in autaptic WT and synapsin I KO cortical neurons and SypHy assay on primary cortical culture from wild-type and BAC human LRRK2 G2019S mice we characterized the role of LRRK2 kinase activity on glutamate release and SV trafficking. Here we reported that synapsin I is phosphorylated by LRRK2 and demonstrated that the interaction between LRRK2 WD40 domain and synapsin I is crucial for this phosphorylation. Moreover, we showed that LRRK2 phosphorylation of synapsin I at threonine 337 and 339 significantly reduces synapsin I-SV/actin interactions. Using complementary experimental approaches, we demonstrated that LRRK2 controls glutamate release and SV dynamics in a kinase activity and synapsin I-dependent manner. Our findings show that synapsin I is a LRRK2 substrate and describe a novel mechanisms of regulation of glutamate release by LRRK2 kinase activity.


Characterizing the nonlinear structure of shared variability in cortical neuron populations using latent variable models.
Sensory neurons often have variable responses to repeated presentations of the same stimulus, which can significantly degrade the stimulus information contained in those responses. This information can in principle be preserved if variability is shared across many neurons, but depends on the structure of the shared variability and its relationship to sensory encoding at the population level. The structure of this shared variability in neural activity can be characterized by latent variable models, although they have thus far typically been used under restrictive mathematical assumptions, such as assuming linear transformations between the latent variables and neural activity. Here we introduce two nonlinear latent variable models for analyzing large-scale neural recordings. We first present a general nonlinear latent variable model that is agnostic to the stimulus tuning properties of the individual neurons, and is hence well suited for exploring neural populations whose tuning properties are not well characterized. This motivates a second class of model, the Generalized Affine Model, which simultaneously determines each neuron's stimulus selectivity and a set of latent variables that modulate these stimulus-driven responses both additively and multiplicatively. While these approaches can detect very general nonlinear relationships in shared neural variability, we find that neural activity recorded in anesthetized primary visual cortex (V1) is best described by a single additive and single multiplicative latent variable, i.e., an "affine model". In contrast, application of the same models to recordings in awake macaque prefrontal cortex discover more general nonlinearities to compactly describe the population response variability. These results thus demonstrate how nonlinear latent variable models can be used to describe population variability, and suggest that a range of methods is necessary to study different brain regions under different experimental conditions.


Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals.
The management of overweight subjects by interventions aimed at reducing inflammation is highly desirable. To date, observational studies have identified a link between increased dietary antioxidant intake and reduced cardiovascular morbidity. However, direct trial evidence regarding the ability of antioxidants to influence inflammation is lacking. Therefore, this study examined lycopene's ability to lower systemic and high-density lipoprotein (HDL)-associated inflammation in moderately overweight middle-aged subjects. Serum was collected before and after a 12-week intervention from 54 moderately overweight, middle-aged individuals. Subjects were randomised to one of three groups: control diet (<10 mg lycopene/week), lycopene-rich diet (224-350 mg lycopene/week) and lycopene supplement (70 mg lycopene/week). HDL was subfractionated into HDL(2&3) by rapid ultracentrifugation. Compliance was monitored by assessing lycopene concentration in serum and HDL(2&3). Systemic and HDL-associated inflammation was assessed by measuring serum amyloid A (SAA) levels. HDL functionality was determined by monitoring the activities of paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP) and lecithin cholesterol acyltransferase (LCAT). Lycopene increased in serum and HDL(2&3) following both lycopene interventions (P<.001, for all), while SAA decreased in serum following the lycopene supplement and in HDL(3) following both lycopene interventions (P<.05 for all). PON-1 activity increased in serum and HDL(2&3) in both lycopene groups (P<.05, for all). Furthermore, the activity of CETP decreased in serum following the lycopene supplement, while the activity of LCAT increased in serum and HDL(3) following both lycopene interventions (P<.05 for all). These results demonstrate that in moderately overweight, middle-aged subjects, increasing lycopene intake leads to changes to HDL(2&3), which we suggest enhanced their antiatherogenic properties. Overall, these results show the heart-protective properties of increased lycopene intake.


CEST-MRI detects metabolite levels altered by breast cancer cell aggressiveness and chemotherapy response.
Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that detects the exchange of protons from distinct hydroxyl, amine, and amide groups to tissue water through the transfer of signal loss, with repeated exchange enhancing their effective signal. We applied CEST to detect systematically 15 common cellular metabolites in a panel of differentially aggressive human breast cancer cell lines. The highest CEST contrast was generated by creatine, myo-inositol, glutamate, and glycerophosphocholine, whose cellular concentrations decreased with increasing breast cancer aggressiveness. These decreased metabolite concentrations resulted in turn in a decreased CEST profile with increasing breast cancer aggressiveness in water-soluble extracts of breast cell lines. Treatment of both breast cancer cell lines with the chemotherapy drug doxorubicin resulted in increased metabolic CEST profiles, which correlated with significant increases in creatine, phosphocreatine, and glycerophosphocholine. CEST can detect breast cancer aggressiveness and response to chemotherapy in water-soluble extracts of breast cell lines. The presented results help shed light on possible contributions from CEST-active metabolites to the CEST contrast produced by breast cancers. The metabolic CEST profile may improve detection sensitivity over conventional MRS, and may have the potential to assess breast cancer aggressiveness and response to chemotherapy non-invasively using MRI if specialized metabolic CEST profile detection can be realized in vivo. Copyright © 2016 John Wiley & Sons, Ltd.


Unilateral progressive osseous heteroplasia.
A 50-year-old male patient presented with firm subcutaneous nodules and plaques with a gritty texture, unilaterally affecting the left side of the trunk and the left limbs. These lesions had had a progressive course since early childhood and caused functional impairment. There was no family history of similar disorders. No phospho-calcium metabolism abnormalities were observed. Biopsies of the affected areas demonstrated osteoma cutis. Analysis of DNA showed no mutation of the GNAS gene. The clinical features were consistent with progressive osseous heteroplasia, atypically presented in a unilateral form, probably revealing a mosaic distribution.


Active magnetoplasmonic ruler.
Plasmon rulers are an emerging concept in which the strong near-field coupling of plasmon nanoantenna elements is employed to obtain structural information at the nanoscale. Here, we combine nanoplasmonics and nanomagnetism to conceptualize a magnetoplasmonic dimer nanoantenna that would be able to report nanoscale distances while optimizing its own spatial orientation. The latter constitutes an active operation in which a dynamically optimized optical response per measured unit length allows for the measurement of small and large nanoscale distances with about 2 orders of magnitude higher precision than current state-of-the-art plasmon rulers. We further propose a concept to optically measure the nanoscale response to the controlled application of force with a magnetic field.


Fundus obliteration and facial nerve outcome in vestibular schwannoma surgery.
The major objectives in vestibular schwannoma (VS) surgery have evolved from reducing mortality to functional preservation of the facial nerve and hearing. Absence of fluid between the lateral end of the VS and the internal auditory canal fundus on magnetic resonance imaging (MRI) appeared to have a negative influence on hearing outcome. Our goal was to study the prognostic significance of fundus obliteration on facial nerve function after VS surgery in patients with clinically normal facial function. We performed a retrospective review in a tertiary referral neurotology unit or 110 consecutive patients with a surgically removed VS and normal preoperative facial nerve function. Facial nerve function was evaluated at 1 month and 1 year by using the House-Brackmann (HB) scale and correlated to fundus obliteration on MRI. Facial nerve function was intact preoperatively in 114 of 123 patients (92.7%). We noticed a statistically significant difference and worse short-term outcome when the fundus was obliterated: 29.7% had HB 3 or more versus 13.0% if no fundus obliteration was seen. This statistically significant difference disappeared at 1 year. Fundus obliteration has a negative prognostic influence on short-term facial nerve function after VS surgery in patients with clinically normal facial function preoperatively.


Scooping Rice Into a Glass and Putting a Cell Phone in the Refrigerator: Action Slips in an Individual With a Diffuse Axonal Injury.
A 39-year-old man with a diffuse axonal injury self-presented to the cognitive function clinic of the Ashikaga Red Cross Hospital complaining of behavioral errors in his daily life, such as scooping hot rice into a glass instead of a bowl or forgetting to turn off the gas stove after cooking. This type of error has been referred to as an action slip-a form of unintentional behavioral error that occurs when an individual attempts to perform an automatic and/or familiar task. In this case, action slips occurred nine times a day on average and had a serious and long-term impact on the man's daily quality of life. To reduce the impact of action slips, we created a one-on-one cognitive intervention that used a combination of mnemonic strategies, such as verbalizing his actions as he carried them out, and external aids, including a waist pouch, a voice-controlled artificial intelligence (AI) speaker, and an AI key finder. After 3 years of intervention, the man reported some improvement in his daily activities and a reduction in the number of action slips. Thus, intervention strategies for individuals with a diffuse axonal injury may benefit from targeting action slips. To our knowledge, this is the first detailed description of action slips in an individual with a diffuse axonal injury.


The evolution of temporal processing in the medial superior olive, an auditory brainstem structure.
A basic concept in neuroscience is to correlate specific functions with specific neuronal structures. By discussing a specific example, an alternative concept is proposed: structures may be linked to rules of processing and these rules may serve different functions in different species or at different stages of evolution. The medial superior olive (MSO), a mammalian auditory brainstem structure, has been thought to solely process interaural time differences (ITD), the main cue for localizing low frequency sounds. Recent findings, however, indicate that this is not its only function since mammals that do not hear low frequencies and do not use ITDs for sound localization also possess a MSO. Recordings from the bat MSO indicate that it processes temporal cues in the milli- and submillisecond range, based on monaural or binaural inputs. In bats, and most likely in other small mammals, this temporal processing is related to pattern recognition and echo suppression rather than sound localization. However, the underlying mechanism, coincidence detection of several inputs, creates an epiphenomenal ITD sensitivity that is of no use for small mammals like bats or ancestral mammals. Such an epiphenomenal ITD sensitivity would have been a pre-adaptation which, when mammals grew larger during evolution and when localization of low frequency sounds became a question of survival, suddenly gained relevance. This way the MSO became involved in a new function without changing its basic rules of processing.


Fiber-based, hybrid terahertz spectrometer using dual fiber combs.
We constructed a fiber-based, hybrid terahertz (THz) spectrometer having two working modes, asynchronous-optical-sampling THz time-domain spectroscopy (AOS-THz-TDS) and multiple-frequency-heterodyning THz comb spectroscopy (MFH-THz-CS), by use of dual fiber-laser-based frequency combs. A spectral range of 2THz and dynamic range of 100 was achieved at the single sweep measurement of 200ms in the AOS-THz-TDS mode, whereas the detailed structure of the THz frequency comb was clearly observed in the MFH-THz-CS mode. The spectrometer features compactness, robustness, flexibility, and cost effectiveness, in addition to high spectral resolution in rapid data acquisition, and has the potential to become a powerful tool for practical applications.


Pathways to resilience: adapting to sea level rise in Los Angeles.
Los Angeles (LA) County's coastal areas are highly valued for their natural benefits and their economic contributions to the region. While LA County already has a high level of exposure to flooding (e.g. people, ports, and harbors), climate change and sea level rise will increase flood risk; anticipating this risk requires adaptation planning to mitigate social, economic, and physical damage. This study provides an overview of the potential effects of sea level rise on coastal LA County and describes adaptation pathways and estimates associated costs in order to cope with sea level rise. An adaptation pathway in this study is defined as the collection of measures (e.g., beach nourishment, dune restoration, flood-proofing buildings, and levees) required to lower flood risk. The aim of using different adaptation pathways is to enable a transition from one methodology to another over time. These pathways address uncertainty in future projections, allowing for flexibility among policies and potentially spreading the costs over time. Maintaining beaches, dunes, and their natural dynamics is the foundation of each of the three adaptation pathways, which address the importance of beaches for recreation, environmental value, and flood protection. In some scenarios, owing to high projections of sea level rise, additional technical engineering options such as levees and sluices may be needed to reduce flood risk. The research suggests three adaptation pathways, anticipating a +1 ft (0.3 m) to +7 ft (+2 m) sea level rise by year 2100. Total adaptation costs vary between $4.3 and $6.4 bn, depending on measures included in the adaptation pathway.


Gamma interferon activates human macrophages to become tumoricidal and leishmanicidal but enhances replication of macrophage-associated mycobacteria.
Recombinant human gamma interferon (rIFN-gamma) was examined for its ability to activate human peripheral blood monocyte-derived macrophages to kill tumor cells and to affect the replication of two phylogenetically distinct intracellular pathogens, Mycobacterium tuberculosis and Leishmania donovani. Macrophages preincubated overnight with doses of rIFN-gamma from 5 to 500 U/ml killed [3H]thymidine-labeled mouse L929 tumor targets, as measured by the release of [3H]thymidine into the supernatant after 48 h. Counts of macrophages initially infected with leishmania promastigotes showed that rIFN-gamma-pretreated macrophages could both inhibit the replication of and kill the resulting intramacrophage amastigotes over a 7-day period. However, rIFN-gamma pretreatment of macrophages actually enhanced mycobacterial replication over a 5- to 7-day period, as assessed by (i) counting acid-fast bacilli or (ii) lysing macrophages to release bacteria and determining the numbers of viable units. Mycobacterial growth was not affected by rIFN-gamma in the absence of macrophages. rIFN-gamma pretreatment had opposite effects on the uptake of mycobacteria and leishmania. As many as 80% fewer activated macrophages ingested mycobacteria compared with controls, whereas 50% more activated macrophages were infected with leishmania. These results suggest that rIFN-gamma may interfere with the immune destruction of intracellular tubercle bacilli and that the mechanisms of immunity against mycobacteria and leishmania may differ.


Associations Between Patient-Reported Outcome Measures of Physical and Psychological Functioning and Willingness to Share Social Media Data for Research Among Adolescents With a Chronic Rheumatic Disease: Cross-Sectional Survey.
Social media data may augment understanding of the disease and treatment experiences and quality of life of youth with chronic medical conditions. Little is known about the willingness to share social media data for health research among youth with chronic medical conditions and the differences in health status between sharing and nonsharing youth with chronic medical conditions. We aimed to evaluate the associations between patient-reported measures of disease symptoms and functioning and the willingness to share social media data. Between February 2018 and August 2019, during routine clinic visits, survey data about social media use and the willingness to share social media data (dependent variable) were collected from adolescents in a national rheumatic disease registry. Survey data were analyzed with patient-reported measures of disease symptoms and functioning and a clinical measure of disease activity, which were collected through a parent study. We used descriptive statistics and multivariate logistic regression to compare patient-reported outcomes between youth with chronic medical conditions who opted to share social media data and those who did not opt to share such data. Among 112 youths, (age: mean 16.1, SD 1.6 y; female: n=72, 64.3%), 83 (74.1%) agreed to share social media data. Female participants were more likely to share (P=.04). In all, 49 (43.8%) and 28 (25%) participants viewed and posted about rheumatic disease, respectively. Compared to nonsharers, sharers reported lower mobility (T-score: mean 49.0, SD 9.4 vs mean 53.9, SD 8.9; P=.02) and more pain interference (T-score: mean 45.7, SD 8.8 vs mean 40.4, SD 8.0; P=.005), fatigue (T-score: mean 49.1, SD 11.0 vs mean 39.7, SD 9.7; P<.001), depression (T-score: mean 48.1, SD 8.9 vs mean 42.2, SD 8.4; P=.003), and anxiety (T-score: mean 45.2, SD 9.3 vs mean 38.5, SD 7.0; P<.001). In regression analyses adjusted for age, sex, study site, and Physician Global Assessment score, each 1-unit increase in symptoms was associated with greater odds of willingness to share social media data, for measures of pain interference (Adjusted Odds Ratio [AOR] 1.07, 95% CI 1.001-1.14), fatigue (AOR 1.08, 95% CI 1.03-1.13), depression (AOR 1.07, 95% CI 1.01-1.13), and anxiety (AOR 1.10, 95% CI 1.03-1.18). High percentages of youth with rheumatic diseases used and were willing to share their social media data for research. Sharers reported worse symptoms and functioning compared to those of nonsharers. Social media may offer a potent information source and engagement pathway for youth with rheumatic diseases, but differences between sharing and nonsharing youth merit consideration when designing studies and evaluating social media-derived findings.


The long-term marriage between autoimmunity and internal medicine: a homage to Manuel Carlos Dias.
Our understanding of autoimmune diseases results from the perfect combination of basic and clinical scientific research, and the figure that is closest to the proposed autoimmunology specialist is certainly the internist. The role of B cells in rheumatoid arthritis, the immunological mechanisms to fibrosis or to tissue specific damage, the classification of Bechet's syndrome, the clinical outcomes of antiphospholid syndrome, and new biomarkers for vascular complications in systemic sclerosis constitute, among others, are ideal examples of this combination. For these reason, this issue includes comprehensive reviews in all these areas and is dedicated to Dr. Manuel Carlos Dias and his career in the perfectioning and teaching of the clinical skills necessary to manage autoimmune disease. We are convinced that these discussions are likely of interest to basic scientists and clinicians alike for the proposed translational applications.


Global gene expression profiling in Escherichia coli K12: effects of oxygen availability and ArcA.
The ArcAB two-component system of Escherichia coli regulates the aerobic/anaerobic expression of genes that encode respiratory proteins whose synthesis is coordinated during aerobic/anaerobic cell growth. A genomic study of E. coli was undertaken to identify other potential targets of oxygen and ArcA regulation. A group of 175 genes generated from this study and our previous study on oxygen regulation (Salmon, K., Hung, S. P., Mekjian, K., Baldi, P., Hatfield, G. W., and Gunsalus, R. P. (2003) J. Biol. Chem. 278, 29837-29855), called our gold standard gene set, have p values <0.00013 and a posterior probability of differential expression value of 0.99. These 175 genes clustered into eight expression patterns and represent genes involved in a large number of cell processes, including small molecule biosynthesis, macromolecular synthesis, and aerobic/anaerobic respiration and fermentation. In addition, 119 of these 175 genes were also identified in our previous study of the fnr allele. A MEME/weight matrix method was used to identify a new putative ArcA-binding site for all genes of the E. coli genome. 16 new sites were identified upstream of genes in our gold standard set. The strict statistical analyses that we have performed on our data allow us to predict that 1139 genes in the E. coli genome are regulated either directly or indirectly by the ArcA protein with a 99% confidence level.


ASTRONOMY: Enhanced: Monsters at the Heart of Galaxy Formation.
Supermassive black holes (BHs) have long been implicated in explaining active galactic nuclei such as quasars. In his Perspective, Kormendy discusses recent work that suggests a larger role for these objects. The Hubble Space Telescope has provided many new detections of BHs, and these new results indicate that they play an important role in the galaxy formation processes.


Microbial defenses against mobile genetic elements and viruses: Who defends whom from what?
Prokaryotes have numerous mobile genetic elements (MGEs) that mediate horizontal gene transfer (HGT) between cells. These elements can be costly, even deadly, and cells use numerous defense systems to filter, control, or inactivate them. Recent studies have shown that prophages, conjugative elements, their parasites (phage satellites and mobilizable elements), and other poorly described MGEs encode defense systems homologous to those of bacteria. These constitute a significant fraction of the repertoire of cellular defense genes. As components of MGEs, these defense systems have presumably evolved to provide them, not the cell, adaptive functions. While the interests of the host and MGEs are aligned when they face a common threat such as an infection by a virulent phage, defensive functions carried by MGEs might also play more selfish roles to fend off other antagonistic MGEs or to ensure their maintenance in the cell. MGEs are eventually lost from the surviving host genomes by mutational processes and their defense systems can be co-opted when they provide an advantage to the cell. The abundance of defense systems in MGEs thus sheds new light on the role, effect, and fate of the so-called "cellular defense systems," whereby they are not only merely microbial defensive weapons in a 2-partner arms race, but also tools of intragenomic conflict between multiple genetic elements with divergent interests that shape cell fate and gene flow at the population level.


TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.
Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy.


Environmental factors and the induction of autoimmunity in primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic cholestatic disease with an autoimmune pathogenesis and an unknown etiology, predominantly affecting postmenopausal women. The term PBC is a misnomer since most cases currently diagnosed have limited probability to develop cirrhosis. Antimitochondrial autoantibodies, elevated IgM and selective destruction of the intrahepatic bile ducts are the hallmarks of PBC. A permissive genetic background is critical in producing susceptibility despite limited associations with alleles within the MHC. The disease has incomplete concordance in monozygotic twins and its geoepidemiology suggests a role for environmental factors in the induction of PBC. This hypothesis is further supported by clinical (risk factors) and experimental evidence. Some of the factors incriminated model molecular mimicry by infectious agents and xenobiotic chemicals. Additional candidates are being proposed through large screening; all proposed associations ultimately require confirmation in animal models and clinical practice.


Growth and Coalescence of 3C-SiC on Si(111) Micro-Pillars by a Phase-Field Approach.
3C-SiC is a promising material for low-voltage power electronic devices but its growth is still challenging. Heteroepitaxy of 3C-SiC on Si micrometer-sized pillars is regarded as a viable method to achieve high crystalline quality, minimizing the effects of lattice and thermal expansion mismatch. Three-dimensional micro-crystals with sharply-faceted profiles are obtained, eventually touching with each other to form a continuous layer, suspended on the underlying pillars. By comparing experimental data and simulation results obtained by a phase-field growth model, here we demonstrate that the evolution of the crystal morphology occurs in a kinetic regime, dominated by the different incorporation times on the crystal facets. These microscopic parameters, effective to characterize the out-of-equilibrium growth process, are estimated by a best-fitting procedure, matching simulation profiles to the experimental one at different deposition stages. Then, simulations are exploited to inspect the role of a different pillar geometry and template effects are recognized. Finally, coalescence of closely spaced crystals ordered into an hexagonal array is investigated. Two possible alignments of the pattern are compared and the most convenient arrangement is evaluated.


How much information about adverse effects of medication do patients want from physicians?
Little information exists concerning the amount of information patients expect from physicians as to the risk for an adverse medication reaction. The present study was designed to determine such opinions in a population sample; to correlate results with sex, age, educational level, and previous experience with adverse effects; and to determine whether patients believe physicians should use discretion in the amount of such information given. Two thousand five hundred sequential adults visiting outpatient clinics filled out a 12-item questionnaire. Percentages of subjects desiring information about varying degrees of risk and those believing physicians should and should not use discretion in the amount of such information provided were recorded. Results were correlated with demographic variables and previous experience of adverse effects. Among the respondents, 76.2% desired to be told of all possible adverse effects; 13.3% only if an adverse effect occurred 1 in 100 000 times; and 10.2% only if such occurrence was 1 in 100 times; 0.4% were not interested in any information. (Percentages have been rounded and do not total 100.) Percentages were closely similar to those for the same question that restricted opinion to serious adverse effects. Desire for maximum information was significantly correlated with lower educational level (P<.00l) and previous frequent experience with adverse effects (P<.001) and in older women (P<.001). The opinion that the physician should give the same information to all patients was given by 67.6% of the sample, and 73.4% opined that physicians were never justified in withholding any information. Most individuals desire from physicians all information concerning possible adverse effects of prescribed medication and do not favor physician discretion in these decisions.


Primary tumor xenografts of human lung adeno and squamous cell carcinoma express distinct proteomic signatures.
Nonsmall cell lung carcinoma (NSCLC) accounts for 80% of lung cancers. The most prevalent subtypes of NSCLC are adenocarcinoma (ADC) and squamous cell carcinoma (SCC), which combined account for approximately 90%. Ten resected NSCLC patient tumors (5 ADC and 5 SCC) were directly introduced into severely immune deficient (NOD-SCID) mice, and the resulting xenograft tumors were analyzed by standard histology and immunohistochemistry (IHC) and by proteomics profiling. Mass spectrometry (MS) methods involving 1- and 2-dimensional LC-MS/MS, and multiplexed selective reaction monitoring (SRM, or MRM), were applied to identify and quantify the xenograft proteomes. Hierarchical clustering of protein profiles distinguished between the ADC and SCC subtypes. The differential expression of 178 proteins, including a comprehensive panel of intermediate filament keratin proteins, was found to constitute a distinctive proteomic signature associated with the NSCLC subtypes. Epidermal growth factor receptor (EGFR) was expressed in ADC and SCC xenografts, and EGFR network activation was assessed by phosphotyrosine profiling by Western blot analysis and SRM measurement of EGFR levels, and mutation analysis. A multiplexed SRM/MRM method provided relative quantification of several keratin proteins, EGFR and plakophilin-1 in single LC-MS/MS runs. The protein quantifications by SRM and MS/MS spectral counting were associated with superior dynamic range and reproducibility but were otherwise consistent with orthogonal methods including IHC and Western immuno blotting. These findings illustrate the potential to develop a comprehensive MS-based platform in oncologic pathology for better classification and potentially treatment of NSCLC patients.


Glutamate Is a Wake-Active Neurotransmitter in Drosophila melanogaster.
In mammals, there is evidence that glutamate has a role as a wake-active neurotransmitter. So using video-based analysis of Drosophila behavior, we undertook a study to examine if glutamate, which has been previously shown to have an excitatory role in neuromuscular junctions in Drosophila, may have a conserved wake-active role in the adult brain. Using 6- to 9-day-old female flies, we examined the effect of perturbations of the glutamatergic signaling on total wakefulness and wake bout architecture. We increased and decreased neuronal activity of glutamatergic neurons in the brains of adult flies using Upstream Activating Sequence (UAS) NaChBac and UAS EKO, respectively. We blocked neurotransmission from glutamatergic neurons in adult flies using the UAS-driven temperature-sensitive dynamin mutation shibirets. We examined the behavior of flies with loss of function mutations of individual subunits of brain-specific ionotropic glutamate receptors. Increasing the activity of glutamatergic neurons in the adult brain led to a significant increase in wakefulness compared to the control groups both in the daytime and nighttime and decreasing the activity of these same neurons reduced wakefulness in the nighttime. Blocking neurotransmitter release in glutamatergic neurons significantly reduced wake in the nighttime. The ionotropic receptor mutants had significantly less wake in the nighttime than their respective genetic background controls. The results show the following: glutamate is indeed a wake-active neurotransmitter in Drosophila; there is a major time of day effect associated with loss of glutamatergic neurotransmission; and it is a major wake-active neurotransmitter in the nighttime.


Ventricular-Arterial Coupling in Children and Infants With Congenital Heart Disease After Cardiopulmonary Bypass Surgery: Observational Study.
Ventricular-arterial coupling represents the interaction between the left ventricle and the arterial system. Ventricular-arterial coupling is measured as the ratio between arterial elastance and ventricular end-systolic elastance. Scant information is available in critically ill children about these variables. The aim of this study was to prospectively assess ventricular-arterial coupling after pediatric cardiac surgery and evaluate its association with other commonly recorded hemodynamic parameters. Single-center retrospective observational study. Pediatric cardiac surgery operating room. Children undergoing corrective cardiac surgery. Hemodynamic monitoring with transesophageal echocardiography. Twenty-seven patients with biventricular congenital heart disease, who underwent elective cardiac surgery with cardiopulmonary bypass, were enrolled before operating room discharge. Chen single-beat modified method was applied to calculate ventricular-arterial coupling. The median arterial elastance and end-systolic elastance values were 5.9 mm Hg/mL (2.2-9.3 mm Hg/mL) and 4.3 mm Hg/mL (1.9-8.3 mm Hg/mL), respectively. The median ventricular- arterial coupling was 1.2 (1.1-1.6). End-systolic elastance differences between patients with a ventricular-arterial coupling below (low ventricular-arterial coupling) and above (high ventricular-arterial coupling) the median value were -5.2 (95% CI, -6.28 to -0.7; p = 0.008). Differently, arterial elastance differences were -2.1 (95% CI, -5.7 to 1.6; p = 0.19). Ventricular-arterial coupling showed a significant association with pre-ejection time (r, 0.44; p = 0.02), total ejection time (r, -0.41; p = 0.003), cardiac cycle efficiency (r, -0.46; p = 0.02), maximal delta pressure over delta time (r, -0.44; p = 0.02), ejection fraction (r, -0.57; p = 0.01), and systemic vascular resistances indexed (0.56; p = 0.003). After adjustment, total ejection time (p = 0.001), pre-ejection time (p = 0.02), and ejection fraction (p = 0.001) remained independently associated with ventricular-arterial coupling. Median ventricular-arterial coupling values in children after cardiac surgery appear high (above 1). Uncoupling was particularly evident in high ventricular-arterial coupling patients who showed the lowest end-systolic elastance values (but not significantly different arterial elastance values) compared with low ventricular-arterial coupling. Ventricular-arterial coupling appears to be inversely proportional to pre-ejection time, total ejection time, and ejection fraction.


Lipid molecular shape affects erythrocyte morphology: a study involving replacement of native phosphatidylcholine with different species followed by treatment of cells with sphingomyelinase C or phospholipase A2.
In a previous report it was shown that the replacement of native erythrocyte phosphatidylcholine (PC) with different PC species which have defined acyl chain compositions can lead to morphological changes (Kuypers, F.A., W. Berendsen, B. Roelofsen, J. A. F. Op den Kamp, and L.L.M. van Deenen, 1984, J. Cell Biol., 99:2260-2267). It was proposed that differences in molecular shape between the introduced PC species and normal erythrocyte PC caused the membrane to bend outwards or inwards, depending on the shape of the PC exchanged. To support this proposal, two requirements would have to be fulfilled: the exchange reaction would take place only with the outer lipid monolayer of the erythrocyte, and the extent of lipid transbilayer movement would be restricted. If this theory is correct, any treatment causing unilateral changes in lipid molecular shape should lead to predictable morphological changes. Since this hypothesis is a refinement of the coupled bilayer hypothesis, but so far lacks experimental support, we have sought other means to change lipid molecular shape unilaterally. Shape changes of human erythrocytes were induced by the replacement of native PC by various PC species using a phosphatidylcholine-specific transfer protein: by hydrolysis of phospholipids in intact cells using sphingomyelinase C or phospholipase A2, and by the combination of both procedures. The morphological changes were predictable; additive when both treatments were applied, and explicable on the basis of the geometry of the lipid molecules involved. The results strongly support the notion that lipid molecular shape affects erythrocyte morphology.


Reduction in wool follicles prior to birth in Merino sheep.
This study was undertaken to identify whether all secondary follicles that are initiated are present at birth in the Merino fetus, and if not, when does net initiation of secondary follicles cease. Skin was sampled from fetal lambs at 36, 26 and 16 days before the estimated date of parturition and from lambs at birth and 2, 4, 6, 8 and 13 weeks after birth. The ratio of secondary to primary follicles (S/P) reached a maximum 16 days before birth and was significantly lower at birth (P<0.002) and at all postnatal ages (P<0.05). There was no difference between S/P at birth and S/P at later ages. Postnatal primary follicle density, secondary follicle density and the percentage of fibre-producing follicles followed similar patterns to those reported by others. This is the first conclusive demonstration that secondary follicle initiation is completed several weeks prior to birth and that there are less secondary follicles at birth than at 134 days of gestation.


Effect of all-trans retinoic acid on airway inflammation in asthmatic rats and its mechanism.
The inhibitive effects of all-trans retinoic acid (ARTA) on airway inflammation in asthmatic rats and its mechanism on the basis of the regulation of nuclear factor kappaB (NF-kappaB) were explored. Thirty-two SD rats were randomly divided into 4 groups: control group, asthma group, dexamethasone treatment group and retinotic acid treatment group. The total and differential cell counts in the collected bronchoalveolar lavage fluid (BALF) were measured. The pathological changes in lung tissues were estimated by scoring. The expression of NF-kappaB inhibitor (IkappaBa), NF-kappaB, intercellular adhering molecule-1 (ICAM-1) in lung tissue was detected by immunohistochemical method. The results showed that in the two treatment groups, the total cell counts and proportion of inflammatory cells in BALF were significantly reduced, but there was no significant difference in differential cell counts in BALF between them. The pathological changes in lung tissues in the treatment groups were significantly attenuated as compared with asthma group. Except the epithelial injury in retinotic acid treatment group was milder than in dexamethasone treatment group, the remaining lesions showed no significant difference between them. In the two treatment groups, the expression of IkappaBa was increased, while the expression of NF-kappaB and ICAM-1 decreased with the difference between the two groups being not significant. It was concluded that the similar anti-inflammatory effects and mechanism of ATRA on airway in asthmatic rats to those of dexamethasone were contributed to the increase of cytoplasmic IkappaBa content and suppression of NF-kappaB activation and expression.


SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue.
SERINC5 is a host restriction factor that impairs infectivity of HIV-1 and other primate lentiviruses and is counteracted by the viral accessory protein Nef. However, the importance of SERINC5 antagonism for viral replication and cytopathicity remained unclear. Here, we show that the Nef protein of the highly divergent SIVcol lineage infecting mantled guerezas (Colobus guereza) is a potent antagonist of SERINC5, although it lacks the CD4, CD3 and CD28 down-modulation activities exerted by other primate lentiviral Nefs. In addition, SIVcol Nefs decrease CXCR4 cell surface expression, suppress TCR-induced actin remodeling, and counteract Colobus but not human tetherin. Unlike HIV-1 Nef proteins, SIVcol Nef induces efficient proteasomal degradation of SERINC5 and counteracts orthologs from highly divergent vertebrate species, such as Xenopus frogs and zebrafish. A single Y86F mutation disrupts SERINC5 and tetherin antagonism but not CXCR4 down-modulation by SIVcol Nef, while mutation of a C-proximal di-leucine motif has the opposite effect. Unexpectedly, the Y86F change in SIVcol Nef had little if any effect on viral replication and CD4+ T cell depletion in preactivated human CD4+ T cells and in ex vivo infected lymphoid tissue. However, SIVcol Nef increased virion infectivity up to 10-fold and moderately increased viral replication in resting peripheral blood mononuclear cells (PBMCs) that were first infected with HIV-1 and activated three or six days later. In conclusion, SIVcol Nef lacks several activities that are conserved in other primate lentiviruses and utilizes a distinct proteasome-dependent mechanism to counteract SERINC5. Our finding that evolutionarily distinct SIVcol Nefs show potent anti-SERINC5 activity supports a relevant role of SERINC5 antagonism for viral fitness in vivo. Our results further suggest this Nef function is particularly important for virion infectivity under conditions of limited CD4+ T cell activation.


Monkeypox virus detection in rodents using real-time 3'-minor groove binder TaqMan assays on the Roche LightCycler.
During the summer of 2003, an outbreak of human monkeypox occurred in the Midwest region of the United States. In all, 52 rodents suspected of being infected with monkeypox virus were collected from an exotic pet dealer and from private homes. The rodents were euthanized and submitted for testing to the United States Army Medical Research Institute of Infectious Diseases by the Galesburg Animal Disease Laboratory, Illinois Department of Agriculture. The rodent tissue samples were appropriately processed and then tested by using an integrated approach involving real-time polymerase chain reaction (PCR) assays, an antigen-detection immunoassay, and virus culture. We designed and extensively tested two specific real-time PCR assays for rapidly detecting monkeypox virus DNA using the Vaccinia virus F3L and N3R genes as targets. The assays were validated against panels of orthopox viral and miscellaneous bacterial DNAs. A pan-orthopox electrochemiluminescence (ECL) assay was used to further confirm the presence of Orthopoxvirus infection of the rodents. Seven of 12 (58%) animals (seven of 52 (15%) of all animals) tested positive in both monkeypox-specific PCR assays and two additional pan-orthopox PCR assays (in at least one tissue). The ECL results showed varying degrees of agreement with PCR. One hamster and three gerbils were positive by both PCR and ECL for all tissues tested. In addition, we attempted to verify the presence of monkeypox virus by culture on multiple cell lines, by immunohistology, and by electron microscopy, with negative results. Sequencing the PCR products from the samples indicated 100% identity with monkeypox virus strain Zaire-96-I-16 (a human isolate from the Congo). These real-time PCR and ECL assays represent a significant addition to the battery of tests for the detection of various orthopoxviruses. In light of the recent monkeypox virus transmissions, early detection of the virus is crucial for both natural outbreaks and potential acts of bioterrorism.


The Endocrine Society's Clinical Practice Guideline on endocrine and nutritional management of the post-bariatric surgery patient: commentary from a European Perspective.
Bariatric and metabolic surgery is experiencing a noteworthy increase worldwide in recent years, but protocols and consensus published in the past decade have not yet established clear evidence-based clinical recommendations. The Endocrine Society, with the participation of the European Society of Endocrinology, has promoted the creation of an expert panel to propose a clinical practice guideline for postoperative management of patients, candidates to bariatric surgery, that places a particular emphasis on evidence-based medical aspects. The main arguments reflected in those recommendations are set out in this article and are subject to analysis and discussion from the specific viewpoint of the current European experience.


Learning curve of ultrasound measurement of subglottic diameter for endotracheal tube selection in pediatric patients.
Endotracheal tube size can be predicted according to ultrasound measurement of subglottic airway diameter. The learning curve for this method is not yet established. The aim was to evaluate the learning curve of anesthesiology residents in ultrasound measurement of subglottic airway diameter for prediction of endotracheal tube size using cumulative sum analysis. Sixteen anesthesiology residents measured transverse subglottic airway diameter in children undergoing general anesthesia with cuffed endotracheal intubation. Each resident performed 30 ultrasound examinations. Primary outcome was the successful prediction of endotracheal tube size according to ultrasound measurement. Cumulative sum analysis was performed with acceptable and unacceptable failure rates set as 20 and 40%, respectively. Ten out of 16 residents (62.5%) were deemed successful as they were able to pass lower decision boundary, whereas six residents' CUSUM scores were between the decisions lines deeming them indeterminate. The overall success rate for determining the correct endotracheal tube size was 77.5%. Median number of attempts to cross lower decision boundary was 29 with minimum of 18 and maximum of 29 attempts among successful residents. Learning curves constructed with cumulative sum analysis in this study showed that only 62.5% of residents were able to correctly predict cuffed endotracheal tube size with 80% success rate. Considerable variability in achieving competency necessitates objective follow-up of individual improvement.


Retrograde air embolization during routine radial artery catheter flushing in adult cardiac surgical patients: an ultrasound study.
Rapid flushing of radial artery catheters may result in retrograde embolization of air into the cerebral circulation. This study examined the incidence of central air embolization during and after flushing of an arterial pressure monitoring system. One hundred adult patients undergoing cardiac surgical procedures were enrolled in this study. Ten ml of saline and blood were withdrawn into a syringe in the arterial flushing-sampling pressure system and then readministered to the patient through a 20-gauge radial artery catheter over 3-12 s. The right carotid artery, left carotid artery, and aortic arch were visualized using ultrasound imaging techniques during three manual flushes of the system. The left and right common carotid arteries were examined for the presence of macrobubbles or microbubbles using a linear array ultrasound transducer. The aortic arch was imaged using transesophageal echocardiography to detect retrograde air emboli. The severity of air embolization was quantified using a modification of an established grading system. A total of 298 ultrasound studies in 100 patients were recorded and analyzed after radial artery catheter flushing. Two aortic arch images were not obtained because of an inability to place the probe. Most clinicians (54%) returned flush solution to patients at near-maximal injection rates (2-3 ml per second). No air emboli (macrobubbles or microbubbles) were detected in the carotid arteries or aortic arch of any subject. Retrograde air embolization is a rare event after routine radial artery catheter flushing in adult patients with stable hemodynamic conditions.


Adrenaline-induced platelet aggregation in patients with chronic urticaria and in patients with multiple drug intolerance.
It is now generally accepted that the beta-adrenergic system may play a role in the pathogenesis of allergic manifestations. One of the most interesting experimental models is the adrenaline induced platelet aggregation test, in which adrenaline selectively stimulates the beta-adrenergic receptors activating adenylcyclase. This test was considered as a model in the study of beta-receptor function in patients with allergic disorders. It therefore seemed worthwhile to submit two different groups of patients to this test, namely: a) Patients with chronic urticaria. Since in the large majority of cases no immunoallergic mechanism has been detected, various hypotheses have been proposed to explain its onset. b) Patients showing intolerance to several drugs: this is a large category of patients, predominantly females, presenting allergic-like reactions, mostly of the urticarioidangioedematous type, occurring following administration of various types of drugs. The investigation was performed on subjects of both sexes, grouped as follows: a) 33 patients with chronic urticaria. b) 31 patients with multiple drug intolerance. c) 28 normal volunteers (control subjects). From the results obtained it can be concluded that a tendency toward hyperagregation was more evident in patients with urticaria and less evident in those with multiple drug intolerance. The only finding of interest concerns the second aggregation wave, which was less frequent in patients with urticaria than in normal subjects, but the difference was not statistically significant. The adrenaline-induced platelet aggregation test does not appear to provide useful information on a deficit of beta-receptor function in the patients studied.


Basic principles of liver allocation and development over the years.
Prior to the enactment of the National Organ Transplant Act in 1984, there was no organized system to allocate donor organs in the United States. The process of liver allocation has come a long way since then, including the development and implementation of the Model for End-stage Liver Disease, which is an objective estimate of risk of mortality among candidates awaiting liver transplantation. The Liver Transplant Community is constantly working to optimize the distribution and allocation of scare organs, which is essential to promote equitable access to a life-saving procedure in the setting of clinical advances in the treatment of liver disease. Over the past 17 years, many changes have been made. Most recently, liver distribution changed such that deceased donor livers will be distributed based on units established by geographic circles around a donor hospital rather than the current policy, which uses donor service areas as the unit of distribution. In addition, a National Liver Review Board was created to standardize the process of determining liver transplant priority for candidates with exceptional medical conditions. The aim of these changes is to allocate and distribute organs in an efficient and equitable fashion. The current review provides a historical perspective of liver allocation and the changing landscape in the United States.


Zn2+-Enhanced Lithium Magnesium Molybdate Ultralow Temperature Cofired Ceramics for Terahertz Wavefront Modulation Applications.
High efficiency, high frequency, low error, and low latency of wavefront modulation are challenges that must be addressed simultaneously in 5G/6G communication systems. In order to cope with these challenges, novel Li2Mg2-xZnxMo3O12 (x = 0.00-0.08) ceramics are prepared by a solid-state reaction method. The microwave dielectric properties (εr = 8.7, Q × f = 61,312 GHz, τf = -59.1 ppm/°C) and terahertz transmission properties (εr1 = 8.3, tanδ1 = 0.00908, Tamplitude = 0.673, Δphase = 27.65°) of this ceramic (x = 0.06, 625 °C) are effectively enhanced by Zn2+. The chemical compatibility between this ceramic and the Al electrode is demonstrated. The reflection amplitude of this ceramic combined with the Al electrode at 0.5 THz is revealed, and the error between simulation and experiment is only 0.06. A terahertz reflective device for wavefront modulation is designed and demonstrated by using this ceramic and Al electrode. This device can deflect the wavefront of cross-polarized waves and has a certain isolation effect on co-polarized waves. This work accelerates the development of dielectric ceramics and ultralow temperature cofired ceramics technology in the terahertz field.


Epidemiology of Pneumocystis jirovecii Pneumonia and (Non-)use of Prophylaxis.
Objectives:Pneumocystis jirovecii pneumonia (PCP) is an AIDS-defining illness. In patients with HIV, the benefit of PCP prophylaxis is well-defined when the CD4 T-cell count decreases below 200 cells/μL. In other immunocompromised patients, the value of PCP prophylaxis is not always as well-established. This study aimed to describe the epidemiology of PCP in recent years and assess how many patients with PCP did or did not receive prophylaxis in the month preceding the infection. Material and Methods: A multicenter retrospective study was performed in 3 tertiary care hospital. A list of patients that underwent broncho-alveolar lavage sampling and Pneumocystis jirovecii (PJ) PCR testing was retrieved from the microbiology laboratories. An in-house PJ quantitative PCR (qPCR) was used in each center. A cycle threshold (Ct) value of ≤ 28.5-30 was considered a probable PCP. For patients with a positive PJ qPCR but above this threshold, a predefined case definition of possible PCP was defined as a qPCR Ct value ≤ 34-35 and both of the following criteria: 1. Clinical and radiological features compatible with PCP and 2. The patient died or received PCP therapy and survived. Patient files from those with a qPCR Ct value ≤ 35 were reviewed to determine whether the patient fulfilled the case definition and if PCP prophylaxis had been used in the weeks preceding the PCP. Disease-specific guidelines, as well as hospital-wide guidelines, were used to evaluate if prophylaxis could be considered indicated. Results: From 2012 to 2018, 482 BAL samples were tested. Two hundred and four had a qPCR Ct value ≤ 35 and were further evaluated: 90 fulfilled the definition of probable and 63 of possible PCP while the remaining 51 were considered colonized. Seventy-four percentages of the patients with PCP were HIV-negative. Only 11 (7%) of the 153 patients had received prophylaxis, despite that in 133 (87%) cases prophylaxis was indicated according to guidelines. Conclusion: In regions where HIV testing and treatment is available without restrictions, PCP is mainly diagnosed in non-HIV immunocompromised patients. More than four out of five patients with PCP had not received prophylaxis. Strategies to improve awareness of antimicrobial prophylaxis guidelines in immunocompromised patients are urgently needed.


Do spouse caregivers of young and older persons with dementia have different needs? A comparative study.
The aim of this study was to explore the needs of spouse caregivers of persons with dementia (PWD) and then to compare them based on the PWD's age at disease onset. This data could be used to adapt support programmes to address differences between the two groups. Thirty-eight spouse caregivers of persons with late-onset dementia and 40 spouse caregivers of persons with early-onset dementia (PEOD) agreed to participate in the study. The mean ± SD age of the PEOD was 57.6 ± 4.0 years, whereas it was 80.9 ± 5.3 years for the persons with late-onset dementia. Interviews were conducted in the spouse caregivers' homes with only the spouse caregiver. The semi-structured interviews were based on the French version of the Carers Outcome Agreement Tool. The interviews were analyzed in two steps. The first step was qualitative to identify needs. The data were thematically analyzed using QSR NVivo 10. The second step was quantitative to compare the needs depending on the PWD's age at onset. The comparison between the two groups was performed using the χ2 test. The results demonstrated that the majority of needs are the same for the two groups of spouse caregivers. All caregivers need to unwind, to stimulate and pay attention to the PWD, to break the isolation, and to be more prepared and confident. However, some differences emerge, with the spouse caregivers of PEOD expressing a greater number of needs. The caregivers of PEOD seem to have a greater need to interact and maintain contacts with other people (P = 0.001), have more general care-related needs (P = 0.005), require more appropriate care structures (P = 0.037), and need greater assistance with administrative procedures (P = 0.004). To improve spouse caregivers' well-being and sense of efficiency, it would be interesting to develop a support programme with a common framework and specific modules depending on the PWD's age at disease onset.


Predictors of brain morphology for the men of the NHLBI twin study.
Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy, accumulation of abnormal cerebral white matter signals, and clinically silent stroke. We extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy, amount of abnormal white matter, and stroke on MRI. Subjects were the 414 surviving members of the prospective National Heart, Lung, and Blood Institute Twin Study, who have been examined on 4 separate occasions, spanning the 25 years between 1969-1973 and 1995-1997. Quantitative measures of brain volume, volume of abnormal white matter signal (WMHI), and volume of stroke, when present, were obtained from those participating in the fourth examination. The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72. 5+/-2.9 years at final examination. Average blood pressure (BP) levels were normal, although 32% of the subjects had received or were currently taking antihypertensive medications. As a group, 31% had symptomatic cardiovascular disease, 11% had symptomatic cerebrovascular disease, and 8% had symptomatic peripheral vascular disease. Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume. Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes. In addition, the magnitude of orthostatic BP change was significantly associated with WMHI volume. Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease, without significant differences in the prevalence of hypertension treatment. Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease. Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease, extensive WMHI may be a subclinical expression of cerebrovascular disease. Careful treatment of midlife BP elevations may diminish these later-life brain changes.


Control of precerebellar neuron development by Olig3 bHLH transcription factor.
The rhombic lip (RL) is the neuroepithelium immediately adjacent to the roof plate of the fourth ventricle, and it gives rise to various brainstem and cerebellar cell types. Our study shows that the bHLH (basic helix-loop-helix) transcription factor Olig3 is expressed in the progenitors of RL, and ablation of Olig3 significantly affects the development of RL. In Olig3-/- caudal RL, the expression level of Math1 in the dorsal interneuron 1 (dI1) domain is reduced, and the formation of four mossy-fiber nuclei is compromised; dI2-dI3 neurons are misspecified to dI4 interneurons, and the climbing-fiber neurons (inferior olive nucleus) are completely lost. In addition, the formation of brainstem (nor)adrenergic centers and first-order relay visceral sensory neurons is also dependent on Olig3. Therefore, Olig3 plays an important role in the fate specification and differentiation of caudal RL-derived neurons.


Occurrence and characteristics of group 1 introns found at three different positions within the 28S ribosomal RNA gene of the dematiaceous Phialophora verrucosa: phylogenetic and secondary structural implications.
Group 1 introns (ribozymes) are among the most ancient and have the broadest phylogenetic distribution among the known self-splicing ribozymes. Fungi are known to be rich in rDNA group 1 introns. In the present study, five sequences of the 28S ribosomal RNA gene (rDNA) regions of pathogenic dematiaceous Phialophora verrucosa were analyzed using PCR by site-specific primers and were found to have three insertions, termed intron-F, G and H, at three positions of the gene. We investigated the distribution of group 1 introns in this fungus by surveying 34 strains of P. verrucosa and seven strains of Phialophora americana as the allied species. Intron-F's (inserted at L798 position) were found in 88% of P. verrucosa strains, while intron-G's (inserted at L1921) at 12% and intron-H's (inserted at L2563) at 18%. There was some correlation between intron distribution and geographic location. In addition, we confirmed that the three kinds of introns are group 1 introns from results of BLAST search, alignment analysis and Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Prediction of secondary structures and phylogenetic analysis of intron sequences identified introns-F and G as belonging to subgroup IC1. In addition, intron-H was identified as IE. The three intron insertions and their insertion position in the 28S rDNA allowed the characterization of the clinical and environmental isolates of P. verrucosa and P. americana into five genotypes. All subgroups of introns-F and G and intron-H were characterized and observed for the first time in both species.


[Fatal cases of adenovirus infection].
Sixteen fatal cases of adenovirus infection in infants (n:10 aged 1 to less than 12 months) and children (n:6 aged 1 to 3, 8/12 years) are reported. Diagnosis were confirmed by direct viral isolation, viral immunofluorescence or both in 15 patients, and by autopsy in 12 of them, including one without positive virological workup. Evidence of multisystemic compromise, particularly that of severe lower respiratory tract infection was observed and lead to death by acute respiratory failure in all cases. White blood cell counts and erythrocyte sedimentation rate did not help to label initially the etiology as either viral or bacterial. Chest roentgenograms showed pulmonary over-inflation and evidence of pneumonitis as well as extensive and rapidly progressive lung opacifications. Most prominent pathologic findings were necrotizing bronchitis, bronchiolitis and broncopneumonia. Several cells containing typical intranuclear inclusion bodies were documented in ten cases and pneumonitis was the only finding in two. Hepatic fat infiltration and lymphocitic depletion of thymus, spleen and lymphatic nodes occurred in all cases. The need of rapid diagnostic tools to avoid nosocomial spread of this kind of infections with such serious consequences is stressed.


Exon level integration of proteomics and microarray data.
Previous studies comparing quantitative proteomics and microarray data have generally found poor correspondence between the two. We hypothesised that this might in part be because the different assays were targeting different parts of the expressed genome and might therefore be subjected to confounding effects from processes such as alternative splicing. Using a genome database as a platform for integration, we combined quantitative protein mass spectrometry with Affymetrix Exon array data at the level of individual exons. We found significantly higher degrees of correlation than have been previously observed (r = 0.808). The study was performed using cell lines in equilibrium in order to reduce a major potential source of biological variation, thus allowing the analysis to focus on the data integration methods in order to establish their performance. We conclude that part of the variation observed when integrating microarray and proteomics data may occur as a consequence both of the data analysis and of the high granularity to which studies have until recently been limited. The approach opens up the possibility for the first time of considering combined microarray and proteomics datasets at the level of individual exons and isoforms, important given the high proportion of alternative splicing observed in the human genome.


Occult papillary thyroid carcinoma: prevalence at autopsy in Turkish people.
The epidemiological features of occult papillary thyroid carcinoma (OPTC) at autopsy have not previously been reported in Turkish people. This study provides data on the prevalence of OPTC in people from the Marmara region in Turkey. The study includes thyroid glands from 93 male and 15 female cadavers between 18 and 80 years of age. The thyroid glands were removed, fixed and sectioned at 2-mm intervals. The sections were stained with hematoxylin and eosin, and were examined by a single pathologist. A total of 108 thyroid glands were examined. Macroscopic lesions were found in 36 (33.3%) glands (95% confidence interval=24-42). OPTC was found in four (3.7%) cases (95% confidence interval=1.0-7.5). It was concluded that in the Turkish people from the Marmara region, the prevalence of OPTC found at autopsy was relatively low. No age or sex predilection was detected.


Tunneled femoral dialysis catheter: Practical pointers.
One of the most challenging aspects of providing end-stage kidney disease care is to achieve adequate long-term access to the bloodstream to support hemodialysis (HD) therapy. Although upper extremity arteriovenous fistula remains the vascular access of choice for patients on HD, complications such as central venous stenosis, access thrombosis, or exhaustion of suitable access sites in the upper extremity, ultimately result in pursuing vascular access creation in the lower extremity. The current review focuses on the indications, contraindications, and clinically relevant practical procedural tips to successfully place a tunneled femoral dialysis catheter. The review highlights some of the prevailing misconceptions regarding femoral catheter placement practices.


Isolated perianal verrucoid familial benign chronic pemphigus.
A case is described in which verrucous perianal lesions of familial benign chronic pemphigus (Hailey-Hailey disease) were initially mistaken for condylomata acuminata. The verrucoid, atypical form of the disease has only relatively recently been recognized and perianal lesions may easily be mistaken as manifestations of other conditions.


Biofilm formation, antibiotic susceptibility and RAPD genotypes in Pseudomonas aeruginosa clinical strains isolated from single centre intensive care unit patients.
The aim of this study was to analyse genotypes, antimicrobial susceptibility patterns and serotypes in Pseudomonas aeruginosa clinical strains, including the clonal dissemination of particular strains throughout various intensive care units in one medical centre. Using random amplified polymorphic DNA (RAPD-PCR) and P. aeruginosa antisera, 22 different genotypes and 8 serotypes were defined among 103 isolates from 48 patients. No direct association between P. aeruginosa strain genotypes and serotypes was observed. RAPD typing in strains with the same serotype revealed different genotypes and, on the contrary, most strains with a different serotype displayed the same amplification pattern. The resulting banding patterns showed a high degree of genetic heterogeneity among all isolates from the patients examined, suggesting a non-clonal relationship between isolates from these patients. A higher degree of antibiotic resistance and stronger biofilm production in common genotypes compared to rare ones and genetic homogeneity of the most resistant strains indicated the role of antibiotic pressure in acquiring resistant and more virulent strains in our hospital. In conclusion, genetic characterisation of P. aeruginosa strains using RAPD method was shown to be more accurate in epidemiological analyses than phenotyping.


The novel nitric oxide synthase inhibitor 4-amino-tetrahydro-L-biopterine prevents brain edema formation and intracranial hypertension following traumatic brain injury in mice.
Brain edema formation, resulting in increased intracranial pressure (ICP), is one of the most deleterious consequences of traumatic brain injury (TBI). Nitric oxide (NO) has previously been shown to be involved in the damage of the blood-brain barrier (BBB) and, thus, in the formation of post-traumatic brain edema; however, this knowledge never resulted in a clinically relevant therapeutic option because available NO synthase inhibitors have serious side effects in man. The aim of the current study was to investigate the therapeutic efficacy of VAS203, a novel tetrahydrobiopterine (BH3)-based NOS inhibitor, in experimental TBI. When added to isolated vessels rings obtained from rat basilar and middle cerebral arteries (n = 32-35) VAS203 showed the same vasoconstrictive effect as the classical NO synthase inhibitor L-(G)-nitro-arginine-methylester (L-NAME). VAS203 passed the BBB both in healthy and traumatized mouse brain (C57/BL6, n = 5 per group) and did not show any systemic side effects at therapeutic concentrations. When administered 30 min after experimental TBI (controlled cortical impact, 2.2 mg/kg/min i.v., n = 7 per group), VAS203 prevented any further increase in ICP or deterioration of cerebral blood flow. This effect was dose-dependent and long-lasting (i.e., 24 h after trauma, brain edema formation was still significantly reduced [-40%, p < 0.008; n = 7 per group] and functional improvements were present up to 7 days after TBI [p < 0.02 on post-trauma day 6; n = 8 per group]). Therefore, VAS203 may represent a promising candidate for the treatment of acute intracranial hypertension following TBI.


Tunable strong coupling of two adjacent optical λ/2 Fabry-Pérot microresonators.
Strong optical mode coupling between two adjacent λ/2 Fabry-Pérot microresonators consisting of three parallel silver mirrors is investigated experimentally and theoretically as a function of their detuning and coupling strength. Mode coupling can be precisely controlled by tuning the mirror spacing of one resonator with respect to the other by piezoelectric actuators. Mode splitting, anti-crossing and asymmetric modal damping are observed and theoretically discussed for the symmetric and antisymmetric supermodes of the coupled system. The spectral profile of the supermodes is obtained from the Fourier transform of the numerically calculated time evolution of the individual resonator modes, taking into account their resonance frequencies, damping and coupling constants, and is in excellent agreement with the experiments. Our microresonator design has potential applications for energy transfer between spatially separated quantum systems in micro optoelectronics and for the emerging field of polaritonic chemistry.


Quality of life of patients with strabismus.
To evaluate the impact of strabismus on quality of life. This cross-sectional study included 101 individuals aged 7-67 years with strabismus. They were interviewed and made to answer a questionnaire with 20 questions intended to assess the individual's interaction with their social and working environment, sensory perception, and limitations in their daily lives. There were five types of possible responses for each question: never, rarely or very few times, sometimes, frequently, and always. The questionnaire was based on the AS-20 and contained 11 questions assessing psychosocial aspects and 9 questions assessing functional aspects. Among those who were interviewed, 24.8% had undergone surgical correction of strabismus. We observed a significant impact of strabismus on the quality of life of the interviewed individuals. Feelings of sadness and inferiority because of strabismus were reported by 74.2% and 58.4% respondents, respectively. In terms of functionality, 12.1% reported difficulty in reading, 14% said they had difficulty in depth perception (stereopsis), and 17.8% frequently or always associated pain or burning sensation in the eyes to strabismus. A significant difference was detected in the quality of life scores for the psychosocial aspect among patients who had and had not undergone surgery (Wilcoxon test, 158; p<0.001). Individuals who had undergone surgery had a better quality of life from the psychosocial perspective. In this evaluation, we found a significant negative interference of strabismus on quality of life from both the functional and psychosocial perspectives. This demonstrated the importance of treatment for strabismus, regardless of age, because it can interfere with the functional well-being of the individual.


Confined phase separation of aqueous-organic nanodroplets.
Nano-confined supercooled water occurs frequently in aqueous-organic aerosol nanodroplets that are ubiquitous in the atmosphere and in many industrial processes such as natural gas refining. The structure of these nanodroplets is important because it influences droplet growth and evaporation rates, nucleation rates, and radiative properties. We used classical molecular dynamics (MD) simulations to study the structures of binary water-butanol nanodroplets for several temperatures and droplet sizes. Water-butanol cross interactions are calculated using a Lennard-Jones (LJ) potential with non-bonded specific parameters adjusted to reproduce the experimentally observed mutual solubilities of water-butanol at 295 K. To compare with the results of the density functional theory (DFT) of aqueous-organic nanodroplets [Phys. Chem. Chem. Phys., 2006, 8, 1266-1270], we focus on T = 250 K. Our simulations show three different nanodroplet structures depending on the butanol concentration. For low concentrations, we observe a core-shell (CS) structure in which a butanol shell completely wets a water-rich core. For high concentrations, a well-mixed (WM) structure occurs as the water and the butanol become fully miscible. For intermediate concentrations of butanol, we find a distinct phase-separated Russian Doll-Shell (RDS) structure. This RDS structure consists of a roughly ellipsoidal water-rich droplet partially wetted by a well-mixed water/butanol convex lens (RD) and this lens-on-sphere structure is coated by a thin shell of butanol. We also examined the stability of our RDS structure at a higher temperature and found that at 295 K, the RDS structure had transformed into a well-mixed droplet, presumably due to the increase in the mutual solubility of water and butanol. Finally, we performed calculations using classical density functional theory for conditions that should favor the RDS structure. The results closely resembled those found using MD.


Trends in stricture management among male Medicare beneficiaries: underuse of urethroplasty?
To analyze the trends in male urethral stricture management using the 1992-2001 Medicare claims data and to determine whether certain racial and ethnic groups have a disproportionate burden of urethral stricture disease. We analyzed the Medicare claims for fiscal years 1992, 1995, 1998, and 2001. The "International Classification of Disease, 9th revision," diagnosis codes were used to identify men with urethral stricture. The demographic characteristics assessed included patient age, race, and comorbidities, as measured using the Charlson index. Treatments were identified using the Physician Current Procedural Terminology Coding System, 4th edition, procedure codes and stratified into 4 treatment types: urethral dilation, direct vision internal urethrotomy, urethral stent/steroid injection, and urethroplasty. The overall rates of stricture diagnosis decreased from 10,088/100,000 population in 1992 to 6897 in 2001 (from 1.4% to 0.9%). The stricture prevalence was greatest among black and Hispanic men, although the urethroplasty rates were greatest among white men. Direct vision internal urethrotomy was the most common treatment, followed by urethral dilation, urethral stent/steroid injection, and urethroplasty. The urethroplasty rates remained stable, but quite low (0.6%-0.8%), during the study period. The overall rates of stricture diagnosis decreased from 1992 to 2001. Despite the poor overall efficacy of urethrotomy and urethral dilation relative to urethroplasty and despite the known complications of stent placement in this setting, the urethroplasty rates were the lowest of all treatments. Although we could not determine the treatment success with these data, these findings suggest an underuse of the most efficacious treatment of urethral stricture disease, urethroplasty.


[Bronchiolo-alveolar cell carcinoma (clear cell adenocarcinoma)--report of 6 cases].
6 cases of bronchiolo-alveolar cell carcinoma proven surgically and histologically were studied. Under the microscope, it was shown that the columnar tumor cells lined the inner alveolar walls and the bronchiolar epithelium revealed malignant changes. Diagnosis of bronchiolo-alveolar cell carcinoma was established. Under the electron microscope, in addition to its adenocarcinomatous features, tongue-like protrusions were present on the cell surface and abundant round electron-dense granules were accumulated above the nuclei. These were in accordance with the characteristics of clear cell adenocarcinoma. In 4 cases, lamella bodies were present in a few tumor cells. It suggests that the clear cell adenocarcinoma be able to synthesize round electron-dense granules and lamella bodies.


Characteristics of Extremely Low Gestational Age Newborns Undergoing Tracheotomy: A Secondary Analysis of the Trial of Late Surfactant Randomized Clinical Trial.
Tracheotomy is sometimes performed in extremely low gestational age newborns requiring prolonged ventilation. Studies suggest better neurodevelopmental outcomes in preterm newborns undergoing earlier tracheotomy (<120 days); however, guidelines for who should undergo tracheotomy and when to perform tracheotomy are unclear regarding infants receiving long-term positive-pressure support. To determine the characteristics associated with tracheotomy in high-risk, extremely low gestational age newborns. This secondary analysis of infants enrolled in the double-blind, randomized clinical trial known as the Trial of Late Surfactant (TOLSURF) was conducted from January 10, 2010, to September 3, 2013, in neonatal intensive care units. Participants included 511 premature infants (≤28 weeks' gestational age) who were intubated and mechanically ventilated anytime between 7 and 14 days of life. Infants were randomized to receive late surfactant plus inhaled nitric oxide or inhaled nitric oxide alone. All data were collected prospectively. A mixed-effects model, with patient-level random effects included to account for individual homogeneity, was used to compare mean airway pressure (MAP) during the first 120 days in infants who did not undergo tracheotomy vs those who underwent tracheotomy. The present analysis was conducted from July 1, 2015, to March 29, 2016. Mean airway pressure, comorbidities of prematurity, airway stenosis, and airway malacia. Tracheotomy. Of the 511 infants enrolled in TOLSURF, the mean (SD) gestational age was 25 (1.2) weeks, with a birth weight of 701 (165) g. Fifteen infants (2.9%) underwent tracheotomy. Among those undergoing tracheotomy, 7 infants (46.7%) had airway stenosis or malacia, none of whom died. Of the 8 infants who underwent tracheotomy without airway stenosis or malacia, 4 (50%) died. Mean age at tracheotomy was 126 days (95% CI, 108-144 days). In general, MAP increased over time in the group undergoing tracheotomy (+0.09 cm H2O/wk; 95% CI, 0.06-0.11 cm H2O/wk) but decreased in those who did not undergo tracheotomy (-0.20 cm H2O/wk; 95% CI, 0.19-0.21 cm H2O/wk; P < .001 for interaction). In this cohort of high-risk, extremely low gestational age newborns, trends in MAP can be a clinical indicator for infants requiring long-term positive-pressure ventilation who are at highest risk for receiving tracheotomy. Knowledge of this information may identify infants who would benefit from earlier consideration for tracheotomy. clinicaltrials.gov Identifier: NCT01022580.


Alloantiserum-induced inhibition of immune response gene product function. I. Cellular distribution of target antigens.
It has been previously shown that alloantisera prepared by reciprocal immunization of strain 2 and strain 13 guinea pigs specifically block the activation of T lymphocytes from immune guinea pigs by antigens, the response to which is controlled by Ir genes. In this report we have examined the effect of absorption of the 13 anti-2 serum with different populations of lymphoid cells. It is unlikely that the inhibitory activity of the anti-2 serum on the proliferation of (2 x 13)F(1) lymphocytes to a DNP derivative of a copolymer of L-glutamic and L-lysine (DNP-GL) is due to the presence of antibodies specific for the unique antigenic determinants (idiotypes) of clonally distributed T-lymphocyte receptors. Thus, cells obtained from a normal animal and a DNP-GL immune animal were equivalent in their absorptive capacity. Populations of T lymphocytes were ineffective in absorbing either the cytotoxic or inhibitory activity of the anti-2 serum, while L(2)C leukemia cells, a malignant B-cell population, were most efficient in absorbing both activities. Thus, the antigen(s) against which the cytotoxic and inhibitory activities are directed are present to a greater extent on B lymphocytes than on T lymphocytes. However, these results do not allow us to definitively determine whether the inhibitory activity of the alloantisera is due to antibodies specific for Ir gene products or antibodies specific for linked antigens in the MHC. We also examined the effect of a number of anti-immunoglobulin reagents which had specificity for the heavy and/or light chains of guinea pig immunoglobulin on the in vitro lymphocyte proliferative response to antigen. Under conditions in which we were able to completely and specifically suppress the response of (2 x 13)F(1) lymphocytes to DNP-GL with anti-2 serum, the anti-immunoglobulin reagents were devoid of inhibitory effect on the response of these same F(1) cells to DNP-GL, a copolymer of L-glutamic and L-tyrosine (GT), or purified protein derivative of tuberculin (PPD). These results strongly suggest that conventional serum-type immunoglobulin is not important in antigen recognition by the T cells involved in the DNA synthetic response.


Ventricle-predominant primary CNS lymphomas: clinical, radiological and pathological evaluation of five cases and review of the literature.
Primary central nervous system lymphomas (PCNSLs) are typically intraparenchymal. A subset of PCNSLs predominantly arises in the ventricles, with minimal parenchymal involvement. We review the clinical, radiological, and pathological features of ventricle-predominant PCNSLs (VP-PCNSLs) in 40 previously reported cases and report 5 additional cases. Including all cases of VP-PCNSLs (n = 45), 38% were diffuse large B-cell lymphomas (DLBCL), 11% were Burkitt lymphomas, 7% were MALT lymphomas, 4% were T-cell lymphomas, and 40% were lymphomas, not otherwise classified. VP-PCNSLs show rapid clinical progression. Patients present at a median age of 60.5 years. Unique clinical and radiological features distinguish them from other intraventricular tumors, including advanced age, edema, multifocality, hyperdensity, early and avid post-contrast enhancement, restricted diffusion, and positron emission tomography (PET) hypermetabolism. Including our cases, which were all DLBCL, and all previously reported DLBCL cases (n = 10), 8 of 10 show germinal center B-cell-like (GCB) phenotype, contrasting the high prevalence of non-germinal center B-cell-like (non-GCB) phenotype of parenchymal DLBCL PCNSLs. MYD88 L265P mutation was detected in three of our five cases. Ventricle-predominant PCNSLs are clinically and radiologically distinct, and the DLBCLs may be pathologically distinct. Further recognition of this entity may help to evaluate the role of therapies, possibly including surgical resection.


Narcissism and discrepancy between self and friends' perceptions of personality.
Most research on narcissism and person perception has used strangers as perceivers. However, research has demonstrated that strangers' ratings are influenced by narcissists' stylish appearance (Back, Schmukle, & Egloff, 2010). In the present study, we recruited participants and their close friends, individuals whose close relationship should immunize them to participants' superficial appearance cues. We investigated the relation between narcissism and personality ratings by self and friends. Participants (N = 66; 38 women; Mage = 20.83 years) completed the Narcissistic Personality Inventory (Raskin & Terry, 1988) and described their personality on the 100-item California Adult Q-Sort (CAQ; Block, 2008). Participants' personality was also described on the CAQ by close friends. The "optimally adjusted individual" prototype was used to summarize participant and friend personality ratings (Block, 2008). Participants with high narcissism scores were ascribed higher optimal adjustment by self than by friends. Narcissistic individuals' self-ratings were extremely positive and more favorable than friends' ratings of them.


Systemic recombinant alpha-2 interferon therapy in relapsing multiple sclerosis.
This report describes the first use of recombinant-DNA-produced human interferon in patients with multiple sclerosis (MS). Ninety-eight patients who were clinically definite for MS with two or more documented exacerbations during the preceding two years were admitted to this placebo-controlled double-blind randomized trial. Although both groups were similar, placebo patients had later MS onset. Patients injected themselves with 2 X 10(6) IU of alpha-2 interferon or placebo three times each week for up to 52 weeks. This dose of interferon was well tolerated in that side effects were minimal. During the trial, the exacerbation rate was sharply reduced in both groups. In the three-month follow-up period after stopping treatment, more patients who were receiving interferon than placebo became worse neurologically. More patients who were receiving interferon than placebo changed from exacerbating MS to progressive MS during the trial. Thus, no clear therapeutic benefit of alpha-2 interferon for MS was detected.


Bioinspired design and assembly of platelet reinforced polymer films.
Although strong and stiff human-made composites have long been developed, the microstructure of today's most advanced composites has yet to achieve the order and sophisticated hierarchy of hybrid materials built up by living organisms in nature. Clay-based nanocomposites with layered structure can reach notable stiffness and strength, but these properties are usually not accompanied by the ductility and flaw tolerance found in the structures generated by natural hybrid materials. By using principles found in natural composites, we showed that layered hybrid films combining high tensile strength and ductile behavior can be obtained through the bottom-up colloidal assembly of strong submicrometer-thick ceramic platelets within a ductile polymer matrix.