Acute dose-response effect of coffee-derived chlorogenic acids on the human vasculature in healthy volunteers: a randomized controlled trial.
Epidemiological studies have reported lower risk of cardiovascular disease with moderate coffee consumption. In addition, emerging evidence indicates that consumption of coffee beverages enriched in chlorogenic acids (CGAs) may influence blood pressure and endothelial function, suggesting that the beneficial cardiovascular effect of coffee may relate to its CGA content. We conducted a double-blind randomized crossover trial to test the effect of acute consumption of a decaffeinated green coffee extract (DGCE), rich in CGAs, on endothelial function in healthy subjects. We compared 3 different doses of DGCE (302, 604, and 906 mg, respectively) with a placebo. Endothelial function was defined as the percentage change in the internal diameter of the brachial artery in response to flow-mediated dilation (%FMD). In addition, we followed the plasma concentration-time profiles of 25 systemic CGA metabolites over 24 h after DGCE consumption and we explored the relation between systemic concentrations of CGAs and the effect on %FMD. The DGCE formulations containing different amounts of CGAs resulted in dose-proportional increases in overall total polyphenol concentrations. The systemic appearance of total CGAs was biphasic, in agreement with previous results suggesting 2 sites of absorption in the gastrointestinal tract. Compared with the placebo group, a significant FMD increase (>1%) was observed 8.5, 10, and 24 h after consumption of 302 mg DGCE (∼156.4 mg CGAs). The differences with placebo observed in the other 2 groups were not statistically significant. Evaluation of the relation between phenolic exposure and %FMD showed a positive tendency toward a larger effect at higher concentrations and different behavior of CGA metabolites depending on the conjugated chemical position. We demonstrated an acute improvement in %FMD over time after ingestion of a DGCE, explained at least partly by the presence in the blood circulation of CGAs and their metabolites. This trial was registered at clinicaltrials.gov as NCT03520452.


Quantum state readout of individual quantum dots by electrostatic force detection.
Electric charge detection by atomic force microscopy (AFM) with single-electron resolution (e-EFM) is a promising way to investigate the electronic level structure of individual quantum dots (QDs). The oscillating AFM tip modulates the energy of the QDs, causing single electrons to tunnel between QDs and an electrode. The resulting oscillating electrostatic force changes the resonant frequency and damping of the AFM cantilever, enabling electrometry with a single-electron sensitivity. Quantitative electronic level spectroscopy is possible by sweeping the bias voltage. Charge stability diagram can be obtained by scanning the AFM tip around the QD. e-EFM technique enables to investigate individual colloidal nanoparticles and self-assembled QDs without nanoscale electrodes. e-EFM is a quantum electromechanical system where the back-action of a tunneling electron is detected by AFM; it can also be considered as a mechanical analog of admittance spectroscopy with a radio frequency resonator, which is emerging as a promising tool for quantum state readout for quantum computing. In combination with the topography imaging capability of the AFM, e-EFM is a powerful tool for investigating new nanoscale material systems which can be used as quantum bits.


Single-system based discriminative optical sensors: different strategies and versatile applications.
Discriminative optical sensors with pattern recognition properties and high-throughput ability have been widely developed as they can distinguish multiple chemically similar analytes. Compared to traditional sensor arrays composed of a series of sensor elements, single-system based discriminative sensors using an array of optical changes at different wavelengths to provide input signals have drawn intensive attention recently. On the one hand, they can provide discrimination ability that is lack in using selective sensors; on the other hand, they can simplify the complex data acquisition process accompanied by multiple-element-based sensor arrays and reduce consumption of sensor samples. This tutorial review gives an overview of the development of single-system based discriminative optical sensors. Different strategies for the construction of single-system based discriminative sensors including dynamic combinatorial libraries, cross-reactive conjugated polymers, DNA G-quadruplex ensembles, combinatorial fluorescent molecular sensors, and fluorophore/surfactant aggregate ensembles are particularly introduced.


Selective induction of Fc gamma RIII on human monocytes by transforming growth factor-beta.
Transforming growth factor-beta (TGF-beta) is a polypeptide that participates in morphogenesis, inflammation, and would repair. Emerging as an important immunomodulatory molecule, TGF-beta may also regulate the phenotype and function of mononuclear cells within an inflammatory site. In this study TGF-beta is shown to induce expression of the gp50-65 receptor for Fc gamma RIII on otherwise negative peripheral blood monocytes. Circulating monocytes express Fc gamma RI and Fc gamma RII, but not Fc gamma RIII, and no inducing agent for Fc gamma RIII has previously been identified. Within hours after exposure of freshly isolated peripheral blood monocytes to picomolar concentrations of TGF-beta 1 or TGF-beta 2, mRNA specific for Fc gamma RIII is detectable followed by expression of the receptors on the cell surface. Neutralizing antibodies to TGF-beta completely inhibit the TGF-beta-induced up-regulation of Fc gamma RIII. In contrast to TGF-beta, other cytokines involved in the inflammatory response are ineffective in regulating Fc gamma RIII expression on human monocytes. Thus, the early release of TGF-beta by platelets in an inflammatory site may foster enhanced immunophagocytosis and contribute to host defense by inducing monocyte Fc gamma RIII expression.


Epigallocatechin gallate suppresses lung cancer cell growth through Ras-GTPase-activating protein SH3 domain-binding protein 1.
Green tea is a highly popular beverage globally. Green tea contains a number of polyphenol compounds referred to as catechins, and (-)-epigallocatechin gallate (EGCG) is believed to be the major biologically active compound found in green tea. EGCG has been reported to suppress lung cancer, but the molecular mechanisms of the inhibitory effects of EGCG are not clear. We found that EGCG interacted with the Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) with high binding affinity (K(d) = 0.4 micromol/L). We also showed that EGCG suppressed anchorage-independent growth of H1299 and CL13 lung cancer cells, which contain an abundance of the G3BP1 protein. EGCG was much less effective in suppressing anchorage-independent growth of H460 lung cancer cells, which express much lower levels of G3BP1. Knockdown shG3BP1-transfected H1299 cells exhibited substantially decreased proliferation and anchorage-independent growth. shG3BP1 H1299 cells were resistant to the inhibitory effects of EGCG on growth and colony formation compared with shMock-transfected H1299 cells. EGCG interfered with the interaction of G3BP1 and the Ras-GTPase-activating protein and further suppressed the activation of Ras. Additional results revealed that EGCG effectively attenuated G3BP1 downstream signaling, including extracellular signal-regulated kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, in wild-type H1299 and shMock H1299 cells but had little effect on H460 or shG3BP1 H1299 cells. Overall, these results strongly indicate that EGCG suppresses lung tumorigenesis through its binding with G3BP1.


Complete mineralization of benzene by aquifer microorganisms under strictly anaerobic conditions.
Benzene was mineralized to CO2 by aquifer-derived microorganisms under strictly anaerobic conditions. The degradation occurred in microcosms containing gasoline-contaminated subsurface sediment from Seal Beach, California, and anaerobic, sulfide-reduced defined mineral medium supplemented with 20 mM sulfate. Benzene, at initial concentrations ranging from 40 to 200 microM, was depleted in all microcosms and more than 90% of 14C-labeled benzene was mineralized to 14CO2.


Slower postnatal motor development in infants of mothers with latent toxoplasmosis during the first 18 months of life.
Toxoplasmosis, a zoonosis caused by a protozoan, Toxoplasma gondii, is probably the most widespread human parasitosis in developed countries. Pregnant women with latent toxoplasmosis have seemingly younger fetuses especially in the 16th week of gestation, which suggests that fetuses of Toxoplasma-infected mothers have slower rates of development in the first trimester of pregnancy. In the present retrospective cohort study, we analyzed data on postnatal motor development of infants from 331 questionnaire respondents including 53 Toxoplasma-infected mothers to search for signs of early postnatal development disorders. During the first year of life, a slower postnatal motor development was observed in infants of mothers with latent toxoplasmosis. These infants significantly later developed the ability to control the head position (p=0.039), to roll from supine to prone position (p=0.022) and were slightly later to begin crawling (p=0.059). Our results are compatible with the hypothesis that the difference in the rates of prenatal and early postnatal development between children of Toxoplasma-negative and Toxoplasma-positive mothers might be caused by a decreased stringency of embryo quality control in partly immunosuppressed Toxoplasma-positive mothers resulting in a higher proportion of infants with genetic or developmental disorders in offspring. However, because of relatively low return rate of questionnaires and an associated risk of a sieve effect, our results should be considered as preliminary and performing a large scale prospective study in the future is critically needed.


Studies on competitive adsorption of dyes onto carbon (XC-72) and regeneration of adsorbent.
Carbon as an adsorbent has been widely studied for wastewater treatment, but the regeneration of adsorbent has been scarcely reported. In this paper, an economical and environmental method was applied to regenerate carbon (XC-72). Results showed that both anhydrous ethanol and deionized water did not obtain optimal effect for the desorption of Acid Orange 7, Ponceau 2R and Rhodamine B, but the desorption effect was dramatically improved when anhydrous ethanol and deionized water were mixed in a certain volume ratio. In addition, the adsorption kinetics of the three dyes were investigated, which showed that the process of adsorption could be well represented by the pseudo-second-order model. For the study of competitive adsorption, this indicated that the interaction between adsorbent and adsorbate had something to do with electrostatic attraction.


Genetically determined lack of CD45R- T cells in healthy individuals. Evidence for a regulatory polymorphism of CD45R antigen expression.
A genetic polymorphism of CD45R expression was identified resulting in a lack of CD45R- lymphocytes in approximately 8% of healthy individuals. Family studies revealed an autosomal dominant mode of inheritance of the variant CD45R expression pattern. PBMC from donors possessing the variant type did not lose the CD45R antigen after in vitro activation, whereas a decrease of CD45R molecules was readily detected in individuals with the normal pattern. The expression of CD45RO antigens, as well as memory cell function, did not differ between both groups. These data show that activation and in vivo priming of T cells is not necessarily associated with a loss of CD45R antigen expression.


Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.
Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).


The role of α9β1 integrin in modulating epithelial cell behaviour.
Integrins initiate signalling in response to the extracellular matrix (ECM), which is important in wound healing and cancer. Previous studies have shown that over-expression of the αvβ6 integrin in oral squamous cell carcinoma (OSCC) cells results in enhanced motility and expression of matrix-degrading proteases, and the aim of this study was to investigate whether this is also the case for the α9β1 integrin. H357 OSCCcells were transfected with the α9 integrin subunit and proliferation, adhesion and migration assays were performed on these along with null vector control and wild-type cells. The effect of ligand engagement on matrix metalloproteinase expression and the plasminogen activator system was measured using ELISA and chromogenic assays. Expression of α9 integrin was examined in oral squamous cell carcinoma tissue by immunohistochemistry. Functionally active α9 integrin mediated specific upregulation of adhesion and migration towards the TNfn3RAA fragment of tenascin-C but reduced proliferation. Migration towards collagen I was also enhanced in transfected cells. Matrix metalloproteinase-2 and metalloproteinase-9 expression was increased upon TNfn3RAA ligand engagement. Cell surface plasmin generation was also enhanced in α9-expressing cells and was the result of enhanced expression of urokinase receptor. In normal oral mucosa, α9 integrin expression was restricted to the suprabasal and prickle cell layers, and expression was heterogeneous in tumours but present in islands infiltrating connective tissue particularly in moderately and well-differentiated lesions. The α9β1 integrin may play a key role in modulation of tumour behaviour including enhanced cell migration and expression of matrix-degrading proteases.


Slow crystallisation of a monodisperse foam stabilised against coarsening.
The evolution of a three-dimensional monodisperse foam was investigated using X-ray tomography over the course of seven days. The coarsening of the sample was inhibited through the use of perfluorohexane gas. The internal configuration of bubbles is seen to change markedly, evolving from a disordered arrangement towards a more ordered state. We chart this ordering process through the use of the coordination number, the bond orientational order parameter (BOOP) and the translational order parameter.


Intergenerational relations before and after offspring arrive: A within-person investigation.
The birth of a child may re-orientate the relations between adult children and their parents; however, the previous studies on the topic are both scarce and methodologically limited. The current study investigates whether younger adults' entry into parenthood (i.e., the birth of the first child) is associated with increased contact frequency, emotional closeness, intimacy and conflict with their own parents. The participants are from the German Panel Analysis of Intimate Relationships and Family Dynamics, which is a prospective survey of younger adults with six annual follow-up waves between 2009 and 2014 (n = 17,662 person-observations from 4821 persons). Within-person regression with a focus on each individual's variation over time was used to detect changes in intergenerational relations. The contact frequency between daughters and mothers increased after the arrival of their first child. In contrast, the emotional closeness and intimacy between sons and mothers decreased after the birth of their first child. The results are discussed with reference to gender-based differences in intergenerational relations.


Adolescent behavior and PTSD 6-7 years after the World Trade Center terrorist attacks of September 11, 2001.
Behavioral problems and psychopathologies were reported in children exposed to the World Trade Center (WTC) attacks in New York City within 2-3 y post-disaster. Little is known of subsequent 9/11 related behavioral and emotional problems. We assessed risk factors for behavioral difficulties and probable posttraumatic stress disorder (PTSD) in 489 adolescent enrollees ages 11-18 y of age in the World Trade Center Health Registry cohort using the Strengths and Difficulties Questionnaire (SDQ) and DISC Predictive Scales (DPS), respectively, as reported by the adolescents. Associations between parental PTSD and adolescent PTSD and behavioral problems were studied in a subset of 166 adolescent-parent pairs in which the parent was also a Registry enrollee. Nearly one-fifth (17.4%) of the adolescents, all of whom were 5-12 y old at the time of the attacks, scored in the abnormal (5.7%) or borderline (11.7%) range of total SDQ. Problems were more frequent in minority, low-income, and single-parent adolescents. Abnormal and borderline SDQ scores were significantly associated with direct WTC exposures and with WTC-related injury or death of a family member. Adolescent PTSD was significantly associated with WTC exposure and with fear of one's own injury or death, and with PTSD in the parent (OR = 5.6; 95% CI 1.1-28.4). This adolescent population should be monitored for persistence or worsening of these problems. Co-occurrence of parent and child mental health symptoms following a disaster may have implications for healthcare practitioners and for disaster response planners.


Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells.
During their migration, cerebellar granule cells switch from a tangential to a radial mode of migration. We have previously demonstrated that this involves the transmembrane semaphorin Sema6A. We show here that plexin-A2 is the receptor that controls Sema6A function in migrating granule cells. In plexin-A2-deficient (Plxna2(-/-)) mice, which were generated by homologous recombination, many granule cells remained in the molecular layer, as we saw in Sema6a mutants. A similar phenotype was observed in mutant mice that were generated by mutagenesis with N-ethyl-N-nitrosourea and had a single amino-acid substitution in the semaphorin domain of plexin-A2. We found that this mutation abolished the ability of Sema6A to bind to plexin-A2. Mouse chimera studies further suggested that plexin-A2 acts in a cell-autonomous manner. We also provide genetic evidence for a ligand-receptor relationship between Sema6A and plexin-A2 in this system. Using time-lapse video microscopy, we found that centrosome-nucleus coupling and coordinated motility were strongly perturbed in Sema6a(-/-) and Plxna2(-/-) granule cells. This suggests that semaphorin-plexin signaling modulates cell migration by controlling centrosome positioning.


Emiliania huxleyi endures N-limitation with an efficient metabolic budgeting and effective ATP synthesis.
Global change will affect patterns of nutrient upwelling in marine environments, potentially becoming even stricter regulators of phytoplankton primary productivity. To better understand phytoplankton nutrient utilization on the subcellular basis, we assessed the transcriptomic responses of the life-cycle stages of the biogeochemically important microalgae Emiliania huxleyi to nitrogen-limitation. Cells grown in batch cultures were harvested at 'early' and 'full' nitrogen-limitation and were compared with non-limited cells. We applied microarray-based transcriptome profilings, covering ~10.000 known E. huxleyi gene models, and screened for expression patterns that indicate the subcellular responses. The diploid life-cycle stage scavenges nitrogen from external organic sources and -like diatoms- uses the ornithine-urea cycle to rapidly turn over cellular nitrogen. The haploid stage reacts similarly, although nitrogen scavenging is less pronounced and lipid oxidation is more prominent. Generally, polyamines and proline appear to constitute major organic pools that back up cellular nitrogen. Both stages induce a malate:quinone-oxidoreductase that efficiently feeds electrons into the respiratory chain and drives ATP generation with reduced respiratory carbon throughput. The use of the ornithine-urea cycle to budget the cellular nitrogen in situations of limitation resembles the responses observed earlier in diatoms. This suggests that underlying biochemical mechanisms are conserved among distant clades of marine phototrophic protists. The ornithine-urea cycle and proline oxidation appear to constitute a sensory-regulatory system that monitors and controls cellular nitrogen budgets under limitation. The similarity between the responses of the life-cycle stages, despite the usage of different genes, also indicates a strong functional consistency in the responses to nitrogen-limitation that appears to be owed to biochemical requirements. The malate:quinone-oxidoreductase is a genomic feature that appears to be absent from diatom genomes, and it is likely to strongly contribute to the uniquely high endurance of E. huxleyi under nutrient limitation.


Sri Lankan National Melioidosis Surveillance Program Uncovers a Nationwide Distribution of Invasive Melioidosis.
The epidemiologic status of melioidosis in Sri Lanka was unclear from the few previous case reports. We established laboratory support for a case definition and started a nationwide case-finding study. Suspected Burkholderia pseudomallei isolates were collated, identified by polymerase chain reaction assay, referred for Matrix Assisted Laser Desorption Ionization-Time of Flight analysis and multilocus sequence typing (MLST), and named according to the international MLST database. Between 2006 and early 2014, there were 32 patients with culture-confirmed melioidosis with an increasing annual total and a falling fatality rate. Patients were predominantly from rural communities, diabetic, and male. The major clinical presentations were sepsis, pneumonia, soft tissue and joint infections, and other focal infection. Burkholderia pseudomallei isolates came from all parts of Sri Lanka except the Sabaragamuwa Province, the south central hill country, and parts of northern Sri Lanka. Bacterial isolates belonged to 18 multilocus sequence types, one of which (ST 1137) was associated with septicemia and a single-organ focus (Fisher's exact, P = 0.004). Melioidosis is an established endemic infection throughout Sri Lanka, and is caused by multiple genotypes of B. pseudomallei, which form a distinct geographic group based upon related sequence types (BURST) cluster at the junction of the southeast Asian and Australasian clades.


The 14q32 maternally imprinted locus is a major source of longitudinally stable circulating microRNAs as measured by small RNA sequencing.
Understanding the normal temporal variation of serum molecules is a critical factor for identifying useful candidate biomarkers for the diagnosis and prognosis of chronic disease. Using small RNA sequencing in a longitudinal study of 66 women with no history of cancer, we determined the distribution and dynamics (via intraclass correlation coefficients, ICCs) of the miRNA profile over 3 time points sampled across 2-5 years in the course of the screening trial, UKCTOCS. We were able to define a subset of longitudinally stable miRNAs (ICC >0.75) that were individually discriminating of women who had no cancer over the study period. These miRNAs were dominated by those originating from the C14MC cluster that is subject to maternal imprinting. This assessment was not significantly affected by common confounders such as age, BMI or time to centrifugation nor alternative methods to data normalisation. Our analysis provides important benchmark data supporting the development of miRNA biomarkers for the impact of life-course exposure as well as diagnosis and prognostication of chronic disease.


Aiming at the Global Elimination of Viral Hepatitis: Challenges Along the Care Continuum.
A recent international workshop, organized by the authors, analyzed the obstacles facing the ambitious goal of eliminating viral hepatitis globally. We identified several policy areas critical to reaching elimination targets. These include providing hepatitis B birth-dose vaccination to all infants within 24 hours of birth, preventing the transmission of blood-borne viruses through the expansion of national hemovigilance schemes, implementing the lessons learned from the HIV epidemic regarding safe medical practices to eliminate iatrogenic infection, adopting point-of-care testing to improve coverage of diagnosis, and providing free or affordable hepatitis C treatment to all. We introduce Egypt as a case study for rapid testing and treatment scale-up: this country offers valuable insights to policy makers internationally, not only regarding how hepatitis C interventions can be expeditiously scaled-up, but also as a guide for how to tackle the problems encountered with such ambitious testing and treatment programs.


Management of depression induced by interferon hepatitis therapies.
Treatment with interferon therapy for hepatitis can induce depression and/or recurrence of affective illness, which could result in cessation of interferon treatment. This article reviews treatment for interferon-induced depression, including antidepressant drugs that may diminish associated symptoms. English-language literature with no date restrictions on the treatment of interferon-induced depression was reviewed via PubMed and MEDLINE using the key words hepatitis, interferon, hepatitis C, interferon-induced depression, pharmacotherapy of interferon-induced depression, and depression prevention. Fourteen of the most pertinent references are cited. Escitalopram is the most prominently noted pharmaceutical prescribed for treating mood symptoms in hepatitis patients with interferon-induced depression. Other antidepressant medicines may have utility as well. Antidepressant drugs can be efficacious in diminishing mood disorders during hepatitis therapies. It remains controversial as to whether antidepressant medications can provide prophylaxis against newly developing interferon-induced depressions in individuals with no past history of a mood disorder. Antidepressant medicines can be effective at improving mood in patients undergoing interferon treatment for hepatitis.


Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk.
A study was conducted to measure breast milk concentrations of fluoxetine and its active metabolite, norfluoxetine, excreted in breast milk in a cohort of nursing women using fluoxetine, and to estimate infant dose from nursing. The study included 10 women nursing 11 infants (median age, 185 days). The mean fluoxetine dose was 0.39 mg/kg/day. Each patient manually collected 3 to 6 milk samples throughout a dosing interval. Concentrations of fluoxetine and norfluoxetine in milk were measured by gas-liquid chromatography. Mothers reported whether they observed adverse effects in their infants. The average infant doses of fluoxetine and norfluoxetine, as estimated for an exclusively breast-fed infant ingesting 1000 mL of milk per day, were 0.077 mg (SD = 0.054 mg) and 0.084 mg (SD = 0.043 mg), respectively. The total dose of fluoxetine and norfluoxetine (expressed as fluoxetine equivalents) was 0.165 mg (SD = 0.092 mg), which was equivalent to 10.8% (SD = 2.2%) of the maternal dose, adjusted on a mg/kg basis in a 4-kg infant. No adverse events were reported by mothers in their infants. Approximately one tenth of the adult therapeutic dose of fluoxetine is excreted in breast milk. Although short-term adverse effects in the infant from exposure through nursing were not reported in this cohort, future studies that assess the potential long-term consequences are needed.


Natural scrapie in a closed flock of Cheviot sheep occurs only in specific PrP genotypes.
Natural scrapie in a closed flock of South Country Cheviot sheep has resulted in 45 deaths between 1986 and 1995. Of these cases, 35 sheep have been analysed for disease-linked PrP gene polymorphisms and all encode valine at codon 136 on at least one allele with 77% homozygous (VV136) and 23% valine/alanine heterozygotes (VA136). Mean survival time was 907 and 1482 days for VV136 and VA136 scrapie affected animals respectively. VV136 animals were all at great risk of disease if allowed to live long enough. However scrapie occurred only in a specific subgroup of VA136 sheep, survival advantage depending on VA136 animals being heterozygous for other polymorphisms at codons 154 or 171. The flock history has been recorded in great detail since its foundation in 1960 however there was no strong evidence for simple maternal or paternal transmission of disease other than inheritance of PrP genotype.


Sequence length determinants for self-assembly of amphipathic β-sheet peptides.
Amphipathic peptides composed of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide, which have a high propensity to self-assemble into β-sheet fibrils. The Ac-(FKFE)2-NH2 peptide has been extensively studied and forms putative β-sheet bilayer fibrils in which the hydrophobic Phe side chains are organized to a single face of each constituent sheet; upon bilayer formation, these hydrophobic benzyl groups are sequestered in the hydrophobic core of the resulting fibril. In order for the Phe side chains to be uniformly displayed on one face of Ac-(FKFE)2-NH2 β-sheets, an antiparallel packing orientation in which one amino acid residue is unpaired must be adopted. Based on molecular models, we hypothesized that truncated seven amino acid derivatives of Ac-(FKFE)2-NH2 in which either the N-terminal Phe residue (Ac-KFEFKFE-NH2) or the C-terminal Glu residue (Ac-FKFEFKF-NH2) is eliminated should readily self-assemble into β-sheet bilayers in which all hydrogen bond and hydrophobic/charge interactions are satisfied. We found, however, that these minute changes in peptide sequence have unanticipated and dramatic effects on the self-assembly of each peptide. Ac-FKFEFKF-NH2 self-assembled into fibrils with unique morphology relative to the parent peptide, whereas the Ac-KFEFKFE-NH2 peptide had a strongly reduced propensity to self-assemble, even failing to self-assemble altogether under some conditions. These findings provide significant insight into the effect of sequence length and strand registry as well as hydrophobicity and charge on the self-assembly of simple amphipathic peptides to illuminate the possibility of tuning self-assembly processes and the resulting structures with minute changes to peptide sequence.


Avian lungs: A novel scaffold for lung bioengineering.
Allogeneic lung transplant is limited both by the shortage of available donor lungs and by the lack of suitable long-term lung assist devices to bridge patients to lung transplantation. Avian lungs have different structure and mechanics resulting in more efficient gas exchange than mammalian lungs. Decellularized avian lungs, recellularized with human lung cells, could therefore provide a powerful novel gas exchange unit for potential use in pulmonary therapeutics. To initially assess this in both small and large avian lung models, chicken (Gallus gallus domesticus) and emu (Dromaius novaehollandiae) lungs were decellularized using modifications of a detergent-based protocol, previously utilized with mammalian lungs. Light and electron microscopy, vascular and airway resistance, quantitation and gel analyses of residual DNA, and immunohistochemical and mass spectrometric analyses of remaining extracellular matrix (ECM) proteins demonstrated maintenance of lung structure, minimal residual DNA, and retention of major ECM proteins in the decellularized scaffolds. Seeding with human bronchial epithelial cells, human pulmonary vascular endothelial cells, human mesenchymal stromal cells, and human lung fibroblasts demonstrated initial cell attachment on decellularized avian lungs and growth over a 7-day period. These initial studies demonstrate that decellularized avian lungs may be a feasible approach for generating functional lung tissue for clinical therapeutics.


Minireview: cracking the metabolic code for thyroid hormone signaling.
Cells are not passive bystanders in the process of hormonal signaling and instead can actively customize hormonal action. Thyroid hormone gains access to the intracellular environment via membrane transporters, and while diffusing from the plasma membrane to the nucleus, thyroid hormone signaling is modified via the action of the deiodinases. Although the type 2 deiodinase (D2) converts the prohormone T(4) to the biologically active T(3), the type 3 deiodinase (D3) converts it to reverse T(3), an inactive metabolite. D3 also inactivates T(3) to T(2), terminating thyroid hormone action. Therefore, D2 confers cells with the capacity to produce extra amounts of T(3) and thus enhances thyroid hormone signaling. In contrast expression of D3 results in the opposite action. The Dio2 and Dio3 genes undergo transcriptional regulation throughout embryonic development, childhood, and adult life. In addition, the D2 protein is unique in that it can be switched off and on via an ubiquitin regulated mechanism, triggered by catalysis of T(4). Induction of D2 enhances local thyroid hormone signaling and energy expenditure during activation of brown adipose tissue by cold exposure or high-fat diet. On the other hand, induction of D3 in myocardium and brain during ischemia and hypoxia decreases energy expenditure as part of a homeostatic mechanism to slow down cell metabolism in the face of limited O(2) supply.


Use of Colistin and Other Critical Antimicrobials on Pig and Chicken Farms in Southern Vietnam and Its Association with Resistance in Commensal Escherichia coli Bacteria.
Antimicrobial resistance (AMR) is a global health problem, and emerging semi-intensive farming systems in Southeast Asia are major contributors to the AMR burden. We accessed 12 pig and chicken farms at key stages of production in Tien Giang Province, Vietnam, to measure antimicrobial usage and to investigate the prevalence of AMR to five critical antimicrobials (β-lactams, third-generation cephalosporins, quinolones, aminoglycosides, and polymyxins) and their corresponding molecular mechanisms among 180 Escherichia coli isolates. Overall, 94.7 mg (interquartile range [IQR], 65.3 to 151.1) and 563.6 mg (IQR, 398.9 to 943.6) of antimicrobials was used to produce 1 kg (live weight) of chicken and pig, respectively. A median of 3 (out of 8) critical antimicrobials were used on pig farms. E. coli isolates exhibited a high prevalence of resistance to ampicillin (97.8% and 94.4% for chickens and pigs, respectively), ciprofloxacin (73.3% and 21.1%), gentamicin (42.2% and 35.6%), and colistin (22.2% and 24.4%). The prevalence of a recently discovered colistin resistance gene, mcr-1, was 19 to 22% and had strong agreement with phenotypic colistin resistance. We conducted plasmid conjugation experiments with 37 mcr-1 gene-positive E. coli isolates and successfully observed transfer of the gene in 54.0% of isolates through a plasmid of approximately 63 kb, consistent with one recently identified in China. We found no significant correlation between total use of antimicrobials at the farm level and AMR. These data provide additional insight into the role of mcr-1 in colistin resistance on farms and outline the dynamics of phenotypic and genotypic AMR in semi-intensive farming systems in Vietnam. Our study provides accurate baseline information on levels of antimicrobial use, as well as on the dynamics of phenotypic and genotypic resistance for antimicrobials of critical importance among E. coli over the different stages of production in emerging pig and poultry production systems in Vietnam. E. coli isolates showed a high prevalence of resistance (>20%) to critically important antimicrobials, such as colistin, ciprofloxacin, and gentamicin. The underlying genetic mechanisms identified for colistin (the mcr-1 gene) and quinolone (gyrA gene mutations) are likely to play a major role in AMR to those compounds. Conjugation experiments led to the identification of a 63-kb plasmid, similar to one recently identified in China, as the potential carrier of the mcr-1 gene. These results should encourage greater restrictions of such antimicrobials in Southeast Asian farming systems.


Medication safety and the administration of intravenous vincristine: international survey of oncology pharmacists.
The risk of medication errors with vincristine administration is well documented. Our objective was to ascertain how vincristine is administered worldwide and determine what strategies for preventing the accidental intrathecal administration of vincristine are in place. A survey, comprising 28 questions, was distributed to 363 International Society of Oncology Pharmacy Practitioners members from 42 countries via email. Questions were asked on methods of vincristine administration, intrathecal drug administration and strategies used to prevent medication errors. A reminder was sent and the survey was available on the International Society of Oncology Pharmacy Practitioners website. Only one survey per institution was requested. In all, 62 responses from 15 countries were received, with the majority from Australia. Vincristine was dispensed in mini-bags in 77.4% of centres, though some also used syringes. Syringes were used in 31.1% of centres, with half these doses prepared undiluted. Administration took 5 to 15 minutes in most centres (78.8%). The most common reasons for still using syringes were perceived risk of extravasation and faster infusion time. Despite numerous vincristine administrations, extravasation was very rare. Other recommended strategies for error prevention were in use in the majority of centres. Comparisons with three previous surveys are difficult as the majority of respondents in those studies were from the USA. A number of areas appear to have improved, particularly the preparation of vincristine in mini-bags, but they are far from perfect. Deaths continue to occur following accidental intrathecal administration of vincristine. International Society of Oncology Pharmacy Practitioner members are urged to lead the way in incorporating strategies for prevention into institutions worldwide.


AI in health and medicine.
Artificial intelligence (AI) is poised to broadly reshape medicine, potentially improving the experiences of both clinicians and patients. We discuss key findings from a 2-year weekly effort to track and share key developments in medical AI. We cover prospective studies and advances in medical image analysis, which have reduced the gap between research and deployment. We also address several promising avenues for novel medical AI research, including non-image data sources, unconventional problem formulations and human-AI collaboration. Finally, we consider serious technical and ethical challenges in issues spanning from data scarcity to racial bias. As these challenges are addressed, AI's potential may be realized, making healthcare more accurate, efficient and accessible for patients worldwide.


Crystal structure of a human ubiquitin E1-ubiquitin complex reveals conserved functional elements essential for activity.
Ubiquitin (Ub) signaling plays a key regulatory role in nearly every aspect of eukaryotic biology and is initiated by E1 enzymes that activate and transfer Ub to E2 Ub-conjugating enzymes. Despite Ub E1's fundamental importance to the cell and its attractiveness as a target for therapeutic intervention in cancer and other diseases, its only available structural information is derived from yeast orthologs of human ubiquitin-like modifier-activating enzyme 1 (hUBA1). To illuminate structural differences between yeast and hUBA1 structures that might be exploited for the development of small-molecule therapeutics, we determined the first crystal structure of a hUBA1-Ub complex. Using structural analysis, molecular modeling, and biochemical analysis, we demonstrate that hUBA1 shares a conserved overall structure and mechanism with previously characterized yeast orthologs, but displays subtle structural differences, particularly within the active site. Computational analysis revealed four potential ligand-binding hot spots on the surface of hUBA1 that might serve as targets to inhibit hUBA1 at the level of Ub activation or E2 recruitment or that might potentially be used in approaches such as protein-targeting chimeric molecules. Taken together, our work enhances our understanding of the hUBA1 mechanism, provides an improved framework for the development of small-molecule inhibitors of UBA1, and serves as a stepping stone for structural studies that involve the enzymes of the human Ub system at the level of both E1 and E2.


Stages in the nuclear association of the herpes simplex virus transcriptional activator protein ICP4.
The nuclear localization of the herpes simplex virus transcriptional activator protein ICP4 was studied by indirect immunofluorescence. At early times after viral infection, ICP4 quickly localized to a diffuse intranuclear distribution. ICP4 later concentrated in globular compartments within the nucleus. The redistribution to the compartments was dependent on viral DNA replication. Double staining for ICP4 and ICP8, the early major DNA-binding protein, revealed that both were found in the same intranuclear globular compartments at late times. These were previously named "replication compartments" (M. P. Quinlan, L. B. Chen, and D. M. Knipe, Cell 36:857-868, 1984). Because ICP4 and ICP8 are known to function in transcriptional activation and DNA replication, respectively, both DNA replication and late transcription may occur in these compartments. The association of ICP4 and ICP8 with the replication compartments appeared to be independent in that the retention of ICP8 in the compartments required ongoing viral DNA synthesis, while the association of ICP4 was independent of viral DNA synthesis once the compartments were formed. Because ICP4 shows a different distribution at early and late times, stimulation of transcription by ICP4 may involve different molecular events or contacts during these two periods of the replicative cycle.


The Investigation of Plasma Glucagon-like Peptide-1 Levels in Newly Diagnosed Type 1 Diabetic Children.
To reveal the possible role of glucagon-like peptide-1 (GLP-1) in newly diagnosed Type 1 diabetic children. Twenty-five newly diagnosed children and 22 healthy children were included in the study. In oral glucose tolerance tests, no correlation was observed between C-peptide and GLP-1 levels at 0 and 30 minutes, and plasma GLP-1 levels in both groups at 0 and 30 minutes were not statistically different. Consequently, fasting and postprandial GLP-1 levels in newly diagnosed Type 1 diabetic children are not different from healthy children. Glucagon-like peptide-1 levels in newly diagnosed Type 1 diabetic children suggest that plasma GLP-1 levels do not have any role in the pathogenesis of Type 1 diabetes mellitus.


Trichinellosis surveillance--United States, 1997-2001.
Trichinellosis is a parasitic disease caused by tissue-dwelling roundworms of the species Trichinella spiralis. The organism is acquired by eating Trichinella-infected meat products. The disease has variable clinical manifestations, ranging from asymptomatic to fatal. In the United States, trichinellosis has caused hundreds of preventable cases of illness and occasional deaths. The national trichinellosis surveillance system has documented a steady decline in the reported incidence of this disease, as well as a change in its epidemiology. This report summarizes surveillance data for trichinellosis in the United States for 1997-2001. Trichinellosis became a nationally reportable disease in 1966, but statistics have been kept on the disease since 1947. The national trichinellosis surveillance system is a passive system that relies on existing resources at the local, state, and federal levels. Cases are diagnosed based on clinical history with laboratory confirmation. Cases are reported weekly to CDC through the National Electronic Telecommunications System for Surveillance (NETSS). Detailed data regarding signs and symptoms, diagnostic tests, and food consumption are gathered by using a supplementary standardized surveillance form and are reported to CDC by fax or mail. This information is compared with NETSS data several times a year by CDC staff. Discrepancies are reviewed with the state health departments. The purpose of the surveillance system is to determine the incidence of trichinellosis, to maintain awareness of the disease, to monitor epidemiologic changes, to identify outbreaks, to guide prevention efforts, and to measure the effectiveness of those efforts. Although trichinellosis was associated historically with eating Trichinella-infected pork from domesticated sources, wild game meat was the most common source of infection during 1997-2001. During this 5-year period, 72 cases were reported to CDC. Of these, 31 (43%) cases were associated with eating wild game: 29 with bear meat, one with cougar meat, and one with wild boar meat. In comparison, only 12 (17%) cases were associated with eating commercial pork products, including four cases traced to a foreign source. Nine (13%) cases were associated with eating noncommercial pork from home-raised or direct-from-farm swine where U.S. commercial pork production industry standards and Regulations do not apply. The majority of the decline in reported trichinellosis cases is a result of improved observance of standards and regulations in the U.S. commercial pork industry, which has altered animal husbandry practices resulting in reduced Trichinella prevalence among swine. Because of the change in epidemiology of trichinellosis and the continued occurrence of cases among consumers of wild game meat and noncommercial pork, more targeted public education is needed to further reduce the incidence of this disease.


Entrustment Decision Making in Clinical Training.
The decision to trust a medical trainee with the critical responsibility to care for a patient is fundamental to clinical training. When carefully and deliberately made, such decisions can serve as significant stimuli for learning and also shape the assessment of trainees. Holding back entrustment decisions too much may hamper the trainee's development toward unsupervised practice. When carelessly made, however, they jeopardize patient safety. Entrustment decision-making processes, therefore, deserve careful analysis.Members (including the authors) of the International Competency-Based Medical Education Collaborative conducted a content analysis of the entrustment decision-making process in health care training during a two-day summit in September 2013 and subsequently reviewed the pertinent literature to arrive at a description of the critical features of this process, which informs this article.The authors discuss theoretical backgrounds and terminology of trust and entrustment in the clinical workplace. The competency-based movement and the introduction of entrustable professional activities force educators to rethink the grounds for assessment in the workplace. Anticipating a decision to grant autonomy at a designated level of supervision appears to align better with health care practice than do most current assessment practices. The authors distinguish different modes of trust and entrustment decisions and elaborate five categories, each with related factors, that determine when decisions to trust trainees are made: the trainee, supervisor, situation, task, and the relationship between trainee and supervisor. The authors' aim in this article is to lay a theoretical foundation for a new approach to workplace training and assessment.


Navigating the chemical space of dipeptidyl peptidase-4 inhibitors.
This study represents the first large-scale study on the chemical space of inhibitors of dipeptidyl peptidase-4 (DPP4), which is a potential therapeutic protein target for the treatment of diabetes mellitus. Herein, a large set of 2,937 compounds evaluated for their ability to inhibit DPP4 was compiled from the literature. Molecular descriptors were generated from the geometrically optimized low-energy conformers of these compounds at the semiempirical AM1 level. The origins of DPP4 inhibitory activity were elucidated from computed molecular descriptors that accounted for the unique physicochemical properties inherently present in the active and inactive sets of compounds as defined by their respective half maximal inhibitory concentration values of less than 1 μM and greater than 10 μM, respectively. Decision tree analysis revealed the importance of molecular weight, total energy of a molecule, topological polar surface area, lowest unoccupied molecular orbital, and number of hydrogen-bond donors, which correspond to molecular size, energy, surface polarity, electron acceptors, and hydrogen bond donors, respectively. The prediction model was subjected to rigorous independent testing via three external sets. Scaffold and chemical fragment analysis was also performed on these active and inactive sets of compounds to shed light on the distinguishing features of the functional moieties. Docking of representative active DPP4 inhibitors was also performed to unravel key interacting residues. The results of this study are anticipated to be useful in guiding the rational design of novel and robust DPP4 inhibitors for the treatment of diabetes.


The changeability and predictive value of dysfunctional cognitions in cognitive behavior therapy for chronic tinnitus.
Multidimensional tinnitus models describe dysfunctional cognitions as a complicating factor in the process of tinnitus habituation. However, this concept has rarely been investigated in previous research. The present study investigated the effects of two cognitive-behavioral treatments on dysfunctional tinnitus-related cognitions in patients with chronic tinnitus. Furthermore, dysfunctional cognitions were examined as possible predictors of the therapeutic effect on tinnitus distress. A total of 128 patients with chronic tinnitus were randomly assigned to either an Internet-delivered guided self-help treatment (Internet-based cognitive-behavioral therapy, ICBT), a conventional face-to-face group therapy (cognitive-behavioral group therapy, GCBT), or an active control group in the form of a web-based discussion forum (DF). To assess tinnitus-related dysfunctional thoughts, the Tinnitus Cognitions Scale (T-Cog) was used at pre- and post-assessment, as well as at the 6- and 12-month follow-up. Multivariate ANOVAs with post hoc tests revealed significant and comparable reductions of dysfunctional tinnitus-related cognitions for both treatments (GCBT and ICBT), which remained stable over a 6- and 12-month period. Negative correlations were found between the catastrophic subscale of the T-Cog and therapy outcome for ICBT, but not for GCBT. This means a higher degree of catastrophic thinking at baseline was associated with lower benefit from ICBT directly after the treatment. Hierarchical regression analysis confirmed catastrophizing as a predictor of poorer therapy outcome regarding emotional tinnitus distress in ICBT. No associations were detected in the follow-up assessments. Both forms of CBT are successful in reducing dysfunctional tinnitus-related cognitions. Catastrophizing significantly predicted a less favorable outcome regarding emotional tinnitus distress in ICBT. Clinical implications of these results are described. Dysfunctional cognitions could be targeted more intensively in therapy and in future research on tinnitus.


Focal hemodynamic patterns of status epilepticus detected by susceptibility weighted imaging (SWI).
To investigate pathological findings in the susceptibility weighted imaging (SWI) of patients experiencing convulsive (CSE) or non-convulsive status epilepticus (NCSE) with focal hyperperfusion in the acute setting. Twelve patients (six with NCSE confirmed by electroencephalogram (EEG) and six patients with CSE with seizure event clinically diagnosed) underwent MRI in this acute setting (mean time between onset of symptoms and MRI was 3 h 8 min), including SWI, dynamic susceptibility contrast MR imaging (DSC) and diffusion-weighted imaging (DWI). MRI sequences were retrospectively evaluated and compared with EEG findings (10/12 patients), and clinical symptoms. Twelve out of 12 (100 %) patients showed a focal parenchymal area with pseudo-narrowed cortical veins on SWI, associated with focal hyperperfused areas (increased cerebral blood flow (CBF) and mean transit time (MTT) shortening), and cortical DWI restriction in 6/12 patients (50 %). Additionally, these areas were associated with ictal or postical EEG patterns in 8/10 patients (80 %). Most frequent acute clinical findings were aphasia and/or hemiparesis in eight patients, and all of them showed pseudo-narrowed veins in those parenchymal areas responsible for these symptoms. In this study series with CSE and NCSE patients, SWI showed focally pseudo-narrowed cortical veins in hyperperfused and ictal parenchymal areas. Therefore, SWI might have the potential to identify an ictal region in CSE/NCSE. • The focal ictal brain regions show hyperperfusion in DSC MR-perfusion imaging. • SWI shows focally diminished cortical veins in hyperperfused ictal regions. • SWI has the potential to identify a focal ictal region in CSE/NCSE.


Can we name Earth's species before they go extinct?
Some people despair that most species will go extinct before they are discovered. However, such worries result from overestimates of how many species may exist, beliefs that the expertise to describe species is decreasing, and alarmist estimates of extinction rates. We argue that the number of species on Earth today is 5 ± 3 million, of which 1.5 million are named. New databases show that there are more taxonomists describing species than ever before, and their number is increasing faster than the rate of species description. Conservation efforts and species survival in secondary habitats are at least delaying extinctions. Extinction rates are, however, poorly quantified, ranging from 0.01 to 1% (at most 5%) per decade. We propose practical actions to improve taxonomic productivity and associated understanding and conservation of biodiversity.


Lineage-specific gene duplication and loss in human and great ape evolution.
Given that gene duplication is a major driving force of evolutionary change and the key mechanism underlying the emergence of new genes and biological processes, this study sought to use a novel genome-wide approach to identify genes that have undergone lineage-specific duplications or contractions among several hominoid lineages. Interspecies cDNA array-based comparative genomic hybridization was used to individually compare copy number variation for 39,711 cDNAs, representing 29,619 human genes, across five hominoid species, including human. We identified 1,005 genes, either as isolated genes or in clusters positionally biased toward rearrangement-prone genomic regions, that produced relative hybridization signals unique to one or more of the hominoid lineages. Measured as a function of the evolutionary age of each lineage, genes showing copy number expansions were most pronounced in human (134) and include a number of genes thought to be involved in the structure and function of the brain. This work represents, to our knowledge, the first genome-wide gene-based survey of gene duplication across hominoid species. The genes identified here likely represent a significant majority of the major gene copy number changes that have occurred over the past 15 million years of human and great ape evolution and are likely to underlie some of the key phenotypic characteristics that distinguish these species.


Cancerous perturbations within the ERK, PI3K/Akt, and Wnt/β-catenin signaling network constitutively activate inter-pathway positive feedback loops.
Perturbations in molecular signaling pathways are a result of genetic or epigenetic alterations, which may lead to malignant transformation of cells. Despite cellular robustness, specific genetic or epigenetic changes of any gene can trigger a cascade of failures, which result in the malfunctioning of cell signaling pathways and lead to cancer phenotypes. The extent of cellular robustness has a link with the architecture of the network such as feedback and feedforward loops. Perturbation in components within feedback loops causes a transition from a regulated to a persistently activated state and results in uncontrolled cell growth. This work represents the mathematical and quantitative modeling of ERK, PI3K/Akt, and Wnt/β-catenin signaling crosstalk to show the dynamics of signaling responses during genetic and epigenetic changes in cancer. ERK, PI3K/Akt, and Wnt/β-catenin signaling crosstalk networks include both intra and inter-pathway feedback loops which function in a controlled fashion in a healthy cell. Our results show that cancerous perturbations of components such as EGFR, Ras, B-Raf, PTEN, and components of the destruction complex cause extreme fragility in the network and constitutively activate inter-pathway positive feedback loops. We observed that the aberrant signaling response due to the failure of specific network components is transmitted throughout the network via crosstalk, generating an additive effect on cancer growth and proliferation.


The T-13910C polymorphism in the lactase phlorizin hydrolase gene is associated with differences in serum calcium levels and calcium intake.
The C-variant of a T-13910C polymorphism (rs4988235; NT_022135.15:g.25316568G > A) upstream of the lactase phlorizin hydrolase (LPH) gene causes lactose intolerance. Association studies with differences in bone parameters and fracture risk have been inconclusive. The objective of this study was to examine the association of LPH rs4988235 with body height and bone parameters and calcium homeostasis in two elderly populations of Dutch Caucasians and assess interaction with vitamin D receptor (VDR) polymorphisms. Genotyping of LPH and VDR polymorphisms was performed in 6367 individuals from the Rotterdam Study and 844 from the Longitudinal Aging Study Amsterdam (LASA). Associations with age, height, weight, bone mineral density (BMD), skeletal morphometric parameters and serum vitamin D and calcium levels, and dietary calcium intake were assessed using ANOVA or analysis of covariance, and allele dose effect was assessed using linear regression analysis. Fracture risk was analyzed using Cox's proportional hazard regression analysis. Associations with body height (p = 2.7 × 10(-8)) and vertebral area (p = .048) found in the Rotterdam Study were explained by population stratification, as assessed by principal-component analyses, and disappeared after additional adjustments. No associations with femoral neck or lumbar spine BMD or with fracture risk were detected. Calcium intake and serum ionized serum calcium were significantly lower in C-homozygotes (p = 9.2 × 10(-7), p = .02, respectively). For none of the parameters studied was interaction between the T-13910C polymorphism and VDR block 5 haplotype 1 observed. We show that the C allele of the T-13910C polymorphism causing lactose intolerance is associated with lower dietary calcium intake and serum calcium levels but not with BMD or fractures. The associations observed with height and vertebral area were the result of population stratification. This demonstrates the impact of population stratification and urges researchers to carefully take this into account in genetic associations, in particular, in dietary intake-related phenotypes, of which LPH and lactose intolerance are a strong example.


Sleep duration, cardiovascular disease, and proinflammatory biomarkers.
Habitual sleep duration has been associated with cardiometabolic disease, via several mechanistic pathways, but few have been thoroughly explored. One hypothesis is that short and/or long sleep duration is associated with a proinflammatory state, which could increase risk for cardiovascular and metabolic diseases. This hypothesis has been largely explored in the context of experimental sleep deprivation studies which have attempted to demonstrate changes in proinflammatory markers following acute sleep loss in the laboratory. Despite the controlled environment available in these studies, samples tend to lack generalization to the population at large and acute sleep deprivation may not be a perfect analog for short sleep. To address these limitations, population based studies have explored associations between proinflammatory markers and habitual sleep duration. This review summarizes what is known from experimental and cross-sectional studies about the association between sleep duration, cardiovascular disease, and proinflammatory biomarkers. First, the association between sleep duration with both morbidity and mortality, with a focus on cardiovascular disease, is reviewed. Then, a brief review of the potential role of proinflammatory markers in cardiovascular disease is presented. The majority of this review details specific findings related to specific molecules, including tumor necrosis factor-α, interleukins-1, -6, and -17, C-reactive protein, coagulation molecules, cellular adhesion molecules, and visfatin. Finally, a discussion of the limitations of current studies and future directions is provided.


Aegilops umbellulata introgression carrying leaf rust and stripe rust resistance genes Lr76 and Yr70 located to 9.47-Mb region on 5DS telomeric end through a combination of chromosome sorting and sequencing.
Lr76 and Yr70 have been fine mapped using the sequence of flow-sorted recombinant 5D chromosome from wheat-Ae. umbellulata introgression line. The alien introgression has been delineated to 9.47-Mb region on short arm of wheat chromosome 5D. Leaf rust and stripe rust are among the most damaging diseases of wheat worldwide. Wheat cultivation based on limited number of rust resistance genes deployed over vast areas expedites the emergence of new pathotypes warranting a continuous deployment of new resistance genes. In this paper, fine mapping of Aegilops umbellulata-derived leaf rust and stripe rust resistance genes Lr76 and Yr70 is being reported. We flow sorted and paired-end sequenced 5U chromosome of Ae. umbellulata, recombinant chromosome 5D (5DIL) from wheat-Ae. umbellulata introgression line pau16057 and 5DRP of recurrent parent WL711. Chromosome 5U reads were mapped against the reference Chinese Spring chromosome 5D sequence, and alien-specific SNPs were identified. Chromosome 5DIL and 5DRP sequences were de novo assembled, and alien introgression-specific markers were designed by selecting 5U- and 5D-specific SNPs. Overall, 27 KASP markers were mapped in high-resolution population consisting of 1404 F5 RILs. The mapping population segregated for single gene each for leaf rust and stripe rust resistance. The physical order of the SNPs in pau16057 was defined by projecting the 27 SNPs against the IWGSC RefSeq v1.0 sequence. Based on this physical map, the size of Ae. umbellulata introgression was determined to be 9.47 Mb on the distal most end of the short arm of chromosome 5D. This non-recombining alien segment carries six NB-LRR encoding genes based on NLR annotation of assembled chromosome 5DIL sequence and IWGSC RefSeq v1.1 gene models. The presence of SNPs and other sequence variations in these genes between pau16057 and WL711 suggested that they are candidates for Lr76 and Yr70.


Composition and abstraction of logical regulatory modules: application to multicellular systems.
Logical (Boolean or multi-valued) modelling is widely used to study regulatory or signalling networks. Even though these discrete models constitute a coarse, yet useful, abstraction of reality, the analysis of large networks faces a classical combinatorial problem. Here, we propose to take advantage of the intrinsic modularity of inter-cellular networks to set up a compositional procedure that enables a significant reduction of the dynamics, yet preserving the reachability of stable states. To that end, we rely on process algebras, a well-established computational technique for the specification and verification of interacting systems. We develop a novel compositional approach to support the logical modelling of interconnected cellular networks. First, we formalize the concept of logical regulatory modules and their composition. Then, we make this framework operational by transposing the composition of logical modules into a process algebra framework. Importantly, the combination of incremental composition, abstraction and minimization using an appropriate equivalence relation (here the safety equivalence) yields huge reductions of the dynamics. We illustrate the potential of this approach with two case-studies: the Segment-Polarity and the Delta-Notch modules.


[Historical evolution of package inserts in Brazil].
In Brazil, package inserts provide key information on pharmaceuticals. The current study analyzes the evolution of package inserts and the impact on this process by scientific research and development, globalization of information, and various health policies. The study began with a retrospective review of Brazilian health legislation until 1920, the year when the National Public Health Department was created. The analysis of documents on the evolution of health regulation in Brazil began with the Brazilian Pharmaceutical Collection-Health Rulings. The second stage of the study involved a search of standards and norms in VISALEGIS: Health Surveillance Legislation, Portal for Legislation from the National Congressional Information System and the Health Legislation System. Package inserts became an important vehicle for information in the country and underwent important regulatory changes in the latter half of the 20th century. From 1946 to 2006, the number of mandatory items increased, with more in-depth description. However, the standardization of information for medicines with the same active ingredient failed to materialize, despite its importance and the various legal initiatives in this direction.


Exploring the potential to remain "Young @ Heart": initial findings of a multi-centre, randomised study of nurse-led, home-based intervention in a hybrid health care system.
Disease management programs have been shown to improve health outcomes in high risk individuals in many but not all health care systems. Young @ Heart is a multi-centre, randomised controlled study of a nurse-led, home-based intervention (HBI) program vs. usual care (UC) in privately insured patients in Australia aged ≥ 45 years following an acute cardiac admission. Intensity of HBI is tailored to an individual's clinical stability, management and risk profile. The primary endpoint is the rate of all-cause stay during a mean of 2.5 years follow-up. A target of 602 adults (72% men) were randomised to HBI (n=306) or UC (n=296); their initial profiles being well matched. At baseline, 71% were overweight (body mass index 29.7 ± 3.9 kg/m(2)) and 66% had an elevated blood pressure (153 ± 18/89 ± 7 mm Hg). Over half had a history of smoking and 39% had a sub-optimal total cholesterol level >4 mmol/L. Overall, 62% (376 cases) were treated for coronary artery disease (27% with multi-vessel disease and 39% underwent cardiac revascularisation). A further 20% (120 cases) were treated for a cardiac arrhythmia (predominantly atrial fibrillation) and 19% type 2 diabetes mellitus. At 7-14 days post-discharge, 293 (96%) HBI patients received a home visit triggering urgent clinical review and/or enhanced clinical management in many patients. The Young @ Heart intervention is a well accepted and potentially effective intervention to reduce recurrent hospital stay in privately insured cardiac patients in Australia.


Cultural competency and patient-centered communication: a study of an isolated outbreak of urinary tract infections in afghanistan.
Personal hygiene is strongly associated with disease prevention and is especially important during prolonged patrol or combat operations. Understanding cultural variances associated with personal hygiene is critical for Special Operation Forces (SOF) medics to prevent, monitor, and treat acquired and transmitted infections while working with host nation personnel. During a multiday, long-range patrol, approximately 40 male Afghan National Army troops between the ages of 22 and 49 presented for treatment of burning or pain while urinating. All patients were empirically diagnosed with urinary tract infections. Methods and Discussion: The high attack rate and isolated nature of the outbreak suggested that personal hygiene or sexual intercourse was the most likely cause of the isolated outbreak. However, the cultural sensitivity of both topics made social history gathering a difficult task. After participating in a detailed medical interview, one patient revealed that he and his comrades were blocking their urethras with clay plugs after voiding to prevent residual urine from dripping onto their clothes. This case study presents what might be an undocumented practice carried throughout many ethnic cultures endogenous to Afghanistan and discusses how cultural barriers can impact effective health care delivery.


Differential axonal conduction patterns of mechano-sensitive and mechano-insensitive nociceptors--a combined experimental and modelling study.
Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels NaV1.7 and NaV1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less Kdr and NaV1.8 in combination with more NaV1.7 and Na+/K+-ATPase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.


An essential and NSF independent role for α-SNAP in store-operated calcium entry.
Store-operated calcium entry (SOCE) by calcium release activated calcium (CRAC) channels constitutes a primary route of calcium entry in most cells. Orai1 forms the pore subunit of CRAC channels and Stim1 is the endoplasmic reticulum (ER) resident Ca(2+) sensor. Upon store-depletion, Stim1 translocates to domains of ER adjacent to the plasma membrane where it interacts with and clusters Orai1 hexamers to form the CRAC channel complex. Molecular steps enabling activation of SOCE via CRAC channel clusters remain incompletely defined. Here we identify an essential role of α-SNAP in mediating functional coupling of Stim1 and Orai1 molecules to activate SOCE. This role for α-SNAP is direct and independent of its known activity in NSF dependent SNARE complex disassembly. Importantly, Stim1-Orai1 clustering still occurs in the absence of α-SNAP but its inability to support SOCE reveals that a previously unsuspected molecular re-arrangement within CRAC channel clusters is necessary for SOCE. DOI:http://dx.doi.org/10.7554/eLife.00802.001.


Chronic consumption of farmed salmon containing persistent organic pollutants causes insulin resistance and obesity in mice.
Dietary interventions are critical in the prevention of metabolic diseases. Yet, the effects of fatty fish consumption on type 2 diabetes remain unclear. The aim of this study was to investigate whether a diet containing farmed salmon prevents or contributes to insulin resistance in mice. Adult male C57BL/6J mice were fed control diet (C), a very high-fat diet without or with farmed Atlantic salmon fillet (VHF and VHF/S, respectively), and Western diet without or with farmed Atlantic salmon fillet (WD and WD/S, respectively). Other mice were fed VHF containing farmed salmon fillet with reduced concentrations of persistent organic pollutants (VHF/S(-POPs)). We assessed body weight gain, fat mass, insulin sensitivity, glucose tolerance, ex vivo muscle glucose uptake, performed histology and immunohistochemistry analysis, and investigated gene and protein expression. In comparison with animals fed VHF and WD, consumption of both VHF/S and WD/S exaggerated insulin resistance, visceral obesity, and glucose intolerance. In addition, the ability of insulin to stimulate Akt phosphorylation and muscle glucose uptake was impaired in mice fed farmed salmon. Relative to VHF/S-fed mice, animals fed VHF/S(-POPs) had less body burdens of POPs, accumulated less visceral fat, and had reduced mRNA levels of TNFα as well as macrophage infiltration in adipose tissue. VHF/S(-POPs)-fed mice further exhibited better insulin sensitivity and glucose tolerance than mice fed VHF/S. Our data indicate that intake of farmed salmon fillet contributes to several metabolic disorders linked to type 2 diabetes and obesity, and suggest a role of POPs in these deleterious effects. Overall, these findings may participate to improve nutritional strategies for the prevention and therapy of insulin resistance.


Meropenem dosing in critically ill patients with sepsis receiving high-volume continuous venovenous hemofiltration.
Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (> or = 4 liters/h); secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter); and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood samples and ultrafiltrate and urine samples. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0); terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3); trough concentration, 7.7 mg/liter (6.2 to 12.9); total clearance, 6.0 liters/h (5.2 to 6.2); hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem (R(2) = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei.


Screening for osteopenia and osteoporosis: do the accepted normal ranges lead to overdiagnosis?
Osteoporosis is a common disease which causes significant morbidity and mortality and in many cases may be preventable. In the absence of fragility fractures the accepted method of identifying those at high risk is based upon bone mineral density (BMD) measurements with defined cut-off points. To correctly delineate normal from abnormal, reliable reference ranges appropriate to the observed population are required. We have studied the age-dependent changes in mean BMD and standard deviation at the lumbar spine and femoral neck in a normal population extracted from 4280 women screened for osteopenia and compared our findings with the manufacturer's normal range (MNR). The recent World Health Organization criteria for the diagnosis of osteopenia and osteoporosis using the 'manufacturer's young normal' (MYN) values and our 'study young normal' (SYN) values have been applied. The study normal population (SNP) included 2068 women (mixed social class; mean age 53 years, range 30-79 years). The distribution of mean lumbar spine BMD with age in SNP was generally similar to the MNR. In contrast mean femoral neck bone density from SNP was significantly different from the MNR, ranging from 3% to 12% lower in each 5-year group analysed (p < 0.05). Comparison of standard deviations in spine BMD in SNP against the fixed MNR standard deviation showed a statistically significant increase commencing at 45 years of age. The magnitude of this increase appeared to rise with age and remained significant in the 75- to 79-year age group (p < 0.05). In contrast, standard deviation in femoral neck BMD in SNP appeared relatively constant with age except in the group of women at and around the time of the menopause. The SYN value for mean lumbar spine BMD was 0.994 g/cm2 (cf. MYN value 1.047, p < 0.0001) with a standard deviation of 0.122 g/cm2 (cf. MYN 0.11, p = 0.0005). Similarly our SYN value for femoral neck BMD was 0.787 (cf. MYN value 0.895, p < 0.0001) with a standard deviation of 0.109 (cf. MYN value 0.10, p = 0.0027). Using SYN values 36% (748) for the spine and 33% (675) for the hip of our normal population are classified as osteopenic or osteoporotic. Using MYN values increases the proportion of women classified as osteopenic or osteoporotic to 52% (1078) for the spine and 68% (1409) for the femur. If both sites of measurement are considered simultaneously SYN classifies 46% (952) as either osteopenic or osteoporotic at one or other site, which is increased to 73% (1513) when the MYN values are used. We observe that manufacturer's reference ranges may not be appropriate for the local population and may lead to an erroneously high diagnosis of osteopenia and osteoporosis, which would lead to unnecessary patient anxiety and perhaps errors regarding treatment.


Dietary restriction of mice on a high-fat diet induces substrate efficiency and improves metabolic health.
High energy intake and, specifically, high dietary fat intake challenge the mammalian metabolism and correlate with many metabolic disorders such as obesity and diabetes. However, dietary restriction (DR) is known to prevent the development of metabolic disorders. The current western diets are highly enriched in fat, and it is as yet unclear whether DR on a certain high-fat (HF) diet elicits similar beneficial effects on health. In this research, we report that HF-DR improves metabolic health of mice compared with mice receiving the same diet on an ad libitum basis (HF-AL). Already after five weeks of restriction, the serum levels of cholesterol and leptin were significantly decreased in HF-DR mice, whereas their glucose sensitivity and serum adiponectin levels were increased. The body weight and measured serum parameters remained stable in the following 7 weeks of restriction, implying metabolic adaptation. To understand the molecular events associated with this adaptation, we analyzed gene expression in white adipose tissue (WAT) with whole genome microarrays. HF-DR strongly influenced gene expression in WAT; in total, 8643 genes were differentially expressed between both groups of mice, with a major role for genes involved in lipid metabolism and mitochondrial functioning. This was confirmed by quantitative real-time reverse transcription-PCR and substantiated by increase in mitochondrial density in WAT of HF-DR mice. These results provide new insights in the metabolic flexibility of dietary restricted animals and suggest the development of substrate efficiency.


Fast source optimization involving quadratic line-contour objectives for the resist image.
In Abbe's formulation, source optimization (SO) is often formulated into a linear or quadratic problem, depending on the choice of objective functions. However, the conventional approach for the resist image, involving a sigmoid transformation of the aerial image, results in an objective with a functional form. The applicability of the resist-image objective to SO or simultaneous source and mask optimization (SMO) is therefore limited. In this paper, we present a linear combination of two quadratic line-contour objectives to approximate the resist image effect for fast convergence. The line-contour objectives are based on the aerial image on drawn edges using a constant threshold resist model and that of pixels associated with an intensity minimum for side-lobe suppression. A conjugate gradient method is employed to assure the convergence to the global minimum within the number of iterations less than that of source variables. We further compare the optimized illumination with the proposed line-contour objectives to that with a sigmoid resist-image using a steepest decent method. The results show a 100x speedup with comparable image fidelity and a slightly improved process window for the two cases studied.


The Relation of Ego Integrity and Despair to Personality Traits and Mental Health.
Existing studies in the Eriksonian tradition found that ego integrity and despair are important indicators of life-span development. The present study relates ego integrity and despair to contemporary theories of personality and mental health. A cross-sectional study of Dutch adults aged between 50 and 95 years (N = 218) was carried out, using the Northwestern Ego Integrity Scale, the subscales for neuroticism, extraversion, and openness to experience of the NEO-FFI, the Mental Health Continuum-Short Form, and the Center for Epidemiological Studies Depression Scale-Short Form. Extraversion and openness to experience have an indirect relation to ego integrity that is mediated by well-being. Neuroticism was related to despair and explained the relationship of depressive symptoms to despair. Chronological age did not moderate these findings. Ego integrity appears to be related to fluctuating states of mental health, whereas despair is more an expression of a general trait-like disposition of neuroticism. Implications for further research are discussed.


Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex.
Astrocytes have long been thought to act as a support network for neurons, with little role in information representation or processing. We used two-photon imaging of calcium signals in the ferret visual cortex in vivo to discover that astrocytes, like neurons, respond to visual stimuli, with distinct spatial receptive fields and sharp tuning to visual stimulus features including orientation and spatial frequency. The stimulus-feature preferences of astrocytes were exquisitely mapped across the cortical surface, in close register with neuronal maps. The spatially restricted stimulus-specific component of the intrinsic hemodynamic mapping signal was highly sensitive to astrocyte activation, indicating that astrocytes have a key role in coupling neuronal organization to mapping signals critical for noninvasive brain imaging. Furthermore, blocking astrocyte glutamate transporters influenced the magnitude and duration of adjacent visually driven neuronal responses.


The polymorphism of Hydra microsatellite sequences provides strain-specific signatures.
Hydra are freshwater polyps widely studied for their amazing regenerative capacity, adult stem cell populations, low senescence and value as ecotoxicological marker. Many wild-type strains of H. vulgaris have been collected worldwide and maintained effectively under laboratory conditions by asexual reproduction, while stable transgenic lines have been continuously produced since 2006. Efforts are now needed to ensure the genetic characterization of all these strains, which despite similar morphologies, show significant variability in their response to gene expression silencing procedures, pharmacological treatments or environmental conditions. Here, we established a rapid and reliable procedure at the single polyp level to produce via PCR amplification of three distinct microsatellite sequences molecular signatures that distinguish between Hydra strains and species. The TG-rich region of an uncharacterized gene (ms-c25145) helps to distinguish between Eurasian H. vulgaris-Pallas strains (Hm-105, Basel1, Basel2 and reg-16), between Eurasian and North American H. vulgaris strains (H. carnea, AEP), and between the H. vulgaris and H. oligactis species. The AT-rich microsatellite sequences located in the AIP gene (Aryl Hydrocarbon Receptor Interaction Protein, ms-AIP) also differ between Eurasian and North American H. vulgaris strains. Finally, the AT-rich microsatellite located in the Myb-Like cyclin D-binding transcription factor1 gene (ms-DMTF1) gene helps to distinguish certain transgenic AEP lines. This study shows that the analysis of microsatellite sequences, which is capable of tracing genomic variations between closely related lineages of Hydra, provides a sensitive and robust tool for characterizing the Hydra strains.


Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy.
To assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV-1 RNA load of < 500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART). HCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a > or = 50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a > or = 50 cells/microL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation. HCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatus.


Pulmonary involvement of idiopathic hypereosinophilic syndrome: CT findings in five patients.
The aim of this study was to assess the CT findings of pulmonary involvement in patients with idiopathic hypereosinophilic syndrome (HES). The study included five patients with idiopathic HES who had pulmonary involvement proven by bronchoalveolar lavage (n = 3) or based on clinical and radiologic findings (n = 2). Four patients had high resolution CT and one had conventional CT. The CT scans were retrospectively reviewed by two chest radiologists for pattern and distribution of disease. All five patients had several small nodules in both lungs at CT scan. Four patients had nodules with a halo of ground-glass attenuation. Three patients had focal areas of ground-glass attenuation in both lungs. These lesions were present in all lung zones and involved mainly the peripheral lung. There was neither lobar predilection nor peribronchovascular distribution. Other organs involved included bone marrow (n = 3), liver (n = 3), stomach (n = 1), and peritoneum (n = 1). The CT findings of pulmonary involvement in patients with idiopathic HES included small nodules with or without a halo of ground-glass attenuation and focal areas of ground-glass attenuation mainly in the lung periphery.


The immunology of DNA vaccines.
The surprising observation that direct inoculation of an expression plasmid encoding a foreign protein into the skin of mice resulted in the induction of antibody responses, demonstrated that injection of "naked" DNA could result in antigen expression in an immunogenic form (1). This observation and the subsequent demonstration that intramuscular injections of plasmid DNA encoding influenza nucleoprotein could protect mice against a challenge with live influenza virus have opened up new avenues for vaccine development (2-3). Immunization with plasmid DNA has been shown to activate both humoral and cellular immune responses, including the generation of antigen-specific CD8(+) cytotoxic T cells as well as CD4(+) T helper cells (4). An increasing number of studies using experimental animal models have demonstrated that plasmid DNA immunization can promote effective immune responses against numerous viruses, including influenza, rabies, HIV, HBV, HCV, and HSV; several bacteria, including: Mycobacterium tuberculosis, Mycoplasma pulmonis, and Borrelia burgdorferi; as well as parasites, such as malaria and leishmania (4). Phase I clinical vaccine trials are currently being performed for HIV, HBV, and influenza virus. With the molecular identification of tumor antigens (5), there has also been increasing interest in the development of DNA-based immunization for cancer. Preclinical studies demonstrate that DNA-based immunizations targeting model tumor antigens such as chicken ovalbumin (6), β-galactosidase (7), or CEA (8) induce protective immune responses leading to rejection of a subsequent, normally lethal challenge with antigen-expressing tumor cells.


Finely stratified cylinder model for radially inhomogeneous cylinders normally irradiated by electromagnetic plane waves.
A finely stratified cylinder model (FSCM) for calculation of the scattered fields of infinitely long, radially inhomogeneous, circular cylinders normally illuminated by electromagnetic plane waves is introduced for the first time, to our knowledge. Because of its capability of using a very large number of layers (more than 80,000), the model is useful for both continuous and discontinuous refractive-index profiles. Numerical results agree well with published solutions for radially inhomogeneous cylinders; for cylinders with a dimensionless size parameter larger than 60, results obtained with the FSCM agree with the geometric optics for both continuous and discontinuous refractive-index profiles.


Electrophysiological evidence of sublexical phonological access in character processing by L2 Chinese learners of L1 alphabetic scripts.
While Chinese character reading relies more on addressed phonology relative to alphabetic scripts, skilled Chinese readers also access sublexical phonological units during recognition of phonograms. However, sublexical orthography-to-phonology mapping has not been found among beginning second language (L2) Chinese learners. This study investigated character reading in more advanced Chinese learners whose native writing system is alphabetic. Phonological regularity and consistency were examined in behavioral responses and event-related potentials (ERPs) in lexical decision and delayed naming tasks. Participants were 18 native English speakers who acquired written Chinese after age 5 years and reached grade 4 Chinese reading level. Behaviorally, regular characters were named more accurately than irregular characters, but consistency had no effect. Similar to native Chinese readers, regularity effects emerged early with regular characters eliciting a greater N170 than irregular characters. Regular characters also elicited greater frontal P200 and smaller N400 than irregular characters in phonograms of low consistency. Additionally, regular-consistent characters and irregular-inconsistent characters had more negative amplitudes than irregular-consistent characters in the N400 and LPC time windows. The overall pattern of brain activities revealed distinct regularity and consistency effects in both tasks. Although orthographic neighbors are activated in character processing of L2 Chinese readers, the timing of their impact seems delayed compared with native Chinese readers. The time courses of regularity and consistency effects across ERP components suggest both assimilation and accommodation of the reading network in learning to read a typologically distinct second orthographic system.


You talkin' to me? Interactive playback is a powerful yet underused tool in animal communication research.
Over the years, playback experiments have helped further our understanding of the wonderful world of animal communication. They have provided fundamental insights into animal behaviour and the function of communicative signals in numerous taxa. As important as these experiments are, however, there is strong evidence to suggest that the information conveyed in a signal may only have value when presented interactively. By their very nature, signalling exchanges are interactive and therefore, an interactive playback design is a powerful tool for examining the function of such exchanges. While researchers working on frog and songbird vocal interactions have long championed interactive playback, it remains surprisingly underused across other taxa. The interactive playback approach is not limited to studies of acoustic signalling, but can be applied to other sensory modalities, including visual, chemical and electrical communication. Here, I discuss interactive playback as a potent yet underused technique in the field of animal behaviour. I present a concise review of studies that have used interactive playback thus far, describe how it can be applied, and discuss its limitations and challenges. My hope is that this review will result in more scientists applying this innovative technique to their own study subjects, as a means of furthering our understanding of the function of signalling interactions in animal communication systems.