Dynamics of Miura-patterned foldable sheets in shear flow.
We study the dynamics of piecewise rigid sheets containing predefined crease lines in shear flow. The crease lines act like hinge joints along which the sheet may fold rigidly, i.e. without bending any other crease line. We choose the crease lines such that they tessellate the sheet into a two-dimensional array of parallelograms. Specifically, we focus on a particular arrangement of crease lines known as a Miura-pattern in the origami community. When all the hinges are fully open the sheet is planar, whereas when all are closed the sheet folds over itself to form a compact flat structure. Due to rigidity constraints, the folded state of a Miura-sheet can be described using a single fold angle. The hinged sheet is modeled using the framework of constrained multibody systems in the absence of inertia. The hydrodynamic drag on each of the rigid panels is calculated based on an inscribed elliptic disk, but intra-panel hydrodynamic interactions are neglected. We find that when the motion of a sheet remains symmetric with respect to the flow-gradient plane, after a sufficiently long time, the sheet either exhibits asymptotically periodic tumbling and breathing, indicating approach to a limit cycle; or it reaches a steady state by completely unfolding, which we show to be a half-stable node in the phase space. In the case of asymmetric motion of the sheet with respect to the flow-gradient plane, we find that the terminal state of motion is one of - (i) steady state with a fully unfolded or fully folded configuration, (ii) asymptotically periodic tumbling, indicating approach to a limit cycle, (iii) cyclic tumbling without repetition, indicating a quasiperiodic orbit, or (iv) cyclic tumbling with repetition after several cycles, indicating a resonant quasiperiodic orbit. No chaotic behavior was found.


Effects of cycloheximide on thermotolerance expression, heat shock protein synthesis, and heat shock protein mRNA accumulation in rat fibroblasts.
A single hyperthermic exposure can render cells transiently resistant to subsequent high temperature stresses. Treatment of rat embryonic fibroblasts with cycloheximide for 6 h after a 20-min interval at 45 degrees C inhibits protein synthesis, including heat shock protein (hsp) synthesis, and results in an accumulation of hsp 70 mRNA, but has no effect on subsequent survival responses to 45 degrees C hyperthermia. hsp 70 mRNA levels decreased within 1 h after removal of cycloheximide but then appeared to stabilize during the next 2 h (3 h after drug removal and 9 h after heat shock). hsp 70 mRNA accumulation could be further increased by a second heat shock at 45 degrees C for 20 min 6 h after the first hyperthermic exposure in cycloheximide-treated cells. Both normal protein and hsp synthesis appeared increased during the 6-h interval after hyperthermia in cultures which received two exposures to 45 degrees C for 20 min compared with those which received only one treatment. No increased hsp synthesis was observed in cultures treated with cycloheximide, even though hsp 70 mRNA levels appeared elevated. These data indicate that, although heat shock induces the accumulation of hsp 70 mRNA in both normal and thermotolerant cells, neither general protein synthesis nor hsp synthesis is required during the interval between two hyperthermic stresses for Rat-1 cells to express either thermotolerance (survival resistance) or resistance to heat shock-induced inhibition of protein synthesis.


Long-term functional recovery of hepatocytes after cryopreservation in a three-dimensional culture configuration.
Hepatocyte cryopreservation is essential to ensure a ready supply of cells for use in transplantation or as part of an extracorporeal liver assist device to provide on-demand liver support. To date, most of the work on hepatocyte cryopreservation has been performed on isolated hepatocytes, and has generally yielded cells which display low viability and greatly reduced short-term function. This report presents the development of a freezing procedure for hepatocytes cultured in a sandwich configuration. A specially designed freezing unit was used to provide controlled temperatures throughout the freeze-thaw cycle. Cooling rate, warming rate, and final freezing temperature were evaluated as to their effect on hepatocyte function as judged by albumin secretion. Under optimized conditions (cooling at 5 degrees C/min and warm at > or = 400 degrees C/min), freezing to -40 degrees C resulted in full recovery of albumin secretion within 2-3 days post-freezing, whereafter albumin secretion levels remained normal for the duration of the experiments (2 wks). Freezing to -80 degrees C lead to an approximate 70% recovery of long-term protein secretion when compared to control cultures. In addition, the overall hepatocyte morphology as judged by light microscopy, closely followed the functional results. The sandwich culture configuration, thus, enables hepatocytes to maintain a satisfactory level of long-term protein secretion after a freeze-thaw cycle under optimized conditions, and offers an attractive tool for further studies into the mechanisms of freezing injury and subsequent hepatocellular recovery. These results are a promising step in the development of satisfactory storage procedures for hepatocytes.


Absence of an effect of high nitrate intake from beetroot juice on blood pressure in treated hypertensive individuals: a randomized controlled trial.
Dietary nitrate, which is in green leafy vegetables and beetroot, decreases blood pressure through the enterosalivary nitrate-nitrite-nitric oxide pathway in healthy individuals. Whether similar effects would occur in individuals with treated hypertension and, therefore, at increased risk of cardiovascular disease is unclear. We assessed whether increased dietary nitrate intake by using beetroot juice for 1 wk lowers blood pressure in treated hypertensive men and women. Participants (n = 27) were recruited to a randomized, placebo-controlled, double-blind crossover trial. The effect of 1-wk intake of nitrate-rich beetroot juice was compared with 1-wk intake of nitrate-depleted beetroot juice (placebo). The primary outcome was blood pressure assessed by measuring home blood pressure during the intervention and 24-h ambulatory blood pressure on day 7 of the intervention. Other outcomes included nitrate metabolism assessed by measuring nitrate and nitrite in plasma, saliva, and urine. Relative to the placebo, 1-wk intake of nitrate-rich beetroot juice resulted in a 3-fold increase in plasma nitrite and nitrate, a 7-fold increase in salivary nitrite, an 8-fold higher salivary nitrate, and a 4-fold increase in both urinary nitrite and nitrate (P < 0.001). However, no differences in home blood pressure and 24-h ambulatory blood pressure were observed with 1-wk intake of nitrate-rich beetroot juice in comparison with the placebo. An increase in dietary nitrate intake may not be an effective short-term approach to further lower blood pressure in treated hypertensive subjects.


Impact of scattering and spherical aberration in contrast sensitivity.
We investigated the impact in spatial visual performance of the combined presence of different amounts of spherical aberration and intraocular scattering in the eye. In a group of subjects, contrast sensitivity at 6 cycles per degree was measured when viewing through holographic diffusers to produce different levels of scattering and with their spherical aberration simultaneously controlled using an adaptive-optics visual simulator. For elevated levels of scattering, the addition of small amounts of spherical aberration either does not decrease, or even may slightly increase, contrast sensitivity under some conditions. This seems to be due to an optical effect also demonstrated in an artificial eye. Although the visual effect is quite small, this finding could suggest a balancing mechanism where larger spherical aberration could keep relatively stable the retinal image quality under the presence of elevated scattering. This is actually the situation in older eyes with both spherical aberration and intraocular scatter being higher than in young eyes.


Divisive gain modulation of motoneurons by inhibition optimizes muscular control.
When using muscles, the precision with which force is delivered is as important as the delivery of force itself. Force is regulated by both the number of recruited motoneurons and their spike frequency. While it is known that the recruitment is ordered to reduce variability in force, it remains unclear whether the motoneuron gain, i.e., the slope of the transformation between synaptic input and spiking output, is also modulated to reduce variability in force. To address this issue, we use turtle hindlimb scratching as a model for fine motor control, since this behavior involves precise limb movement to rub the location of somatic nuisance touch. We recorded intracellularly from motoneurons in a reduced preparation where the limbs were removed to increase mechanical stability and the motor nerve activity served as a surrogate for muscle force. We found that not only is the gain of motoneurons regulated on a subsecond timescale, it is also adjusted to minimize variability. The modulation is likely achieved via an expansive nonlinearity between spike rate and membrane potential with inhibition having a divisive influence. These findings reveal a versatile mechanism of modulating neuronal sensitivity and suggest that such modulation is fundamentally linked to optimization.


Challenges in merging Medicaid and Medicare databases to obtain healthcare costs for dual-eligible beneficiaries: using diabetes as an example.
Dual-eligible Medicaid-Medicare beneficiaries represent a group of people who are in the lowest income bracket in the US, have numerous co-morbidities and place a heavy financial burden on the US healthcare system. As cost-effectiveness analyses are used to inform national policy decisions and to determine the value of implemented chronic disease control programmes, it is imperative that complete and valid determination of healthcare utilization and costs can be obtained from existing state and federal databases. Differences and inconsistencies between the Medicaid and Medicare databases have presented significant challenges when extracting accurate data for dual-eligible beneficiaries. To describe the challenges inherent in merging Medicaid and Medicare claims databases and to present a protocol that would allow successful linkage between these two disparate databases. Healthcare claims and costs were extracted from both Medicaid and Medicare databases for King County, Seattle, WA, USA. Three Medicaid files were linked to eight Medicare files for unique dual-eligible beneficiaries with type 2 diabetes mellitus. Although major differences were identified in how variables and claims were defined in each database, our method enabled us to link these two different databases to compile a complete and accurate assessment of healthcare use and costs for dual-eligible beneficiaries with a costly chronic condition. For example, of the 1759 dual-eligible beneficiaries with diabetes, the average cost of healthcare was USD 15,981 per capita, with an average of 76 claims per person per year. The resulting merged database provides a virtually complete documentation of both utilization and costs of medical care for a population who receives coverage from two different programmes. By identifying differences and implementing our linkage protocol, the merged database serves as a foundation for a broad array of analyses on healthcare use and costs for effectiveness research.


Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice.
The development of insulin resistance is tightly linked to fatty liver disease and is considered a major health concern worldwide, although their mechanistic relationship remains controversial. Activin has emerging roles in nutrient homeostasis, but its metabolic effects on hepatocytes remain unknown. In this study, we investigated the effects of increased endogenous activin bioactivity on hepatic nutrient homeostasis by creating mice with inactivating mutations that deplete the circulating activin antagonists follistatin-like-3 (FSTL3) or the follistatin 315 isoform (FST315; FST288-only mice). We investigated liver histology and lipid content, hepatic insulin sensitivity, and metabolic gene expression including the HepG2 cell and primary hepatocyte response to activin treatment. Both FSTL3-knockout and FST288-only mice had extensive hepatic steatosis and elevated hepatic triglyceride content. Unexpectedly, insulin signaling, as assessed by phospho-Akt (a.k.a. protein kinase B), was enhanced in both mouse models. Pretreatment of HepG2 cells with activin A increased their response to subsequent insulin challenge. Gene expression analysis suggests that increased lipid uptake, enhanced de novo lipid synthesis, decreased lipolysis, and/or enhanced glucose uptake contribute to increased hepatic triglyceride content in these models. However, activin treatment recapitulated only some of these gene changes, suggesting that increased activin bioactivity may be only partially responsible for this phenotype. Nevertheless, our results indicate that activin enhances hepatocyte insulin response, which ultimately leads to hepatic steatosis despite the increased insulin sensitivity. Thus, regulation of activin bioactivity is critical for maintaining normal liver lipid homeostasis and response to insulin, whereas activin agonists may be useful for increasing liver insulin sensitivity.


MicroRNAs Regulate Sleep and Sleep Homeostasis in Drosophila.
To discover microRNAs that regulate sleep, we performed a genetic screen using a library of miRNA sponge-expressing flies. We identified 25 miRNAs that regulate baseline sleep; 17 were sleep-promoting and 8 promoted wake. We identified one miRNA that is required for recovery sleep after deprivation and 8 miRNAs that limit the extent of recovery sleep. 65% of the hits belong to human-conserved families. Interestingly, the majority (75%), but not all, of the baseline sleep-regulating miRNAs are required in neurons. Sponges that target miRNAs in the same family, including the miR-92a/92b/310 family and the miR-263a/263b family, have similar effects. Finally, mutation of one of the screen's strongest hits, let-7, using CRISPR/Cas-9, phenocopies sponge-mediated let-7 inhibition. Cell-type-specific and temporally restricted let-7 sponge expression experiments suggest that let-7 is required in the mushroom body both during development and in adulthood. This screen sets the stage for understanding the role of miRNAs in sleep.


Hypertension in post-renal transplant patients: pilot study.
Post-transplant hypertension is a major risk factor for graft loss and patient survival; therefore, hypertension following renal transplantation must be treated strictly. There seems to be a strong association between hypertension, total body water (TBW) and dry weight. In this study, we report the relationship of body water and body composition with hypertension in post-renal transplant patients. Forty-five post-transplant patients were enrolled in the study. Blood pressure (BP) was labeled as controlled if BP was 120/80 mm Hg and not under good control if BP was above 120/80 mm Hg. Based on the number of antihypertensive medications a patient was taking, patients were divided into two groups: Group 1 patients on one antihypertensive drug and Group 2 patients on more than one antihypertensive drug. Nutritional status of the patients was assessed. Body composition (water compartments, body fat and lean mass) was assessed using bioelectrical impedance analysis (BIA). Patient data were compared with 30 healthy volunteers. In patients, systolic BP was associated with TBW (P = 0.016), extracellular water (ECW Lt; r = 0.99), ECW% (r = 0.78) and diastolic BP with TBW% (P = 0.003), dry weight (r = 0.76) ECW% (r = 0.95) and percent intracellular water (ICW%) (r = 0.79). Compared with controls, ECW and ECW% was higher in patients, and the ICW% was less in patients. There was significant difference in the actual weight of the patients and BIA-derived dry weight, although patients were clinically not edematous. The study showed a significant increase in diastolic BP with increase in dry weight. Significant difference in TBW was observed when the patients were grouped on the basis of the antihypertensive medication a patient was taking (one antihypertensive drug versus more than one antihypertensive drug). This study also showed an association between hypertension and overhydration. BIA may be a useful tool for the clinical assessment of overhydration in non-edematous patients.


Enhancement of the critical current density in single-crystal Bi2Sr2CaCu2O8 superconductors by chemically induced disorder.
The effect of metal substitution on the critical current densities of single-crystal PbxBi2-xSr2CaCu2O8 (x = 0 or x = 0.7) superconductors has been investigated. Substitution of lead was found to increase the average critical current density from 1 x 10(5) A/cm2 to 2 x 10(6) A/cm2 at 5 K in an applied magnetic field of 10 kilooersteds (1 oersted = 80 A/m). The order of magnitude increase in the critical current density was observed for temperatures up to the flux vortex lattice melting point; the flux lattice melting point was also found to increase to 30 K (from 22 K) in the lead-substituted materials. Diffraction and microscopy investigations of the structural parameters indicate that the fundamental atomic lattices are virtually the same for both materials. Scanning tunneling microscopy images demonstrate, however, that lead substitution causes significant disorder (or defects) in the one-dimensional superstructure found in Bi2Sr2CaCu2O8. Since crystal defects can increase the critical current density by pinning the motion of flux vortices, it is likely that this lead-induced disorder enhances vortex pinning. The lead-induced disorder is specific to the nonsuperconducting Bi-O layers, and thus our results suggest that chemical substitutions may be utilized to control selectively flux pinning and the critical current density in these materials.


Biomarkers come of age: PD1 in the frontline and cell cycle therapy swells the ranks of personalised therapy in the European Society of Medical Oncology (ESMO) congress, Copenhagen, 7-10 October 2016.
After years of trials, Programmed Death Ligand and Receptor targeting finally debuts as a firstline therapy in combination and as a single agent regimen at the 2016 European Society of Medical Oncology (ESMO) Congress. The meeting brought together 20,522 attendees, from over 120 countries, to share updates and novel technologies from a wide swathe of oncology research. This year's theme, From Disease Treatment to Patient Care, was matched by abstract presentations starting from inception of care regimens to new standards of care in high-risk patient subgroups, to wellbeing of care providers, and finally the funding obstacles at each continental level.


Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial.
The AMPLIFY trial compared apixaban with enoxaparin followed by warfarin for the treatment of acute venous thromboembolism (VTE). To perform a subgroup analysis to compare the efficacy and safety of apixaban and enoxaparin followed by warfarin for the treatment of VTE in patients with cancer enrolled in AMPLIFY. Patients with symptomatic VTE were randomized to a 6-month course of apixaban or enoxaparin followed by warfarin. The primary efficacy outcome and principal safety outcome were recurrent VTE or VTE-related death and major bleeding, respectively. Of the 5395 patients randomized, 169 (3.1%) had active cancer at baseline, and 365 (6.8%) had a history of cancer without active cancer at baseline. Among patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (relative risk [RR] 0.56, 95% confidence interval [CI] 0.13-2.37); major bleeding occurred in 2.3% and 5.0% of evaluable patients, respectively (RR 0.45, 95% CI 0.08-2.46). Among patients with a history of cancer, recurrent VTE occurred in 1.1% and 6.3% of evaluable patients in the apixaban and enoxaparin/warfarin groups, respectively (RR 0.17, 95% CI 0.04-0.78); major bleeding occurred in 0.5% and 2.8% of treated patients, respectively (RR 0.20, 95% CI 0.02-1.65). The results of this subgroup analysis suggest that apixaban is a convenient option for cancer patients with VTE. However, additional studies are needed to confirm this concept and to compare apixaban with low molecular weight heparin in these patients.


International assessment of massive transfusion protocol contents and indications for activation.
Massive transfusion protocols (MTPs) provide blood products rapidly and in fixed amounts. MTPs are commonly used in trauma but may also be used in other clinical settings, although evidence to support fixed-ratio resuscitation in nontraumatic hemorrhage is lacking. The goals of this study were to describe the types and contents of available MTPs and the clinical indications for MTP activation. A survey was distributed to 353 transfusion medicine specialists to assess the types and contents of available MTPs. Survey participants were invited to provide the clinical indications for consecutive adult and pediatric MTP activations for at least 6 months during 2015 to 2017. There were 125 completed surveys (35% response rate) including three from children's specialty hospitals. Most hospitals that treated adult patients (90/122, 74%) utilized only one MTP for all adult bleeding emergencies, while one hospital had no MTP. Of the 31 hospitals that provided more than one adult MTP, 20 provided MTPs specific for obstetric bleeding cases. Of these, 50% (10/20) included at least one pool of cryoprecipitate or fibrinogen concentrate in the first MTP round, compared with 14% (13/90) of the hospitals with one MTP (p = 0.0012). Fifty-seven hospitals provided the clinical indication for 4176 adult and 155 pediatric MTP activations. Although trauma was the single most common indication, the majority of adult (58%) and pediatric (65%) activations were for nontrauma indications. The majority of hospitals use a single MTP to manage massive hemorrhage. The majority of MTP activations were for nontrauma indications.


Learning Pullback HMM Distances.
Recent work in action recognition has exposed the limitations of methods which directly classify local features extracted from spatio-temporal video volumes. In opposition, encoding the actions' dynamics via generative dynamical models has a number of attractive features: however, using all-purpose distances for their classification does not necessarily deliver good results. We propose a general framework for learning distance functions for generative dynamical models, given a training set of labelled videos. The optimal distance function is selected among a family of pullback ones, induced by a parametrised automorphism of the space of models. We focus here on hidden Markov models and their model space, and design an appropriate automorphism there. Experimental results are presented which show how pullback learning greatly improves action recognition performances with respect to base distances.


Preanalytical Stability of Antibodies to Pathogenic Antigens.
Background: Serologic testing for antibodies against epitopes from pathogens is a valuable tool for investigating the relationship between infection and disease. This study comprehensively evaluates the impact of preanalytic variation on antibody seropositivities to a selected set of antigens arising from delays in processing of blood samples, preprocessing storage temperature, and vacutainer type.Methods: We assessed peripheral blood collected from 29 volunteers in four different Vacutainer types [ethylenediaminoetetraacetic acid (EDTA), acid-citrate-dextrose (ACD), lithium heparin (LH), serum separator tubes (SST)], and stored at 4°C or room temperature for 0, 1, 2, 3, 4, 5, and 6 days before processing. Multiplex serology was used to determine antibody reactivity against 35 antigens derived from human papillomaviruses, human polyomaviruses, Epstein-Barr virus, and Helicobacter pylori Cohen's κ statistic was used to measure agreement on seropositivity status between samples exposed to standard and nonstandard clinical practice conditions.Results: For samples processed without delay, κ was not associated with storage-temperature (P value range 0.23 to 0.95) or vacutainer type (P value range, 0.35-0.89). Kappa did not significantly decline with increasing delays in processing for any vacutainer-type storage temperature combination (P slope range, 0.06-1.00).Conclusions: Antibodies to epitopes from various pathogenic infectious agents can be measured reliably from samples stored in SST, EDTA, ACD, or LH vacutainers at either room temperature or 4°C for up to 6 days before processing.Impact: Serologic testing is robust to several preanalytic options. These findings are particularly important for epidemiologic studies recruiting participants from remote settings where sample exposure to preanalytic conditions can vary considerably. Cancer Epidemiol Biomarkers Prev; 26(8); 1337-44. ©2017 AACR.


Near-infrared lymphography as a minimally invasive modality for imaging lymphatic reconstitution in a rat orthotopic hind limb transplantation model.
Wider application of vascularized composite allotransplantation (VCA) is limited by the need for chronic immunosuppression. Recent data suggest that the lymphatic system plays an important role in mediating rejection. This study used near-infrared (NIR) lymphography to describe lymphatic reconstitution in a rat VCA model. Syngeneic (Lewis-Lewis) and allogeneic (Brown Norway-Lewis) rat orthotopic hind limb transplants were performed without immunosuppression. Animals were imaged pre- and postoperatively using indocyanine green (ICG) lymphography. Images were collected using an NIR imaging system. Co-localization was achieved through use of an acrylic paint/hydrogen peroxide mixture. In all transplants, ICG first crossed graft suture lines on postoperative day (POD) 5. Clinical signs of rejection also appeared on POD 5 in allogeneic transplants, with most exhibiting Grade 3 rejection by POD 6. Injection of an acrylic paint/hydrogen peroxide mixture on POD 5 confirmed the existence of continuous lymphatic vessels crossing the suture line and draining into the inguinal lymph node. NIR lymphography is a minimally invasive imaging modality that can be used to study lymphatic vessels in a rat VCA model. In allogeneic transplants, lymphatic reconstitution correlated with clinical rejection. Lymphatic reconstitution may represent an early target for immunomodulation.


Halophilic Protein Adaptation Results from Synergistic Residue-Ion Interactions in the Folded and Unfolded States.
Halophilic organisms thrive in environments with extreme salt concentrations and have adapted by allowing molar quantities of cosolutes, mainly KCl, to accumulate in their cytoplasm. To cope with this high intracellular salinity, halophilic organisms modified the chemical composition of their proteins to enrich their surface with acidic and short polar side chains, while lysines and bulky hydrophobic residues got depleted. We have emulated the evolutionary process of haloadaptation with natural and designed halophilic polypeptides and applied novel nuclear magnetic resonance (NMR) methodology to study the different mechanisms contributing to protein haloadaptation at a per residue level. Our analysis of an extensive set of NMR observables, determined over several proteins, allowed us to disentangle the synergistic contributions of protein haloadaptation: cation exclusion and electrostatic repulsion between negatively charged residues destabilize the denatured state ensemble while cumulative weak cation-protein interactions stabilize the folded conformations.


Comparison of domain adaptation techniques for white matter hyperintensity segmentation in brain MR images.
Robust automated segmentation of white matter hyperintensities (WMHs) in different datasets (domains) is highly challenging due to differences in acquisition (scanner, sequence), population (WMH amount and location) and limited availability of manual segmentations to train supervised algorithms. In this work we explore various domain adaptation techniques such as transfer learning and domain adversarial learning methods, including domain adversarial neural networks and domain unlearning, to improve the generalisability of our recently proposed triplanar ensemble network, which is our baseline model. We used datasets with variations in intensity profile, lesion characteristics and acquired using different scanners. For the source domain, we considered a dataset consisting of data acquired from 3 different scanners, while the target domain consisted of 2 datasets. We evaluated the domain adaptation techniques on the target domain datasets, and additionally evaluated the performance on the source domain test dataset for the adversarial techniques. For transfer learning, we also studied various training options such as minimal number of unfrozen layers and subjects required for fine-tuning in the target domain. On comparing the performance of different techniques on the target dataset, domain adversarial training of neural network gave the best performance, making the technique promising for robust WMH segmentation.


Transcriptomic analysis reveals differences in the regulation of amino acid metabolism in asexual and sexual planarians.
Many flatworms can alternate between asexual and sexual reproduction. This is a powerful reproductive strategy enabling them to benefit from the features of the two reproductive modes, namely, rapid multiplication and genetic shuffling. The two reproductive modes are enabled by the presence of pluripotent adult stem cells (neoblasts), by generating any type of tissue in the asexual mode, and producing and maintaining germ cells in the sexual mode. In the current study, RNA sequencing (RNA-seq) was used to compare the transcriptomes of two phenotypes of the planarian Dugesia ryukyuensis: an asexual OH strain and an experimentally sexualized OH strain. Pathway enrichment analysis revealed striking differences in amino acid metabolism in the two worm types. Further, the analysis identified serotonin as a new bioactive substance that induced the planarian ovary de novo in a postembryonic manner. These findings suggest that different metabolic states and physiological conditions evoked by sex-inducing substances likely modulate stem cell behavior, depending on their different function in the asexual and sexual reproductive modes. The combination of RNA-seq and a feeding assay in D. ryukyuensis is a powerful tool for studying the alternation of reproductive modes, disentangling the relationship between gene expression and chemical signaling molecules.


Pelargonium sidoides root extract for the treatment of acute cough due to lower respiratory tract infection in adults: a feasibility double-blind, placebo-controlled randomised trial.
Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or "Kaloba®", is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries. Feasibility double-blind randomised placebo-controlled clinical trial. We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2-4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial. Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18-21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex. It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition. HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .


A Single Amino Acid Substitution Changes the Self-Assembly Status of a Type IV Piliation Secretin.
Secretins form large multimeric complexes in the outer membranes of many Gram-negative bacteria, where they function as dedicated gateways that allow proteins to access the extracellular environment. Despite their overall relatedness, different secretins use different specific and general mechanisms for their targeting, assembly, and membrane insertion. We report that all tested secretins from several type II secretion systems and from the filamentous bacteriophage f1 can spontaneously multimerize and insert into liposomes in an in vitro transcription-translation system. Phylogenetic analyses indicate that these secretins form a group distinct from the secretins of the type IV piliation and type III secretion systems, which do not autoassemble in vitro. A mutation causing a proline-to-leucine substitution allowed PilQ secretins from two different type IV piliation systems to assemble in vitro, albeit with very low efficiency, suggesting that autoassembly is an inherent property of all secretins.


Effect of unilateral spinal adjustments on goniometrically-assessed cervical lateral-flexion end-range asymmetries in otherwise asymptomatic subjects.
A triple blinded, multiple-measure, experimental protocol was employed in order to investigate the effectiveness of unilateral cervical adjustments on goniometrically assessed cervical lateral-flexion asymmetries. On pretest, subjects selected for the experiments exhibited mean left-right lateral-flexion differences of approximately 14 degrees. In subjects which either received no intervention, or had been subjected only to preliminary palpatory and set-up procedures but no thrust, asymmetry magnitudes were found to be unchanged on goniometric posttesting done 30-45 min later. However, in subjects which received lower cervical adjustments performed on the side of most restricted end-range, there was a dramatic reduction in asymmetry magnitudes. Furthermore, the adjustment procedure used in this investigation appeared to be relatively side-specific, since adjustments, when delivered to the less restricted side, were only marginally effective in ameliorating the asymmetries. Potential clinical relevance as well as the possible structural or physiological mechanisms responsible for the results obtained in the study are discussed.


A novel experience-based internet intervention for smoking cessation: feasibility randomised controlled trial.
The internet is frequently used to share experiences of health and illness, but this phenomenon has not been harnessed as an intervention to achieve health behaviour change. The aim of this study was to determine the feasibility of a randomised trial assessing the effects of a novel, experience-based website as a smoking cessation intervention. The secondary aim was to measure the potential impact on smoking behaviour of both the intervention and a comparator website. A feasibility randomised controlled single-blind trial assessed a novel, experience-based website containing personal accounts of quitting smoking as a cessation intervention, and a comparator website providing factual information. Feasibility measures including recruitment, and usage of the interventions were recorded, and the following participant-reported outcomes were also measured: Smoking Abstinence Self-Efficacy Questionnaire, the single-item Motivation to Stop Scale, self-reported abstinence, quit attempts and health status outcomes. Eligible smokers from two English regions were entered into the trial and given access to their allocated website for two weeks. Eighty-seven smokers were randomised, 65 completed follow-up (75 %). Median usage was 15 min for the intervention, and 5 min for the comparator (range 0.5-213 min). Median logins for both sites was 2 (range 1-20). All participant-reported outcomes were similar between groups. It was technically feasible to deliver a novel intervention harnessing the online sharing of personal experiences as a tool for smoking cessation, but recruitment was slow and actual use was relatively low, with attrition from the trial. Future work needs to maximize engagement and to understand how best to assess the value of such interventions in everyday use, rather than as an isolated 'dose of information'. ISRCTN29549695 DOI 10.1186/ISRCTN29549695 . Registered 17/05/2013.


CoRAL: predicting non-coding RNAs from small RNA-sequencing data.
The surprising observation that virtually the entire human genome is transcribed means we know little about the function of many emerging classes of RNAs, except their astounding diversities. Traditional RNA function prediction methods rely on sequence or alignment information, which are limited in their abilities to classify the various collections of non-coding RNAs (ncRNAs). To address this, we developed Classification of RNAs by Analysis of Length (CoRAL), a machine learning-based approach for classification of RNA molecules. CoRAL uses biologically interpretable features including fragment length and cleavage specificity to distinguish between different ncRNA populations. We evaluated CoRAL using genome-wide small RNA sequencing data sets from four human tissue types and were able to classify six different types of RNAs with ∼80% cross-validation accuracy. Analysis by CoRAL revealed that microRNAs, small nucleolar and transposon-derived RNAs are highly discernible and consistent across all human tissue types assessed, whereas long intergenic ncRNAs, small cytoplasmic RNAs and small nuclear RNAs show less consistent patterns. The ability to reliably annotate loci across tissue types demonstrates the potential of CoRAL to characterize ncRNAs using small RNA sequencing data in less well-characterized organisms.


Twin-Twin Transfusion Syndrome: study protocol for developing, disseminating, and implementing a core outcome set.
Twin-Twin Transfusion Syndrome (TTTS) is associated with an increased risk of perinatal mortality and morbidity. Several treatment interventions have been described for TTTS, including fetoscopic laser surgery, amnioreduction, septostomy, expectant management, and pregnancy termination. Over the last decade, fetoscopic laser surgery has become the primary treatment. The literature to date reports on many different outcomes, making it difficult to compare results or combine data from individual studies, limiting the value of research to guide clinical practice. With the advent and ongoing development of new therapeutic techniques, this is more important than ever. The development and use of a core outcome set has been proposed to address these issues, prioritising outcomes important to the key stakeholders, including patients. We aim to produce, disseminate, and implement a core outcome set for TTTS. An international steering group has been established to oversee the development of this core outcome set. This group includes healthcare professionals, researchers and patients. A systematic review is planned to identify previously reported outcomes following treatment for TTTS. Following completion, the identified outcomes will be evaluated by stakeholders using an international, multi-perspective online modified Delphi method to build consensus on core outcomes. This method encourages the participants towards consensus 'core' outcomes. All key stakeholders will be invited to participate. The steering group will then hold a consensus meeting to discuss results and form a core outcome set to be introduced and measured. Once core outcomes have been agreed, the next step will be to determine how they should be measured, disseminated, and implemented within an international context. The development, dissemination, and implementation of a core outcome set in TTTS will enable its use in future clinical trials, systematic reviews and clinical practice guidelines. This is likely to advance the quality of research studies and their effective use in order to guide clinical practice and improve patient care, maternal, short-term perinatal outcomes and long-term neurodevelopmental outcomes. Core Outcome Measures in Effectiveness Trials (COMET), 921 Registered on July 2016. International Prospective Register of Systematic Reviews (PROSPERO), CRD42016043999 . Registered on 2 August 2016.


How many lives does CLIMP-63 have?
In 1995, in the Biochemical Society Transactions, Mundy published the first review on CLIMP-63 (cytoskeleton-linking membrane protein 63) or CKPA4 (cytoskeleton-associated protein 4), initially just p63 [1]. Here we review the following 20 years of research on this still mysterious protein. CLIMP-63 is a type II transmembrane protein, the cytosolic domain of which has the capacity to bind microtubules whereas the luminal domain can form homo-oligomeric complexes, not only with neighbouring molecules but also, in trans, with CLIMP-63 molecules on the other side of the endoplasmic reticulum (ER) lumen, thus promoting the formation of ER sheets. CLIMP-63 however also appears to have a life at the cell surface where it acts as a ligand-activated receptor. The still rudimentary information of how CLIMP-63 fulfills these different roles, what these are exactly and how post-translational modifications control them, will be discussed.


Flexible positions, managed hopes: the promissory bioeconomy of a whole genome sequencing cancer study.
Genomic research has rapidly expanded its scope and ambition over the past decade, promoted by both public and private sectors as having the potential to revolutionize clinical medicine. This promissory bioeconomy of genomic research and technology is generated by, and in turn generates, the hopes and expectations shared by investors, researchers and clinicians, patients, and the general public alike. Examinations of such bioeconomies have often focused on the public discourse, media representations, and capital investments that fuel these "regimes of hope," but also crucial are the more intimate contexts of small-scale medical research, and the private hopes, dreams, and disappointments of those involved. Here we examine one local site of production in a university-based clinical research project that sought to identify novel cancer predisposition genes through whole genome sequencing in individuals at high risk for cancer. In-depth interviews with 24 adults who donated samples to the study revealed an ability to shift flexibly between positioning themselves as research participants on the one hand, and as patients or as family members of patients, on the other. Similarly, interviews with members of the research team highlighted the dual nature of their positions as researchers and as clinicians. For both parties, this dual positioning shaped their investment in the project and valuing of its possible outcomes. In their narratives, all parties shifted between these different relational positions as they managed hopes and expectations for the research project. We suggest that this flexibility facilitated study implementation and participation in the face of potential and probable disappointment on one or more fronts, and acted as a key element in the resilience of this local promissory bioeconomy. We conclude that these multiple dimensions of relationality and positionality are inherent and essential in the creation of any complex economy, "bio" or otherwise.


Rapid life-history diversification of an introduced fish species across a localized thermal gradient.
Climatic variations are known to engender life-history diversification of species and populations at large spatial scales. However, the extent to which microgeographic variations in climate (e.g., those occurring within a single large ecosystem) can also drive life-history divergence is generally poorly documented. We exploited a spatial gradient in water temperatures at three sites across a large montane lake in southwest China (Lake Erhai) to examine the extent to which life histories of a short-lived fish species (icefish, Neosalanx taihuensis) diversified in response to thermal regime following introduction 25 y prior. In general, warmwater icefish variants grew faster, had larger adult body size and higher condition and fecundity, but matured at smaller sizes. Conversely, coldwater variants had smaller adult body size and lower condition, but matured at larger sizes and had larger eggs. These life-history differences strongly suggest that key ecological trade-offs exist for icefish populations exposed to different thermal regimes, and these trade-offs have driven relatively rapid diversification in the life histories of icefish within Lake Erhai. Results are surprisingly concordant with current knowledge on life-history evolution at macroecological scales, and suggest that improved conservation management might be possible by focusing on patterns operating at microgeographical, including, within-ecosystem scales.


Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations.
A high proportion of patients with lower-risk del(5q) myelodysplastic syndromes will respond to treatment with lenalidomide. The median duration of transfusion-independence is 2 years with some long-lasting responses, but almost 40% of patients progress to acute leukemia by 5 years after starting treatment. The mechanisms underlying disease progression other than the well-established finding of small TP53-mutated subclones at diagnosis remain unclear. We studied a longitudinal cohort of 35 low- and intermediate-1-risk del(5q) patients treated with lenalidomide (n=22) or not (n=13) by flow cytometric surveillance of hematopoietic stem and progenitor cell subsets, targeted sequencing of mutational patterns, and changes in the bone marrow microenvironment. All 13 patients with disease progression were identified by a limited number of mutations in TP53, RUNX1, and TET2, respectively, with PTPN11 and SF3B1 occurring in one patient each. TP53 mutations were found in seven of nine patients who developed acute leukemia, and were documented to be present in the earliest sample (n=1) and acquired during lenalidomide treatment (n=6). By contrast, analysis of the microenvironment, and of hematopoietic stem and progenitor cells by flow cytometry was of limited prognostic value. Based on our data, we advocate conducting a prospective study aimed at investigating, in a larger number of cases of del(5q) myelodysplastic syndromes, whether the detection of such mutations before and after lenalidomide treatment can guide clinical decision-making.


Restless Legs Syndrome in Iranian People With Type 2 Diabetes Mellitus: The Role in Quality of Life and Quality of Sleep.
To investigate the prevalence of restless legs syndrome (RLS) in patients with type 2 diabetes mellitus (T2DM) and explore its role in quality of life (QoL) and quality of sleep of these patients. This is a cross-sectional study performed on 210 Iranian people with T2DM. The diagnosis of RLS was established based on the essential diagnostic criteria for RLS recommended by the National Institutes of Health. Sleep quality and QoL were assessed in all participants using Pittsburgh Sleep Quality Index and EuroQol five-dimension questionnaire, respectively. Regression models were used for final analysis of data. The prevalence of RLS was 19.5%; of whom 38.1% had poor quality of sleep. Male sex, being single, body mass index (BMI), and RLS were associated with poor quality of sleep. Patients with RLS were almost three times as likely as the patients without RLS to have poor sleep quality. Moreover, being female, BMI value, level of glycosylated hemoglobine (HbA1C), and RLS were associated with lower QoL. RLS lowers the score of QoL even more than BMI and HbA1C. In addition, the QoL and sleep quality of this population of patients with diabetes have not been affected by the severity of RLS as well as presence or absence of neuropathy. RLS has an independent and significant role in sleep quality and QoL in the patients with diabetes. Neuropathy with RLS does not confer any additive burden on QoL and sleep quality of this population of patients with diabetes.


Systemic complement activation in age-related macular degeneration.
Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.


RNAcentral: an international database of ncRNA sequences.
The field of non-coding RNA biology has been hampered by the lack of availability of a comprehensive, up-to-date collection of accessioned RNA sequences. Here we present the first release of RNAcentral, a database that collates and integrates information from an international consortium of established RNA sequence databases. The initial release contains over 8.1 million sequences, including representatives of all major functional classes. A web portal (http://rnacentral.org) provides free access to data, search functionality, cross-references, source code and an integrated genome browser for selected species.


Emotional expression modulates perceived gaze direction.
Gaze perception is an important social skill, as it portrays information about what another person is attending to. Gaze direction has been shown to affect interpretation of emotional expression. Here the authors investigate whether the emotional facial expression has a reciprocal influence on interpretation of gaze direction. In a forced-choice yes-no task, participants were asked to judge whether three faces expressing different emotions (anger, fear, happiness, and neutral) in different viewing angles were looking at them or not. Happy faces were more likely to be judged as looking at the observer than were angry, fearful, or neutral faces. Angry faces were more often judged as looking at the observer than were fearful and neutral expressions. These findings are discussed on the background of approach and avoidance orientation of emotions and of the self-referential positivity bias.


Energy landscapes for machine learning.
Machine learning techniques are being increasingly used as flexible non-linear fitting and prediction tools in the physical sciences. Fitting functions that exhibit multiple solutions as local minima can be analysed in terms of the corresponding machine learning landscape. Methods to explore and visualise molecular potential energy landscapes can be applied to these machine learning landscapes to gain new insight into the solution space involved in training and the nature of the corresponding predictions. In particular, we can define quantities analogous to molecular structure, thermodynamics, and kinetics, and relate these emergent properties to the structure of the underlying landscape. This Perspective aims to describe these analogies with examples from recent applications, and suggest avenues for new interdisciplinary research.


AME position statement on adrenal incidentaloma.
To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.


Segmented fast linear canonical transform.
Investigation of the discrete and fast linear canonical transforms is becoming one of the hottest research topics in modern signal processing and optics. How to handle and obtain the linear canonical frequency spectrum of very large input data based on equipment with limited memory space is one of the key problems. To focus on this problem, a new kind of segmented fast linear canonical transform has been proposed in this paper. First, the large data is segmented into short data. Thereby, the proposed algorithms can calculate very large input data and simultaneously keep the ideal frequency resolution. Second, the complexity of the derived algorithms has been analyzed in detail for different kinds of signals. Their performance with regard to resolution and precision are compared with the existing fast linear canonical transforms. Finally, experimental results are presented to verify the correctness of the results obtained.


Safety and immunogenicity of DNA vaccines encoding Ebolavirus and Marburgvirus wild-type glycoproteins in a phase I clinical trial.
Ebolavirus and Marburgvirus cause severe hemorrhagic fever with high mortality and are potential bioterrorism agents. There are no available vaccines or therapeutic agents. Previous clinical trials evaluated transmembrane-deleted and point-mutation Ebolavirus glycoproteins (GPs) in candidate vaccines. Constructs evaluated in this trial encode wild-type (WT) GP from Ebolavirus Zaire and Sudan species and the Marburgvirus Angola strain expressed in a DNA vaccine. The VRC 206 study evaluated the safety and immunogenicity of these DNA vaccines (4 mg administered intramuscularly by Biojector) at weeks 0, 4, and 8, with a homologous boost at or after week 32. Safety evaluations included solicited reactogenicity and coagulation parameters. Primary immune assessment was done by means of GP-specific enzyme-linked immunosorbent assay. The vaccines were well tolerated, with no serious adverse events; 80% of subjects had positive enzyme-linked immunosorbent assay results (≥30) at week 12. The fourth DNA vaccination boosted the immune responses. The investigational Ebolavirus and Marburgvirus WT GP DNA vaccines were safe, well tolerated, and immunogenic in this phase I study. These results will further inform filovirus vaccine research toward a goal of inducing protective immunity by using WT GP antigens in candidate vaccine regimens. NCT00605514.


Quantitative systematic review of the associations between short-term exposure to nitrogen dioxide and mortality and hospital admissions.
Short-term exposure to NO₂ has been associated with adverse health effects and there is increasing concern that NO₂ is causally related to health effects, not merely a marker of traffic-generated pollution. No comprehensive meta-analysis of the time-series evidence on NO₂ has been published since 2007. To quantitatively assess the evidence from epidemiological time-series studies published worldwide to determine whether and to what extent short-term exposure to NO₂ is associated with increased numbers of daily deaths and hospital admissions. We conducted a quantitative systematic review of 204 time-series studies of NO₂ and daily mortality and hospital admissions for several diagnoses and ages, which were indexed in three bibliographic databases up to May 2011. We calculated random-effects estimates by different geographic regions and globally, and also tested for heterogeneity and small study bias. Sufficient estimates for meta-analysis were available for 43 cause-specific and age-specific combinations of mortality or hospital admissions (25 for 24 h NO₂ and 18 of the same combinations for 1 h measures). For the all-age group, a 10 µg/m(3) increase in 24 h NO₂ was associated with increases in all-cause, cardiovascular and respiratory mortality (0.71% (95% CI 0.43% to 1.00%), 0.88% (0.63% to 1.13%) and 1.09% (0.75% to 1.42%), respectively), and with hospital admissions for respiratory (0.57% (0.33% to 0.82%)) and cardiovascular (0.66% (0.32% to 1.01%)) diseases. Evidence of heterogeneity between geographical region-specific estimates was identified in more than half of the combinations analysed. Our review provides clear evidence of health effects associated with short-term exposure to NO₂ although further work is required to understand reasons for the regional heterogeneity observed. The growing literature, incorporating large multicentre studies and new evidence from less well-studied regions of the world, supports further quantitative review to assess the independence of NO₂ health effects from other air pollutants.


Striated pattern on scrotal ultrasonography: A marker for Non-hodgkins lymphoma of testis.
We present a case of 52 year old man who presented with bilateral painless testicular swelling. On evaluation with high resolution ultrasonography of the scrotum, typical "striated pattern" which is highly suggestive of Non Hodgkins lymphoma of the testis was seen. The patient underwent bilateral inguinal orchidectomy and the histopathological examination confirmed the diagnosis of Non Hodgkins lymphoma.


One Abutment at One Time Concept for Platform-Switched Morse Implants: Systematic Review and Meta-Analysis.
The aim of this systematic review and meta-analysis was to compare the peri-implant vertical bone loss of immediate loading of implant crowns using the one abutment at one time (AOT) protocol and implants with abutment removal (AR). This systematic review with meta-analysis was reported according to the PRISMA statement, with guidance from the Cochrane Collaboration Handbook. A total of 103 publications were identified in the PubMed database and reference lists of examined articles. After the screening of titles and abstracts, the eligibility of eight full-text articles was assessed. Five studies published between 2010 and 2015 were included in the meta-analysis. There was less peri-implant vertical bone loss at implants using an AOT protocol than at implants using AR protocol (WMD -0.19, 95% CI -0.26 to -0.13; p<0.0001; random-effects model). In conclusion, the use of the AOT protocol with platform-switched Morse implants results in less bone loss than do AR procedures, but this effect may not be clinically relevant. The preservation of marginal bone level achieved with the AOT protocol may not enhance the aesthetics. These results should be interpreted with caution.


Long-term trends in the use of complementary and alternative medical therapies in the United States.
Although recent research has shown that many people in the United States use complementary and alternative medical (CAM) therapies, little is known about time trends in use. To present data on time trends in CAM therapy use in the United States over the past half-century. Nationally representative telephone survey of 2055 respondents that obtained information on current use, lifetime use, and age at first use for 20 CAM therapies. The 48 contiguous U.S. states. Household residents 18 years of age and older. Retrospective self-reports of age at first use for each of 20 CAM therapies. Previously reported analyses of these data showed that more than one third of the U.S. population was currently using CAM therapy in the year of the interview (1997). Subsequent analyses of lifetime use and age at onset showed that 67.6% of respondents had used at least one CAM therapy in their lifetime. Lifetime use steadily increased with age across three age cohorts: Approximately 3 of every 10 respondents in the pre-baby boom cohort, 5 of 10 in the baby boom cohort, and 7 of 10 in the post-baby boom cohort reported using some type of CAM therapy by age 33 years. Of respondents who ever used a CAM therapy, nearly half continued to use many years later. A wide range of individual CAM therapies increased in use over time, and the growth was similar across all major sociodemographic sectors of the study sample. Use of CAM therapies by a large proportion of the study sample is the result of a secular trend that began at least a half century ago. This trend suggests a continuing demand for CAM therapies that will affect health care delivery for the foreseeable future.


Functional Defects in Color Vision in Patients With Choroideremia.
To characterize defects in color vision in patients with choroideremia. Prospective cohort study. Thirty patients with choroideremia (41 eyes) and 10 age-matched male controls (19 eyes) with visual acuity of ≥6/36 attending outpatient clinics in Oxford Eye Hospital underwent color vision testing with the Farnsworth-Munsell 100 hue test, visual acuity testing, and autofluorescence imaging. To exclude changes caused by degeneration of the fovea, a subgroup of 14 patients with a visual acuity ≥6/6 was analyzed. Calculated color vision total error scores were compared between the groups and related to a range of factors using a random-effects model. Mean color vision total error scores were 120 (95% confidence interval [CI] 92, 156) in the ≥6/6 choroideremia group, 206 (95% CI 161, 266) in the <6/6 visual acuity choroideremia group, and 47 (95% CI 32, 69) in the control group. Covariate analysis showed a significant difference in color vision total error score between the groups (P < .001 between each group). Patients with choroideremia have a functional defect in color vision compared with age-matched controls. The color vision defect deteriorates as the degeneration encroaches on the fovea. The presence of an early functional defect in color vision provides a useful biomarker against which to assess successful gene transfer in gene therapy trials.


Of honey and health policy: the limits of sweet, sticky substances in reforming primary care.
It is a well-known axiom that one attracts more flies with honey than vinegar. Nowhere has this approach been taken more to heart than in the past decade of primary care policy in Canada. Governments, physician and nursing organizations and regional health authorities have invested in a lot of "honey" to draw healthcare providers onto a path from single-physician offices to team-based care with flexible hours and a population-based approach. In the lead essay for this edition of Healthcare Papers, Kates and colleagues have outlined a framework that embraces this paradigm. Their articulation of a framework is a place to start, but it can only be a start. To make that framework come alive, a wider variety of policy tools will be needed than have been used thus far, and by a wider variety of actors. Within the healthcare workforce itself, leadership, vision and the courage to hold ourselves to account for changes to primary care are needed.


Meeting rural demand: a case for combining community-based distribution and social marketing of injectable contraceptives in Tigray, Ethiopia.
In Sub-Saharan Africa, policy changes have begun to pave the way for community distribution of injectable contraceptives but sustaining such efforts remains challenging. Combining social marketing with community-based distribution provides an opportunity to recover some program costs and compensate workers with proceeds from contraceptive sales. This paper proposes a model for increasing access to injectable contraceptives in rural settings by using community-based distributers as social marketing agents and incorporating financing systems to improve sustainability. This intervention was implemented in three districts of the Central Zone of Tigray, Ethiopia and program data has been collected from November 2011 through October 2012. A total of 137 Community Based Reproductive Health Agents (CBRHAs) were trained to provide injectable contraceptives and were provided with a loan of 25 injectable contraceptives from a drug revolving fund, created with project funds. The price of a single dose credited to a CBRHA was 3 birr ($0.17) and they provide injections to women for 5 birr ($0.29), determined with willingness-to-pay data. Social marketing was used to create awareness and generate demand. Both quantitative and qualitative methods were used to examine important feasibility aspects of the intervention. Forty-four percent of CBRHAs were providing family planning methods at the time of the training and 96% believed providing injectable contraceptives would improve their services. By October 2012, 137 CBRHAs had successfully completed training and provided 2541 injections. Of total injections, 47% were provided to new users of injectable contraceptives. Approximately 31% of injections were given for free to the poorest women, including adolescents. Insights gained from the first year of implementation of the model provide a framework for further expansion in Tigray, Ethiopia. Our experience highlights how program planners can tailor interventions to match family planning preferences and create more sustainable contraceptive service provision with greater impact.


Human breast cancer cell metastasis is attenuated by lysyl oxidase inhibitors through down-regulation of focal adhesion kinase and the paxillin-signaling pathway.
The extracellular matrix (ECM) plays a critical role in the development and invasion of primary breast tumors. Lysyl oxidase (LOX), which is an ECM remodeling enzyme, appears to play roles in promoting cancer cell motility and invasion. To ascertain whether LOX overexpression in breast tumor tissues from Asian patients is associated with decreases in metastasis-free and overall survival in breast cancer patients, the mRNA levels of LOX were examined in paired tumor/normal tissue samples using real-time RT-PCR analysis (n = 246 pair-matched samples). To test whether specifically targeting LOX by inhibiting its activity (using beta-aminopropionitrile (β-APN), a LOX inhibitor), mRNA expression (using siRNA), or protein expression (using 25 μM magnolol) attenuates the invasion of MDA-MB-231 breast cancer cells, a cancer cell migration assay was performed. Interestingly, only 78.5% (n = 193) of the breast cancer tumors displayed detectable LOX expression. Nearly 60% (n = 120) of the cases fell into Group 1 (tumor > normal, T > N); in this group, the mean LOX expression in the tumor cells was 20.2-fold greater than in normal cells. However, in Group 2 (normal > tumor, N > T), the LOX expression level in most of the normal tissues examined (80%, 59/73) was less than fivefold greater than in the tumor tissues. The increased level of active LOX in the invasive breast cancer cell line MDA-MB-231 was accompanied by the increased phosphorylation of focal adhesion kinase at Tyr-576 and of paxillin at Tyr-118. We also found that the addition of β-APN (300 μM) and magnolol (25 μM), synergistically inhibited the migration and invasion of MDA-MB-231 cells. In this article, we describe, for the first time, higher expression of a LOX protein in breast tumors compared with normal tissues from Asian patients. Moreover, the results indicate that the inhibition of LOX using magnolol may represent a more desirable strategy for breast cancer therapy than the use of β-APN.


Chinch bug (Hemiptera: Blissidae) mouthpart morphology, probing frequencies, and locations on resistant and susceptible germplasm.
Chinch bugs are common pests of many agronomic and horticulturally important crops and turfgrasses. Previous research has indicated that some grasses exhibit resistance to multiple chinch bug species, whereas others are resistant to only one species. The objectives of this research were to document differences in the probing frequencies and locations among Blissus species as well as differences in mouthpart morphology as a first step in understanding the differential responses of grasses to chinch bug feeding. Scanning electron microscopy detected differences in the total lengths of proboscises as well as individual mouthpart segments among the four species studied. Blissus occiduus Barber probed significantly more often on buffalograss, Buchloë dactyloides (Nuttall) Engelmann, than any other plant material. Probing locations of B. occiduus and Blissus leucopterus leucopterus (Say) were similar on both B. occiduus-resistant and susceptible buffalograsses and KS94 sorghum, Sorghum bicolor (L.) Moench (B. occiduus-resistant, B. l. leucopterus-resistant). However, on 'Wheatland' sorghum (B. occiduus-resistant, B. l. leucopterus-susceptible), stylet tracts of B. l. leucopterus most often terminated in the bundle sheath cells, whereas those of B. occiduus generally terminated in the vascular tissues.


Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients.
Although tuberculosis (TB) causes more deaths than any other pathogen, most infected individuals harbor the pathogen without signs of disease. We explored the metabolome of >400 small molecules in serum of uninfected individuals, latently infected healthy individuals and patients with active TB. We identified changes in amino acid, lipid and nucleotide metabolism pathways, providing evidence for anti-inflammatory metabolomic changes in TB. Metabolic profiles indicate increased activity of indoleamine 2,3 dioxygenase 1 (IDO1), decreased phospholipase activity, increased abundance of adenosine metabolism products, as well as indicators of fibrotic lesions in active disease as compared to latent infection. Consistent with our predictions, we experimentally demonstrate TB-induced IDO1 activity. Furthermore, we demonstrate a link between metabolic profiles and cytokine signaling. Finally, we show that 20 metabolites are sufficient for robust discrimination of TB patients from healthy individuals. Our results provide specific insights into the biology of TB and pave the way for the rational development of metabolic biomarkers for TB.


Mung bean (Phaseolus radiatus L.) polyphenol extract attenuates aluminum-induced cardiotoxicity through an ROS-triggered Ca2+/JNK/NF-κB signaling pathway in rats.
Aluminum (Al) has been linked to the development of some cardiovascular diseases and mung bean is a functional food with the ability to detoxify. We aimed to evaluate the preventive effect and possible underlying mechanisms of the mung bean polyphenol extract (MPE) on Al-induced cardiotoxicity. Control, AlCl3 (171.8 mg Al per kg body weight), MPE + AlCl3 (Al-treatment plus 200 mg MPE per kg body weight), and a group of MPE per se were used. Al intake induced a significant increase of serum CK and LDH activity and the level of Na+, Ca2+, malondialdehyde and advanced oxidation protein products in the AlCl3-treated rats' heart tissue. Administration of MPE significantly improved the integrity and normal ion levels of heart tissue, and attenuated oxidative damage and the accumulation of Al in Al-treated rats. MPE significantly inhibited Al-induced increase of myocardial p-JNK, cytoplasmic NF-κB, cytochrome C, and caspase-9 protein expressions. Therefore, these results showed that MPE has a cardiac protective effect against Al-induced biotoxicity through ROS-JNK and NF-κB-mediated caspase pathways. Furthermore, the stability constant for the vitexin-Al complex was analyzed (log K = log K1 + log K2 = 4.91 + 4.85 = 9.76). We found that MPE-mediated protection against Al-cardiotoxicity is connected both with MPE antioxidant and chelation properties.


Spontaneous Coronary Artery Dissection Masquerading as Coronary Artery Stenosis in a Young Patient.
BACKGROUND Spontaneous coronary artery dissection (SCAD) is primarily found in females. SCAD can have many precipitating factors such as exercise, trauma, pregnancy, drugs, and connective tissue disease. Prognosis is poor for left main stem, left anterior descending (LAD) artery, and multivessel involvement, especially for females. CASE REPORT We present a case of young African American male with sickle cell disease who presented with chest pain associated with shortness of breath. He was found to have non-ST elevation myocardial infarction (NSTEMI). He was diagnosed with SCAD during catheterization with the help of intravascular ultrasound imaging. Three drug-eluting stents were placed to cover the proximal LAD vessel along its whole length until resolution of the lesion. The patients' hospital course was complicated by an additional finding of left ventricular thrombus, possibly a complication of NSTEMI, which was treated with anticoagulation to complete resolution. CONCLUSIONS SCAD is fatal, it can proceed to cause myocardial infarction as in this particular patient's case, and sudden death if not recognized early. It can be missed on angiography alone; further intracoronary imaging such as intravascular ultrasound and optical computed tomography should be used to confirm the diagnosis of SCAD so that early and appropriate treatment can ensue.


Physical training improves skeletal muscle metabolism in patients with chronic heart failure.
This study investigated the effects of physical training on skeletal muscle metabolism in patients with chronic heart failure. Skeletal muscle metabolic abnormalities in patients with chronic heart failure have been associated with exercise intolerance. Muscle deconditioning is a possible mechanism for the intrinsic skeletal muscle metabolic changes seen in chronic heart failure. We used phosphorus-31 nuclear magnetic resonance spectroscopy to study muscle metabolism during exercise in 12 patients with stable ischemic chronic heart failure undergoing 8 weeks of home-based bicycle exercise training in a randomized crossover controlled trial. Changes in muscle pH and concentrations of phosphocreatine and adenosine diphosphate (ADP) were measured in phosphorus-31 spectra of calf muscle obtained at rest, throughout incremental work load plantar flexion until exhaustion and during recovery from exercise. Results were compared with those in 15 age-matched control subjects who performed a single study only. Before training, phosphocreatine depletion, muscle acidification and the increase in ADP during the 1st 4 min of plantar flexion exercise were all increased (p < 0.04) compared with values in control subjects. Training produced an increase (p < 0.002) in incremental plantar flexion exercise tolerance. After training, phosphocreatine depletion and the increase in ADP during exercise were reduced significantly (p < 0.003) at all matched submaximal work loads and at peak exercise, although there was no significant change in the response of muscle pH to exercise. After training, changes in ADP were not significantly different from those in control subjects, although phosphocreatine depletion was still greater (p < 0.05) in trained patients than in control subjects. The phosphocreatine recovery half-time was significantly (p < 0.05) shorter after training, although there was no significant change in the half-time of adenosine diphosphate recovery. In untrained subjects, the initial rate of phosphocreatine resynthesis after exercise (a measure of the rate of oxidative adenosine triphosphate [ATP] synthesis) and the inferred maximal rate of mitochondrial ATP synthesis were reduced compared with rates in control subjects (p < 0.003) and both were significantly increased (p < 0.05) by training, so that they were not significantly different from values in control subjects. The reduction in phosphocreatine depletion and in the increase in ADP during exercise, and the enhanced rate of phosphocreatine resynthesis in recovery (which is independent of muscle mass) indicate that a substantial correction of the impaired oxidative capacity of skeletal muscle in chronic heart failure can be achieved by exercise training.


Expression pattern of glycoside hydrolase genes in Lutzomyia longipalpis reveals key enzymes involved in larval digestion.
The sand fly Lutzomyia longipalpis is the most important vector of American Visceral Leishmaniasis. Adults are phytophagous (males and females) or blood feeders (females only), and larvae feed on solid detritus. Digestion in sand fly larvae has scarcely been studied, but some glycosidase activities putatively involved in microorganism digestion were already described. Nevertheless, the molecular nature of these enzymes, as the corresponding genes and transcripts, were not explored yet. Catabolism of microbial carbohydrates in insects generally involves β-1,3-glucanases, chitinases, and digestive lysozymes. In this work, the transcripts of digestive β-1,3-glucanase and chitinases were identified in the L. longipalpis larvae throughout analysis of sequences and expression patterns of glycoside hydrolases families 16, 18, and 22. The activity of one i-type lysozyme was also registered. Interestingly, this lysozyme seems to play a role in immunity, rather than digestion. This is the first attempt to identify the molecular nature of sand fly larval digestive enzymes.


Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments.
To define rod and cone function further in terms of visual cycle mechanism, the retinal phenotype resulting from Rpe65 (retinoid isomerase I) deficiency in Nrl(-)(/)(-) mice having a single class of photoreceptors resembling wild-type cones was characterized and outcomes of retinoid supplementation evaluated. Rpe65(-)(/)(-)/Nrl(-)(/)(-) mice were generated by breeding Rpe65(-)(/)(-) and Nrl(-)(/)(-) strains. Retinal histology, protein expression, retinoid content, and electroretinographic (ERG) responses were evaluated before and after treatment with 11-cis retinal by intraperitoneal injection. Results Retinas of young Rpe65(-)(/-)/Nrl(-)(/-) mice exhibited normal lamination, but lacked intact photoreceptor outer segments at all ages examined. Rpe65, Nrl, and rhodopsin were not detected, and S-opsin and M/L-opsin levels were reduced. Retinyl esters were the only retinoids present. In contrast, Nrl(-)(/)(-) mice exhibited decreased levels of retinaldehydes and retinyl esters, and elevated levels of retinols. ERG responses were elicited from Rpe65(-)(/-)/Nrl(-)(/-) mice only at the two highest intensities over a 4-log-unit range. Significant retinal thinning and outer nuclear layer loss occurred in Rpe65(-)(/-)/Nrl(-)(/-) mice with aging. Administration of exogenous 11-cis retinal did not rescue retinal morphology or markedly improve ERG responses. The findings provide clarification of reported cone loss of function in Rpe65(-)(/-)/Nrl(-)(/-) mice, now showing that chromophore absence results in destabilized cone outer segments and rapid retinal degeneration. The data support the view that rod-dominant retinas do not have a cone-specific mechanism for 11-cis retinal synthesis and have potential significance for therapeutic strategies for rescue of cone-rich retinal regions affected by disease in the aging human population.


The digit ratio (2D:4D) and economic preferences: no robust associations in a sample of 330 women.
Many studies report on the association between 2D:4D, a putative marker for prenatal testosterone exposure, and economic preferences. However, most of these studies have limited sample sizes and test multiple hypotheses (without preregistration). In this study we mainly replicate the common specifications found in the literature for the association between the 2D:4D ratio and risk taking, the willingness to compete, and dictator game giving separately. In a sample of 330 women we find no robust associations between any of these economic preferences and 2D:4D. We find no evidence of a statistically significant relation for 16 of the 18 total regressions we run. The two regression specifications which are statistically significant have not previously been reported and the associations are not in the expected direction, and therefore they are unlikely to represent a real effect.


State of the art in surgery for early stage NSCLC-does the number of resected lymph nodes matter?
Surgery is the treatment of choice in patients with early stage NSCLC. However, the results remain poor in these patients. Lymph node involvement is the main prognostic factor in patients with NSCLC, but there is still no clear definition of the number of nodes required to consider a lymphadenectomy as complete. Although there is no defined minimum number of lymph nodes required for a complete lymphadenectomy, there are some recommendations to perform this procedure, published by different scientific societies. Current practice in thoracic surgery regarding lymphadenectomy, differs on some points from the guidelines recommendations, with data regarding patients with no mediastinal assessment between 30-45% according to some of the published data. Different studies have probed the fact that the probability of finding a positive node increases with the number of lymph nodes analyzed. Therefore, a complete lymphadenectomy provides proper staging, which helps to identify the patient's real prognosis. Several nonrandomized studies and retrospective series have shown that survival increases in the group of patients with a higher number of lymph nodes removed. There is no contraindication to performing a complete lymphadenectomy. The increase in survival in patients with a complete lymphadenectomy may be due to more accurate staging. Therefore, complete lymphadenectomy should be mandatory even in early stage patients.


Increased levels of fibroblast growth factor-like activity in urine from patients with bladder or kidney cancer.
Growth factor activity was partially purified from human renal tumors and a human bladder cancer cell line by heparin-Sepharose chromatography. This activity stimulated bovine capillary endothelial cell proliferation and DNA synthesis in BALB/c 3T3 cells. Partially purified growth factor preparations from these tumors contained a protein with an approximate molecular weight of 17,000 which was recognized by a polyclonal antiserum raised against a peptide fragment of basic fibroblast growth factor (FGF). This growth factor activity appears to be related to basic fibroblast growth factor. Measurement of FGF-like activity in 50 urine samples from 32 adult males showed that 55% (6 of 11) of the urine samples from patients with bladder cancer and 100% (7 of 7) of the urine samples from patients with kidney cancer contained activity equivalent to more than 20 ng of basic FGF/h of urine production. In contrast, only 6% (2 of 32) of the urine samples from controls, patients with a benign disease, or patients with a history of bladder or kidney cancer contained this level of growth factor activity. These results suggest that patients with bladder or kidney cancer release an FGF-like factor into urine which may be used as a marker for these tumors.


Inhibiting the mTOR pathway synergistically enhances cytotoxicity in ovarian cancer cells induced by etoposide through upregulation of c-Jun.
The mTOR pathway is thought to be a central regulator of proliferation and survival of cells. Rapamycin and its analogs are undergoing clinical trials in patients with epithelial ovarian cancer. This study aimed to assess the potential to use rapamycin and anticancer agents in combination for first- and second-line chemotherapy to treat ovarian cancer. We used six ovarian serous adenocarcinoma cell lines (KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, and TU-OS-4) in this study. We treated the cells with rapamycin and anticancer agents, then assessed cell viability, apoptosis, and the expression of protein in apoptotic pathways and molecules downstream of the mTOR signaling pathways. We also investigated the effect of these drug combinations on survival in nude mouse xenograft models. Synergistic effects were observed in five cell lines from the combination of etoposide and rapamycin. However, we observed antagonistic effects when rapamycin was combined with gemcitabine, cisplatin, or paclitaxel on more than two cell lines. Rapamycin dramatically enhanced apoptosis induced by etoposide and the expression of cleaved caspase 9. This effect was associated with upregulation of phosphorylated c-Jun and downregulation of Bcl-xL. The synergistic interaction of rapamycin and etoposide was lower when the c-Jun pathway was suppressed by a c-Jun N-terminal kinase inhibitor (SP600125). Finally, treating nude mice with rapamycin and etoposide significantly prolonged survival in the model mice with ovarian cancer xenografts. Chemotherapy with rapamycin and etoposide combined is worth exploring as a treatment modality for women with epithelial ovarian cancer.


An evidence-based evaluation of health information on erectile dysfunction from 10 nationwide daily newspapers in Korea.
A rapid growth in the socioeconomic status of Koreans has triggered an unprecedented explosion of health information for the general population. Despite its obvious benefits, this increase in information could also result in potentially harmful effects for both consumers and professionals who do not use it appropriately. Thus, this study was conducted to evaluate the quality and accuracy of health information on erectile dysfunction from 10 nationwide daily newspapers. This study analyzed health information from 10 nationwide daily newspapers in Korea from January 2011 through December 2011. We reviewed the health information for quality by using evidence-based medicine tools and evaluated the accuracy of the information provided. Articles that simply summarized scientific congresses or journal articles and that did not include direct quotations were excluded, as were advertisements. A total of 47 articles were gathered. Among them, 27 (57.4%) contained inaccurate or misleading statements on the basis of an evidence-based medicine evaluation. These statements included using inappropriate surrogate outcomes as clinical endpoints (three cases, 6.4%), extrapolating nonhuman results to humans (two cases, 4.3%), exaggerating the significance of results (eight cases, 17.0%), and using incorrect words (14 cases, 29.8%). The rate of error was higher in the information from Korean sources than in that from international sources (22 cases vs. 5 cases). Approximately 57% of all articles on erectile dysfunction from 10 nationwide daily newspapers were found to contain inaccuracies.


Noise masking of S-cone increments and decrements.
S-cone increment and decrement detection thresholds were measured in the presence of bipolar, dynamic noise masks. Noise chromaticities were the L-, M-, and S-cone directions, as well as L-M, L+M, and achromatic (L+M+S) directions. Noise contrast power was varied to measure threshold Energy versus Noise (EvN) functions. S+ and S- thresholds were similarly, and weakly, raised by achromatic noise. However, S+ thresholds were much more elevated by S, L+M, L-M, L- and M-cone noises than were S- thresholds, even though the noises consisted of two symmetric chromatic polarities of equal contrast power. A linear cone combination model accounts for the overall pattern of masking of a single test polarity well. L and M cones have opposite signs in their effects upon raising S+ and S- thresholds. The results strongly indicate that the psychophysical mechanisms responsible for S+ and S- detection, presumably based on S-ON and S-OFF pathways, are distinct, unipolar mechanisms, and that they have different spatiotemporal sampling characteristics, or contrast gains, or both.


Peroxide processing in photosynthesis: antioxidant coupling and redox signalling.
Photosynthesis has a high capacity for production of hydrogen peroxide (H2O2), but the intracellular levels of this relatively weak oxidant are controlled by the antioxidant system, comprising a network of enzymatic and non-enzymatic components that notably includes reactions linked to the intracellular ascorbate and glutathione pools. Mutants and transformed plants with specific decreases in key components offer the opp ortunity to dissect the complex system that maintains redox homeostasis. Since H2O2 is a signal-transducing molecule relaying information on intracellular redox state, the pool size must be rigorously controlled within each compartment of the cell. This review focuses on compartment-specific differences in the stringency of redox coupling between ascorbate and glutathione, and the significance this may have for the flexibility of the control of gene expression that is linked to photosynthetic H2O2 production.


The importance of existential dimensions in the context of the presence of older patients at team meetings—in the light of Heidegger and Merleau-Ponty's philosophy.
The aim of the present study is to explore interpersonal dimensions of the presence of older patients at team meetings. The theoretical foundation of the study is grounded in caring science and lifeworld phenomenology. The results from two empirical studies, that indicated the need for a more in-depth examination of the interpersonal relationships when an older patient is present at a team meeting, were further explicated by philosophical examination in the light of Heidegger and Merleau-Ponty's philosophy. The empirical studies were performed in a hospital ward for older people, where the traditional rounds had been replaced by a team meeting, to which the patients were invited. The analysis of the general structure and philosophical examination followed the principles of reflective lifeworld research. The philosophical examination is presented in four meaning structures: mood as a force in existence; to exist in a world with others; loneliness in the presence of others; and the lived body as extending. In conclusion, professionals must consider patients' existential issues in the way they are expressed by the patients. Existence extends beyond the present situation. Accordingly, the team meeting must be seen in a larger context, including the patients' life as a whole, as well as the ontological and epistemological foundations on which healthcare is based.


Amino acid neurotransmitter candidates: sodium-dependent high-affinity uptake by unique synaptosomal fractions.
Glutamic and aspartic acids and glycine are accumulated by high-affinity uptake systems into synaptosomal preparations in central nervous tissue. Sodium is required by these high-affinity transports, but not by the low-affinity transports for these and other amino acids. The sodium-requiring amino acid uptake systems label unique synaptosomal fractions. Observations suggest that these amino acids serve specific synaptic functions, presumably as neurotransmitters.


Markers of Collagen Remodeling Detect Clinically Significant Fibrosis in Chronic Hepatitis C Patients.
Detection of advanced fibrosis (Metavir F≥3) is important to identify patients with a high urgency of antiviral treatments vs. those whose treatment could be deferred (F≤2). The aim was to assess the diagnostic value of novel serological extracellular matrix protein fragments as potential biomarkers for clinically significant and advanced fibrosis. Specific protein fragments of matrix metalloprotease degraded type I, III, IV and VI collagen (C1M, C3M, C4M, C6M) and type III and IV collagen formation (Pro-C3 and P4NP7S) were assessed in plasma from 403 chronic hepatitis C patients by specific ELISAs. Patients were stratified according to Metavir Fibrosis stage; F0 (n = 46), F1 (n = 161), F2 (n = 95), F3 (n = 44) and F4 (n = 33) based on liver biopsy. Pro-C3 was significantly elevated in patients with significant fibrosis (≥F2) compared to F0-F1 (p<0.05), while the markers C3M, C4M, C6M and P4NP7S were significantly elevated in patients with advanced fibrosis (≥F3) compared to F0-F2 (p<0.05). C1M showed no difference between fibrosis stages. Using Receiver Operating Characteristics analysis, the best marker for detecting ≥F2 and ≥F3 was Pro-C3 with AUC = 0.75 and AUC = 0.86. Combination of Pro-C3 and C4M with age, BMI and gender in a multiple ordered logistic regression model improved the diagnostic value for detecting ≥F2 and ≥F3 with AUC = 0.80 and AUC = 0.88. The Pro-C3 protein fragment provided clinically relevant diagnostic accuracy as a single marker of liver fibrosis. A model combining Pro-C3 and C4M along with patient's age, body mass index and gender increased the diagnostic power for identifying clinically significant fibrosis.


Detection of Burkholderia pseudomallei O-antigen serotypes in near-neighbor species.
Burkholderia pseudomallei is the etiological agent of melioidosis and a CDC category B select agent with no available effective vaccine. Previous immunizations in mice have utilized the lipopolysaccharide (LPS) as a potential vaccine target because it is known as one of the most important antigenic epitopes in B. pseudomallei. Complicating this strategy are the four different B. pseudomallei LPS O-antigen types: A, B, B2, and rough. Sero-crossreactivity is common among O-antigens of Burkholderia species. Here, we identified the presence of multiple B. pseudomallei O-antigen types and sero-crossreactivity in its near-neighbor species. PCR screening of O-antigen biosynthesis genes, phenotypic characterization using SDS-PAGE, and immunoblot analysis showed that majority of B. mallei and B. thailandensis strains contained the typical O-antigen type A. In contrast, most of B. ubonensis and B. thailandensis-like strains expressed the atypical O-antigen types B and B2, respectively. Most B. oklahomensis strains expressed a distinct and non-seroreactive O-antigen type, except strain E0147 which expressed O-antigen type A. O-antigen type B2 was also detected in B. thailandensis 82172, B. ubonensis MSMB108, and Burkholderia sp. MSMB175. Interestingly, B. thailandensis-like MSMB43 contained a novel serotype B positive O-antigen. This study expands the number of species which express B. pseudomallei O-antigen types. Further work is required to elucidate the full structures and how closely these are to the B. pseudomallei O-antigens, which will ultimately determine the efficacy of the near-neighbor B serotypes for vaccine development.