Human Fibrinogen Inhibits Amyloid Assembly of Most Phenol-Soluble Modulins from Staphylococcus aureus.
Functional amyloids are highly organized protein/peptide structures that inter alia promote biofilm formation in different bacteria. One such example is provided by a family of 20-45 residue-long peptides called phenol-soluble modulins (PSMs) from Staphylococcus aureus. External components such as eukaryotic host proteins, which alter self-assembly of bacterial amyloids, can affect the biofilm matrix. Here, we studied the effect of the highly prevalent human plasma protein fibrinogen (Fg) on fibrillation of PSMs. Fg inhibits or suppresses fibrillation of most PSMs tested (PSMα1, PSMβ1, and PSMβ2) except for PSMα3, whose already rapid aggregation is accelerated even further by Fg but leads to amorphous β-rich aggregates rather than fibrils. Fg also induces PSMβ2 to form amorphous aggregates and diverts PSMα1 into off-pathway oligomers which consist of both Fg and PSMα1 and cannot seed fibrillation. Peptide arrays showed that Fg bound to the N-terminus of PSMα1, while it bound to the entire length of PSMα3 (except the C terminus) and to the C-termini of PSMβ1 and PSMβ2. The latter peptides are all positively charged, while Fg is negatively charged at physiological pH. The positive charges complement Fg's net negative charge of -7.6 at pH 7.4. Fg's ability to inhibit PSM fibrillation reveals a potential host-defense mechanism to prevent bacterial biofilm growth and infections in the human body.


Pulse bursts with a controllable number of pulses from a mode-locked Yb-doped all fiber laser system.
Pulse bursts with a controllable number of pulses per burst have been produced directly from a mode-locked Yb-doped fiber laser for the first time. Each output burst contained numerous pulses with a high pulse repetition rate of 29.4 MHz. The duration of a single pulse was 680 ps. The pulse burst had a repetition rate of 251.6 kHz. The pulse burst could easily be further amplified to a total pulse burst energy of ~795 nJ, corresponding to a total average power of 200 mW.


Modeling the Self-Assembly of Protein Complexes through a Rigid-Body Rotational Reaction-Diffusion Algorithm.
The reaction-diffusion equations provide a powerful framework for modeling nonequilibrium, cell-scale dynamics over the long time scales that are inaccessible by traditional molecular modeling approaches. Single-particle reaction-diffusion offers the highest resolution technique for tracking such dynamics, but it has not been applied to the study of protein self-assembly due to its treatment of reactive species as single-point particles. Here, we develop a relatively simple but accurate approach for building rigid structure and rotation into single-particle reaction-diffusion methods, providing a rate-based method for studying protein self-assembly. Our simplifying assumption is that reactive collisions can be evaluated purely on the basis of the separations between the sites, and not their orientations. The challenge of evaluating reaction probabilities can then be performed using well-known equations based on translational diffusion in both 3D and 2D, by employing an effective diffusion constant we derive here. We show how our approach reproduces both the kinetics of association, which is altered by rotational diffusion, and the equilibrium of reversible association, which is not. Importantly, the macroscopic kinetics of association can be predicted on the basis of the microscopic parameters of our structurally resolved model, allowing for critical comparisons with theory and other rate-based simulations. We demonstrate this method for efficient, rate-based simulations of self-assembly of clathrin trimers, highlighting how formation of regular lattices impacts the kinetics of association.


Mechanisms of cancer prevention by green and black tea polyphenols.
Drinking green tea is associated with decreased frequency of cancer development. This review outlines the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Cell cycle arrest or apoptosis involved caspase activation and altered Bcl-2 family member expression. EGCG inhibited telomerase activity and led to telomere fragmentation. While at high concentrations polyphenols had pro-oxidative activities, at much lower levels, anti-oxidative effects occurred. Nitric oxide production was reduced by EGCG and black tea theaflavins by suppressing inducible nitric oxide synthase via blocking nuclear translocation of the transcription factor nuclear factor-kappaB as a result of decreased IkappaB kinase activity. Polyphenols up- or down-regulated activity of a number of key enzymes, including mitogen-activated protein kinases and protein kinase C, and increased or decreased protein/mRNA levels, including that of cyclins, oncogenes, and tumor suppressor genes. Metastasis was inhibited via effects on urokinase and matrix metalloproteinases. Polyphenols reduced angiogenesis, in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor an-tagonist by directly binding the receptor's molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.


Assessment of radiation safety in cardiac CT angiography.
This study investigates the radiation dose and image quality of patients not receiving β-blockers for cardiac CT angiography (CCTA) with or without the optimization of electrocardiographic (ECG) pulsing window. The differences in patient characteristics are also characterized.Normal-weight and obese patients (n = 154) with heart rates between 65 and 80 beats per minutes (bpm) during the prospective axial scanning were enrolled retrospectively. The ECG pulsing windows were set at 50% to 75% (Group A) or 60% to 75% (Group B) of the R-R interval for patients with heart rate variability higher than or not exceeding ±5 bpm, respectively. The effective doses of individual patient were estimated from the dose length product of the CCTA scan. Two radiologists independently reviewed the images and applied a 4-point Likert scale for image quality assessment. The patients' characteristics were compared along with the patients' effective doses between groups.The optimized pulsing window significantly reduced the average radiation dose for normal-weight and obese patients by 33% and 27%, respectively. The CCTA image quality of patients in Group A was not different overall from those obtained from Group B. Nondiabetic obese patients were more likely to be accepted for the use of the optimized pulsing window. Unlike obese patients, normal-weight patients revealed no characteristic difference between Groups A and B.This study indicates an equivalent efficacy of using optimized pulsing windows for reducing the radiation dose for patients without β-blocker administration between different body weight groups. Nevertheless, gender and diabetic status became prominent characteristics in the obese group when matching up with the optimized pulsing window.


Graph Clustering System for Text-Based Records in a Clinical Pathway.
The progressive digitization of medical records has resulted in the accumulation of large amounts of data. Electronic medical data include structured numerical data and unstructured text data. Although text-based medical record processing has been researched, few studies contribute to medical practice. The analysis of unstructured text data can improve medical processes. Hence, this study presents a clustering approach for detecting typical patient's condition from text-based medical record of clinical pathway. In this approach, the sentences in a cluster are merged to generate a "sentence graph" of the cluster after classified feature word by Louvain method. An analysis of real text-based medical records indicates that sentence graphs can represent the medical treatment and patient's condition in a medical process. This method could help the standardization of text-based medical records and the recognition of feature medical processes for improving medical treatment.


The role of nod factor substituents in actin cytoskeleton rearrangements in Phaseolus vulgaris.
In order to define the symbiotic role of some of the chemical substituents in the Rhizobium etli Nod factors (NFs), we purified Nod metabolites secreted by the SM25 strain, which carries most of the nodulation genes, and SM17 with an insertion in nodS. These NFs were analyzed for their capabilities to induce root hair curling and cytoskeletal rearrangements. The NFs secreted by strain SM17 lack the carbamoyl and methyl substituents on the nonreducing terminal residue and an acetyl moiety on the fucosyl residue on the reducing-terminal residue as determined by mass spectrometry. We have reported previously that the root hair cell actin cytoskeleton from bean responds with a rapid fragmentation of the actin bundles within 5 min of NF exposure, and also is accompanied by increases in the apical influxes and intracellular calcium levels. In this article, we report that methyl-bearing NFs are more active in inducing root hair curling and actin cytoskeleton rearrangements than nonmethylated NFs. However, the carbamoyl residue on the nonreducing terminal residue and the acetyl group at the fucosyl residue on the reducing terminal residue do not seem to have any effect on root hair curling induction or in actin cytoskeleton rearrangement.


The Dutch hypothesis (chronic non-specific lung disease) revisited.
In 1961 the hypothesis (later referred to as the Dutch Hypothesis (DH)) was put forward that asthma, chronic bronchitis and emphysema should be considered as different expressions of one disease entity, in which both endogenous (host) and exogenous (environmental) factors play a role in the pathogenesis. A hereditary predisposition to develop allergy and bronchial hyperreactivity were considered to be important denominators of disease susceptibility. Complications and complicating diseases would also contribute to the ultimate phenotype of the patient. In the present paper we discuss the relevance of this hypothesis in 1990. Until now it has not been refuted; circumstantial evidence in its favour has accumulated, but formal proof is still lacking. Further research should pay more attention to the genetic aspects of the disease. Arguments are presented against the use of the terms asthma, chronic bronchitis, and emphysema as indicators of disease entities, and in favour of the use of an umbrella-term, e.g. chronic non-specific lung disease (CNSLD), provided that, in addition, every patient is characterized using so-called defining criteria.


Endothelium-dependent modulation of endothelin-induced vasoconstriction and membrane depolarization in cat cerebral arteries.
Effects of endothelin, the newly discovered, endothelium-derived vasoactive peptide, were examined on isolated, pressurized cat arteries. Responses to increasing concentrations of porcine endothelin (10(-12) to 10(-8) M) were compared in endothelium intact and denuded vessel segments utilizing diameter and membrane potential measurements. Endothelin produced a concentration-dependent contraction in arteries with intact endothelium with a maximal response of 26 +/- 2.8% of the initial diameter in physiological saline solution at 100 mm Hg of intraluminal pressure. Removal of the endothelium sensitized the smooth muscle to endothelin and increased the maximal response to 48 +/- 2.3% of the initial diameter. After incubation of the intact vessels with 10(-5) M indomethacin, the endothelin response was potentiated to the maximal value of 66 +/- 1.26% of the initial diameter of the intact vessels, and to 61 +/- 2.6% of the denuded arteries. The arterial smooth muscle cells were depolarized by 6 +/- 0.45 mV after administration of endothelin to the vessels, and by 10 +/- 0.8 mV in the denuded vessels. This depolarization was not altered by indomethacin. Our data suggest that endothelin has a direct effect on the smooth muscle of cat cerebral vascular tissue, and the sensitivity of these vessels to endothelin may be modulated by the release of dilatory cyclooxygenase products derived from the intact endothelium.


Investigating the effect of ionic strength on the suppression of dendrite formation during metal electrodeposition.
The effect of ionic strength on the electrodeposition of silver has been investigated in acetonitrile (MeCN) containing TBAPF6 or in the ionic liquid [EMIm][OTf]. The use of an ionic liquid allows a greater ionic strength to be investigated as the solubility limits of supporting electrolytes in organic solvents can be overcome using neat ionic liquid. The SEM and XRD data show that polycrystalline silver is deposited in a fcc structure and that dendrite formation is retarded at high ionic strength. Electrochemical measurements undertaken in electrolytes of low ionic strength indicate that the deposition and growth of a few nuclei is preferred and leads to dendrite formation. However, at higher ionic strength, the deposition and growth of significantly more nuclei is observed and therefore dendrite growth rates and tip currents are lower leading to the deposition of spherical particulates. Crucially, the data shows that if the ionic strength of the electrolyte is controlled there are no differences between ionic liquids and molecular solvents for the electrodeposition of silver.


Factors affecting trajectory patterns of self-rated health (SRH) in an older population--a community-based longitudinal study.
Self-rated health (SRH) is considered a relevant and important predictor for major health outcomes in the older population. SRH status may interact with certain factors and change over a person's lifetime. In this study, we sought to characterize profiles of older people over time by constructing prototypical trajectories of the variable of interest, namely SRH. The underlying assumption was that the collection of observed individual trajectories could be efficiently summarized by a smaller set of latent clusters of those trajectories. Data was obtained from the Longitudinal Survey of Health and Living Status of the Elderly in Taiwan, which was conducted between 1989 and 2003 and included five separate waves of survey. A total of 3937 subjects aged 60 or older (2251 males and 1686 females) comprised the major analytic cohort. Latent Class Growth Analysis (LCGA) was used to identify developmental classes of trajectory patterns in SRH. The results showed that during a 14-year period, SRH developed five major longitudinal trajectories. Less than one-third of the older population was able to maintain their formerly good or moderate health status; when change occurred, decline was more likely than improvement. In addition, LCGA indicated that many demographic characteristics, as well as physical and psychological propensities, were associated with poor SRH in the older population. Specifically, these factors played a role in involving baseline SRH level and its trend toward deterioration in later life. Health care professionals must understand the various longitudinal patterns and factors affecting SRH trajectories if they are to develop programs aimed at maintaining the older population's health and well-being.


Hierarchy of neural organization in the embryonic spinal cord: Granger-causality graph analysis of in vivo calcium imaging data.
The recent development of genetically encoded calcium indicators enables monitoring in vivo the activity of neuronal populations. Most analysis of these calcium transients relies on linear regression analysis based on the sensory stimulus applied or the behavior observed. To estimate the basic properties of the functional neural circuitry, we propose a network approach to calcium imaging recorded at single cell resolution. Differently from previous analysis based on cross-correlation, we used Granger-causality estimates to infer information propagation between the activities of different neurons. The resulting functional network was then modeled as a directed graph and characterized in terms of connectivity and node centralities. We applied our approach to calcium transients recorded at low frequency (4 Hz) in ventral neurons of the zebrafish spinal cord at the embryonic stage when spontaneous coiling of the tail occurs. Our analysis on population calcium imaging data revealed a strong ipsilateral connectivity and a characteristic hierarchical organization of the network hubs that supported established propagation of activity from rostral to caudal spinal cord. Our method could be used for detecting functional defects in neuronal circuitry during development and pathological conditions.


Aorto-Right Ventricular Tunnel: A Case Series and Literature Review.
Aorto-right ventricular tunnel (ARVT) is a rare cardiac congenital anomaly where an extracardiac channel connects the ascending aorta above the sinutubular junction to the right ventricle. This defect is caused by an abnormal development of the cushions of the aorto-pulmonary outflow tract. A case series and literature review are described. Two cases of ARVT are described. A literature review was conducted, in which 31 cases were reported. In our 2 cases, both ARVTs connected the ascending aorta above the left aortic sinus to the right ventricle (one to the right ventricular outflow tract and one to the right ventricular apex). Both patients underwent successful surgical correction by patch closure of both tunnel orifices, with uneventful postoperative course. Of the 31 ARVT cases described in our review, only 10 patients (32.3%) had an anatomy similar to the 2 cases described. Coronary artery anomalies can be associated, as reported in our 2 patients and in 16 cases (51.6%) in the review. Surgical correction can be achieved by direct closure or, more often, by patch closure of one or both tunnel orifices, depending mostly on coronary anatomy. Two cases of transcatheter device closure were described in literature, in favorable anatomy cases. Careful attention is required during repair to avoid coronary lesions, due to the high incidence of comorbid coronary anomalies.


In search of general mechanisms for long-lasting plasticity: Aplysia and the hippocampus.
Long-term synaptic plasticity is thought to underlie many forms of long-lasting memory. Long-lasting plasticity has been most extensively studied in the marine snail Aplysia and in the mammalian hippocampus, where Bliss and Lømo first described long-term potentiation 30 years ago. The molecular mechanisms of plasticity in these two systems have proven to have many similarities. Here, we briefly describe some of these areas of overlap. We then summarize recent advances in our understanding of the mechanisms of long-lasting synaptic facilitation in Aplysia and suggest that these may prove fruitful areas for future investigation in the mammalian hippocampus and at other synapses in the mammalian brain.


Comparative floc-bed sediment trace element partitioning across variably contaminated aquatic ecosystems.
Significantly higher concentrations of Ag, As, Cu, Ni and Co are found in floc compared to bed sediments across six variably impacted aquatic ecosystems. In contrast to the observed element and site-specific bed sediment trace element (TE) partitioning patterns, floc TE sequestration is consistently dominated by amorphous oxyhydroxides (FeOOH), which account for 30-79% of floc total TE concentrations, irrespective of system physico-chemistry or elements involved. FeOOH consistently occur in significantly higher concentrations in floc than within bed sediments. Further, comparative concentration factors indicate significantly higher TE reactivity of floc-FeOOH relative to sediment-FeOOH in all systems investigated, indicating that both the greater abundance and higher reactivity of floc-FeOOH contribute to enhanced floc TE uptake. Results indicate that floc-organics (live cells and exopolymeric substances, EPS) directly predict floc-FeOOH concentrations, suggesting an organic structural role in the collection/templating of FeOOH. This, in turn, facilitates the sequestration of TEs associated with floc-FeOOH formation, imparting the conserved FeOOH "signature" on floc TE geochemistry across sites. Results demonstrate that the organic rich nature of floc exerts an important control over TE geochemistry in aquatic environments, ultimately creating a distinct solid with differing controls over TE behavior than bed sediments in close proximity (<0.5 m).


Learning a 3D Human Pose Distance Metric from Geometric Pose Descriptor.
Estimating 3D pose similarity is a fundamental problem on 3D motion data. Most previous work calculates L2-like distance of joint orientations or coordinates, which does not sufficiently reflect the pose similarity of human perception. In this paper, we present a new pose distance metric. First, we propose a new rich pose feature set called Geometric Pose Descriptor (GPD). GPD is more effective in encoding pose similarity by utilizing features on geometric relations among body parts, as well as temporal information such as velocities and accelerations. Based on GPD, we propose a semisupervised distance metric learning algorithm called Regularized Distance Metric Learning with Sparse Representation (RDSR), which integrates information from both unsupervised data relationship and labels. We apply the proposed pose distance metric to applications of motion transition decision and content-based pose retrieval. Quantitative evaluations demonstrate that our method achieves better results with only a small amount of human labels, showing that the proposed pose distance metric is a promising building block for various 3D-motion related applications.


Physical Examinations via Video for Patients With Heart Failure: Qualitative Study Using Conversation Analysis.
Video consultations are increasingly seen as a possible replacement for face-to-face consultations. Direct physical examination of the patient is impossible; however, a limited examination may be undertaken via video (eg, using visual signals or asking a patient to press their lower legs and assess fluid retention). Little is currently known about what such video examinations involve. This study aimed to explore the opportunities and challenges of remote physical examination of patients with heart failure using video-mediated communication technology. We conducted a microanalysis of video examinations using conversation analysis (CA), an established approach for studying the details of communication and interaction. In all, seven video consultations (using FaceTime) between patients with heart failure and their community-based specialist nurses were video recorded with consent. We used CA to identify the challenges of remote physical examination over video and the verbal and nonverbal communication strategies used to address them. Apart from a general visual overview, remote physical examination in patients with heart failure was restricted to assessing fluid retention (by the patient or relative feeling for leg edema), blood pressure with pulse rate and rhythm (using a self-inflating blood pressure monitor incorporating an irregular heartbeat indicator and put on by the patient or relative), and oxygen saturation (using a finger clip device). In all seven cases, one or more of these examinations were accomplished via video, generating accurate biometric data for assessment by the clinician. However, video examinations proved challenging for all involved. Participants (patients, clinicians, and, sometimes, relatives) needed to collaboratively negotiate three recurrent challenges: (1) adequate design of instructions to guide video examinations (with nurses required to explain tasks using lay language and to check instructions were followed), (2) accommodation of the patient's desire for autonomy (on the part of nurses and relatives) in light of opportunities for involvement in their own physical assessment, and (3) doing the physical examination while simultaneously making it visible to the nurse (with patients and relatives needing adequate technological knowledge to operate a device and make the examination visible to the nurse as well as basic biomedical knowledge to follow nurses' instructions). Nurses remained responsible for making a clinical judgment of the adequacy of the examination and the trustworthiness of the data. In sum, despite significant challenges, selected participants in heart failure consultations managed to successfully complete video examinations. Video examinations are possible in the context of heart failure services. However, they are limited, time consuming, and challenging for all involved. Guidance and training are needed to support rollout of this new service model, along with research to understand if the challenges identified are relevant to different patients and conditions and how they can be successfully negotiated.


Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation.
Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer's disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through the human neuronal α7 acetylcholine receptor in the presence of the α7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond α7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit's transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation.


Cone photoreceptor abnormalities correlate with vision loss in patients with Stargardt disease.
PURPOSE. To study the relationship between macular cone structure, fundus autofluorescence (AF), and visual function in patients with Stargardt disease (STGD). METHODS. High-resolution images of the macula were obtained with adaptive optics scanning laser ophthalmoscopy (AOSLO) and spectral domain optical coherence tomography in 12 patients with STGD and 27 age-matched healthy subjects. Measures of retinal structure and AF were correlated with visual function, including best-corrected visual acuity, color vision, kinetic and static perimetry, fundus-guided microperimetry, and full-field electroretinography. Mutation analysis of the ABCA4 gene was completed in all patients. RESULTS. Patients were 15 to 55 years old, and visual acuity ranged from 20/25-20/320. Central scotomas were present in all patients, although the fovea was spared in three patients. The earliest cone spacing abnormalities were observed in regions of homogeneous AF, normal visual function, and normal outer retinal structure. Outer retinal structure and AF were most normal near the optic disc. Longitudinal studies showed progressive increases in AF followed by reduced AF associated with losses of visual sensitivity, outer retinal layers, and cones. At least one disease-causing mutation in the ABCA4 gene was identified in 11 of 12 patients studied; 1 of 12 patients showed no disease-causing ABCA4 mutations. CONCLUSIONS. AOSLO imaging demonstrated abnormal cone spacing in regions of abnormal fundus AF and reduced visual function. These findings provide support for a model of disease progression in which lipofuscin accumulation results in homogeneously increased AF with cone spacing abnormalities, followed by heterogeneously increased AF with cone loss, then reduced AF with cone and RPE cell death.


Effects of a 4-week dynamic-balance-training program supplemented with Graston instrument-assisted soft-tissue mobilization for chronic ankle instability.
A dynamic-balance-training (DBT) program supplemented with the Graston instrument-assisted soft-tissue mobilization (GISTM) technique has not been evaluated collectively as a treatment in subjects with chronic ankle instability (CAI). To examine the effects of GISTM in conjunction with a DBT program on outcomes associated with CAI, including pain and disability, range of motion (ROM), and dynamic postural control. Pretest/posttest, repeated measures. High school and a Division I mid-Atlantic university. Thirty-six healthy, physically active individuals (5 female, 31 male; age 17.7 ± 1.9 y; height 175.3 ± 14.6 cm) with a history of CAI as determined by an ankle-instability questionnaire volunteered to be in this study. Subjects were randomly assigned to 1 of 3 intervention groups: both treatments (DBT/GISTM, n = 13), DBT and a sham GISTM treatment (DBT/GISTM-S, n = 12), or DBT and control-no GISTM (DBT/C, n = 11). All groups participated in a 4-wk DBT program consisting of low-impact and dynamic activities that was progressed from week to week. The DBT/GISTM and DBT/GISTM-S groups received the GISTM treatment or sham treatment twice a week for 8 min before performing the DBT program. Pretest and posttest measurements included the Foot and Ankle Ability Measure (FAAM), FAAM Sport, the visual analog scale (VAS), ankle ROM in 4 directions, and the Star Excursion Balance Test (SEBT) in 3 directions. FAAM and FAAM-Sport scores, VAS, goniometric ROM (plantar flexion, dorsiflexion, inversion, eversion), and SEBT (anterior, posteromedial, posterolateral). Subjects in all groups posttest demonstrated an increase in FAAM, FAAM Sport, ROM, and SEBT in all directions but not in VAS, which decreased. No other results were significant. For subjects with CAI, dynamic postural control, ROM, pain and disability improved pretest to posttest regardless of group membership, with the largest effects found in most measures in the DBT/GISTM group.


The effect of donor body mass index on graft function in liver transplantation: A systematic review.
The impact of donor body mass index (BMI) on graft function outcomes in liver transplantation (LT) is still controversial. The aim of this study was to review the current evidence investigating the effect of donor BMI on outcomes in patients undergoing LT. A systematic review was performed to evaluate relevant outcomes such as the availability of data on donor BMI as well as graft and patient survival after LT. Screening of 901 articles resulted in 11 observational studies for data extraction. In adult deceased donor after brain death and living donor LT, donor BMI was not associated with graft and patient survival. However, high donor BMI was associated with a higher chance of macrosteatosis besides a significantly higher incidence of declined livers. In pediatric LT, severe obesity in adult donors with BMI ≥35 was associated with graft loss and mortality, whereas obesity in pediatric donors was not associated with graft loss and mortality. Accordingly, donor BMI is not associated with long-term outcomes in adult patients undergoing LT. However, further research should be conducted to identify the effect of donor BMI on outcomes in LT.


Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.
Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone. This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820. Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0·499 (95% CI 0·454-0·549) with ibandronic acid and 0·435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362). The upper CI was greater than the margin of non-inferiority of 1·08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (91 [corrected] [13%] vs 85 [corrected] [12%]), joint pain (41 [corrected] [6%] vs 38 [5%]), infection (31 [5%] vs 23 [corrected] [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]). Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions. Roche Products Ltd (educational grant), supported by National Institute for Health Research Cancer Network, following endorsement by Cancer Research UK (CRUKE/04/022).


HIV and Africa's elderly: the problems and possibilities.
Demographic changes and the increasing availability and coverage of antiretroviral therapy imply that the burden of HIV is shifting to older age groups in sub-Saharan Africa. However, very little is known about the burden of disease and the unique considerations required to adequately treat and retain older Africans. In this review, we summarize the epidemiological data on HIV prevalence among older Africans, and review progress and barriers to accessing treatment and care. The unique clinical considerations distinguishing the management of older HIV-infected Africans are summarized, with a focus on cardiovascular disease, neuropsychiatric conditions, oncologic illness, and musculoskeletal morbidity. The review concludes by suggesting opportunities for improving our knowledge about and management of HIV among older Africans, including prevention opportunities and potential technologies, including a polypill for reducing comorbidity in this under-recognized highly vulnerable group.


Familism Values, Family Time, and Mexican-Origin Young Adults' Depressive Symptoms.
Using longitudinal data across eight years, this study examined how parents' familism values in early adolescence predicted youths' depressive symptoms in young adulthood via youths' familism values and family time. We examined these processes among 246 Mexican-origin families using interview and phone-diary data. Findings revealed that fathers' familism values predicted male and female youths' familism values in middle adolescence. For female youth only, fathers' familism values also predicted youths' family time in late adolescence. The link between family time and young adults' depressive symptoms depended on parental acceptance and adolescent gender: Among female and male youth, family time predicted fewer depressive symptoms, but only when paternal acceptance was high. For female adolescents only, family time predicted fewer depressive symptoms when maternal acceptance was high but more depressive symptoms when maternal acceptance was low. Findings highlight family dynamics as the mechanisms through which familism values have implications for youths' adjustment.


Impact of an expeditor on emergency department patient throughput.
Our hypothesis was that an individual whose primary role was to assist with patient throughput would decrease emergency department (ED) length of stay (LOS), elopements and ambulance diversion. The objective of this study was to measure how the use of an expeditor affected these throughput metrics. This pre-and post-intervention study analyzed ED patients ≥ 21-years-old between June 2008 and June 2009, at a level one trauma center in an academic medical center with an annual ED census of 40,000 patients. We created the expeditor position as our study intervention in December 2008, by modifying the job responsibilities of an existing paramedic position. An expeditor was on duty from 1PM-1AM daily. The pre-intervention period was June to November 2008, and the post-intervention period was January to June 2009. We used multivariable to assess the impact of the expeditor on throughput metrics after adjusting for confounding variables. We included a total of 13,680 visits in the analysis. There was a significant decrease in LOS after expeditor implementation by 0.4 hours, despite an increased average daily census (109 vs. 121, p<0.001). The expeditor had no impact on elopements. The probability that the ED experienced complete ambulance diversion during a 24-hour period decreased from 55.2% to 16.0% (OR:0.17, 95%CI:0.05-0.67). The use of an expeditor was associated with a decreased LOS and ambulance diversion. These findings suggest that EDs may be able to improve patient flow by using expeditors. This tool is under the control of the ED and does not require larger buy-in, resources, or overall hospital changes.


Differentially expressed and secreted major immunoreactive protein orthologs of Ehrlichia canis and E. chaffeensis elicit early antibody responses to epitopes on glycosylated tandem repeats.
Ehrlichia canis major immunoreactive proteins of 36 and 19 kDa elicit the earliest detectable antibody responses during the acute phase of canine monocytic ehrlichiosis. Genes encoding the major immunoreactive 36-kDa protein of E. canis and the corresponding ortholog of E. chaffeensis (47 kDa) were identified and the proteins characterized. The molecular masses of the strongly immunoreactive recombinant proteins were larger than predicted (26.7 and 32.9 kDa, respectively) but were consistent with those of the corresponding native proteins (36 and 47 kDa). Similar to other reported ehrlichial immunoreactive glycoproteins, carbohydrate was detected on the recombinant expressed proteins, indicating that they were glycoproteins. Both glycoproteins (gp36 and gp47) have carboxy-terminal serine/threonine-rich tandem repeat regions containing repeats that vary in number (4 to 16 repeats) and amino acid sequence among different isolates of each species. E. canis gp36 was recognized by early acute-phase antibodies (day 14), and species-specific antibody epitopes were mapped to C-terminal nonhomologous repeat units of gp36 and gp47. Periodate treatment of recombinant gp36 reduced the antibody reactivity, and nonglycosylated synthetic peptide repeat units from E. canis gp36 and E. chaffeensis gp47 were substantially less immunoreactive than corresponding recombinant peptides, demonstrating that glycans are important epitope determinants that are structurally conserved on the recombinant proteins expressed in Escherichia coli. E. canis gp36 and E. chaffeensis gp47 were differentially expressed only on the surface of dense-cored ehrlichiae and detected in the Ehrlichia-free supernatants, indicating that these proteins are released extracellularly during infection.


Structural insight into the dual ligand specificity and mode of high density lipoprotein association of apolipoprotein D.
Human apolipoprotein D (ApoD) occurs in plasma associated with high density lipoprotein. Apart from the involvement in lipid metabolism, its binding activity for progesterone and arachidonic acid plays a role in cancer development and neurological diseases. The crystal structures of free ApoD and its complex with progesterone were determined at 1.8A resolution and reveal a lipocalin fold. The narrow, mainly uncharged pocket within the typical beta-barrel accommodates progesterone with its acetyl side chain oriented toward the bottom. The cavity adopts essentially the same shape in the absence of progesterone and allows complexation of arachidonic acid as another cognate ligand. Three of the four extended loops at the open end of the beta-barrel expose hydrophobic side chains, which is an unusual feature for lipocalins and probably effects association with the high density lipoprotein particle by mediating insertion into the lipid phase. This mechanism is in line with an unpaired Cys residue in the same surface region that can form a disulfide cross-link with apolipoprotein A-II.


A physiologically based nonhomogeneous Poisson counter model of visual identification.
A physiologically based nonhomogeneous Poisson counter model of visual identification is presented. The model was developed in the framework of a Theory of Visual Attention (Bundesen, 1990; Kyllingsbæk, Markussen, & Bundesen, 2012) and meant for modeling visual identification of objects that are mutually confusable and hard to see. The model assumes that the visual system's initial sensory response consists in tentative visual categorizations, which are accumulated by leaky integration of both transient and sustained components comparable with those found in spike density patterns of early sensory neurons. The sensory response (tentative categorizations) feeds independent Poisson counters, each of which accumulates tentative object categorizations of a particular type to guide overt identification performance. We tested the model's ability to predict the effect of stimulus duration on observed distributions of responses in a nonspeeded (pure accuracy) identification task with eight response alternatives. The time courses of correct and erroneous categorizations were well accounted for when the event-rates of competing Poisson counters were allowed to vary independently over time in a way that mimicked the dynamics of receptive field selectivity as found in neurophysiological studies. Furthermore, the initial sensory response yielded theoretical hazard rate functions that closely resembled empirically estimated ones. Finally, supplied with a Naka-Rushton type contrast gain control, the model provided an explanation for Bloch's law. (PsycINFO Database Record


Dynamic causal modelling revisited.
This paper revisits the dynamic causal modelling of fMRI timeseries by replacing the usual (Taylor) approximation to neuronal dynamics with a neural mass model of the canonical microcircuit. This provides a generative or dynamic causal model of laminar specific responses that can generate haemodynamic and electrophysiological measurements. In principle, this allows the fusion of haemodynamic and (event related or induced) electrophysiological responses. Furthermore, it enables Bayesian model comparison of competing hypotheses about physiologically plausible synaptic effects; for example, does attentional modulation act on superficial or deep pyramidal cells - or both? In this technical note, we describe the resulting dynamic causal model and provide an illustrative application to the attention to visual motion dataset used in previous papers. Our focus here is on how to answer long-standing questions in fMRI; for example, do haemodynamic responses reflect extrinsic (afferent) input from distant cortical regions, or do they reflect intrinsic (recurrent) neuronal activity? To what extent do inhibitory interneurons contribute to neurovascular coupling? What is the relationship between haemodynamic responses and the frequency of induced neuronal activity? This paper does not pretend to answer these questions; rather it shows how they can be addressed using neural mass models of fMRI timeseries.


Effects of modifiers of glycosaminoglycan biosynthesis on outflow facility in perfusion culture.
Glycosaminoglycans (GAGs) have been implicated in the regulation of outflow resistance of aqueous humor flow through the trabecular meshwork (TM). Their role was further investigated by assessment of the effects of chlorate, an inhibitor of sulfation, and beta-xyloside, which provides a competitive nucleation point for addition of disaccharide units, in anterior segment perfusion culture. Outflow facility was measured in perfused porcine and human anterior organ cultures treated with 20 or 50 mM sodium chlorate, or 1 mM beta-xyloside. Perturbation of extracellular matrix (ECM) components was assessed in paraffin-embedded sections by immunofluorescence and confocal microscopy. Parallel experiments were conducted on cultured TM cells. Outflow facility increased in porcine eyes with chlorate (3-fold) and beta-xyloside (3.5-fold) treatments. In human eyes, outflow increased approximately 1.5-fold and took longer (>48 hours) to occur. By confocal microscopy, immunostaining for chondroitin and heparan sulfates was observed on edges of human TM beams in nontreated eyes, with intense staining in the juxtacanalicular tissue (JCT) region. In treated eyes, staining of beam edges was severely reduced and was instead found in plaques. Chlorate treatment resulted in a striated pattern of GAG staining in the human JCT region. Fibronectin immunostaining was altered in beta-xyloside-treated eyes, whereas in cell culture, chlorate induced formation of thick fibronectin fibrils, to which tenascin C colocalized. Disrupting GAG chain biosynthesis increased outflow facility in perfusion culture and induced atypical ECM molecule interactions in cell culture. This study provides direct evidence of the critical role of GAG chains in regulating outflow resistance in human TM.


Human lens epithelial layer in cortical cataract.
Normal and cataractous human eye lenses were studied by morphology and protein analysis. A marked decrease in protein sulfhydryl (PSH) and nonprotein sulfhydryl (NSPH) was observed in nuclear and cortical cataractous epithelia. Moreover, decrease in PSH contents and an increase in insoluble proteins were found to be correlated only in cortical cataractous epithelium which is also accompanied by various morphological abnormalities. In nuclear cataractous epithelium, however, there was very little insolubilisation of proteins. The epithelial morphology in nuclear cataracts was almost similar to normal lens epithelium. Hence, it is assumed that the protein insolubilisation and various morphological abnormalities are characteristics of cortical cataractous epithelium. This leads us to believe that opacification in cortical cataract might initiate in the epithelial layer.


Comparison of polymerization of ancrod and thrombin fibrin monomers.
The polymerization of thrombin and ancrod fibrin monomers was studied with a standardized technique that evaluated turbidity changes and protein incorporation into the clot. Ancrod fibrin monomers were found to polymerize more slowly and form less turbid clots (at identical protein concentrations). Changes in ionic strength and pH influences ancrod fibrin monomer polymerization to a greater extent than thrombin fibrin monomer polymerization. Benzyltriethylammonium chloride was shown to be a potent inhibitor of fibrin monomer polymerization, with a greater inhibitory effect on ancrod fibrin monomers than on thrombin fibrin monomers. The differences between ancrod and thrombin fibrin may play a role in the infrequent thrombotic complications reported with ancrod therapy.


Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) study.
To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders. Clinical trial registry information-Treatment of Schizophrenia and Related Disorders in Children and Adolescents; URL: http://www.clinicaltrials.gov, unique identifier: NCT00053703.


Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit.
Neurogenesis continues throughout adulthood in the dentate gyrus in mice, and is regulated by environmental, endocrine, and pharmacological stimuli. Although running wheel exercises have been reported to enhance neurogenesis, details of molecule mechanisms of the enhancement are not well understood. We report here that the hippocampal neurogenesis is enhanced when wild-type mice are raised in cages with running wheels for 3 weeks, but the wheel exercise does not enhance the neurogenesis in mice lacking the NMDA receptor epsilon1 subunit. Brain-derived neurotrophic factor (BDNF) has been reported to affect neuronal cell proliferation and survival. We examined the BDNF levels in the hippocampi of wild-type and epsilon1 knockout mice, and found that the BDNF level was increased through wheel exercises in the wild-type but not in the knockout mice. The enhancement of neurogenesis by the wheel exercise was also found to be reversible: when the exercise-stimulated wild-type mice were returned to the environment without running wheels for 3 weeks, the neurogenesis was the same as that in the mice which had never experienced the exercise. These results suggest that the wheel exercise may activate NMDA receptors in the hippocampus, which in turn may enhance BDNF production and neurogenesis.


Two novel genes in the center of the 11p15 imprinted domain escape genomic imprinting.
We previously reported the isolation of a 2.5 Mb tumor-suppressing subchromosomal transferable fragment (STF) from human chromosome 11p15 and the identification of nine known genes and four novel genes within this STF. We now report the isolation of two novel cDNAs, designated here as TSSC4 and TSSC6 (tumor-suppressing STF cDNA 4 and 6), located within the STF. TSSC4 and TSSC6 encode predicted proteins of 329 and 290 amino acids, respectively, with no close similarity to previously reported proteins. TSSC4 and TSSC6 are both located in the center of a 1 Mb imprinted domain, which contains the imprinted genes TSSC3, TSSC5, p57(KIP2), KVLQT1, ASCL2, IGF2 and H19. However, we found that neither TSSC4 nor TSSC6 was significantly imprinted in any of the fetal or extra-embryonic tissues examined. Based on this result, the imprinted gene domain of 11p15 appears to contain at least two imprinted subdomains, between which TSSC4 and TSSC6 substantially escape imprinting, due either to lack of initial silencing or to an early developmental relaxation of imprinting.


Prevalence and Antimicrobial Susceptibility of Campylobacter spp. in Oklahoma Conventional and Organic Retail Poultry.
Campylobacter is one of the most important foodborne pathogens that cause bacterial gastroenteritis.This study was conducted to investigate the prevalence and antimicrobial resistance of Campylobacter in conventional and organic retail poultry samples purchased from grocery stores in Tulsa, Oklahoma.One hundred and fifty six chilled retail chicken samples (85 conventional and 71 organic) and 65 chilled retail conventional turkey samples were collected in this study. The prevalence of Campylobacter in the conventional chicken samples 32/85 (38%) was higher than in the organic ones 21/71 (30%). The prevalence of Campylobacter in the conventional turkey samples was 11/65 (17%). Of the 53 positive chicken samples, 42 were C. jejuni, 8 were C. coli and three isolates were contaminated with both species. Of the 11 positive turkey samples, 8 contained C. jejuni and 3 harbored C. coli isolates. The antimicrobial susceptibility of one hundred and forty nine recovered Campylobacter isolates (130 chickens and 19 turkeys) towards sixteen antimicrobials was determined. The majority of the recovered turkey isolates (13/19) showed resistance to more than 7 antimicrobials while most of the recovered chicken ones (82/130) were resistant to 5 to 7 antimicrobials. Multidrug resistance was not limited to isolates from conventional sources but was also available in isolates of an organic background and was generally lower in C. jejuni isolates when compared to the C. coli ones.


Clomiphene citrate for unexplained subfertility in women.
The effectiveness of clomiphene citrate has been demonstrated in the treatment of subfertility associated with infrequent or irregular ovulation. The physiologic effects and clinical benefits in ovulatory women with unexplained subfertility are less clear. The drug is associated with an increased risk of multiple pregnancy and a suggestion of potentially increased ovarian cancer risks. In light of these concerns, defining the effectiveness of clomiphene citrate for ovulatory women with unexplained subfertility is extremely important. To determine the effectiveness of clomiphene citrate in improving pregnancy outcomes in women with unexplained subfertility, used in a dose range of 50 to 250 mg for up to 10 days. The primary outcome was live births. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (June 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to June 2009), EMBASE (1980 to June 2009) and reference lists of articles. Only randomised controlled trials were included. Quasi-randomised designs were excluded. Fourteen potentially relevant trials were identified of which seven were included in this review. All trials were assessed for risk of bias using standardised Menstrual Disorders and Subfertility Group methodology. Data relating to 1159 participants from seven trials were collated. There was no evidence that clomiphene citrate was more effective than no treatment or placebo for live birth (odds ratio (OR) 0.79, 95% CI 0.45 to 1.38; P = 0.41) or for clinical pregnancy per woman randomised both with intrauterine insemination (IUI) (OR 2.40, 95% CI 0.70 to 8.19; P = 0.16), without IUI (OR 1.03, 95% CI 0.64 to 1.66; P = 0.91) and without IUI but using human chorionic gonadotropin (hCG) (OR 1.66, 95% CI 0.56 to 4.80; P = 0.35). It should be noted that heterogeneity between studies ranged from 34% to 58% using the I(2) statistic. There is no evidence of clinical benefit of clomiphene citrate for unexplained fertility. When making this treatment choice, potential side effects should be discussed. These include the increased risk of multiple pregnancy and the concern that use for more that 12 cycles has been associated with a three-fold increase in risk of ovarian cancer.


Whole mitogenome of the Endangered dwarf sawfish Pristis clavata (Rajiformes: Pristidae).
In this study, we describe the first complete mitochondrial sequence for the Endangered dwarf sawfish Pristis clavata. The base composition of the 16,804 bp long mitogenome is 31.9% A, 26.5% C, 13.3% G and 28.3% T and the gene arrangement and transcriptional direction are the same as those found in most vertebrates. All protein-coding genes start with ATG except the COI gene, which starts with GTG. Stop codons include incomplete T, AGG and TAA; however, TAG is not found in the mitogenome of this euryhaline elasmobranch species.


Mechanisms of facial emotion recognition in autism spectrum disorders: Insights from eye tracking and electroencephalography.
While behavioural difficulties in facial emotion recognition (FER) have been observed in individuals with Autism Spectrum Disorder (ASD), behavioural studies alone are not suited to elucidate the specific nature of FER challenges in ASD. Eye tracking (ET) and electroencephalography (EEG) provide insights in to the attentional and neurological correlates of performance, and may therefore provide insight in to the mechanisms underpinning FER in ASD. Given that these processes develop over the course of the developmental trajectory, there is a need to synthesise findings in regard to the developmental stages to determine how the maturation of these systems may impact FER in ASD. We conducted a systematic review of fifty-four studies investigating ET or EEG meeting inclusion criteria. Findings indicate divergence of visual processing pathways in individuals with ASD. Altered function of the social brain in ASD impacts the processing of facial emotion across the developmental trajectory, resulting in observable differences in ET and EEG outcomes.


Construction of efficient bioelectrochemical devices: Improved electricity production from cyanobacteria (Leptolyngbia sp.) based on π-conjugated conducting polymer/gold nanoparticle composite interfaces.
In this study, gold electrodes (GE) were coated with conducting polymers to obtain a high photocurrent using cyanobacteria from a novel bioelectrochemical fuel cell. For this purpose, 4-(4H-ditiheno[3,2-b:2',3'-d]pyrol-4-yl) aniline and 5-(4H-dithieno[3,2-b:2',3'-d]pyrol-4-yl) napthtalane-1-amine monomers were coated on GE by performing an electropolymerization process. After that, gold nanoparticles (AuNP) were specifically modified by 2-mercaptoethane sulfonic acid and p-aminothiophenol to attach to the electrode surface. The conducting polymers GE coat was modified with functionalized AuNP using a cross-linker. The resulting electrode structures were characterized by cyclic voltammetry and chronoamperometry under on-off illumination using a fiber optic light source. Cyanobacteria Leptolyngbia sp. was added to the GE/conducting polymer/AuNP electrode surface and stabilized by using a cellulose membrane. During the illumination, water was oxidized by the photosynthesis, and oxygen was released. The released oxygen was electrocatalytically reduced at the cathode surface and a 25 nA/cm 2 photocurrent was observed in GE/ Leptolyngbia sp. After the electrode modifications, a significant improvement in the photocurrent up to 630 nA/cm 2 was achieved.


The socioeconomic burden of chronic lung disease in low-resource settings across the globe - an observational FRESH AIR study.
Low-resource settings are disproportionally burdened by chronic lung disease due to early childhood disadvantages and indoor/outdoor air pollution. However, data on the socioeconomic impact of respiratory diseases in these settings are largely lacking. Therefore, we aimed to estimate the chronic lung disease-related socioeconomic burden in diverse low-resource settings across the globe. To inform governmental and health policy, we focused on work productivity and activity impairment and its modifiable clinical and environmental risk factors. We performed a cross-sectional, observational FRESH AIR study in Uganda, Vietnam, Kyrgyzstan, and Greece. We assessed the chronic lung disease-related socioeconomic burden using validated questionnaires among spirometry-diagnosed COPD and/or asthma patients (total N = 1040). Predictors for a higher burden were studied using multivariable linear regression models including demographics (e.g. age, gender), health parameters (breathlessness, comorbidities), and risk factors for chronic lung disease (smoking, solid fuel use). We applied identical models per country, which we subsequently meta-analyzed. Employed patients reported a median [IQR] overall work impairment due to chronic lung disease of 30% [1.8-51.7] and decreased productivity (presenteeism) of 20.0% [0.0-40.0]. Remarkably, work time missed (absenteeism) was 0.0% [0.0-16.7]. The total population reported 40.0% [20.0-60.0] impairment in daily activities. Breathlessness severity (MRC-scale) (B = 8.92, 95%CI = 7.47-10.36), smoking (B = 5.97, 95%CI = 1.73-10.22), and solid fuel use (B = 3.94, 95%CI = 0.56-7.31) were potentially modifiable risk factors for impairment. In low-resource settings, chronic lung disease-related absenteeism is relatively low compared to the substantial presenteeism and activity impairment. Possibly, given the lack of social security systems, relatively few people take days off work at the expense of decreased productivity. Breathlessness (MRC-score), smoking, and solid fuel use are potentially modifiable predictors for higher impairment. Results warrant increased awareness, preventive actions and clinical management of lung diseases in low-resource settings from health policymakers and healthcare workers.


Health sector responses to intimate partner violence: a literature review.
Intimate partner violence (IPV) is a common and serious public health concern, particularly in South Africa, but it is not well managed in primary care. This review aims to summarise the current state of knowledge regarding health sector-based interventions for IPV, their integration into health systems and services and the perspectives of service users and healthcare workers on IPV care, focusing on the South African context. PubMed, CINAHL, PsycINFO and Google Scholar were searched between January 2012 and May 2014. All types of study design were included, critically appraised and summarised. Exposure to IPV leads to wide-ranging and serious health effects. There is sufficient evidence that intervening in IPV in primary care can improve outcomes. Women who have experienced IPV have described an appropriate response by healthcare providers to be non-judgmental, understanding and empathetic. IPV interventions that are complex, comprehensive and utilise systems-wide approaches have been most effective, but system- and society-level barriers hamper implementation. Gender inequities should not be overlooked when responding to IPV. Further evaluations of health sector responses to IPV are needed, in order to assist health services to determine the most appropriate models of care, how these can be integrated into current systems and how they can be supported in managing IPV. The need for this research should not prevent health services and healthcare providers from implementing IPV care, but rather should guide the development of rigorous contextually-appropriate evaluations.


Coexistence of schizophrenia and epilepsy: record-linkage studies.
For many years, there has been interest in a possible link between epilepsy and schizophrenia. A recent study found a strong, bidirectional link between the two conditions: people with one had a higher than average risk of having the other. Using two large data sets of hospital admission data, we investigated whether schizophrenia and epilepsy occur together in individuals more commonly than expected by chance. We undertook a retrospective cohort study using the Oxford Record Linkage Study (ORLS) and English national linked Hospital Episode Statistics to investigate the coexistence of these conditions. There was an elevated risk of epilepsy in people admitted to hospital with schizophrenia (ORLS rate ratio 2.1, 95% confidence interval 1.6-2.6; England 3.0, 2.9-3.1) and an elevated risk of schizophrenia in people admitted to hospital with epilepsy (ORLS 5.1, 4.1-6.2; England 4.5, 4.3-4.6). We found no consistent difference between male and female patients. Schizophrenia and epilepsy occur together in individuals more frequently than expected by chance.


The quality of medical products for cardiovascular diseases: a gap in global cardiac care.
Good quality cardiovascular medicines and devices are crucial in the prevention and management of the ever-growing threats of cardiovascular diseases (CVDs) globally. Yet our current understanding of the extent and impact of substandard and falsified (SF) cardiovascular medical products is poor. Our objective was to review the available literature on SF cardiovascular medicines/devices, with a focus on prevalence studies to discuss their impacts on public health. Searches were conducted in Embase, PubMed, Web of Science, Google Scholar, Google and websites with interest in medicines/devices quality up to 31 August 2020. Articles in English and French identified in these searches were screened for eligibility. The Medicine Quality Assessment Reporting Guidelines was used to assess the quality of prevalence surveys, and we report according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A total of 279 articles were included, which were subcategorised into prevalence surveys (n=28), equivalence studies (n=118), stability studies (n=5), routine quality control analyses (n=15), bioavailability studies (n=2), recalls/seizures/case reports (n=77), general discussions (n=24) and reviews (n=10). A failure frequency (defined as the proportion of samples that failed at least one quality test described in the report) of 525 (15.4%) was observed for the 3414 samples tested for quality in the 27 prevalence surveys with sufficient information for inclusion in our quantitative analysis. Nineteen surveys (70.4%) used convenience outlet sampling. The majority (88.8%, 3032/3414) of samples included in prevalence surveys were collected from low-income and middle-income countries. The most common defects were out-of-specification active ingredient(s) content, impurity/contaminant content and impaired dissolution. We found 26 incidents describing SF cardiovascular devices with 181 related deaths but no prevalence surveys. The data suggest that SF cardiovascular products are likely to be a serious public health problem that has received limited attention. We do not suggest that 15.4% of cardiovascular medicines are SF, and our findings highlight the need for more research with robust methodology to provide more accurate prevalence estimates in order to inform policy and implement measures to ensure the quality of cardiovascular medicines and devices within the supply chain. Ensuring that CVD medical products are of good quality would help ensure effectiveness and that the benefits of therapy are realised in the prevention and treatment of CVDs.


Relationship between metabolic phenotypes and genotypes of CYP1A2 and CYP2A6 in the Nigerian population.
CYP1A2 and CYP2A6 are polymorphic drug-metabolising enzymes that are also implicated in the activation of procarcinogens in humans. Some of their alleles and haplotypes, often varied in prevalence across populations, are thought to influence activity despite the known contribution of environmental factors. This study assessed the potential influence of some genetic variants of CYP1A2 and CYP2A6 on metabolic phenotypes in Nigerians. Genomic DNA was extracted from blood samples of 100 healthy, unrelated subjects for whom CYP1A2 and CYP2A6 phenotypes had previously been determined, alongside an additional 80 other individuals for whom phenotype data were unavailable. The samples were screened for CYP1A2 (*1C,*1D,*1E,*1F, *3,*4,*6,*7) and CYP2A6 (*9,*11,*17) alleles using the Sequenom MassARRAY platform for some alleles and direct Sanger sequencing for others. The genetic data acquired were subsequently analysed for haplotypes and assessed for concordance with phenotypes. All five CYP1A2 haplotypes (CYP1A2*1F, 1J, 1N, 1L, 1W) identified in the Nigerian population were not significantly predictive of metabolic phenotypes. Heterozygous CYP1A2*1J carriers and homozygous CYP1A2*1W carriers showed statistically insignificant decrease in CYP1A2 activity. The CYP2A6*9/*17 genotype was, however, significantly associated with the CYP2A6-poor metabolic phenotype, whereas CYP2A6*9 or CYP2A6*17 alone did not show any such association. CYP2A6*11 was not detected in the population. Our findings suggest that CYP1A2 alleles or haplotypes were not predictive of metabolic phenotypes in the Nigerian population. Carriers of CYP2A6*9/*17 genotype are likely to be poor metabolisers of CYP2A6 substrates and may experience adverse reactions or poor efficacy while using drugs metabolised mainly by CYP2A6.


Congruence and diversity of butterfly-host plant associations at higher taxonomic levels.
We aggregated data on butterfly-host plant associations from existing sources in order to address the following questions: (1) is there a general correlation between host diversity and butterfly species richness?, (2) has the evolution of host plant use followed consistent patterns across butterfly lineages?, (3) what is the common ancestral host plant for all butterfly lineages? The compilation included 44,148 records from 5,152 butterfly species (28.6% of worldwide species of Papilionoidea) and 1,193 genera (66.3%). The overwhelming majority of butterflies use angiosperms as host plants. Fabales is used by most species (1,007 spp.) from all seven butterfly families and most subfamilies, Poales is the second most frequently used order, but is mostly restricted to two species-rich subfamilies: Hesperiinae (56.5% of all Hesperiidae), and Satyrinae (42.6% of all Nymphalidae). We found a significant and strong correlation between host plant diversity and butterfly species richness. A global test for congruence (Parafit test) was sensitive to uncertainty in the butterfly cladogram, and suggests a mixed system with congruent associations between Papilionidae and magnoliids, Hesperiidae and monocots, and the remaining subfamilies with the eudicots (fabids and malvids), but also numerous random associations. The congruent associations are also recovered as the most probable ancestral states in each node using maximum likelihood methods. The shift from basal groups to eudicots appears to be more likely than the other way around, with the only exception being a Satyrine-clade within the Nymphalidae that feed on monocots. Our analysis contributes to the visualization of the complex pattern of interactions at superfamily level and provides a context to discuss the timing of changes in host plant utilization that might have promoted diversification in some butterfly lineages.


Novel System for Real-Time Integration of 3-D Echocardiography and Fluoroscopy for Image-Guided Cardiac Interventions: Preclinical Validation and Clinical Feasibility Evaluation.
Real-time imaging is required to guide minimally invasive catheter-based cardiac interventions. While transesophageal echocardiography allows for high-quality visualization of cardiac anatomy, X-ray fluoroscopy provides excellent visualization of devices. We have developed a novel image fusion system that allows real-time integration of 3-D echocardiography and the X-ray fluoroscopy. The system was validated in the following two stages: 1) preclinical to determine function and validate accuracy; and 2) in the clinical setting to assess clinical workflow feasibility and determine overall system accuracy. In the preclinical phase, the system was assessed using both phantom and porcine experimental studies. Median 2-D projection errors of 4.5 and 3.3 mm were found for the phantom and porcine studies, respectively. The clinical phase focused on extending the use of the system to interventions in patients undergoing either atrial fibrillation catheter ablation (CA) or transcatheter aortic valve implantation (TAVI). Eleven patients were studied with nine in the CA group and two in the TAVI group. Successful real-time view synchronization was achieved in all cases with a calculated median distance error of 2.2 mm in the CA group and 3.4 mm in the TAVI group. A standard clinical workflow was established using the image fusion system. These pilot data confirm the technical feasibility of accurate real-time echo-fluoroscopic image overlay in clinical practice, which may be a useful adjunct for real-time guidance during interventional cardiac procedures.


Lactoferrin from Milk: Nutraceutical and Pharmacological Properties.
Lactoferrin is an iron-binding protein present in large quantities in colostrum and in breast milk, in external secretions and in polymorphonuclear leukocytes. Lactoferrin's main function is non-immune protection. Among several protective activities shown by lactoferrin, those displayed by orally administered lactoferrin are: (i) antimicrobial activity, which has been presumed due to iron deprivation, but more recently attributed also to a specific interaction with the bacterial cell wall and extended to viruses and parasites; (ii) immunomodulatory activity, with a direct effect on the development of the immune system in the newborn, together with a specific antinflammatory effects; (iii) a more recently discovered anticancer activity. It is worth noting that most of the protective activities of lactoferrin have been found, sometimes to a greater extent, also in peptides derived from limited proteolysis of lactoferrin that could be generated after lactoferrin ingestion. Lactoferrin could therefore be considered an ideal nutraceutic product because of its relatively cheap production from bovine milk and of its widely recognized tolerance after ingestion, along with its well demonstrated protective activities. The most important protective activities shown by orally administered bovine lactoferrin are reviewed in this article.


Transmission of 40-Gb/s QPSK upstream signal in RSOA-based coherent WDM PON using offset PDM technique.
We demonstrate the 40-Gb/s upstream transmission in the 60-km reach wavelength-division-multiplexed passive optical network (WDM PON) implemented by using directly modulated reflective semiconductor optical amplifiers (RSOAs) and self-homodyne receivers. It is difficult to operate the RSOA at 40 Gb/s due to its limited modulation bandwidth. To overcome this problem and generate 40-Gb/s upstream signal, we utilize the quadrature phase-shift-keying (QPSK) format and the offset polarization-division-multiplexing (PDM) technique. For this purpose, we install two RSOAs at each ONU and provide the seed light for these RSOAs by polarization-multiplexing the outputs of two lasers with a small frequency offset (20 GHz). This frequency offset is used to separate the polarization-multiplexed seed light by using a simple delay-line interferometer (DLI), instead of the polarization-beam splitter and polarization controller, at the ONU. The separated seed light is modulated by each RSOA at 20 Gb/s in the QPSK format, and then combined again by the DLI before sent back to the central office (CO). The results show that this WDM PON can support the transmission of 40-Gb/s channels spaced at 50 GHz over 60 km without using any remote optical amplifiers.


Pre-operative laboratory testing: A prospective study on comparison and cost analysis.
Pre-operative investigations are performed before any surgical intervention under anaesthesia. Many are considered as routine. However, there are no clear guidelines regarding these in India. We aim to look at the relevance of the laboratory investigations ordered routinely and their cost implications compared with the National Institute of Clinical Excellence (NICE) guidelines. This prospective study was carried out at a tertiary care hospital. A total of 163 patients scheduled for elective surgical procedures were included in this study. Neither the surgeons nor anaesthesiologists involved in the case were aware of the study. The laboratory investigations of the patients who underwent surgery were noted. All values were categorised as normal or abnormal and they were assessed as indicated or unindicated based on NICE guidelines. One hundred and sixty-three patients were subjected to a total of 984 tests. Forty three patients (26%) were subjected to tests as per NICE guidelines. Of the 984 tests, 515 tests were unindicated (52%). Out of the 515 unindicated tests, 7 (1.3%) were abnormal. None of these seven tests required any intervention or change of anaesthetic plan. The most common unindicated tests done were cardiac echocardiography and chest X-ray (92.5% and 93% respectively). The additional cost incurred towards unindicated tests was 63% of the total cost for the tests. Pre-operative laboratory investigations add to cost significantly. Patient premorbid conditions and surgical grade should guide the clinician to request for the relevant laboratory tests.


Compound- and context-dependent effects of antibiotics on greenhouse gas emissions from livestock.
The use of antibiotics in livestock production may trigger ecosystem disservices, including increased emissions of greenhouse gases. To evaluate this, we conducted two separate animal experiments, administering two widely used antibiotic compounds (benzylpenicillin and tetracycline) to dairy cows over a 4- or 5-day period locally and/or systemically. We then recorded enteric methane production, total gas production from dung decomposing under aerobic versus anaerobic conditions, prokaryotic community composition in rumen and dung, and accompanying changes in nutrient intake, rumen fermentation, and digestibility resulting from antibiotic administration. The focal antibiotics had no detectable effect on gas emissions from enteric fermentation or dung in aerobic conditions, while they decreased total gas production from anaerobic dung. Microbiome-level effects of benzylpenicillin proved markedly different from those previously recorded for tetracycline in dung, and did not differ by the mode of administration (local or systemic). Antibiotic effects on gas production differed substantially between dung maintained under aerobic versus anaerobic conditions and between compounds. These findings demonstrate compound- and context-dependent impacts of antibiotics on methane emissions and underlying processes, and highlight the need for a global synthesis of data on agricultural antibiotic use before understanding their climatic impacts.


Binding strength of sodium ions in cellulose for different water contents.
The interaction strength of sodium ions (Na(+)) with cellulose is investigated from first principles for varying degrees of water content. We find that the interaction of water molecules and Na(+) can be studied independently at the various OH groups in cellulose which we categorize as two different types. In the absence of water, Na(+) forms strong ionic bonds with the OH groups of cellulose. When water molecules are anchored to the OH groups via hydrogen bonds, Na(+) can eventually no longer bind to the OH groups, but will instead interact with the oxygen atoms of the water molecules. Due to the rather weak attachment of the latter to the OH groups, Na(+) becomes effectively more mobile in the fully hydrated cellulose framework. The present study thus represents a significant step toward a first-principles understanding of the experimentally observed dependence of ionic conductivity on the level of hydration in cellulose network.


A Phase II Study of Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory or Poor-Risk Acute Myeloid Leukemia Patients.
Exogenous arginine is required for growth in some argininosuccinate synthetase (ASS)-deficient cancers. Arginine deiminase (ADI) inhibits growth in various ASS-deficient cancers by depleting arginine. The efficacy of pegylated ADI (ADI-PEG20) in relapsed/refractory/poor-risk acute myeloid leukemia (AML) was evaluated in 43 patients in a prospective, phase II trial (NCT01910012 (10/07/2013), https://clinicaltrials.gov/ct2/show/NCT01910012?term = ADI-PEG20&rank = 12 ). Despite almost all pre-treatment tumor samples showing ASS deficiency, the best response among 21 evaluable patients was complete response (CR) in 2 (9.5%) and stable disease in 7 (33.3%), yielding a disease control rate (DCR) of 42.9%. The response durations of the two patients with CR were 7.5 and 8.8 months. DCR was correlated with a median of 8 weeks of arginine depletion to ≤10 μM. Using whole transcriptome sequencing, we compared gene expression profiling of pre- and post-treatment bone marrow samples of the two responders and three non-responders. The expression levels of some markers for AML subtypes and c-MYC regulated genes were considered potential predictors of response to ADI-PEG20. These results suggest that ASS deficiency is a prerequisite but not a sufficient condition for response to ADI-PEG20 monotherapy in AML. Predictive biomarkers and mechanistic explorations will be critical for identifying appropriate patients for future AML trials of ADI-PEG20.


A simple mechanistic model of sprout spacing in tumour-associated angiogenesis.
This paper develops a simple mathematical model of the sitting of capillary sprouts on an existing blood vessel during the initiation of tumour-induced angiogenesis. The model represents an inceptive attempt to address the question of how unchecked sprouting of the parent vessel is avoided at the initiation of angiogenesis, based on the idea that feedback regulation processes play the dominant role. No chemical interaction between the proangiogenic and antiangiogenic factors is assumed. The model is based on corneal pocket experiments, and provides a mathematical analysis of the initial spacing of angiogenic sprouts.


The role of nebivolol in the prevention of contrast-induced nephropathy in patients with renal dysfunction.
This prospective study was designed to evaluate the potential protective effect of nebivolol compared with metoprolol on the development of contrast-induced nephropathy (CIN) following coronary angiography in patients with renal dysfunction. Ninety patients with stable coronary angina pectoris with renal insufficiency (creatinine value ≥1.2 mg/dl) were included for this prospective study. Patients were divided into two groups. Patients in group 1 (n=55) received oral administration of nebivolol 5 mg/daily for coronary artery disease and/or hypertension. Group 2 consisted of 35 patients who received metoprolol 50 mg/daily for the same indications. All patients were hydrated with 0.9% NaCl at a rate of 1 mL/kg/hr for 12 hours before and 24 hours after the procedure. Patients were also given N-acetylcysteine (NAC) 600 mg twice a day, beginning 24 hours before and continuing 48 hours after the procedure. All patients underwent routine coronary angiography. Serum creatinine was assessed just before, immediately after and 48 hours after the procedure. CIN was defined as an increase in serum creatinine concentration of ≥25% within 48 hours after the procedure compared to the patient's baseline value. Tests for significance between groups were conducted using the independent sample t-test for continuous variables and Chi-square test for categorical variables. Baseline serum creatinine levels were statistically comparable in two groups. Following angiography, serum creatinine levels increased in both groups. Post-angiographic creatinine levels were not statistically different in the nebivolol and the metoprolol groups. Contrast induced nephropathy developed in 13 patients (24%) of the nebivolol group and in 12 patients (33%) of the metoprolol group. The incidence of CIN was statistically significantly lower in the nebivolol group comparing with the metoprolol group (p=0.03). The use of oral nebivolol for one week at a dose of 5 mg per day may decrease the incidence of contrast-induced nephropathy in patients who underwent coronary angiography with renal dysfunction. The small numbers of this study do not allow to draw final conclusion on the use of nebivolol in the prevention of CIN. Therefore, larger studies may be necessary to address the definite role of nebivolol in this setting.


Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.
Warfarin reduces the risk for ischemic stroke in patients with atrial fibrillation (AF) but increases the risk for hemorrhage. Dabigatran is a fixed-dose, oral direct thrombin inhibitor with similar or reduced rates of ischemic stroke and intracranial hemorrhage in patients with AF compared with those of warfarin. To estimate the quality-adjusted survival, costs, and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular AF. Markov decision model. The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial and other published studies of anticoagulation. The cost of dabigatran was estimated on the basis of pricing in the United Kingdom. Patients aged 65 years or older with nonvalvular AF and risk factors for stroke (CHADS₂ score ≥1 or equivalent) and no contraindications to anticoagulation. Lifetime. Societal. Warfarin anticoagulation (target international normalized ratio, 2.0 to 3.0); dabigatran, 110 mg twice daily (low dose); and dabigatran, 150 mg twice daily (high dose). Quality-adjusted life-years (QALYs), costs (in 2008 U.S. dollars), and incremental cost-effectiveness ratios. The quality-adjusted life expectancy was 10.28 QALYs with warfarin, 10.70 QALYs with low-dose dabigatran, and 10.84 QALYs with high-dose dabigatran. Total costs were $143 193 for warfarin, $164 576 for low-dose dabigatran, and $168 398 for high-dose dabigatran. The incremental cost-effectiveness ratios compared with warfarin were $51 229 per QALY for low-dose dabigatran and $45 372 per QALY for high-dose dabigatran. The model was sensitive to the cost of dabigatran but was relatively insensitive to other model inputs. The incremental cost-effectiveness ratio increased to $50 000 per QALY at a cost of $13.70 per day for high-dose dabigatran but remained less than $85 000 per QALY over the full range of model inputs evaluated. The cost-effectiveness of high-dose dabigatran improved with increasing risk for stroke and intracranial hemorrhage. Event rates were largely derived from a single randomized clinical trial and extrapolated to a 35-year time frame from clinical trials with approximately 2-year follow-up. In patients aged 65 years or older with nonvalvular AF at increased risk for stroke (CHADS₂ score ≥1 or equivalent), dabigatran may be a cost-effective alternative to warfarin depending on pricing in the United States. American Heart Association and Veterans Affairs Health Services Research & Development Service.


Cardiac sarcoidosis-state of the art review.
Sarcoidosis is a multi-system inflammatory disorder of unknown etiology resulting in formation of non-caseating granulomas. Cardiac involvement-which is associated with worse prognosis-has been detected in approximately 25% of individuals based on autopsy or cardiac imaging studies. Nevertheless, the diagnosis of cardiac sarcoidosis is challenging due to the low yield of endomyocardial biopsy, and the limited accuracy of various clinical criteria. Thus, no gold standard diagnostic criterion exists. This review will summarize the pathophysiology, diagnosis, and treatment of cardiac sarcoidosis with a focus on advanced cardiovascular imaging, We review the evidence to support a role for cardiac magnetic resonance (CMR) imaging in the initial evaluation of selected patients with suspected cardiac sarcoidosis, with cardiac positron emission tomography (PET) as an alternative or complementary initial diagnostic test in a subgroup of patients in whom CMR may be contra-indicated or when CMR is negative with continued clinical concern for myocardial inflammation. In addition to the diagnostic value of these tests, CMR and PET are also useful in identifying patients who have higher risk of adverse events such as ventricular tachycardia or death, in whom preventive therapies such as defibrillators should be more strongly considered. Although no randomized controlled trials for treatment of cardiac sarcoidosis exist, immunosuppressive therapy is often used. We review emerging evidence regarding the use of cardiac PET to identify and quantity the amount of myocardial inflammation as well as to guide the use of immunotherapy. Future studies are needed to determine the benefit of imaging guided therapies aimed at improving patient outcomes.


Effect of low doses of estradiol and tamoxifen on breast cancer cell karyotypes.
Evidence supports a role of 17&-estradiol (E2) in carcinogenesis and the large majority of breast carcinomas are dependent on estrogen. The anti-estrogen tamoxifen (TAM) is widely used for both treatment and prevention of breast cancer; however, it is also carcinogenic in human uterus and rat liver, highlighting the profound complexity of its actions. The nature of E2- or TAM-induced chromosomal damage has been explored using relatively high concentrations of these agents, and only some numerical aberrations and chromosomal breaks have been analyzed. This study aimed to determine the effects of low doses of E2 and TAM (10(&8 )mol L(&1) and 10(&6 )mol L(&1) respectively) on karyotypes of MCF7, T47D, BT474, and SKBR3 breast cancer cells by comparing the results of conventional karyotyping and multi-FISH painting with cell proliferation. Estrogen receptor (ER)-positive (+) cells showed an increase in cell proliferation after E2 treatment (MCF7, T47D, and BT474) and a decrease after TAM treatment (MCF7 and T47D), whereas in ER& cells (SKBR3), no alterations in cell proliferation were observed, except for a small increase at 96 h. Karyotypes of both ER+ and ER& breast cancer cells increased in complexity after treatments with E2 and TAM leading to specific chromosomal abnormalities, some of which were consistent throughout the treatment duration. This genotoxic effect was higher in HER2+ cells. The ER&/HER2+ SKBR3 cells were found to be sensitive to TAM, exhibiting an increase in chromosomal aberrations. These in vitro results provide insights into the potential role of low doses of E2 and TAM in inducing chromosomal rearrangements in breast cancer cells.


Aligned nanofibrillar collagen scaffolds - Guiding lymphangiogenesis for treatment of acquired lymphedema.
Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.


Time-estimation error following Weber-Fechner law may explain subadditive time-discounting.
Impulsivity in drug addicts have been associated with impatience in intertemporal choice, i.e., high degrees to which delayed rewards are discounted, indicating the importance of reducing the degree of discounting in drug addicts. Intertemporal choice (delay discounting) has been attracting attention in neuropsychopharmacology and behavioral neuroeconomics. Recently, behavioral economists have reported that impatience/impulsivity in intertemporal choice is increased if a delay period is presented as a sum of divided time-blocks, which is referred to as subadditive discounting (i.e., "total patience" over the delay period is larger than the "sum of patience" over divided delay periods). This finding implies that abstinent drug addicts may more readily relapse into addiction if an abstinence period is presented as a series of shorter abstinent periods, rather than a single block of a long abstinence period. Therefore, understanding of neuropsychological processing underlying subadditive discounting is important for establishing medical treatments of drug addiction, although to date, no study has addressed this question. In this study, we propose that time-estimation following Weber-Fechner law, formerly introduced for explaining hyperbolic discounting, may also explain subadditive discounting. Our present hypothesis also predicts that possibility of relapse into drug dependence can be decreased by helping abstinent patients to perceive time-duration of an abstinence/withdrawal period precisely.


Variola virus immune evasion design: expression of a highly efficient inhibitor of human complement.
Variola virus, the most virulent member of the genus Orthopoxvirus, specifically infects humans and has no other animal reservoir. Variola causes the contagious disease smallpox, which has a 30-40% mortality rate. Conversely, the prototype orthopoxvirus, vaccinia, causes no disease in immunocompetent humans and was used in the global eradication of smallpox, which ended in 1977. However, the threat of smallpox persists because clandestine stockpiles of variola still exist. Although variola and vaccinia share remarkable DNA homology, the strict human tropism of variola suggests that its proteins are better suited than those of vaccinia to overcome the human immune response. Here, we demonstrate the functional advantage of a variola complement regulatory protein over that of its vaccinia homologue. Because authentic variola proteins are not available for study, we molecularly engineered and characterized the smallpox inhibitor of complement enzymes (SPICE), a homologue of a vaccinia virulence factor, vaccinia virus complement control protein (VCP). SPICE is nearly 100-fold more potent than VCP at inactivating human C3b and 6-fold more potent at inactivating C4b. SPICE is also more human complement-specific than is VCP. By inactivating complement components, SPICE serves to inhibit the formation of the C3/C5 convertases necessary for complement-mediated viral clearance. SPICE provides the first evidence that variola proteins are particularly adept at overcoming human immunity, and the decreased function of VCP suggests one reason why the vaccinia virus vaccine was associated with relatively low mortality. Disabling SPICE may be therapeutically useful if smallpox reemerges.