Constraints on the diameter and albedo of 2060 chiron.
Asteroid 2060 Chiron is the largest known object exhibiting cometary activity. Radiometric observations made in 1983 from a ground-based telescope and the Infrared Astronomical Satellite are used to examine the limits on Chiron's diameter and albedo. It is argued that Chiron's surface temperature distribution at that time is best described by an "isothermal latitude" or "rapid-rotator" model. Consequently, Chiron has a maximum diameter of 372 kilometers and a minimum geometric albedo of 2.7%. This is much bigger and darker than previous estimates, and suggests that gravity may play a significant role in the evolution of gas and dust emissions. It is also found that for large obliquities, surface temperatures can vary dramatically on time scales of a decade, and that such geometry may play a critical role in explaining Chiron's observed photometric behavior since its discovery in 1977.


Implant-retained maxillary overdentures on milled bar suprastructures: a 10-year follow-up of surgical and prosthetic care and aftercare.
The aim of this study was to evaluate surgical and prosthetic care and aftercare of maxillary overdentures supported by six endosseous implants and a milled bar mesostructure with Ceka attachments. Thirty-nine consecutive patients with an edentulous maxilla who reported problems wearing a conventional maxillary denture were treated with an overdenture supported by six endosseous implants and a milled bar mesostructure (solid bar with position Ceka attachments). Prosthetic and surgical care and aftercare were scored from the first visit until 10 years after the augmentation of the maxilla. Patient satisfaction was assessed at the end of follow-up. On the basis of problems patients experienced with wearing their conventional dentures, three groups of patients were distinguished: patients with lack of retention of their conventional maxillary denture related to anatomic problems (n = 24), patients with gagging problems (n = 9), and patients not tolerating a conventional maxillary denture due to subjective problems not related to an anatomic substratum (n = 6). The need for care and aftercare was comparable between the three groups. The overall 10-year implant survival rate was 86.1%. Loss of implants occurred mostly during the first year after placement. Surgical aftercare predominately consisted of care related to the removal and replacement of implants (ie, reaugmentation, replacement of implants, and abutment connection). Prosthetic aftercare consisted mainly of routine inspections, oral hygiene care, and activation or replacement of Ceka attachments. Finally, all patients functioned well with their overdentures and remained satisfied throughout the study. Irrespective of the mentioned underlying reasons for not functioning with a conventional maxillary denture, an implant-retained maxillary overdenture, opposed by either an implant-retained mandibular overdenture or natural dentition, was shown to be an effective, predictable, and reliable treatment option that did not need much aftercare other than adjustments of the Ceka attachments.


MiR-101 downregulation is involved in cyclooxygenase-2 overexpression in human colon cancer cells.
Overexpressed cyclooxygenase-2 (COX-2) strongly contributes to the growth and invasiveness of tumoral cells in patients affected by colorectal cancer (CRC). It has been demonstrated that COX-2 overexpression depends on different cellular pathways involving both transcriptional and post-transcriptional regulations. We assumed that COX-2 expression could be regulated also by microRNAs (miRNAs) since these short RNA molecules participate to the fine regulation of several genes implicated in cell growth and differentiation. In this paper, we report the inverse correlation between COX-2 and miR-101 expression in colon cancer cell lines and we demonstrated in vitro the direct inhibition of COX-2 mRNA translation mediated by miR-101. Moreover, this correlation was supported by data collected ex vivo, in which colon cancer tissues and liver metastases derived from CRC patients were analyzed. These findings provide a novel molecular insight in the modulation of COX-2 at post-transcriptional level by miR-101 and strengthen the observation that miRNAs are highly implicated in the control of gene expression. An impairment of miR-101 levels could represent one of the leading causes of COX-2 overexpression in colon cancer cells.


Cisplatin-induced posterior reversible encephalopathy syndrome and successful re-treatment in a patient with non-seminomatous germ cell tumor: a case report.
Cisplatin is a platinum compound that has revolutionized the treatment of various solid organ tumors. Cisplatin is associated with a variety of side effects and has recently been indicted in the development of posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome is a potentially reversible condition, with the mainstay of therapy being correction of the underlying cause and withdrawal of the offending drug. However, there are no clear guidelines regarding the possibility of subsequent re-treatment with the causative agent. A 23-year-old Asian man presented to our Emergency Department with a four-month history of concomitant abdominal pain and backache and a two-week history of left-sided leg swelling. Diagnostic investigations revealed bilateral pulmonary embolism, extensive deep venous thrombosis and widespread lung and liver metastatic deposits with abdomino-pelvic lymphadenopathy. His biopsy and tumor markers were consistent with non-seminomatous germ cell tumor and he was subsequently started on an initial cycle of cisplatin and etoposide chemotherapy. On the second day of treatment he developed posterior reversible encephalopathy syndrome clinically and radiologically. Cisplatin was stopped for the next two days while etoposide was continued, resulting in complete resolution of his symptoms. He was re-challenged with cisplatin on day five of chemotherapy because a platin-based chemotherapy regimen was his only hope of potential cure. He tolerated it well, with no recurrence of his neurological symptoms and the remainder of his in-patient stay remained uneventful. He was discharged on day eight. He has since then completed treatment and is currently in remission. The occurrence of posterior reversible encephalopathy syndrome after cisplatin use has been well reported in the literature. We strongly believe that our patient also developed posterior reversible encephalopathy syndrome secondary to cisplatin. The uniqueness of our patient's case lies in the successful re-treatment of our patient with the offending drug. To the best of our knowledge, this is the first instance where a patient was successfully re-treated with cisplatin after having developed posterior reversible encephalopathy syndrome as a result of cisplatin use. The excellent response to re-treatment without recurrence of neurological symptoms in our patient's case provides insight into re-treatment as an option in scenarios where treatment options are limited.


PROMISE: a tool to identify genomic features with a specific biologically interesting pattern of associations with multiple endpoint variables.
In some applications, prior biological knowledge can be used to define a specific pattern of association of multiple endpoint variables with a genomic variable that is biologically most interesting. However, to our knowledge, there is no statistical procedure designed to detect specific patterns of association with multiple endpoint variables. Projection onto the most interesting statistical evidence (PROMISE) is proposed as a general procedure to identify genomic variables that exhibit a specific biologically interesting pattern of association with multiple endpoint variables. Biological knowledge of the endpoint variables is used to define a vector that represents the biologically most interesting values for statistics that characterize the associations of the endpoint variables with a genomic variable. A test statistic is defined as the dot-product of the vector of the observed association statistics and the vector of the most interesting values of the association statistics. By definition, this test statistic is proportional to the length of the projection of the observed vector of correlations onto the vector of most interesting associations. Statistical significance is determined via permutation. In simulation studies and an example application, PROMISE shows greater statistical power to identify genes with the interesting pattern of associations than classical multivariate procedures, individual endpoint analyses or listing genes that have the pattern of interest and are significant in more than one individual endpoint analysis. Documented R routines are freely available from www.stjuderesearch.org/depts/biostats and will soon be available as a Bioconductor package from www.bioconductor.org.


Keratin: dissolution, extraction and biomedical application.
Keratinous materials such as wool, feathers and hooves are tough unique biological co-products that usually have high sulfur and protein contents. A high cystine content (7-13%) differentiates keratins from other structural proteins, such as collagen and elastin. Dissolution and extraction of keratin is a difficult process compared to other natural polymers, such as chitosan, starch, collagen, and a large-scale use of keratin depends on employing a relatively fast, cost-effective and time efficient extraction method. Keratin has some inherent ability to facilitate cell adhesion, proliferation, and regeneration of the tissue, therefore keratin biomaterials can provide a biocompatible matrix for regrowth and regeneration of the defective tissue. Additionally, due to its amino acid constituents, keratin can be tailored and finely tuned to meet the exact requirement of degradation, drug release or incorporation of different hydrophobic or hydrophilic tails. This review discusses the various methods available for the dissolution and extraction of keratin with emphasis on their advantages and limitations. The impacts of various methods and chemicals used on the structure and the properties of keratin are discussed with the aim of highlighting options available toward commercial keratin production. This review also reports the properties of various keratin-based biomaterials and critically examines how these materials are influenced by the keratin extraction procedure, discussing the features that make them effective as biomedical applications, as well as some of the mechanisms of action and physiological roles of keratin. Particular attention is given to the practical application of keratin biomaterials, namely addressing the advantages and limitations on the use of keratin films, 3D composite scaffolds and keratin hydrogels for tissue engineering, wound healing, hemostatic and controlled drug release.


Direct interaction of filamin (ABP-280) with the beta 2-integrin subunit CD18.
beta 2-Integrins mediate leukocyte extravasation into inflamed tissues, phagocytosis, and target cell killing, functions that require an intact actin cytoskeleton. Previous studies have focused on elucidating interactions of the cytoplasmic tails of integrins with the cytoskeleton at focal contacts in stationary cells. As integrins are also located at other types of cell-substratum junctions, such as the leading edge of migrating cells, additional cytosolic proteins abundant at these sites may also interact with integrins. In this study, we have identified the actin-binding protein, filamin (ABP-280), as a major cytoskeletal protein that binds to the cytoplasmic tail of the beta 2-integrin subunit CD18. Filamin bound to cytoplasmic CD18 directly and specifically, co-immunoprecipitated with beta 2-integrins in detergent cell lysate and co-immunolocalized with cross-linked beta 2-integrins in intact cells. The filamin binding site in CD18 was localized to the N-terminal (amino acids (aa) 724 to 747) but not to the C-terminal (aa 743 to 769) half of cytoplasmic CD18. Filamin did not bind to the major alpha-actinin binding site (aa 733 to 742), however, suggesting that these two cytoskeletal proteins bind to distinct but overlapping sites. Given the conservation of the filamin binding region among beta-integrin subunits, these findings suggest the presence of similar associations between filamin and other integrins. These associations may be important in the spreading and extension of lamellipodia at the leading edge during cell movement and, if interrupted, may contribute to the dramatic decrease in cell locomotion observed in genetic deletions involving filamin or integrins.


Weight-bearing MRI of the knee: a review of advantages and limits.
Standard knee imaging with MRI is usually performed with patient in recumbent position under non-weight-bearing conditions. Recently, magnetic resonance imaging systems to scan the knee joint under weight bearing conditions has been proposed as an approach to improve the clinical utility of musculoskeletal MRI. Imaging under loading can be useful to understand the natural motion behavior of the knee joint and to identify conditions that are challenging to diagnose by using standard position. We reviewed the literature on weight-bearing MR imaging of the knee to describe the current state of use of such MRI technologies, evaluating the advantages and the potential limitations of these technologies.


Bidirectional cavopulmonary shunt for cyanotic heart disease: surgical experience from a developing country.
The importance of bidirectional cavopulmonary anastomosis for palliation of complex cyanotic congenital heart disease is widely recognized. This study was conducted to highlight our surgical experience with this procedure in a developing country. A retrospective study was conducted using medical records at the Aga Khan University Hospital, Karachi, Pakistan. Clinical findings at presentation, anatomical defects seen on transthoracic echocardiography, pre-operative McGoon index, cardiopulmonary bypass time, use of cardioplegia, post-procedure oxygen saturations and complications were evaluated. A total of 8 patients underwent bidirectional cavopulmonary anastomosis. There were 6 males (75%) and 2 females (25%). Ages and weights at operation averaged 5.7 +/- 3.7 years (range 2-14 years) and 18.6 +/- 10.4 kg (range 8.5-35.5 kg) respectively. The most common symptoms were the presence of cyanosis in all (100%) patients followed by recurrent respiratory tract infections in 3 (37.5%) patients. Transthoracic echocardiography revealed 6 (75%) patients with atrial septal defects, 5 (62.5%) with tricuspid atresia, 3 (37.5%) with ventricular septal defects, 3 (37.5%) with malposition of great vessels, 2 (25%) with pulmonary stenosis and 2 (25%) with double inlet left ventricles. The mean pre-procedure McGoon index was 2.1 +/- 0.5 (range 1.37-2.80). All patients received cardioplegia. Cardiopulmonary bypass was used in all patients for a mean time of 154.1 +/- 83.6 minutes (range 60-298 minutes). All patients were ventilated for a mean period of 1.5 +/- 0.7 days (range 1-3 days). The ICU stay was 3.0 +/- 0.6 days (range 2-5 days) with a total hospital stay of 9.8 +/- 3.8 days (range 7-18 days). The mean post-procedure oxygen saturation was 82.6 +/- 3.5% (range 76-86%). The most common post-operative complication was supraventricular arrhythmia in 2 (25.0%) patients. There were no intra-operative or early (within 7 days of procedure) deaths. One patient developed pulmonary artery hypertension and died 23 months later due to cardiac arrest. Patients tolerated the procedure well. After a mean follow-up of 10 months, 6 patients were assessed to be in New York Heart Association (NYHA) functional class I and one patient in NYHA class II. Clinical and post-procedural data gathered from our experience confirms the safety of bidirectional cavopulmonary anastomosis.


Successful thoracoscopic repair of esophageal atresia with tracheoesophageal fistula in a newborn with single ventricle physiology.
A neonate with VACTERL association including tricuspid atresia was scheduled for thoracoscopic esophageal atresia with tracheoesophageal fistula (EA/TEF) repair and laparoscopic gastrostomy tube placement. In addition to standard noninvasive monitoring, arterial blood pressure, central venous pressure, and cerebral oxygen saturation were monitored. Gastric distension resulting from positive pressure ventilation prevented laparoscopic gastrostomy tube placement. Thoracoscopy with a CO2 insufflation pressure of 6 mm Hg at low flow (1 L/min) was well tolerated hemodynamically despite hypercarbia and cerebral oxygen saturation was maintained. Careful monitoring and good communication were critical to the safe management of this single ventricle patient during thoracoscopic EA/TEF repair. Esophageal and tracheoesophageal fistula in conjunction with single ventricle physiology carries a significant risk of mortality. We present the anesthetic management of a neonate with unpalliated tricuspid atresia who underwent thoracoscopic tracheoesophageal fistula repair.


They need to be recognized as a person in everyday life: Teachers' and helpers' experiences of teacher-student relationships in upper secondary school.
The aim of this study was to explore how teachers and helpers experience that teacher-student relationship (TSR) is developed and promoted in upper secondary school.We also explored their experiences of qualities of TSR with students with mental health problems or at risk of dropping out. The study used a qualitative and participative approach; key stakeholders were included as co-researchers. Focus group interviews were held with 27 teachers and helpers. A thematic analysis was conducted. The participants' descriptions of important experiential dimensions of TSR were clustered around four themes: (1) to be recognized as a person with strengths and challenges in everyday life, (2) collaborative relationships between students and teachers, (3) flexible boundaries in the relationship between teachers and students and (4) organization of classes and procedures set the stage for TSR. Collaborative, emotional and contextual qualities were found important to the development of TSR in upper secondary school. Experiences of negative qualities of TSR can contribute to push students out of school. Teachers and helpers experience that TSR may have the potential to play a role in promoting mental health in students' everyday life.


Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer.
Sulindac, a non-steroidal anti-inflammatory prodrug, is metabolized into pharmacologically active sulfide and sulfone derivatives. Sulindac sulfide, but not sulindac sulfone, inhibits cyclooxygenase (COX) enzyme activities, yet both derivatives have growth inhibitory effects on colon cancer cells. Microarray analysis was used to detect COX-independent effects of sulindac on gene expression in human colorectal cells. Spermidine/sperm-ine N1-acetyltransferase (SSAT) gene, which encodes a polyamine catabolic enzyme, was induced by clinically relevant sulindac sulfone concentrations. Northern blots confirmed increased SSAT RNA levels in these colon cancer cells. Deletion analysis and mutational studies were done to map the sulindac sulfone-dependent response sequences in the SSAT 5'-flanking sequences. This led us to the identification of two peroxisome proliferator-activated receptor (PPAR) response elements (PPREs) in the SSAT gene. PPRE-2, at +48 bases relative to the transcription start site, is required for the induction of SSAT by sulindac sulfone and is specifically bound by PPAR gamma in the Caco-2 cells as shown by transfection and gel shift experiments. PPRE-1, at-323 bases relative to the start site, is not required for the induction of SSAT by sulindac sulfone but can be bound by both PPAR delta and PPAR gamma. Sulindac sulfone reduced cellular polyamine contents in the absence but not in the presence of verapamil, an inhibitor of the export of monoacetyl diamines, inhibited cell proliferation and induced apoptosis. The induced apoptosis could be partially rescued by exogenous putrescine. These data suggest that apoptosis induced by sulindac sulfone is mediated, in part, by the COX-independent, PPAR-dependent transcriptional activation of SSAT, leading to reduced tissue polyamine contents in human colon cancer cells.


Water contamination reduces the tolerance of coral larvae to thermal stress.
Coral reefs are highly susceptible to climate change, with elevated sea surface temperatures (SST) posing one of the main threats to coral survival. Successful recruitment of new colonies is important for the recovery of degraded reefs following mortality events. Coral larvae require relatively uncontaminated substratum on which to metamorphose into sessile polyps, and the increasing pollution of coastal waters therefore constitutes an additional threat to reef resilience. Here we develop and analyse a model of larval metamorphosis success for two common coral species to quantify the interactive effects of water pollution (copper contamination) and SST. We identify thresholds of temperature and pollution that prevent larval metamorphosis, and evaluate synergistic interactions between these stressors. Our analyses show that halving the concentration of Cu can protect corals from the negative effects of a 2-3°C increase in SST. These results demonstrate that effective mitigation of local impacts can reduce negative effects of global stressors.


Fractalkine activates NRF2/NFE2L2 and heme oxygenase 1 to restrain tauopathy-induced microgliosis.
The chemokine fractalkine modulates microglial responses in neurodegenerative diseases, including tauopathies, but the mechanistic processes and their relevance in human brain pathologies is not yet known. Here, we show that hippocampal HT22 cells expressing human TAU(P301L) mutant protein produce fractalkine, which in microglia activates AKT, inhibits glycogen synthase kinase-3β and upregulates the transcription factor NRF2/NFE2L2 and its target genes including heme oxygenase 1. In a mouse model of tauopathy based on stereotaxic delivery in hippocampus of an adeno-associated viral vector for expression of TAU(P301L), we confirmed that tau-injured neurons express fractalkine. NRF2- and fractalkine receptor-knockout mice did not express heme oxygenase 1 in microglia and exhibited increased microgliosis and astrogliosis in response to neuronal TAU(P301L) expression, demonstrating a crucial role of the fractalkine/NRF2/heme oxygenase 1 pathway in attenuation of the pro-inflammatory phenotype. The hippocampus of patients with Alzheimer's disease also exhibits increased expression of fractalkine in TAU-injured neurons that recruit microglia. These events correlated with increased levels of NRF2 and heme oxygenase 1 proteins, suggesting an attempt of the diseased brain to limit microgliosis. Our combined results indicate that fractalkine mobilizes NRF2 to limit over-activation of microglia and identify this new target to control unremitting neuroinflammation in tauopathies.


Reliable Dual Tensor Model Estimation in Single and Crossing Fibers Based on Jeffreys Prior.
This paper presents and studies a framework for reliable modeling of diffusion MRI using a data-acquisition adaptive prior. Automated relevance determination estimates the mean of the posterior distribution of a rank-2 dual tensor model exploiting Jeffreys prior (JARD). This data-acquisition prior is based on the Fisher information matrix and enables the assessment whether two tensors are mandatory to describe the data. The method is compared to Maximum Likelihood Estimation (MLE) of the dual tensor model and to FSL's ball-and-stick approach. Monte Carlo experiments demonstrated that JARD's volume fractions correlated well with the ground truth for single and crossing fiber configurations. In single fiber configurations JARD automatically reduced the volume fraction of one compartment to (almost) zero. The variance in fractional anisotropy (FA) of the main tensor component was thereby reduced compared to MLE. JARD and MLE gave a comparable outcome in data simulating crossing fibers. On brain data, JARD yielded a smaller spread in FA along the corpus callosum compared to MLE. Tract-based spatial statistics demonstrated a higher sensitivity in detecting age-related white matter atrophy using JARD compared to both MLE and the ball-and-stick approach. The proposed framework offers accurate and precise estimation of diffusion properties in single and dual fiber regions.


Subjective Evaluation of Balance by the Dizziness Handicap Inventory Does Not Predict Fall Risk in Older Adults Visiting Otolaryngology Clinics.
Subjective symptoms of dizziness in older adults are affected not only by objective data such as postural balance, but also by complex psychological factors. Published data analyzing how simultaneous evaluations of both objective and subjective assessments of balance can predict fall risk remain lacking. This study examined how fall risk can be predicted based on both objective data for balance and hearing and subjective symptoms of dizziness among older adults visiting otolaryngology clinics. Medical charts of 76 patients ≥65 years old with dizziness/vertigo who visited the otolaryngology clinic were reviewed. Objective data were evaluated by postural balance (posturographic data with eyes open and closed, and one-leg standing test), spontaneous nystagmus, and mean hearing levels. Subjective handicap associated with dizziness/vertigo was assessed using the Dizziness Handicap Inventory (DHI). Subjective mental status of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Information on history (cardiovascular diseases) and fall accidents within the preceding year was collected using an in-house interview sheet. Objective data on postural balance did not correlate with subjective symptoms on DHI or HADS (P > .05, Pearson's correlation coefficient). Adjusted logistic regression modeling with the outcome of incident falls revealed that poor postural balance significantly predicted fall risk (P < .05; 4.9 [1.4-16.8] per 10-cm2 increment). Nystagmus tended to be associated with fall risk. In contrast, DHI score did not predict fall risk (P = .43; 1.0 [0.9-1.03]). Receiver operating characteristic analysis proposed a cut-off for postural sway with eyes closed >6.1 cm2 as optimal to predict falls in patients with nystagmus (AUC, 0.74; 95% confidence interval, 0.48-0.997). Poor postural balance is associated with increased fall risk after adjusting for subjective symptoms in older adults at otolaryngology clinics. Conversely, the self-perceived dizziness handicap of DHI score is an insufficient tool to evaluate their fall risk.


Airway Obstruction during Sleep due to Diaphragm Pacing Precludes Decannulation in Young Children with CCHS.
Children with congenital central hypoventilation syndrome (CCHS) have a PHOX2B mutation-induced control of breathing deficit necessitating artificial ventilation as life support. A subset of CCHS families seek phrenic nerve-diaphragm pacing (DP) during sleep with the goal of tracheal decannulation. Published data regarding DP during sleep as life support in the decannulated child with CCHS and related airway dynamics in young children are limited. We report a series of 3 children, ages 3.3-4.3 years, who underwent decannulation. Sleep endoscopy performed during DP revealed varied (oropharynx, supraglottic, glottic, etc.) levels of complete airway obstruction despite modification of pacer settings. Real-time analysis of end tidal CO2 and SpO2 confirmed inadequate gas exchange. Because the families declined re-tracheostomy, all 3 patients rely on noninvasive mask ventilation as a means of life support while asleep. These results emphasize the need for extreme caution in proceeding with tracheal decannulation in young children with CCHS who expect to use DP during sleep as life support. Parents and patients should anticipate that they will depend on noninvasive mask ventilation (rather than DP) during sleep after undergoing decannulation. This information may improve management and guide expectations regarding potential decannulation in young paced children with CCHS.


Aerobic capacity mediates susceptibility for the transition from steatosis to steatohepatitis.
Low intrinsic aerobic capacity is associated with increased all-cause and liver-related mortality in humans. Low intrinsic aerobic capacity in the low capacity runner (LCR) rat increases susceptibility to acute and chronic high-fat/high-sucrose diet-induced steatosis, without observed increases in liver inflammation. Addition of excess cholesterol to a high-fat/high-sucrose diet produced greater steatosis in LCR and high capacity runner (HCR) rats. However, the LCR rat demonstrated greater susceptibility to increased liver inflammatory and apoptotic markers compared to the HCR rat. The progressive non-alcoholic fatty liver disease observed in the LCR rats following western diet feeding was associated with further declines in liver fatty acid oxidation and mitochondrial respiratory capacity compared to HCR rats. Low aerobic capacity increases risk for non-alcoholic fatty liver disease and liver-related disease mortality, but mechanisms mediating these effects remain unknown. We recently reported that rats bred for low aerobic capacity (low capacity runner; LCR) displayed susceptibility to high fat diet-induced steatosis in association with reduced hepatic mitochondrial fatty acid oxidation (FAO) and respiratory capacity compared to high aerobic capacity (high capacity runner; HCR) rats. Here we tested the impact of aerobic capacity on susceptibility for progressive liver disease following a 16-week 'western diet' (WD) high in fat (45% kcal), cholesterol (1% w/w) and sucrose (15% kcal). Unlike previously with a diet high in fat and sucrose alone, the inclusion of cholesterol in the WD induced hepatomegaly and steatosis in both HCR and LCR rats, while producing greater cholesterol ester accumulation in LCR compared to HCR rats. Importantly, WD-fed low-fitness LCR rats displayed greater inflammatory cell infiltration, serum alanine transaminase, expression of hepatic inflammatory markers (F4/80, MCP-1, TLR4, TLR2 and IL-1β) and effector caspase (caspase 3 and 7) activation compared to HCR rats. Further, LCR rats had greater WD-induced decreases in complete FAO and mitochondrial respiratory capacity. Intrinsic aerobic capacity had no impact on WD-induced hepatic steatosis; however, rats bred for low aerobic capacity developed greater hepatic inflammation, which was associated with reduced hepatic mitochondrial FAO and respiratory capacity and increased accumulation of cholesterol esters. These results confirm epidemiological reports that aerobic capacity impacts progression of liver disease and suggest that these effects are mediated through alterations in hepatic mitochondrial function.


Clinical assessment of three-dimensional ultrasound prostate localization for external beam radiotherapy.
Three-dimensional ultrasound localization has been performed for external beam prostate treatments at our institution since September 2001. This article presents data from the daily shifts for 221 patients and 5005 fractions, and the results of tests performed to assess the system's performance under clinical conditions. Three tests are presented: (1) To measure the accuracy of the shifts, eight patients treated on a helical tomotherapy machine were localized daily using both ultrasound (US) and a megavoltage computed tomography (MVCT) scan. Comparison of the shifts showed that US localization improved alignment for six of the eight patients when compared to alignment using skin marks alone. The mean US-MVCT vector for these six patients was 3.1+/-1.3 mm, compared to 5.1+/-2.1 mm between the MVCT and the skin marks. The other two patients were identified as poor candidates for US prior to their first treatment fraction. (2) To assess the extent of intrafraction motion, US localization was repeated after treatment for six patients and a total of 29 fractions. The mean intrafraction prostate shift was 1.9+/-1.0 mm, and the shift was within the 3 mm localization uncertainty [Tomé et al., Med. Phys. 29, 1781-1788 (2002); in New Technologies in Radiation Oncology, edited by W. Schlegel, T. Bortfelde, and A. Grosu (Springer, Berlin, 2005)] of the system for 25 of 29 fractions. (3) To assess the interuser variation in shifts, four experienced operators independently localized five patients for five consecutive fractions. The standard deviation of the users' shifts was found to be approximately the same as the system's localization uncertainty. For shifts larger than the system localization uncertainty, the standard deviation of the users' shifts was nearly always much smaller than the mean shift. Taken together with the results of the US-MVCT comparison, this indicates that the shifts improved patient localization despite differences between users.


Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments.
Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J. Am. Chem. Soc., 2013, 135(8), 2907]. Recently, much attention has been drawn to the competing intermolecular interactions that drive the self-assembly of peptide-based amphiphiles into supramolecular filaments. Recently, we reported on long-time atomistic molecular dynamics simulations to characterize the structure and growth of chiral filaments by the self-assembly of a DA containing the aromatic anti-cancer drug camptothecin [Kang et al., Macromolecules, 2016, 49(3), 994]. We found that the π-π stacking of the aromatic drug governs the early stages of the self-assembly process, while also contributing towards the chirality of the self-assembled filament. Based on these all-atomistic simulations, we now build a chemically accurate coarse-grained model that can capture the structure and stability of these supramolecular filaments at long time-scales (microseconds). These coarse-grained models successfully recapitulate the growth of the molecular clusters (and their elongation trends) compared with previously reported atomistic simulations. Furthermore, the interfacial structure and the helicity of the filaments are conserved. Next, we focus on characterization of the disassembly process of a 0.675 μm DA filament at microsecond time-scales. These results provide very useful tools for the rational design of functional supramolecular filaments, in particular supramolecular filaments for drug delivery applications.


Transcriptome sequencing of Festulolium accessions under salt stress.
The objective of this study was to establish transcriptome assemblies of Festulolium hybrids under salt stress, and identify genes regulated across the hybrids in response to salt stress. The development of transcriptome assemblies for Festulolium hybrids and cataloguing of genes regulated under salt stress will facilitate further downstream studies. Plants were grown at three salt concentrations (0.5%, 1% and 1.5%) and phenotypic and transcriptomic data was collected. Salt stress was confirmed by progressive loss of green leaves as salt concentration increased from 0 to 1.5%. We generated de-novo transcriptome assemblies for two Festulolium pabulare festucoid genotypes, for a single Festulolium braunii genotype, and a single F. pabulare loloid genotype. We also identified 1555 transcripts that were up regulated and 1264 transcripts that were down regulated in response to salt stress in the Festulolium hybrids. Some of the identified transcripts showed significant sequence similarity with genes known to be regulated during salt and other abiotic stresses.


Biogeography and speciation of terrestrial fauna in the south-western Australian biodiversity hotspot.
The south-western land division of Western Australia (SWWA), bordering the temperate Southern and Indian Oceans, is the only global biodiversity hotspot recognised in Australia. Renowned for its extraordinary diversity of endemic plants, and for some of the largest and most botanically significant temperate heathlands and woodlands on Earth, SWWA has long fascinated biogeographers. Its flat, highly weathered topography and the apparent absence of major geographic factors usually implicated in biotic diversification have challenged attempts to explain patterns of biogeography and mechanisms of speciation in the region. Botanical studies have always been central to understanding the biodiversity values of SWWA, although surprisingly few quantitative botanical analyses have allowed for an understanding of historical biogeographic processes in both space and time. Faunistic studies, by contrast, have played little or no role in defining hotspot concepts, despite several decades of accumulating quantitative research on the phylogeny and phylogeography of multiple lineages. In this review we critically analyse datasets with explicit supporting phylogenetic data and estimates of the time since divergence for all available elements of the terrestrial fauna, and compare these datasets to those available for plants. In situ speciation has played more of a role in shaping the south-western Australian fauna than has long been supposed, and has occurred in numerous endemic lineages of freshwater fish, frogs, reptiles, snails and less-vagile arthropods. By contrast, relatively low levels of endemism are found in birds, mammals and highly dispersive insects, and in situ speciation has played a negligible role in generating local endemism in birds and mammals. Quantitative studies provide evidence for at least four mechanisms driving patterns of endemism in south-western Australian animals, including: (i) relictualism of ancient Gondwanan or Pangaean taxa in the High Rainfall Province; (ii) vicariant isolation of lineages west of the Nullarbor divide; (iii) in situ speciation; and (iv) recent population subdivision. From dated quantitative studies we derive four testable models of historical biogeography for animal taxa in SWWA, each explicit in providing a spatial, temporal and topological perspective on patterns of speciation or divergence. For each model we also propose candidate lineages that may be worthy of further study, given what we know of their taxonomy, distributions or relationships. These models formalise four of the strongest patterns seen in many animal taxa from SWWA, although other models are clearly required to explain particular, idiosyncratic patterns. Generating numerous new datasets for suites of co-occurring lineages in SWWA will help refine our understanding of the historical biogeography of the region, highlight gaps in our knowledge, and allow us to derive general postulates from quantitative (rather than qualitative) results. For animals, this process has now begun in earnest, as has the process of taxonomically documenting many of the more diverse invertebrate lineages. The latter remains central to any attempt to appreciate holistically biogeographic patterns and processes in SWWA, and molecular phylogenetic studies should - where possible - also lead to tangible taxonomic outcomes.


Working Conditions and Lifestyle of Female Surgeons Affiliated to the Japan Neurosurgical Society: Findings of Individual and Institutional Surveys.
To investigate the working conditions of female neurosurgeons in Japan, two surveys were conducted by The Japan Neurosurgical Society: one involving female neurosurgeons themselves and the other involving the chiefs of neurosurgical departments. The responses were received from 224 (43.8%) female neurosurgeons and 496 (61.2%) departmental chiefs. About half (50.2%) of the female neurosurgeons were married and 39.2% had children (average number of children, 1.27). Their work was full-time in 80.6% of cases; on average, they worked 51.9 h per week, had night duty 2.8 times per month, and had 5.7 days off per month. Many of them stated that they were satisfied with their job status, but about half of them reported difficulty in maintaining a correct work-life balance. Among the institutions surveyed, 29% had female neurosurgeons. The survey of departmental chiefs revealed that the proxies for maternity leave were not available at most institutions, and that there was only limited availability of night child care (41%) or sick child care (39%); female neurosurgeons did not appear to be well-informed of these support systems. These findings suggest that apart from systematic approaches already in place, female neurosurgeons would prefer to have more understanding from their peers and chiefs.


Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.
The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint. This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing. Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant. Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. Merck Sharp & Dohme.


Efficient Phytase Secretion and Phytate Degradation by Recombinant Bifidobacterium longum JCM 1217.
Genetic engineering of probiotics, like bifidobacteria, may improve their microbial cell factory economy. This work designed a novel shuttle plasmid pBPES, which bears exogenous appA and is stable within Bifidobacterium longum JCM 1217. Cloning of three predicted promoters into pBPES proved that all of them drive appA expression in B. longum JCM 1217. Transformation of plasmids pBPES-tu and pBPES-groEL into B. longum JCM1217 resulted in much more phytase secretion suggests P tu and P groEL are strong promoters. Further in vitro and in vivo experiments suggested B. longum JCM 1217/pBPES-tu degrades phytate efficiently. In conclusion, the study screened two stronger promoters and constructed a recombinant live probiotic strain for effectively phytase secretion and phytate degradation in gut. The strategy used in the study provided a novel technique for improving the bioaccessibility of phytate and decreasing phosphorus excretion.


The gold-standard genome of Aspergillus niger NRRL 3 enables a detailed view of the diversity of sugar catabolism in fungi.
The fungal kingdom is too large to be discovered exclusively by classical genetics. The access to omics data opens a new opportunity to study the diversity within the fungal kingdom and how adaptation to new environments shapes fungal metabolism. Genomes are the foundation of modern science but their quality is crucial when analysing omics data. In this study, we demonstrate how one gold-standard genome can improve functional prediction across closely related species to be able to identify key enzymes, reactions and pathways with the focus on primary carbon metabolism. Based on this approach we identified alternative genes encoding various steps of the different sugar catabolic pathways, and as such provided leads for functional studies into this topic. We also revealed significant diversity with respect to genome content, although this did not always correlate to the ability of the species to use the corresponding sugar as a carbon source.


Phenotypic diversity and genotypic flexibility of Burkholderia cenocepacia during long-term chronic infection of cystic fibrosis lungs.
Chronic bacterial infections of the lung are the leading cause of morbidity and mortality in cystic fibrosis patients. Tracking bacterial evolution during chronic infections can provide insights into how host selection pressures-including immune responses and therapeutic interventions-shape bacterial genomes. We carried out genomic and phenotypic analyses of 215 serially collected Burkholderia cenocepacia isolates from 16 cystic fibrosis patients, spanning a period of 2-20 yr and a broad range of epidemic lineages. Systematic phenotypic tests identified longitudinal bacterial series that manifested progressive changes in liquid media growth, motility, biofilm formation, and acute insect virulence, but not in mucoidy. The results suggest that distinct lineages follow distinct evolutionary trajectories during lung infection. Pan-genome analysis identified 10,110 homologous gene clusters present only in a subset of strains, including genes restricted to different molecular types. Our phylogenetic analysis based on 2148 orthologous gene clusters from all isolates is consistent with patient-specific clades. This suggests that initial colonization of patients was likely by individual strains, followed by subsequent diversification. Evidence of clonal lineages shared by some patients was observed, suggesting inter-patient transmission. We observed recurrent gene losses in multiple independent longitudinal series, including complete loss of Chromosome III and deletions on other chromosomes. Recurrently observed loss-of-function mutations were associated with decreases in motility and biofilm formation. Together, our study provides the first comprehensive genome-phenome analyses of B. cenocepacia infection in cystic fibrosis lungs and serves as a valuable resource for understanding the genomic and phenotypic underpinnings of bacterial evolution.


Epidemiological relatedness and clonal types of natural populations of Escherichia coli strains producing Shiga toxins in separate populations of cattle and sheep.
Two separate animal populations consisting of a herd of cattle (19 animals) and a flock of sheep (25 animals) were investigated for strains of Escherichia coli producing Shiga toxins (STEC) over a time period of 6 months. Thirty-three STEC were isolated from 63.2% of cattle and grouped into 11 serotypes and eight electrophoretic types (ETs) by multilocus enzyme analysis. In sheep, 88% of the animals excreted STEC (n = 67 isolates) belonging to 17 different serotypes and 12 different ETs. STEC from cattle and sheep differed with respect to serotype, and only 4 of the 16 ETs occurred in both animal populations. In cattle, ET14 (O116:H21) strains predominated, whereas other STEC serotypes occurred only sporadically. The predominating STEC types in sheep were ET4 (O125 strains), ET11 (O128:H2 and others), and ET14 (O146:H21). In contrast to their diversity, STEC originating from the same animal population were similar with respect to Shiga toxin (stxy genes. Almost all STEC isolated from cattle were positive for stx2 and stx2c; only one was positive for stx1. In sheep, almost all STEC isolated were positive for stx1 and stx2, whereas stx2c was not found. XbaI-digested DNAs of genetically closely related O146:H21 strains have different restriction profiles which were associated with size alterations in XbaI fragments hybridizing with stx1- and stx2-specific DNA probes. Our results indicate that stx-encoding bacteriophages might be the origin of the genetic heterogeneity in STEC from animals.


Effect of aging on myocardial adenosine production, adenosine uptake and adenosine kinase activity in rats.
Adenosine levels present in the interstitial fluid and coronary effluent of the aged heart exceed those of the young adult heart. The present study investigated mechanisms in the Fischer 344 rat heart which may be responsible for the observed differences. (1) Total production of adenosine was determined in isolated perfused hearts by measuring coronary effluent adenosine content while inhibiting adenosine deamination and rephosphorylation with erythrohydroxy-nonyladenosine (EHNA) and iodotubercidin (ITC), respectively. Total adenosine production was similar in both young (3-4 month) and aged (20-21 month) hearts at 31.8 +/- 6.6 and 38.4 +/- 3.3 nmol/min/g dry wt, respectively. However, stimulation with the beta-adrenergic agent, isoproterenol, elicited a significantly greater increase in adenosine production in the young vs. aged heart. (2) Adenosine transport was evaluated in isolated perfused hearts by determining 14C uptake by the myocardium after 20 min of 14C-adenosine perfusion. Adenosine uptake in the agent-free heart was found to be decreased 17 to 25% in aged compared to young adult hearts. (3) Adenosine transport characteristics were determined with nitrobenzylthioinosine saturation-binding studies in ventricular membrane preparations. The Bmax values were significantly lower in aged than young adult hearts (140.2 +/- 1.5 fmol/mg and 191.9 +/- 2.3 fmol/mg in aged and young hearts, respectively) indicating a decreased number of transporter sites in the aged heart. However, the values for Kd were decreased with aging, suggesting an increase in the affinity of the transporter for adenosine in the aged vs. young adult heart. (4) The activities and kinetics of adenosine kinase were determined in homogenates of aged and young adult ventricular myocardium. No statistical difference was found between the two activities. Taken together these results suggest that increased interstitial adenosine levels in the aged heart result from decreased uptake of adenosine by the ventricular myocardium.


[Heavy episodic drinking among adolescents: the association with negative mood states and family factors].
Heavy episodic drinking is widespread among adolescents, with serious health risks, including abuse / dependence in adulthood. The aim of this paper is to analyze the influence of negative mood states and some family variables on this type of drinking behavior among Catalan adolescents. Cross sectional study of a representative sample of adolescents (age 14-18 years) from Catalonia (Second Wave, Panel of Families and Children) (2006-2010). Separate logistic regression models are run for women (n = 1,459) and men (n = 1,105) to assess whether negative mood states (self-perceived) are associated with heavy episodic drinking measured as binge drinking at least twice a month or more in the last year. It is estimated to what extent these effects are attributable to familial factors. Feelings of sadness are associated with binge drinking among male adolescents (OR 2.7). Feeling pressured by parents keeps also a positive association with binge drinking among both sexes (OR 1.8 for males and OR 2.1 for women). Women from low-middle and high income groups are more likely to engage in binge drinking (OR 1.6 and OR, 1.7 respectively). Migrant family background (OR 0.4) and parental control of arrival home on weekend (OR 0.6) are negatively related to binge drinking among female adolescents. Negative mood states are associated with heavy episodic drinking. Socio-economic and family factors have stronger effect on women than on men.


Progress in the function and regulation of ADP-Ribosylation.
Adenosine 5'-diphosphate (ADP)-ribosylation is a protein posttranslational modification that is catalyzed by ADP-ribosyltransferases (ARTs), using nicotinamide adenine dinucleotide (NAD(+)) as a substrate. Mono-ribosylation can be extended into polymers of ADP-ribose (PAR). Poly(ADP-ribosyl)polymerase (PARP) 1, the best-characterized cellular enzyme catalyzing this process, is the prototypical member of a family of mono- and poly(ADP-ribosyl)transferases. The physiological consequences of ADP-ribosylation are inadequately understood. PARP2010, the 18th International Conference on ADP-Ribosylation, attracted scientists from all over the world to Zurich, Switzerland. Highlights from this meeting include promising clinical trials with PARP inhibitors and new insights into cell, structural, and developmental biology of ARTs and the (glyco)hydrolase proteins that catalyze de-ADP-ribosylation of mono- or poly-ADP-ribosylated proteins. Moreover, potential links to the NAD-dependent sirtuin family were explored on the basis of a shared dependence on cellular NAD(+) concentrations and the relationship of ADP-ribosylation with intermediary metabolism and cellular energetics.


Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.
Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy.


Versatility and HIV vulnerability: investigating the proportion of Australian gay men having both insertive and receptive anal intercourse.
There is a lack of recent data on the extent to which gay men engage in insertive anal intercourse (IAI) and receptive anal intercourse (RAI). Accurate assessments of the overall risk of infection from HIV and other sexually transmitted infections (STIs) require such data because versatile men who engage in both roles have heightened vulnerability for becoming infected and infecting others. To investigate the extent to which gay men are versatile with regard to having IAI and RAI. Percentages of gay men who reported engaging in IAI, RAI, or both during the past 12 months and in their most recent sexual encounter. Eight hundred fifty-six Australian gay men completed an online survey to retrospectively report on their sexual practices over the past 12 months. Of men who had anal intercourse in the past 12 months, 83% had both IAI and RAI, of whom 57% were highly versatile in that they had approximately equal numbers of partners for IAI and RAI. Of men who had anal intercourse in their most recent sexual encounter, as many as one in five (20%) had reciprocal anal intercourse, having both IAI and RAI with the same partner in a single encounter. Condom use was significantly less likely with reciprocal (38%) than nonreciprocal anal intercourse (50%; P = 0.04). While highly versatile men were less likely to know their HIV status, practices at most recent sexual encounter such as reciprocal anal intercourse and condom use were not significantly related to either their HIV status or that of their partner. Engaging in both IAI and RAI appears to be common among gay men. HIV/STI prevention strategies would benefit from paying attention to the implications of high rates of versatile sexual practices, particularly the tendency for condoms to be used less often when having reciprocal anal intercourse.


Further evidence for the concept of bovine plasma arylesterase as a lipoprotein.
Purified preparations of bovine plasma arylesterase were obtained by isoelectric focusing of enzyme prepared by (NH4)2SO4 fractionation of plasma and chromatography on DEAE-cellulose and Sephadex G-200. Although the high-density-lipoprotein fraction (HDL2) of serum provides an alternative source of enzyme, the enzymic activity of preparations made from it is much less stable. The purified arylesterase preparation has a molecular weight of 440000 and a partial specific volume of 0.91 ml/g, properties indistinguishable from those of the less highly purified enzyme. Extraction with acetone and ether removes neutral lipids from the enzyme, but the resulting lipid-depleted preparation retains most of the phospholipid present initially. A partial specific volume of 0.81 ml/g and a minimum molecular weight of approx. 100000 were determined for the lipid-depleted preparations of arylesterase. The present results support the concept of bovine plasma arylesterase as a lipoprotein in its own right, rather than as an enzymic polypeptide that is loosely associated with the HDL2 fraction of serum.


Long-term stability of thujone, fenchone, and pinocamphone in vintage preban absinthe.
Research was conducted to ascertain whether analyses of vintage absinthe samples represent their original composition in the early 1900s. Absinthe stored in traditional green glass bottles and irradiated with ultraviolet light for up to 200 h exhibited unchanged composition. Samples stored in clear glass exhibited an 18% reduction in beta-thujone content and a concurrent decoloration. These experiments indicate the stability of thujone in vintage absinthes, as these were stored in green glass bottles. The preserved color of the preban absinthes subjected to analysis indicates that no significant light exposure occurred throughout the duration of storage, and therefore provides indirect proof that no loss of terpenes occurred. The stability of absinthe was further demonstrated through the reanalysis of samples from 2001-2005, which exhibited no changes in thujone content as of 2008. A previous evaluation of preban absinthe was therefore valid and not confounded by significant thujone deterioration over time.


Effect of CPAP treatment on endothelial function and plasma CRP levels in patients with sleep apnea.
Continuous positive airway pressure (CPAP) is the most effective method for treating obstructive sleep apnea syndrome (OSAS) and alleviating symptoms. Improved sleep quality with effective CPAP therapy might also contribute to attenuated systemic inflammation and improved endothelial function, with subsequent reduction of cardiovascular risk. The aim of this study was to assess the effect of 3-month CPAP therapy on brachial artery flow-mediated dilation (FMD) and plasma C-reactive protein (CRP) levels in patients with OSAS. Our study group consisted of 38 male patients with no prior history of cardiovascular disease. Twenty patients with an Apnea-Hypopnea Index (AHI) ≥15 were assigned to receive CPAP treatment and 18 subjects with an AHI<5 were included in the control group. Six patients failed to comply with the CPAP treatment. Measurement of FMD and blood analysis was performed at baseline and 3 months after CPAP therapy. Baseline FMD values were negatively correlated with age, BMI, AHI, DSI,% of time <90% Sa02, and CRP (p<0.05). Plasma CRP values were positively correlated with BMI, AHI, DSI and% of time <90% Sa02 (p<0.05). In the group of patients who complied with the CPAP treatment, there was a significant increase in the FMD values (9.18 ± 0.55 vs. 6.27 ± 0.50) and a decrease in the levels of CRP (0.67 ± 0.15 vs. 0.84 ± 0.18) (p<0.05). Appropriate CPAP therapy improved both CRP and FMD values, suggesting its potentially beneficial role in reducing cardiovascular risk in OSAS patients.


Evolution of modern birds revealed by mitogenomics: timing the radiation and origin of major orders.
Mitochondrial (mt) genes and genomes are among the major sources of data for evolutionary studies in birds. This places mitogenomic studies in birds at the core of intense debates in avian evolutionary biology. Indeed, complete mt genomes are actively been used to unveil the phylogenetic relationships among major orders, whereas single genes (e.g., cytochrome c oxidase I [COX1]) are considered standard for species identification and defining species boundaries (DNA barcoding). In this investigation, we study the time of origin and evolutionary relationships among Neoaves orders using complete mt genomes. First, we were able to solve polytomies previously observed at the deep nodes of the Neoaves phylogeny by analyzing 80 mt genomes, including 17 new sequences reported in this investigation. As an example, we found evidence indicating that columbiforms and charadriforms are sister groups. Overall, our analyses indicate that by improving the taxonomic sampling, complete mt genomes can solve the evolutionary relationships among major bird groups. Second, we used our phylogenetic hypotheses to estimate the time of origin of major avian orders as a way to test if their diversification took place prior to the Cretaceous/Tertiary (K/T) boundary. Such timetrees were estimated using several molecular dating approaches and conservative calibration points. Whereas we found time estimates slightly younger than those reported by others, most of the major orders originated prior to the K/T boundary. Finally, we used our timetrees to estimate the rate of evolution of each mt gene. We found great variation on the mutation rates among mt genes and within different bird groups. COX1 was the gene with less variation among Neoaves orders and the one with the least amount of rate heterogeneity across lineages. Such findings support the choice of COX 1 among mt genes as target for developing DNA barcoding approaches in birds.


Using research to prepare for outbreaks of severe acute respiratory infection.
Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-specific factors, geography and management features were less reliable than baseline severity for predicting ultimate outcome. These findings may help in planning future outbreak severity assessments, but more globally representative data are required.


Enriching Cognitive Behavior Therapy with Emotion Regulation Training for Patients with Multiple Medically Unexplained Symptoms (ENCERT): Design and implementation of a multicenter, randomized, active-controlled trial.
Although cognitive behavior therapy (CBT) is the best evidenced psychological treatment for medically unexplained symptoms (MUS), effect sizes are rather moderate. Empirically evidenced deficits in emotion processing in patients with MUS make a CBT enriched with an emotion regulation training (ENCERT) a promising approach to increase treatment effects. This protocol describes the development and implementation of a multicenter, randomized, active-controlled study with blinded outcome assessors to compare the efficacy of ENCERT with a conventional CBT for MUS. Individuals presenting with ≥3 disabling, chronic MUS and fulfilling other predefined inclusion criteria are randomized to 20 sessions either of ENCERT or conventional CBT. Power calculations are based on the severity index of the Screening of Somatoform Disorders-7T and obtained an optimal sample size of N=244. Questionnaires on symptom severity, symptom-related psychological features, and emotion regulation skills are administered at baseline, end of therapy, and 6-months follow-up. An every-session monitoring of therapy progress, and regular patients'/therapists' ratings of quality of therapy, working alliance, outcome expectations, and adverse events are conducted. Primary statistical analysis shall verify the hypothesis of ENCERT being more efficacious than conventional CBT regarding symptom severity. Enriching CBT with transdiagnostic therapeutic strategies addressing emotion regulation is a promising and new approach to target not only somatic symptom coping but also symptom-associated problems and comorbid mental disorders. The current trial will not only allow examining the efficacy of ENCERT but also important variables and mechanisms of the process of therapy. NCT01908855.


Green tea polyphenols and cancer chemoprevention of genitourinary cancer.
Green tea, which has higher concentrations of polyphenols than other teas, has been correlated with reduced risk of various malignancies with most data supporting a potential protective role in prostate neoplasia. Preclinical studies over the last 25 years implicate constituent green tea catechins, epigallocatechin-3-gallate (EGCG) being the predominant form, as the main mechanistic ingredient in the observed biologic effects, which vary from proapoptotic effects to inhibition of androgen receptor and signal transduction pathways. There have been few prospective clinical trials of green tea polyphenols (GTP), especially with well-characterized formulations and doses. Although there have been hints of beneficial clinical activity in prostate neoplasia, other studies have raised concerns about the limited bioavailability and very low target-tissue concentrations of GTPs. At present there is no proven role for GTP supplementation in the prevention of genitourinary (GU) malignancies, but novel GTP formulations and further clinical testing may still support a future for GTP supplementation in GU cancer prevention.


Healthcare use before and after a workplace injury in British Columbia, Canada.
There is growing evidence that occupational injuries influence workers' emotional and physical wellbeing, extending healthcare use beyond what is covered by the Workers' Compensation Board (WCB). The authors used an administrative database that links individual publicly funded healthcare and WCB data for the population of British Columbia (BC), Canada. They examined change in service use, relative to one year before the injury, for workers who required time off for their injuries (lost time = LT) and compared them to other injured workers (no lost time = NLT) and individuals in the population who were not injured (non-injured = NI). LT workers increased physician visits (22%), hospital days (50%), and mental healthcare use (43% physician visits; and 70% hospital days) five years after the injury, relative to the year before the injury, at a higher rate than the NI group. For the NLT workers, the level of increased use following the injury was between that of these two groups. These patterns persisted when adjusting for registration in the BC Medical Service Plan (MSP) and several workplace characteristics. Although the WCB system is the primary mechanism for processing claims and providing information about workplace injury, it is clear that the consequences of workplace injury extend beyond what is covered by the WCB into the publicly funded healthcare system.


Perspectives Regarding the Role of Biochanin A in Humans.
Biochanin A (BCA) is an isoflavone mainly found in red clover with poor solubility and oral absorption that is known to have various effects, including anti-inflammatory, estrogen-like, and glucose and lipid metabolism modulatory activity, as well as cancer preventive, neuroprotective, and drug interaction effects. BCA is already commercially available and is among the main ingredients in many types of supplements used to alleviate postmenopausal symptoms in women. The activity of BCA has not been adequately evaluated in humans. However, the results of many in vitro and in vivo studies investigating the potential health benefits of BCA are available, and the complex mechanisms by which BCA modulates transcription, apoptosis, metabolism, and immune responses have been revealed. Many efforts have been exerted to improve the poor bioavailability of BCA, and very promising results have been reported. This review focuses on the major effects of BCA and its possible molecular targets, potential uses, and limitations in health maintenance and treatment.


Structural homology guided alignment of cysteine rich proteins.
Cysteine rich protein families are notoriously difficult to align due to low sequence identity and frequent insertions and deletions. Here we present an alignment method that ensures homologous cysteines align by assigning a unique 10 amino acid barcode to those identified as structurally homologous by the DALI webserver. The free inter-cysteine regions of the barcoded sequences can then be aligned using any standard algorithm. Finally the barcodes are replaced with the original columns to yield an alignment which requires the minimum of manual refinement. Using structural homology information to constrain sequence alignments allows the alignment of highly divergent, repetitive sequences that are poorly dealt with by existing algorithms. Tools are provided to perform this method online using the CysBar web-tool (http://CysBar.science.latrobe.edu.au) and offline (python script available from http://github.com/ts404/CysBar).


Improved genome annotation through untargeted detection of pathway-specific metabolites.
Mass spectrometry-based metabolomics analyses have the potential to complement sequence-based methods of genome annotation, but only if raw mass spectral data can be linked to specific metabolic pathways. In untargeted metabolomics, the measured mass of a detected compound is used to define the location of the compound in chemical space, but uncertainties in mass measurements lead to "degeneracies" in chemical space since multiple chemical formulae correspond to the same measured mass. We compare two methods to eliminate these degeneracies. One method relies on natural isotopic abundances, and the other relies on the use of stable-isotope labeling (SIL) to directly determine C and N atom counts. Both depend on combinatorial explorations of the "chemical space" comprised of all possible chemical formulae comprised of biologically relevant chemical elements. Of 1532 metabolic pathways curated in the MetaCyc database, 412 contain a metabolite having a chemical formula unique to that metabolic pathway. Thus, chemical formulae alone can suffice to infer the presence of some metabolic pathways. Of 248,928 unique chemical formulae selected from the PubChem database, more than 95% had at least one degeneracy on the basis of accurate mass information alone. Consideration of natural isotopic abundance reduced degeneracy to 64%, but mainly for formulae less than 500 Da in molecular weight, and only if the error in the relative isotopic peak intensity was less than 10%. Knowledge of exact C and N atom counts as determined by SIL enabled reduced degeneracy, allowing for determination of unique chemical formula for 55% of the PubChem formulae. To facilitate the assignment of chemical formulae to unknown mass-spectral features, profiling can be performed on cultures uniformly labeled with stable isotopes of nitrogen (15N) or carbon (13C). This makes it possible to accurately count the number of carbon and nitrogen atoms in each molecule, providing a robust means for reducing the degeneracy of chemical space and thus obtaining unique chemical formulae for features measured in untargeted metabolomics having a mass greater than 500 Da, with relative errors in measured isotopic peak intensity greater than 10%, and without the use of a chemical formula generator dependent on heuristic filtering. These chemical formulae can serve as indicators for the presence of particular metabolic pathways.


Influence of a fluorobenzene nucleobase analogue on the conformational flexibility of RNA studied by molecular dynamics simulations.
Chemically modified bases are frequently used to stabilize nucleic acids, to study the driving forces for nucleic acid structure formation and to tune DNA and RNA hybridization conditions. In particular, fluorobenzene and fluorobenzimidazole base analogues can act as universal bases able to pair with any natural base and to stabilize RNA duplex formation. Although these base analogues are compatible with an A-form RNA geometry, little is known about the influence on the fine structure and conformational dynamics of RNA. In the present study, nano-second molecular dynamics (MD) simulations have been performed to characterize the dynamics of RNA duplexes containing a central 1'-deoxy-1'-(2,4-difluorophenyl)-beta-D-ribofuranose base pair or opposite to an adenine base. For comparison, RNA with a central uridine:adenine pair and a 1'-deoxy-1'-(phenyl)-beta-D-ribofuranose opposite to an adenine was also investigated. The MD simulations indicate a stable overall A-form geometry for the RNAs with base analogues. However, the presence of the base analogues caused a locally enhanced mobility of the central bases inducing mainly base pair shear and opening motions. No stable 'base-paired' geometry was found for the base analogue pair or the base analogue:adenine pairs, which explains in part the universal base character of these analogues. Instead, the conformational fluctuations of the base analogues lead to an enhanced accessibility of the bases in the major and minor grooves of the helix compared with a regular base pair.


The relationship between membrane potential and calcium dynamics in glucose-stimulated beta cell syncytium in acute mouse pancreas tissue slices.
Oscillatory electrical activity is regarded as a hallmark of the pancreatic beta cell glucose-dependent excitability pattern. Electrophysiologically recorded membrane potential oscillations in beta cells are associated with in-phase oscillatory cytosolic calcium activity ([Ca(2+)]i) measured with fluorescent probes. Recent high spatial and temporal resolution confocal imaging revealed that glucose stimulation of beta cells in intact islets within acute tissue slices produces a [Ca(2+)]i change with initial transient phase followed by a plateau phase with highly synchronized [Ca(2+)]i oscillations. Here, we aimed to correlate the plateau [Ca(2+)]i oscillations with the oscillations of membrane potential using patch-clamp and for the first time high resolution voltage-sensitive dye based confocal imaging. Our results demonstrated that the glucose-evoked membrane potential oscillations spread over the islet in a wave-like manner, their durations and wave velocities being comparable to the ones for [Ca(2+)]i oscillations and waves. High temporal resolution simultaneous records of membrane potential and [Ca(2+)]i confirmed tight but nevertheless limited coupling of the two processes, with membrane depolarization preceding the [Ca(2+)]i increase. The potassium channel blocker tetraethylammonium increased the velocity at which oscillations advanced over the islet by several-fold while, at the same time, emphasized differences in kinetics of the membrane potential and the [Ca(2+)]i. The combination of both imaging techniques provides a powerful tool that will help us attain deeper knowledge of the beta cell network.


Neurogenic orthostatic hypotension: pathophysiology and diagnosis.
Although orthostatic hypotension in elderly patients is common, neurogenic orthostatic hypotension (NOH) is a condition with substantial morbidity and a variable prognosis. Patients with severe NOH have difficulty standing for any period of time and must scrupulously avoid orthostatic stressors that exacerbate their condition. In about half of patients, supine hypertension complicates management. The diagnosis is based on measurements of supine and standing blood pressures or head-up tilt testing and is confirmed by autonomic testing. Two self-report questionnaires, the Orthostatic Hypotension Questionnaire and the Orthostatic Grading Scale, can help evaluate a patient's level of impairment, document progression, and assess the response to pharmacotherapy in clinical practice. There are many gaps in our knowledge of this rare disorder; this review summarizes what is currently known about the pathophysiology, epidemiology, prognosis, signs and symptoms, and the diagnosis of NOH.


Effectiveness of offering healthy labelled meals in improving the nutritional quality of lunch meals eaten in a worksite canteen.
Healthier meal selections at restaurants and canteens are often limited and not actively promoted. In this Danish study the effectiveness of a healthy labelling certification program in improving dietary intake and influencing edible plate waste was evaluated in a quasi-experimental study design. Employees from an intervention worksite canteen and a matched control canteen were included in the study at baseline (February 2012), after completing the certification process (end-point) and six month from end-point (follow-up) (total n=270). In order to estimate nutrient composition of the consumed lunch meals and plate waste a validated digital photographic method was used combining estimation of food intake with food nutrient composition data. Food satisfaction was rated by participants using a questionnaire. Several significant positive nutritional effects were observed at the intervention canteen including a mean decrease in energy density in the consumed meals from 561kJ/100g at baseline to 368 and 407kJ/100g at end-point and follow-up, respectively (P<0.001). No significant changes were seen with regard to food satisfaction and plate waste. In the control canteen no positive nutritional effects were observed. The results of the study highlight the potential of using healthy labelling certification programs as a possible driver for increasing both the availability and awareness of healthy meal choices, thereby improving dietary intake when eating out.


Picky comprehensively detects high-resolution structural variants in nanopore long reads.
Acquired genomic structural variants (SVs) are major hallmarks of cancer genomes, but they are challenging to reconstruct from short-read sequencing data. Here we exploited the long reads of the nanopore platform using our customized pipeline, Picky ( https://github.com/TheJacksonLaboratory/Picky ), to reveal SVs of diverse architecture in a breast cancer model. We identified the full spectrum of SVs with superior specificity and sensitivity relative to short-read analyses, and uncovered repetitive DNA as the major source of variation. Examination of genome-wide breakpoints at nucleotide resolution uncovered micro-insertions as the common structural features associated with SVs. Breakpoint density across the genome is associated with the propensity for interchromosomal connectivity and was found to be enriched in promoters and transcribed regions of the genome. Furthermore, we observed an over-representation of reciprocal translocations from chromosomal double-crossovers through phased SVs. We demonstrate that Picky analysis is an effective tool for comprehensive detection of SVs in cancer genomes from long-read data.


Frontal Functional Network Disruption Associated with Amyotrophic Lateral Sclerosis: An fNIRS-Based Minimum Spanning Tree Analysis.
Recent evidence increasingly associates network disruption in brain organization with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a rare terminal disease. However, the comparability of brain network characteristics across different studies remains a challenge for conventional graph theoretical methods. One suggested method to address this issue is minimum spanning tree (MST) analysis, which provides a less biased comparison. Here, we assessed the novel application of MST network analysis to hemodynamic responses recorded by functional near-infrared spectroscopy (fNIRS) neuroimaging modality, during an activity-based paradigm to investigate hypothetical disruptions in frontal functional brain network topology as a marker of the executive dysfunction, one of the most prevalent cognitive deficit reported across ALS studies. We analyzed data recorded from nine participants with ALS and ten age-matched healthy controls by first estimating functional connectivity, using phase-locking value (PLV) analysis, and then constructing the corresponding individual and group MSTs. Our results showed significant between-group differences in several MST topological properties, including leaf fraction, maximum degree, diameter, eccentricity, and degree divergence. We further observed a global shift toward more centralized frontal network organizations in the ALS group, interpreted as a more random or dysregulated network in this cohort. Moreover, the similarity analysis demonstrated marginally significantly increased overlap in the individual MSTs from the control group, implying a reference network with lower topological variation in the healthy cohort. Our nodal analysis characterized the main local hubs in healthy controls as distributed more evenly over the frontal cortex, with slightly higher occurrence in the left prefrontal cortex (PFC), while in the ALS group, the most frequent hubs were asymmetrical, observed primarily in the right prefrontal cortex. Furthermore, it was demonstrated that the global PLV (gPLV) synchronization metric is associated with disease progression, and a few topological properties, including leaf fraction and tree hierarchy, are linked to disease duration. These results suggest that dysregulation, centralization, and asymmetry of the hemodynamic-based frontal functional network during activity are potential neuro-topological markers of ALS pathogenesis. Our findings can possibly support new bedside assessments of the functional status of ALS' brain network and could hypothetically extend to applications in other neurodegenerative diseases.


Donor Troponin and Survival After Cardiac Transplantation: An Analysis of the United Network of Organ Sharing Registry.
Despite a limited supply of organs, only 1 in 3 potential donor hearts is accepted for transplantation. Elevated donor troponin levels have generally been considered a contraindication to heart transplantation; however, the data supporting this practice are limited. We identified 10 943 adult (≥18 years) heart transplant recipients in the United Network of Organ Sharing (UNOS) database with preserved donor left ventricular ejection fraction (≥50%) and where peak donor troponin I values were available. When analyzed as a continuous variable, there was no association between peak donor troponin levels and recipient mortality up to 1 year follow-up in unadjusted (hazards ratio, 0.999; 95% confidence interval, 0.997-1.002; P=0.856) and adjusted Cox models (hazards ratio, 1.000; 95% confidence interval, 0.997-1.002; P=0.950). Next, we divided the entire cohort into 3 groups based on donor troponin I values: <1 ng/mL (n=7812), 1 to 10 ng/mL (n=2770), and >10 ng/mL (n=361). Using unadjusted and adjusted Cox models and Kaplan-Meier analysis, there was no significant difference in recipient mortality at 30 days, 1 year, 3 years, or 5 years between the 3 groups. Similarly, cardiac allograft vasculopathy up to 5 years and primary graft failure up to 30 days of follow-up post transplant did not differ between the 3 donor troponin groups. The median length of hospital stay post transplant was also similar across groups. Elevated donor troponin I levels in the setting of preserved left ventricular ejection fraction were not associated with intermediate-term mortality, cardiac allograft vasculopathy, or primary graft failure rates in hearts accepted for transplantation. This finding could help expand the donor pool.


Dynamic contrast-enhanced computed tomography as a potential biomarker in patients with metastatic renal cell carcinoma: preliminary results from the Danish Renal Cancer Group Study-1.
The aim of this study was to explore the impact of dynamic contrast-enhanced (DCE) computer tomography (CT) as a biomarker in metastatic renal cell carcinoma (mRCC). Twelve patients with favorable or intermediate Memorial Sloan Kettering Cancer Center risk group and clear cell mRCC participating in an ongoing prospective randomized phase II trial comprising interleukin-2-based immunotherapy and bevacizumab were included in this preliminary analysis. All patients had a follow-up time of at least 2 years. Interpretation of DCE-CT (max slope method) was performed blinded to treatment group. The DCE-CT scans were performed at baseline, at weeks 5 and 10, and thereafter every third month. Blood flow (BF; mL/min/100 mL), peak enhancement (Hounsfield units), time to peak (seconds), and blood volume (BV; mL/100 g) were calculated. Parameters for DCE-CT were correlated with sum of diameters (defined by Response Evaluation Criteria in Solid Tumors 1.1), progression-free survival (PFS), and overall survival (OS) using Wilcoxon, Man-Whitney, Kaplan-Meier, and log rank statistics, as appropriate. Blood flow at baseline ranged from 4.9 to 148.1 mL/min/100 mL (median, 62.2; 25th percentile, 25.8; 75th percentile, 110.0). Patients with high baseline BF (using quartiles as cutoffs) had significantly longer OS (not reached vs 5.2 months, P = 0.011) and longer PFS (not reached vs 3.9 months, P = 0.026). Blood volume at baseline ranged from 8.8 to 74.1 mL/100 g tissue (median, 21.5), and at week 5, from 4.9 to 34.7 mL/100 g (median, 17.2). Relative changes in BV between baseline and week 5 ranged from -64% to +68% (median, -16%; 25th percentile, -41%; 75th percentile, +2%) and were significantly associated with OS using quartiles as cutoffs (5.2 months vs not reached, P = 0.038) and PFS using the median as cutoff (5.3 months vs not reached, P = 0.009), with larger reductions associated with longer survival. Using medians as cutoffs, relative changes in both BF and BV between baseline and week 10 were significantly associated with OS (for both, 8.6 months vs not reached, P = 0.031). Dynamic contrast-enhanced CT is a potential biomarker in patients with mRCC. High baseline BF and reductions in BF and BV during early treatment are associated with improved outcome. Large-scale studies are required.


Plasma CXCL10, sCD163 and sCD14 Levels Have Distinct Associations with Antiretroviral Treatment and Cardiovascular Disease Risk Factors.
We investigate the associations of three established plasma biomarkers in the context of HIV and treatment-related variables including a comprehensive cardiovascular disease risk assessment, within a large ambulatory HIV cohort. Patients were recruited in 2010 to form the Royal Perth Hospital HIV/CVD risk cohort. Plasma sCD14, sCD163 and CXCL10 levels were measured in 475 consecutive patients with documented CVD risk (age, ethnicity, gender, smoking, blood pressure, BMI, fasting metabolic profile) and HIV treatment history including immunological/virological outcomes. The biomarkers assessed showed distinct associations with virological response: CXCL10 strongly correlated with HIV-1 RNA (p<0.001), sCD163 was significantly reduced among 'aviraemic' patients only (p = 0.02), while sCD14 was unaffected by virological status under 10,000 copies/mL (p>0.2). Associations between higher sCD163 and protease inhibitor therapy (p = 0.05) and lower sCD14 with integrase inhibitor therapy (p = 0.02) were observed. Levels of sCD163 were also associated with CVD risk factors (age, ethnicity, HDL, BMI), with a favourable influence of Framingham score <10% (p = 0.04). Soluble CD14 levels were higher among smokers (p = 0.002), with no effect of other CVD risk factors, except age (p = 0.045). Our findings confirm CXCL10, sCD163 and sCD14 have distinct associations with different aspects of HIV infection and treatment. Levels of CXCL10 correlated with routinely monitored variables, sCD163 levels reflect a deeper level of virological suppression and influence of CVD risk factors, while sCD14 levels were not associated with routinely monitored variables, with evidence of specific effects of smoking and integrase inhibitor therapy warranting further investigation.


Paraventricular Nucleus Modulates Excitatory Cardiovascular Reflexes during Electroacupuncture.
The paraventricular nucleus (PVN) regulates sympathetic outflow and blood pressure. Somatic afferent stimulation activates neurons in the hypothalamic PVN. Parvocellular PVN neurons project to sympathoexcitatory cardiovascular regions of the rostral ventrolateral medulla (rVLM). Electroacupuncture (EA) stimulates the median nerve (P5-P6) to modulate sympathoexcitatory responses. We hypothesized that the PVN and its projections to the rVLM participate in the EA-modulation of sympathoexcitatory cardiovascular responses. Cats were anesthetized and ventilated. Heart rate and mean blood pressure were monitored. Application of bradykinin every 10-min on the gallbladder induced consistent pressor reflex responses. Thirty-min of bilateral EA stimulation at acupoints P5-P6 reduced the pressor responses for at least 60-min. Inhibition of the PVN with naloxone reversed the EA-inhibition. Responses of cardiovascular barosensitive rVLM neurons evoked by splanchnic nerve stimulation were reduced by EA and then restored with opioid receptor blockade in the PVN. EA at P5-P6 decreased splanchnic evoked activity of cardiovascular barosensitive PVN neurons that also project directly to the rVLM. PVN neurons labeled with retrograde tracer from rVLM were co-labeled with μ-opioid receptors and juxtaposed to endorphinergic fibers. Thus, the PVN and its projection to rVLM are important in processing acupuncture modulation of elevated blood pressure responses through a PVN opioid mechanism.


Bend translation in multimode fiber imaging.
Light propagation in multimode fibers is typically assumed to be extremely sensitive to changes in geometry. We study here a particular configuration where an S-shaped bend is translated between two sections of fiber. In this sliding bend configuration, we show that nearly constant propagation characteristics can be obtained in certain fibers. Several fibers were tested using a bend with a peak radius of curvature of 25 mm. We found large differences in bending behavior between fibers of varying core diameters and numerical apertures. Fibers with a large numerical aperture are found to be more stable. In several fibers, the bend can be translated over a distance of 25 mm with a limited impact on imaging performance. The experimental results are confirmed using simulations. Our findings shed a new light on bending sensitivity in multimode fibers, and open up more possibilities for their use as imaging devices.


Using emergency department-based inception cohorts to determine genetic characteristics associated with long term patient outcomes after motor vehicle collision: methodology of the CRASH study.
Persistent musculoskeletal pain and psychological sequelae following minor motor vehicle collision (MVC) are common problems with a large economic cost. Prospective studies of pain following MVC have demonstrated that demographic characteristics, including female gender and low education level, and psychological characteristics, including high pre-collision anxiety, are independent predictors of persistent pain. These results have contributed to the psychological and social components of a biopsychosocial model of post-MVC pain pathogenesis, but the biological contributors to the model remain poorly defined. Recent experimental studies indicate that genetic variations in adrenergic system function influence the vulnerability to post-traumatic pain, but no studies have examined the contribution of genetic factors to existing predictive models of vulnerability to persistent pain. The Project CRASH study is a federally supported, multicenter, prospective study designed to determine whether variations in genes affecting synaptic catecholamine levels and alpha and beta adrenergic receptor function augment social and psychological factors in a predictive model of persistent musculoskeletal pain and posttraumatic stress disorder (PTSD) following minor MVC. The Project CRASH study will assess pain, pain interference and PTSD symptoms at 6 weeks, 6 months, and 1 year in approximately 1,000 patients enrolled from 8 Emergency Departments in four states with no-fault accident laws. The results from this study will provide insights into the pathophysiology of persistent pain and PTSD following MVC and may serve to improve the ability of clinicians and researchers to identify individuals at high risk for adverse outcomes following minor MVC.


Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals.
The development of protease inhibitors (PIs) such as telaprevir and boceprevir constitutes a milestone in chronic hepatitis C antiviral treatment since it has achieved sustained virological response (SVR) rates of up to 75% in naïve and 29-88% in treatment-experienced patients with genotype 1 infection. Both require combination treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) as PI monotherapy results in resistant mutations. New direct acting antiviral agents (DAAs) have recently been approved or their approval is imminent. Simeprevir administered orally as one pill per day in combination with PEG-IFN/RBV will be the next PI to be approved. The SVR rates at about 72-80% for treatment-naïve patients are not a major improvement over telaprevir or boceprevir. However, this treble combination has fewer side effects and drug-drug interactions and most patients undergo shorter treatment duration (24 months) due to earlier treatment responses. Sofosbuvir is the first available once-daily NS5B polymerase inhibitor which has been approved in combination with PEG-IFN/RBV for just 12 weeks with 89% SVR in treatment-naïve patients with genotype 1 infection and 83-100% in treatment-experienced patients with genotypes 2/3. The current review focuses on the recent rapid and continuous developments in the management of chronic HCV infection with DAAs in combination with PEG-IFN/RBV.


Transactivation of geminivirus AR1 and BR1 gene expression by the viral AL2 gene product occurs at the level of transcription.
Tomato golden mosaic virus is a bipartite geminivirus whose genome is divided between two circular DNA molecules. DNA A encodes functions necessary for viral DNA replication and encapsidation, whereas DNA B provides functions needed for movement in the host. Previous studies have shown that the viral AL2 gene product transactivates expression of the coat protein gene (AR1). We have investigated the role of the AL2 protein in the regulation of B component gene expression and examined the transcriptional and post-transcriptional components of this regulation. We found that AL2 protein is required for efficient expression of both the AR1 and BR1 genes, but not the BL1 gene. A comparison of steady state transcript levels and transcript levels determined by nuclear run-on analysis showed that activation of AR1 and BR1 gene expression by the AL2 protein occurs primarily at the level of transcription. These results provide an explanation for the lack of infectivity demonstrated by AL2 mutants, and suggest that the AL2 protein interacts with the cellular transcription machinery to activate the expression of rightward viral genes.