Dopamine agonists for the treatment of cocaine dependence.
Cocaine misuse is a disorder for which no pharmacological treatment of proven efficacy exists. Advances in neurobiology could guide future medication development. To investigate the efficacy and acceptability of dopamine agonists alone or in combination with any psychosocial intervention for the treatment of of people who misuse cocaine. We run the search on 12 January 2015. We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE, CINAHL, PsycINFO, ICTRP, clinicaltrials.gov and screened reference lists. Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing dopamine agonists alone or associated with psychosocial intervention with placebo, no treatment or other pharmacological interventions. We used standard Cochrane methodological procedures. Twenty four studies, including 2147 participants, met the inclusion criteria. Comparing any dopamine agonist versus placebo, we found no differences for any of the outcomes considered: dropout (moderate quality of evidence), abstinence (low quality of evidence), severity of dependence (low quality of evidence), adverse events (moderate quality of evidence). This was also observed when single dopamine agonists were compared against placebo. Comparing amantadine versus antidepressants, we found low quality of evidence that antidepressants performed better for abstinence (RR 0.25, 95% CI 0.12 to 0.53) based on two studies with 44 participants. No differences were found for dropout or adverse events, for both moderate quality of evidence.The major flaws of the included studies concerned selection bias because most studies did not report information about sequence generation (80%) and allocation concealment methods (86%): half of the included studies were judged at unclear risk of performance bias and 62.5% at unclear risk of detection bias for what concerns subjective outcomes. Current evidence from RCTs does not support the use of dopamine agonists for treating cocaine misuse. This absence of evidence may leave to clinicians the alternative of balancing the possible benefits against the potential adverse effects of the treatment. Even the potential benefit of combining a dopamine agonist with a more potent psychosocial intervention, which was suggested by the previous Cochrane Review (Soares 2003), is not supported by the results of this Cochrane Review update.


Analysis of the halo background in femtosecond slicing experiments.
The slicing facility FemtoSpeX at BESSY II offers unique opportunities to study photo-induced dynamics on femtosecond time scales by means of X-ray magnetic circular dichroism, resonant and non-resonant X-ray diffraction, and X-ray absorption spectroscopy experiments in the soft X-ray regime. Besides femtosecond X-ray pulses, slicing sources inherently also produce a so-called `halo' background with a different time structure, polarization and pointing. Here a detailed experimental characterization of the halo radiation is presented, and a method is demonstrated for its correct and unambiguous removal from femtosecond time-resolved data using a special laser triggering scheme as well as analytical models. Examples are given for time-resolved measurements with corresponding halo correction, and errors of the relevant physical quantities caused by either neglecting or by applying a simplified model to describe this background are estimated.


Patterns of antischistosomal drug usage in Qalyubia Governorate of the Nile Delta.
To further investigate factors responsible for the recently documented changes in schistosomiasis patterns in the Nile Delta, questionnaire-derived information on antischistosomal drug usage was obtained from a 25% systematic sample of 609 residents of a stable village in the south-central Delta. Ten percent of the population had received antischistosomal drugs during the previous 4 years. Most of the drugs administered were injectable compounds, and 92% of individuals receiving them failed to complete the treatment regimen. Additional sources of information from a village physician, a pharmacist and a major pharmaceutical corporation confirmed and expanded the survey findings, indicating that antischistosomal drug usage cannot explain the recently observed changing patterns of human schistosome infections in the Nile Delta region.


Substance Use Disorder in Early Midlife: A National Prospective Study on Health and Well-Being Correlates and Long-Term Predictors.
This study used national multicohort panel data from the Monitoring the Future study (N = 25,536 from senior year classes 1977-1997 followed up to the age of 35 years in 1994-2014) to examine how early midlife (age 35 years) alcohol use disorder (AUD) and cannabis use disorder (CUD) are associated with adolescent and adult sociodemographics and health and well-being risk factors. Survey items adapted from DSM-5 diagnostic criteria were used to identify individuals who (a) showed symptoms consistent with criteria for AUD or CUD at age 35 years, (b) used the substance without qualifying for a disorder (nondisordered users), and (c) abstained from using alcohol or marijuana during the past five years. At age 35 years, the estimated prevalence of past five-year AUD was 28.0%, and that of CUD was 6.1%. Multinomial logistic regressions were used to identify variations in the relative risk of disorder symptoms as a function of sociodemographic characteristics, age 18 educational and social indices and substance use, and age 35 health and satisfaction indices and substance use. In the full models, age 18 binge drinking and marijuana use were found to be among the strongest predictors of age 35 AUD and CUD, respectively. Among age 35 health and well-being indicators, lower overall health, more frequent cognitive difficulties, and lower satisfaction with spouse/partner were consistently associated with greater risks of AUD and CUD. Some evidence was found for a J-shaped association between age 35 AUD or CUD status and health and well-being indices, such that nondisordered users were sometimes better off than both abstainers and those experiencing disorder. Finally, nondisordered cannabis use, but not CUD, was found to be more common in more recent cohorts. Implications are discussed regarding the importance of placing early midlife substance use disorder within the context of both adolescent substance use and adult health and well-being.


Predicting the lateral direction of deceptive and non-deceptive penalty kicks in football from the kinematics of the kicker.
This study addresses the utility of the kinematics of penalty takers for goalkeepers in association football. Twelve professional and semi-professional players shot to one side of the goal with (deceptive condition) or without (non-deceptive condition) simulating a shot to the opposite side. The body kinematics of the penalty takers were registered with motion-capture apparatus. Correlation and regression techniques were used to determine the relation between the shot direction and aspects of the penalty taker's kinematics at different moments. Several kinematic variables were strongly correlated with shot direction, especially those related to the lower part of the body. Some of these variables, including the angle of the non-kicking foot, acquired high correlations at time intervals that are useful to goalkeepers. Compound variables, here defined as linear combinations of variables, were found to be more useful than locally defined variables. Whereas some kinematic variables showed substantial differences in their relation to ball direction depending on deception, other kinematic variables were less affected by deception. Results are interpreted with the hypothesis of non-substitutability of genuine action. The study can also be interpreted as extending the correlation and regression methodology, often used to analyze variables defined at single moments, to the analysis of variables in a time continuous fashion.


Ginsenoside Rb1 improves leptin sensitivity in the prefrontal cortex in obese mice.
Obesity impairs leptin-induced regulation of brain-derived neurotrophic factor (BDNF) expression and synaptogenesis, which has been considered to be associated with the incidence of neuronal degenerative diseases, cognitive decline, and depression. Ginsenoside Rb1 (Rb1), a major bioactive component of ginseng, is known to have an antiobesity effect and improve cognition. This study examined whether Rb1 can improve central leptin effects on BDNF expression and synaptogenesis in the prefrontal cortex during obesity using an in vivo and an in vitro model. Ginsenoside Rb1 (Rb1) chronic treatment improved central leptin sensitivity, leptin-JAK2-STAT3 signaling, and leptin-induced regulation of BDNF expression in the prefrontal cortex of high-fat diet-induced obese mice. In cultured prefrontal cortical neurons, palmitic acid, the saturated fat, impaired leptin-induced BDNF expression, reduced the immunoreactivity and mRNA expression of synaptic proteins, and impaired leptin-induced neurite outgrowth and synaptogenesis. Importantly, Rb1 significantly prevented these pernicious effects induced by palmitic acid. These results indicate that Rb1 reverses central leptin resistance and improves leptin-BDNF-neurite outgrowth and synaptogenesis in the prefrontal cortical neurons. Thus, Rb1 supplementation may be a beneficial avenue to treat obesity-associated neurodegenerative disorders.


Association of moderate-to-vigorous physical activity with neck circumference in eight Latin American countries.
Physical activity is a cornerstone in the prevention and treatment of obesity. There are relatively few studies that explore the effect of accelerometer-determined moderate-to-vigorous physical activity (MVPA) on neck circumference (NC), most of them confined to single high-income countries. The present study investigated the association of accelerometer-determined MVPA with NC in adolescents and adults from eight Latin American countries, which are mostly upper-middle income countries. The sample consisted of 2370 participants (47.8% male) from the Latin American Study of Nutrition and Health, a multicenter cross-sectional nutrition and health surveillance study of a nationally representative sample from eight Latin American countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Peru, and Venezuela). Times (min/day) in MVPA (defined as time accumulated at ≥1952 activity counts/min) was assessed by ActiGraph GT3X+ accelerometer over 7 days. NC for adolescent was categorized as abnormal if circumference was > 34.5 cm for boys and > 31.25 for girls, whereas for adults the cut-off points for abnormal were > 39 cm for men and > 35 cm women. Multilevel logistic models, including country and region as random effects and adjusted for sex, age, socioeconomic level, and educational level, were used to study the association between MVPA and NC. The average time of MVPA was 34.88 min/day, ranging from 31.16 in Venezuela to 40.27 in Chile. Concerning NC, 37.0% of the sample was classified as having elevated NC. Chile was the country with the highest percentage of people with elevated NC (56.9%), and Colombia had the lowest percentage (24.8%). Overall, the MVPA (min/day) was associated with elevated NC (OR = 0.994, CI95% = 0.990-0.998). In Costa Rica and Peru, there were significant associations between MVPA and NC when analyzed by country. The present study provided evidence of significant associations between MVPA and NC in adolescents and adults from Latin America, independent of sex, age, socioeconomic level, and educational level. This analysis of accelerometry data and NC represents the first examination of these associations in eight Latin America countries. Further research is required to understand the differences between countries in the observed associations. ClinicalTrials.Gov NCT02226627 . Retrospectively registered on August 27, 2014.


An ultra-sensitive colorimetric assay for reliable visual detection of telomerase activity.
The visual detection of a disease biomarker is a promising strategy due to its simplicity and low cost, but the complexity of biological samples limits its application. Herein, a reliable and ultrasensitive colorimetric assay was proposed for detecting telomerase activity in crude cancer cell extracts. A telomerase substrate (TS) primer was immobilized onto magnetic beads (MBs) to form a MB/TS complex. In the presence of telomerase and deoxyribonucleotide triphosphates (dNTPs), the TS primer was elongated by adding multiple telomeric repeats (TTAGGG)n to the 3' end of the TS. The telomeric repeats of the elongated TS (ETS) hybridized with its short complementary DNA (cDNA) to specifically capture peroxidase onto MBs. After magnetic separation, the activity of telomerase was detected by monitoring the change in the color or absorbance of the peroxidase-catalyzed H2O2/TMB reaction. Magnetic separation greatly eliminated the non-specific interference to ensure reliability and improve the signal-to-noise (S/N) ratio. The mean telomerase activity equivalent to 5 HeLa cells and 1 HeLa cell was reliably detected with the naked eye and UV-vis spectroscopy, respectively. More importantly, the telomerase activity of 5 and 20 HeLa cells was detected via UV-vis spectroscopy and the naked eye, respectively. The differences in the telomerase activity of four carcinoma cell lines and one normal cell line were discriminated visually. Even more strikingly, the telomerase activity of 10 and 50 HeLa cells in human serum was detected by change in the absorbance and color of the TMB/H2O2 solution, respectively. Therefore, it offers an ultrasensitive and reliable colorimetric assay for the visual detection of telomerase activity, which holds promising potential to detect telomerase activity in a complex pathological sample.


Microbes and asthma: Opportunities for intervention.
The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.


Tetanus neurotoxin-insensitive vesicle-associated membrane protein localizes to a presynaptic membrane compartment in selected terminal subsets of the rat brain.
Tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) is a vesicular soluble N-ethyl maleimide-sensitive fusion protein attachment protein receptor (SNARE) that has been implicated in neurite outgrowth. It has previously been reported that TI-VAMP is localised in the somatodendritic compartment of neurons indicating a role in membrane fusion events within dendrites. Using a newly produced monoclonal antibody to TI-VAMP that improves signal/noise immunodetection, we report that TI-VAMP is also present in subsets of axon terminals of the adult rat brain. Four distinctive populations of labelled axon terminals were identified: 1) the hippocampal mossy fibres of the dentate gyrus and of CA3, 2) the striatal peridendritic terminal plexuses in the globus pallidus (GP), substantia nigra pars reticulata (SNr), 3) peridendritic plexuses in the central nucleus of the amygdala, and 4) the primary sensory afferents in the dorsal horn of the spinal cord. The presynaptic localisation of TI-VAMP in these locations was demonstrated by co-localisation with synaptophysin. Ultrastructural studies showed TI-VAMP labelling over synaptic vesicles in the mossy fibres, whereas it was localised in tubulo-vesicular structures and multivesicular bodies in the pyramidal cell dendrites. The presynaptic localisation of TI-VAMP occurred by P15, so relatively late during development. In contrast, dendritic labelling was most prominent during the early post-natal period. Co-localisation with markers of neurotransmitters showed that TI-VAMP-positive terminals are GABAergic in the GP and SNr and glutamatergic in the mossy fibre system and in the dorsal root afferents. Most of these terminals are known to co-localise with neuropeptides. We found met-enkephalin-immunoreactivity in a sizeable fraction of the TI-VAMP positive terminals in the GP, amygdala, and dorsal horn, as well as in a few mossy fibre terminals. The function of TI-VAMP in subsets of mature axon terminals remains to be elucidated; it could participate in the exocytotic molecular machinery and/or be implicated in particular growth properties of the mature axon terminals. Thus, the presence of TI-VAMP in the mossy fibres may correspond to the high degree of plasticity that characterises this pathway throughout adult life.


Dynamic biomechanical examination of the lumbar spine with implanted total spinal segment replacement (TSSR) utilizing a pendulum testing system.
Biomechanical investigations of spinal motion preserving implants help in the understanding of their in vivo behavior. In this study, we hypothesized that the lumbar spine with implanted total spinal segment replacement (TSSR) would exhibit decreased dynamic stiffness and more rapid energy absorption compared to native functional spinal units under simulated physiologic motion when tested with the pendulum system. Five unembalmed, frozen human lumbar functional spinal units were tested on the pendulum system with axial compressive loads of 181 N, 282 N, 385 N, and 488 N before and after Flexuspine total spinal segment replacement implantation. Testing in flexion, extension, and lateral bending began by rotating the pendulum to 5°; resulting in unconstrained oscillatory motion. The number of rotations to equilibrium was recorded and bending stiffness (N-m/°) was calculated and compared for each testing mode. The total spinal segment replacement reached equilibrium with significantly fewer cycles to equilibrium compared to the intact functional spinal unit at all loads in flexion (p<0.011), and at loads of 385 N and 488 N in lateral bending (p<0.020). Mean bending stiffness in flexion, extension, and lateral bending increased with increasing load for both the intact functional spinal unit and total spinal segment replacement constructs (p<0.001), with no significant differences in stiffness between the intact functional spinal unit and total spinal segment replacement in any of the test modes (p>0.18). Lumbar functional spinal units with implanted total spinal segment replacement were found to have similar dynamic bending stiffness, but absorbed energy at a more rapid rate than intact functional spinal units during cyclic loading with an unconstrained pendulum system. Although the effects on clinical performance of motion preserving devices is not fully known, these results provide further insight into the biomechanical behavior of this device under approximated physiologic loading conditions.


Associations between interarm differences in blood pressure and cardiovascular disease outcomes: protocol for an individual patient data meta-analysis and development of a prognostic algorithm.
Individual cohort studies in various populations and study-level meta-analyses have shown interarm differences (IAD) in blood pressure to be associated with increased cardiovascular and all-cause mortality. However, key questions remain, such as follows: (1) What is the additional contribution of IAD to prognostic risk estimation for cardiovascular and all-cause mortality? (2) What is the minimum cut-off value for IAD that defines elevated risk? (3) Is there a prognostic value of IAD and do different methods of IAD measurement impact on the prognostic value of IAD? We aim to address these questions by conducting an individual patient data (IPD) meta-analysis. This study will identify prospective cohort studies that measured blood pressure in both arms during recruitment, and invite authors to contribute IPD datasets to this collaboration. All patient data received will be combined into a single dataset. Using one-stage meta-analysis, we will undertake multivariable time-to-event regression modelling, with the aim of developing a new prognostic model for cardiovascular risk estimation that includes IAD. We will explore variations in risk contribution of IAD across predefined population subgroups (eg, hypertensives, diabetics), establish the lower limit of IAD that is associated with additional cardiovascular risk and assess the impact of different methods of IAD measurement on risk prediction. This study will not include any patient identifiable data. Included datasets will already have ethical approval and consent from their sponsors. Findings will be presented to international conferences and published in peer reviewed journals, and we have a comprehensive dissemination strategy in place with integrated patient and public involvement. CRD42015031227.


A novel role for helix 12 of retinoid X receptor in regulating repression.
Nutrients, drugs, and hormones influence transcription during differentiation and metabolism by binding to high-affinity nuclear receptors. In the absence of ligand, some but not all nuclear receptors repress transcription as a heterodimer with retinoid X receptor (RXR). Here we define a novel role for helix 12 (H12) in sterically masking the corepressor (CoR) binding site in apo-RXR. Removing H12 converts RXR to a potent transcriptional repressor. The length but not the specific sequence of H12 is critical for masking RXR's intrinsic repression function. This contrasts with the amphipathic character required for mediating ligand-dependent activation and coactivator recruitment. Physiologically, we show that heterodimerization of RXR with apo-thyroid hormone receptor (TR) unmasks the CoR binding site in RXR and allows the TR-RXR heterodimer to repress. A molecular mechanism that involves sequence-specific interaction between RXR H12 and the coactivator-binding surface of the nuclear receptor is proposed for this heterodimerization-mediated unmasking. Peroxisome proliferator-activated receptor gamma does not interact as well with RXR H12, thus explaining its inability to repress transcription as an RXR heterodimer. The requirement to unmask RXR's latent repression function explains why only certain RXR partners repress transcription.


Carriage and Acquisition of Extended-spectrum β-Lactamase-producing Enterobacterales Among Neonates Admitted to Hospital in Kilifi, Kenya.
Infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) among hospitalized neonates in sub-Saharan Africa pose significant clinical challenges. Data on prevalence and acquisition of ESBL-E carriage among hospitalized neonates in the region are few, and risk factors for transmission are not clearly defined. In a cohort study of consecutive neonatal admissions to Kilifi County Hospital from July 2013 through August 2014, we estimated ESBL-E carriage prevalence on admission using rectal swab cultures and identified risk factors using logistic regression. Using twice-weekly follow-up swabs, we estimated the incidence and identified risk factors for ESBL-E acquisition in hospital using Poisson regression. The prevalence of ESBL-E carriage at admission was 10% (59/569). Cesarean delivery, older neonatal age, and smaller household size were significant risk factors. Of the 510 infants admitted without ESBL-E carriage, 238 (55%) acquired carriage during their hospital stay. The incidence of acquisition was 21.4% (95% confidence interval, 19.0%-24.0%) per day. The rate was positively associated with the number of known neonatal ESBL-E carriers and with the total number of neonates on the same ward. Carriage of ESBL-E was common among neonates on admission, and in-hospital acquisition was rapid. The dissemination and selection of ESBL-E appears to be driven by hospital exposures, operative delivery, and neonatal ward patient density. Further attention to infection control, patient crowding, and carriage surveillance is warranted.


Recursive dynamic programming for adaptive sequence and structure alignment.
We propose a new alignment procedure that is capable of aligning protein sequences and structures in a unified manner. Recursive dynamic programming (RDP) is a hierarchical method which, on each level of the hierarchy, identifies locally optimal solutions and assembles them into partial alignments of sequences and/or structures. In contrast to classical dynamic programming, RDP can also handle alignment problems that use objective functions not obeying the principle of prefix optimality, e.g. scoring schemes derived from energy potentials of mean force. For such alignment problems, RDP aims at computing solutions that are near-optimal with respect to the involved cost function and biologically meaningful at the same time. Towards this goal, RDP maintains a dynamic balance between different factors governing alignment fitness such as evolutionary relationships and structural preferences. As in the RDP method gaps are not scored explicitly, the problematic assignment of gap cost parameters is circumvented. In order to evaluate the RDP approach we analyse whether known and accepted multiple alignments based on structural information can be reproduced with the RDP method. For this purpose, we consider the family of ferredoxins as our prime example. Our experiments show that, if properly tuned, the RDP method can outperform methods based on classical sequence alignment algorithms as well as methods that take purely structural information into account.


Health literacy and antidepressant medication adherence among adults with diabetes: the diabetes study of Northern California (DISTANCE).
Previous studies have reported that health literacy limitations are associated with poorer disease control for chronic conditions, but have not evaluated potential associations with medication adherence. To determine whether health literacy limitations are associated with poorer antidepressant medication adherence. Observational new prescription cohort follow-up study. Adults with type 2 diabetes who completed a survey in 2006 and received a new antidepressant prescription during 2006-2010 (N = 1,366) at Kaiser Permanente Northern California. Validated three-item self-report scale measured health literacy. Discrete indices of adherence based on pharmacy dispensing data according to validated methods: primary non-adherence (medication never dispensed); early non-persistence (dispensed once, never refilled); non-persistence at 180 and 365 days; and new prescription medication gap (NPMG; proportion of time that the person is without medication during 12 months after the prescription date). Seventy-two percent of patients were classified as having health literacy limitations. After adjusting for sociodemographic and clinical covariates, patients with health literacy limitations had significantly poorer adherence compared to patients with no limitations, whether measured as early non-persistence (46 % versus 38 %, p < 0.05), non-persistence at 180 days (55 % versus 46 %, p < 0.05), or NPMG (41 % versus 36%, p < 0.01). There were no significant associations with primary adherence or non-persistence at 365 days. Poorer antidepressant adherence among adults with diabetes and health literacy limitations may jeopardize the continuation and maintenance phases of depression pharmacotherapy. Findings underscore the importance of national efforts to address health literacy, simplify health communications regarding treatment options, improve public understanding of depression treatment, and monitor antidepressant adherence.


Automated detection of infectious disease outbreaks in hospitals: a retrospective cohort study.
Detection of outbreaks of hospital-acquired infections is often based on simple rules, such as the occurrence of three new cases of a single pathogen in two weeks on the same ward. These rules typically focus on only a few pathogens, and they do not account for the pathogens' underlying prevalence, the normal random variation in rates, and clusters that may occur beyond a single ward, such as those associated with specialty services. Ideally, outbreak detection programs should evaluate many pathogens, using a wide array of data sources. We applied a space-time permutation scan statistic to microbiology data from patients admitted to a 750-bed academic medical center in 2002-2006, using WHONET-SaTScan laboratory information software from the World Health Organization (WHO) Collaborating Centre for Surveillance of Antimicrobial Resistance. We evaluated patients' first isolates for each potential pathogenic species. In order to evaluate hospital-associated infections, only pathogens first isolated >2 d after admission were included. Clusters were sought daily across the entire hospital, as well as in hospital wards, specialty services, and using similar antimicrobial susceptibility profiles. We assessed clusters that had a likelihood of occurring by chance less than once per year. For methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE), WHONET-SaTScan-generated clusters were compared to those previously identified by the Infection Control program, which were based on a rule-based criterion of three occurrences in two weeks in the same ward. Two hospital epidemiologists independently classified each cluster's importance. From 2002 to 2006, WHONET-SaTScan found 59 clusters involving 2-27 patients (median 4). Clusters were identified by antimicrobial resistance profile (41%), wards (29%), service (13%), and hospital-wide assessments (17%). WHONET-SaTScan rapidly detected the two previously known gram-negative pathogen clusters. Compared to rule-based thresholds, WHONET-SaTScan considered only one of 73 previously designated MRSA clusters and 0 of 87 VRE clusters as episodes statistically unlikely to have occurred by chance. WHONET-SaTScan identified six MRSA and four VRE clusters that were previously unknown. Epidemiologists considered more than 95% of the 59 detected clusters to merit consideration, with 27% warranting active investigation or intervention. Automated statistical software identified hospital clusters that had escaped routine detection. It also classified many previously identified clusters as events likely to occur because of normal random fluctuations. This automated method has the potential to provide valuable real-time guidance both by identifying otherwise unrecognized outbreaks and by preventing the unnecessary implementation of resource-intensive infection control measures that interfere with regular patient care. Please see later in the article for the Editors' Summary.


A Multidisciplinary Integrative Medicine Team in the Treatment of Chronic Low-Back Pain: An Observational Comparative Effectiveness Study.
Chronic low-back pain (CLBP) is burdensome and costly, and a common condition for which adults use integrative therapies. The effectiveness of multidisciplinary integrative approaches has not been well studied. The purpose of this observational study was to compare characteristics and outcomes of CLBP patients treated at the Osher Clinical Center (OCC) versus other clinics at Brigham and Women's Hospital. Observational comparative effectiveness study. Tertiary care hospital. Patients ≥21 years with 3+ months of CLBP or 6+ months of intermittent low-back pain. All patients were observed for 12 months. OCC patients received care at the integrative clinic (7.3 visits on average over 13 weeks); non-OCC patients received usual care at other clinics of the same hospital. Primary outcomes: change from baseline to 6 months in functional status (Roland Disability Questionnaire [RDQ]) and bothersomeness of pain (BOP). change in RDQ and BOP at 3 and 12 months, percentages of patients with clinically meaningful (≥30%) improvements. One hundred fifty-six OCC and 153 non-OCC participants were enrolled; follow-up was 90.4 and 98.0%, respectively, at 12 months. There were substantial differences in baseline characteristics between groups. For RDQ, the adjusted mean group difference was nonsignificant at 6 months; for BOP, the differences were significant, but clinically small. At 12 months, the observed benefit on RDQ was significant and clinically meaningful; for BOP, there were significant, but clinically small differences. Percentages of patients with ≥30% improvements in RDQ were significantly greater in the OCC group only at 12 months, and both 6 and 12 months for BOP. Baseline characteristics can differ between those who select different sources of healthcare for CLBP. While benefits seen in the OCC versus non-OCC clinics were not large, further evaluation through randomized trials might be warranted to provide a more definitive evaluation.


Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15).
Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.


Role of D₁/D₂ dopamin receptors antagonist perphenazine in morphine analgesia and tolerance in rats.
While opioid receptors have been implicated in the development of tolerance, the subsequent mechanisms involved in these phenomena have not been completely understood. The purpose of this study was to investigate effects of D1/D2 dopamine receptors antagonist perphenazine on morphine analgesia and tolerance in rats. Male Wistar albino rats weighing 190-205 g were used in these experiments. To constitute of morphine tolerance, animals received morphine (50 mg/kg) once daily for 3 days. After last dose of morphine was injected on day 4, morphine tolerance was evaluated by the analgesia tests. The analgesic effects of perphenazine (1, 5, and 10 mg/kg ), D1-dopamine receptor antagonist SCH 23390 (1 mg/kg), D2-dopamine receptor antagonist eticlopride (1 mg/kg), and morphine were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Obtained data suggested that D1/D2 dopamine receptors antagonist perphenazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting D2-dopamine receptor. Because the data indicated that D2-dopamine receptor antagonist eticloride, but not D1-dopamine receptor antagonist SCH 23390, significantly decreased morphine tolerance in analgesia tests. In addition, administration of perphenazine with morphine increased morphine analgesia. Results from the present study suggested that dopamine receptors play a significant role in the morphine analgesic tolerance. In particular, D2-dopamine receptor has an important role rather than D1-dopamine receptor in development tolerance to morphine.


Randomized trials of invasive cardiovascular interventions that include a placebo control: a systematic review and meta-analysis.
The difference in the benefit of invasive cardiovascular interventions compared with placebo controls has not been analysed systematically. MEDLINE and Web of Science were searched through 29 March 2020. Randomized, placebo-controlled trials of invasive cardiovascular interventions (including catheter-based interventions and pacemaker-like devices) investigating predefined primary outcomes were included. Standardized mean differences (SMD) and odds ratios were calculated for continuous and dichotomous outcomes, respectively. Meta-regression analyses were performed to assess whether estimates of treatment effects were associated with methodological characteristics of trials. Thirty trials, including 4102 patients, were analysed. The overall risk of bias was judged to be low in only 43% of the trials. Ten trials (33%) demonstrated statistically significant superiority of invasive interventions over placebo controls for the respective predefined primary outcomes. In almost half of the 16 trials investigating continuous predefined primary outcomes, the SMD between the active and placebo procedure indicated a small (n = 4) to moderate (n = 3) treatment effect of active treatment over placebo. In contrast, one trial indicated a small treatment effect in favour of the placebo procedure. In the remaining trials, there was no relevant treatment effect of active treatment over placebo. In trials with a protocol-mandated stable and symmetrical use of co-interventions, the superiority of active procedures vs. invasive placebo procedures was significantly larger as compared with trials with frequent or unbalanced changes in co-interventions (P for interaction 0.027). The additional treatment effect of invasive cardiovascular interventions compared with placebo controls was small in most trials.


Home blood pressure measurements associated with better blood pressure control: the J-HOME study.
The usefulness of self-measurements of blood pressure (BP) at home (home BP measurements) in hypertensive patients has been reported by many studies. Several national guidelines recommend the use of home BP measurements to achieve better hypertension control. The objective of this study was to clarify the association between home BP measurements and hypertension treatment among 2363 essential hypertensive patients taking antihypertensive drugs. Compared to the 543 (23.0%) patients who had not taken home BP measurements, the 1820 (77.0%) patients who had taken home BP measurements were significantly older, included a higher proportion of males, included a higher proportion with a family history of hypertension, took a greater number of antihypertensive drugs and alpha blockers and took antihypertensive drugs more often in the evening. Home BP measurements were associated with significantly better control of home and office BP levels. Compared to patients who had not taken home BP measurements, the adjusted odds ratios for good control of morning home BPs, evening home BPs and office BPs in patients who had taken home BP measurements were 1.46 (95% confidential interval (CI) 1.33-1.57), 1.35 (95% CI 1.21-1.47) and 1.23 (95% CI 1.06-1.37), respectively. Home BP measurements were associated with good hypertensive management. Our findings suggest that it is important that physicians recommend home BP measurements to their patients.


Ulmus minor bark hydro-alcoholic extract ameliorates histological parameters and testosterone level in an experimental model of PCOS rats.
Polycystic ovary syndrome (PCOS) is a common and multifactorial disease associated with female factor infertility. Ulmus minor bark (UMB) is one of the medicinal plants used in Persian folklore as a fertility enhancer. In the current study, we aimed to elucidate the effect of UMB hydro-alcoholic extract on histological parameters and testosterone condition in an experimental model of PCOS rats. Thirty female rats were randomly divided into five groups: (1) control, (2) vehicle, (3) PCOS/50 mg [6 mg/kg dehydroepiandrosterone (DHEA) + 50 mg/kg UMB hydro-alcoholic extract], (4) PCOS/150 mg (6 mg/kg DHEA + 150 mg/kg UMB hydro-alcoholic extract), and (5) PCOS (6 mg/kg DHEA). All interventions were performed for 21 days. Afterwards, stereological analysis was done for determination of ovarian volume and follicle number. The serum level of testosterone was measured by ELISA kit. UMB hydro-alcoholic extract improved the total number of the corpus luteum in the treatment groups when compared to the PCOS group (p<0.05). PCOS/150 mg and PCOS/50 mg groups showed significantly lower total number of the primordial, primary, and secondary follicles as well as testosterone level compared to the PCOS group (p<0.05). The total number of antral follicles and volume of ovary did not differ significantly between groups. UMB extract may be an effective and good alternative in improving PCOS histo-logical and testosterone disturbances although further studies are warranted to confirm the safety of UMB plant in human.


An Intrapatient Concordance Study of Mismatch Repair Protein Immunohistochemical Staining Patterns in Patients With Muir-Torre Syndrome.
Appropriate use criteria for Muir-Torre syndrome (MTS) screening suggest that mismatch repair protein (MMRP) immunohistochemical (IHC) testing is usually appropriate in patients with 2 or more sebaceous neoplasms (SNs). While MTS is known to be caused by a germline mutation in mismatch repair genes, data are limited as to whether individual sebaceous tumors in these patients with multiple lesions show identical MMRP IHC staining patterns. To determine concordance of MMRP IHC staining patterns in lesions of patients with MTS who have multiple SNs. This retrospective single-center case series evaluated 38 SNs in 11 patients with MTS confirmed by genetic testing for MMRP IHC staining patterns. Tumor sites were classified as either facial or extrafacial. Data were collected between January 1, 2007, and January 1, 2018. In each patient, MMRP IHC staining patterns for SNs were compared with one another to evaluate intrapatient concordance between lesions, and to the patient's known germline mutation. A total of 11 patients (7 women and 4 men) with MTS, with a mean (SD) age of 59.3 (10.6) years at time of SN biopsy, were identified. There was high concordance between MMRP IHC staining results (2-4 lesions per patient) and the patient's mutation status, with 36 of 38 total lesions (95%) matching (sensitivity, 94.7%; 95% CI, 82.3%-99.4%). Extrafacial site tumors represented 16 of 38 total lesions (42%) and demonstrated 100% concordance of IHC results to germline mutation. Only 1 of 11 patients (9%) demonstrated discordant results, with both lesions in this patient occurring on a facial site. In patients with known MTS, SNs present with highly concordant MMRP IHC staining profiles across multiple lesions. There is also a strong association with underlying germline mutations. A diagnosis of MTS might be supported by MMRP IHC when the pretest probability is high.


Combating highly resistant emerging pathogen Mycobacterium abscessus and Mycobacterium tuberculosis with novel salicylanilide esters and carbamates.
In the Mycobacterium genus over one hundred species are already described and new ones are periodically reported. Species that form colonies in a week are classified as rapid growers, those requiring longer periods (up to three months) are the mostly pathogenic slow growers. More recently, new emerging species have been identified to lengthen the list, all rapid growers. Of these, Mycobacterium abscessus is also an intracellular pathogen and it is the most chemotherapy-resistant rapid-growing mycobacterium. In addition, the cases of multidrug-resistant Mycobacterium tuberculosis infection are also increasing. Therefore there is an urgent need to find new active molecules against these threatening strains. Based on previous results, a series of salicylanilides, salicylanilide 5-chloropyrazinoates and carbamates was designed, synthesized and characterised. The compounds were evaluated for their in vitro activity on M. abscessus, susceptible M. tuberculosis H37Rv, multidrug-resistant (MDR) M. tuberculosis MDR A8, M. tuberculosis MDR 9449/2006 and on the extremely-resistant Praha 131 (XDR) strains. All derivatives exhibited a significant activity with minimum inhibitory concentrations (MICs) in the low micromolar range. Eight salicylanilide carbamates and two salicylanilide esters exhibited an excellent in vitro activity on M. abscessus with MICs from 0.2 to 2.1 μM, thus being more effective than ciprofloxacin and gentamicin. This finding is potentially promising, particularly, as M. abscessus is a threateningly chemotherapy-resistant species. M. tuberculosis H37Rv was inhibited with MICs from 0.2 μM, and eleven compounds have lower MICs than isoniazid. Salicylanilide esters and carbamates were found that they were effective also on MDR and XDR M. tuberculosis strains with MICs ≥1.0 μM. The in vitro cytotoxicity (IC50) was also determined on human MonoMac-6 cells, and selectivity index (SI) of the compounds was established. In general, salicylanilide derivatives substituted by halogens on both salicyl and aniline rings showed better activity, than 4-benzoylaniline derivatives. The ester or carbamate bond formation of parent salicylanilides mostly retained or improved antimycobacterial potency with moderate selectivity.


Gastric Cancer in Asia: Unique Features and Management.
Gastric cancer (GC) poses a burden to patients across the globe as the third leading cause of cancer deaths worldwide. Incidence of GC is particularly high in Asian countries, which is attributed to the prevalence of Helicobacter pylori (H. pylori) infection and has prompted the establishment of unique treatment strategies. D2 gastrectomy, which was established in the 1950s in Japan, has served as a gold standard for locally advanced GC for over half a century. Since the beginning of the 21st century, endoscopic resection (ER) techniques and minimally invasive laparoscopic surgery have greatly changed the treatment of patients with early GC. S-1, which showed a striking survival benefit in a large randomized trial in Japan, has been used as adjuvant therapy for the last decade. Likewise, S-1-based chemotherapy regimens are currently the standard of care for the treatment of unresectable/metastatic GC in Asia. Along with the development of standardized therapy, novel techniques and new drugs have been rapidly brought into clinical practice. State-of-the-art sentinel node (SN) navigation surgery enables clinicians to perform truly minimally invasive surgery for early GC, and appropriate chemotherapy regimens are now determined by a tumor's molecular expression. New classifications based on gene signatures are proposed and may replace conventional clinical classifications. Such highly individualized treatment has the potential to alter our clinical practice in GC in the near future. The best practice in each geographic region should be shared and integrated, resulting in the best practice without borders.


Palmitoyl-acyl carrier protein (ACP) thioesterase and the evolutionary origin of plant acyl-ACP thioesterases.
Acyl-acyl carrier protein (ACP) thioesterases play an essential role in chain termination during de novo fatty acid synthesis and in the channeling of carbon flux between the two lipid biosynthesis pathways in plants. We have discovered that there are two distinct but related thioesterase gene classes in higher plants, termed FatA and FatB, whose evolutionary divergence appears to be ancient. FatA encodes the already described 18:1-ACP thioesterase. In contrast, FatB representatives encode thioesterases preferring acyl-ACPs having saturated acyl groups. We unexpectedly obtained a 16:0-ACP thioesterase cDNA from Cuphea hookeriana seed, which accumulate predominantly 8:0 and 10:0. The 16:0 thioesterase transcripts were found in non-seed tissues, and expression in transgenic Brassica napus led to the production of a 16:0-rich oil. We present evidence that this type of FatB gene is ancient and ubiquitous in plants and that specialized plant medium-chain thioesterases have evolved independently from such enzymes several times during angiosperm evolution. Also, the ubiquitous 18:1-ACP thioesterase appears to be a derivative of a 16:0 thioesterase.


Health care professionals' views on discussing sexual wellbeing with patients who have had a stroke: a qualitative study.
To examine the experiences of health care professionals discussing sexual wellbeing with patients who have had a stroke. In-depth qualitative interview study with purposive sampling and thematic analysis. 30 health care professionals purposively recruited to include different roles and settings along the stroke patient pathway in secondary and primary care. Two hospitals and three general practices in the West Midlands, UK. Sexual wellbeing was a topic that participants did not raise with patients and was infrequently raised by patients. Barriers to raising discussion were on four levels: structural, health care professional, patient, and professional-patient interface. Barriers within these levels included: sexual wellbeing not present within hospital stroke policy; the perception that sexual wellbeing was not within participants' role; participants' concern that raising the issue could cause harm to the patient; and the views that discussion would be inappropriate with older people or unimportant to women. Resources exist to aid discussion but many participants were unaware of them, and most of those that were, did not use them routinely. Participants lacked motivation, ownership, and the confidence and skills to raise sexual wellbeing routinely after stroke. Similar findings have been reported in cancer care and other taboo subjects such as incontinence potentially resulting in a sub-optimal experience for patients. Normalisation of the inclusion of sensitive topics in discussions post-stroke does not seem to need significant structural intervention and simple changes such as information provision and legitimisation through consideration of the issue in standard care policies may be all that is required. The experiences recounted by professionals in this study suggest that such changes are needed now.


GATOR2-dependent mTORC1 activity is a therapeutic vulnerability in FOXO1 fusion-positive rhabdomyosarcoma.
Oncogenic FOXO1 gene fusions drive a subset of rhabdomyosarcoma (RMS) with poor survival; to date, these cancer drivers are therapeutically intractable. To identify new therapies for this disease, we undertook an isogenic CRISPR-interference screen to define PAX3-FOXO1-specific genetic dependencies and identified genes in the GATOR2 complex. GATOR2 loss in RMS abrogated aa-induced lysosomal localization of mTORC1 and consequent downstream signaling, slowing G1-S cell cycle transition. In vivo suppression of GATOR2 impaired the growth of tumor xenografts and favored the outgrowth of cells lacking PAX3-FOXO1. Loss of a subset of GATOR2 members can be compensated by direct genetic activation of mTORC1. RAS mutations are also sufficient to decouple mTORC1 activation from GATOR2, and indeed, fusion-negative RMS harboring such mutations exhibit aa-independent mTORC1 activity. A bisteric, mTORC1-selective small molecule induced tumor regressions in fusion-positive patient-derived tumor xenografts. These findings highlight a vulnerability in FOXO1 fusion-positive RMS and provide rationale for the clinical evaluation of bisteric mTORC1 inhibitors, currently in phase I testing, to treat this disease. Isogenic genetic screens can, thus, identify potentially exploitable vulnerabilities in fusion-driven pediatric cancers that otherwise remain mostly undruggable.


Effects of a 10% carbamide peroxide bleaching agent on rat oral epithelium proliferation.
The purpose of the present study was to evaluate the influence of short course topical application of carbamide peroxide on proliferating cell nuclear antigen (PCNA) immunohistochemical expression in the oral tongue mucosa of rats. Twelve male Wistar rats were submitted to topical application of 10% carbamide peroxide on one side of the dorsal tongue once a week for three consecutive weeks. Only distilled water was applied on the control side. The animals were killed on days 0, 10, and 20 after the last application. The tongue was fixed in buffered formalin for 24 h and embedded in paraffin. Tissue blocks (3 microns) were subjected to the biotin-streptavidin amplified system for identification of PCNA. The percentage of epithelial-positive basal cells in each side of the tongue mucosa was calculated. The results demonstrated that topical application of 10% carbamide peroxide increases PCNA immunohistochemical expression on the basal layer of the oral mucosa epithelium of rats on day 0 after treatment. In conclusion, short-course use of carbamide peroxide induces transient epithelial cell proliferation of the oral mucosa of rats.


IFN-γ is essential for alveolar macrophage-driven pulmonary inflammation in macrophage activation syndrome.
Macrophage activation syndrome (MAS) is a life-threatening cytokine storm complicating systemic juvenile idiopathic arthritis (SJIA) driven by IFN-γ. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-γ pathways pathologically linking SJIA-LD and MAS. Our objective was to mechanistically define the potentially novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-γ, IFN-induced chemokines, and alveolar macrophage (AMϕ) expression of IFN-γ-induced genes. Single-cell RNA sequencing confirmed IFN-driven transcriptional changes across lung cell types with myeloid expansion and detection of MAS-specific macrophage populations. Systemic MAS resolution was associated with increased AMϕ and interstitial lymphocytic infiltration. AMϕ transcriptomic analysis confirmed IFN-γ-induced proinflammatory polarization during acute MAS, which switches toward an antiinflammatory phenotype after systemic MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and it reset AMϕ polarization toward a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-γ, both systemic features of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-γ-driven pulmonary inflammation replicating key features of SJIA-LD and provides a model system for testing potentially novel treatments directed toward SJIA-LD.


[Dialogy of Laughter: a new concept introducing joy for health promotion based on dialogue, laughter, joy and the art of the clown].
The Dialogy of Laughter - a concept based upon the praxis of general health education performed with joy - is presented and discussed. Health is seen as a resource for life rather than a goal in life and promotion of health is a positive reaction leading to a broader, integrated and complex perception linking the environment, education, people, quality and style of life. Laughter can then be incorporated as a tool in health promotion as defended here. Considerations on dialogue, laughter, joy and the clown giving rise to the Dialogy of Laughter concept are presented. Dialogue, namely an exchange between two or more persons for the comprehension and transfer of ideas, is a methodology for joint thinking to produce new ideas and to share meaning, which is the essence of communication. Laughter is a universal phenomenon linked to aspects of culture, philosophy, history and health. It is dialogic, since through humor the comedy and the wit contained in each laugh, which is a communication code inherent to human nature, are revealed. Joy as a strategy for health promotion is highlighted and the art of the clown, using this art as an educational tool that can be integrated as a social technology, are adopted.


All-optical linear reconfigurable logic with nonlinear phase erasure.
We introduce a novel all-optical logic architecture whereby the gates may be readily reconfigured to reprogram their logic to implement (N)AND/(N)OR/X(N)OR. A single gate structure may be used throughout the logic circuit to implement multiple truth tables. The reconfiguration is effected by an optical reference signal. The reference may also be adapted to an arbitrary Boolean complex alphabet at the gate logic inputs and calibrated to correct gate imperfections. The all-optical gate structure is partitioned into a linear interferometric front end and a nonlinear back end. In the linear section, two optical logic inputs, along with a reference signal, linearly interfere. The nonlinear back end realizes a phase-erasure (or phase-reset) function. The reconfiguration and recalibration capabilities, along with the functional decoupling between the linear and nonlinear sections of each gate, facilitate the potential aggregation of large gate counts into logic arrays. A fundamental lower bound for the expended energy per gate is derived as 3hnu+kT ln2 Joules per bit.


A framework for assessing global change risks to forest carbon stocks in the United States.
Among terrestrial environments, forests are not only the largest long-term sink of atmospheric carbon (C), but are also susceptible to global change themselves, with potential consequences including alterations of C cycles and potential C emission. To inform global change risk assessment of forest C across large spatial/temporal scales, this study constructed and evaluated a basic risk framework which combined the magnitude of C stocks and their associated probability of stock change in the context of global change across the US. For the purposes of this analysis, forest C was divided into five pools, two live (aboveground and belowground biomass) and three dead (dead wood, soil organic matter, and forest floor) with a risk framework parameterized using the US's national greenhouse gas inventory and associated forest inventory data across current and projected future Köppen-Geiger climate zones (A1F1 scenario). Results suggest that an initial forest C risk matrix may be constructed to focus attention on short- and long-term risks to forest C stocks (as opposed to implementation in decision making) using inventory-based estimates of total stocks and associated estimates of variability (i.e., coefficient of variation) among climate zones. The empirical parameterization of such a risk matrix highlighted numerous knowledge gaps: 1) robust measures of the likelihood of forest C stock change under climate change scenarios, 2) projections of forest C stocks given unforeseen socioeconomic conditions (i.e., land-use change), and 3) appropriate social responses to global change events for which there is no contemporary climate/disturbance analog (e.g., severe droughts in the Lake States). Coupling these current technical/social limits of developing a risk matrix to the biological processes of forest ecosystems (i.e., disturbance events and interaction among diverse forest C pools, potential positive feedbacks, and forest resiliency/recovery) suggests an operational forest C risk matrix remains elusive.


Chronic subdural hygroma with thrombocythemia: first case report.
Subdural hygroma is a frequent delayed complication of head trauma. It is a rare form of bleeding. Most hygromas are clinically silent and a few cases have shown slow deterioration in the chronic stage. We report a case of a 72-years-old male presented with a mild headache, consciousness disturbance and gait ataxia after head injury. Cranial computed tomography revealed subdural hygroma. The hygroma was associated to thrombocythemia. The patient was treated with chemotherapy with hydroxyurea with rapid resolution. In conclusion subdural hygroma may resolve spontaneously. Surgery might be deferred except in emergency conditions or in patients with normal neurological findings. Subdural hygroma in patient with thrombocythemia is first time presenting.


Locally expressed IGF1 propeptide improves mouse heart function in induced dilated cardiomyopathy by blocking myocardial fibrosis and SRF-dependent CTGF induction.
Cardiac fibrosis is critically involved in the adverse remodeling accompanying dilated cardiomyopathies (DCMs), which leads to cardiac dysfunction and heart failure (HF). Connective tissue growth factor (CTGF), a profibrotic cytokine, plays a key role in this deleterious process. Some beneficial effects of IGF1 on cardiomyopathy have been described, but its potential role in improving DCM is less well characterized. We investigated the consequences of expressing a cardiac-specific transgene encoding locally acting IGF1 propeptide (muscle-produced IGF1; mIGF1) on disease progression in a mouse model of DCM [cardiac-specific and inducible serum response factor (SRF) gene disruption] that mimics some forms of human DCM. Cardiac-specific mIGF1 expression substantially extended the lifespan of SRF mutant mice, markedly improved cardiac functions, and delayed both DCM and HF. These protective effects were accompanied by an overall improvement in cardiomyocyte architecture and a massive reduction of myocardial fibrosis with a concomitant amelioration of inflammation. At least some of the beneficial effects of mIGF1 transgene expression were due to mIGF1 counteracting the strong increase in CTGF expression within cardiomyocytes caused by SRF deficiency, resulting in the blockade of fibroblast proliferation and related myocardial fibrosis. These findings demonstrate that SRF plays a key role in the modulation of cardiac fibrosis through repression of cardiomyocyte CTGF expression in a paracrine fashion. They also explain how impaired SRF function observed in human HF promotes fibrosis and adverse cardiac remodeling. Locally acting mIGF1 efficiently protects the myocardium from these adverse processes, and might thus represent a therapeutic avenue to counter DCM.


Comparative study on Allium schoenoprasum cultivated plant and Allium schoenoprasum tissue culture organs antioxidant status.
This study was designed to examine Allium schoenoprasum tissue culture organs antioxidant and scavenging activity and to make a comparison between Allium schoenoprasum cultivated plant and Allium schoenoprasum tissue culture organs antioxidant activity. This study reports the results on the root, stalk and leaf antioxidant enzyme activities (superoxide dismutase, catalase, guaiacol peroxidase and glutathione peroxidase), reduced glutathione quantity, flavonoids and soluble protein contents and quantities of malonyldialdehyde and ·OH radical. In Allium schoenoprasum tissue culture organs the total antioxidant capacity was determined by the FRAP method and scavenger activity by the DPPH method. The present results indicated that the crude extract of Allium schoenoprasum tissue culture exhibited antioxidant and scavenging abilities in all investigated plant parts, especially in the roots. According to our results, the tissue culture plants exhibited the highest activities in the roots in contrast to the cultivated plants where highest activities were observed in the leaves.


Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate.
It is generally thought that venlafaxine raises blood pressure at higher doses; however, some studies have found no effect or a decrease in blood pressure. The aim of this study was to evaluate the cardiovascular (CV) effects of 3 weeks of dosing with venlafaxine, pregabalin and placebo on young healthy adults. Fifty-four participants, of mean age 23.1 years (sd 4.68), 29 male, were randomised into three parallel groups. Each group received one of the three drugs, dosed incrementally over a 3-week period to reach daily doses of 150 mg/day venlafaxine and 200 mg/day pregabalin. Blood pressure sphygmomanometer measurements, heart rate measurements, and orthostatic challenges recorded continuously beat-to-beat were performed weekly over this period and 5 days after treatment cessation. Results showed resting systolic blood pressure (SBP) and resting and standing diastolic blood pressure (DBP) and heart rate (HR) were significantly raised by venlafaxine compared with the pregabalin and placebo groups. SBP drop on standing was larger, the resulting overshoot was smaller, and recovery was slower on venlafaxine. HR recovery was significantly impaired by venlafaxine. CV changes were observed after only 1 week of dosing at 112.5 mg/day. These effects of venlafaxine are likely to be due to its action of noradrenergic reuptake inhibition.


Surface modification of cell culture carriers: routes to anhydride functionalization of polystyrene.
Physico-chemical and topographical cues allow to control the behavior of adherent cells. Towards this goal, commercially available cell culture carriers can be finished with a laterally microstructured biomolecular functionalization. As shown in a previous study [Biomacromolecules 4 (2003) 1072], the anhydride moiety facilitates a simple and versatile way to protein binding. The present work addresses the technical issue of anhydride surface functionalization of polystyrene, the most common material for cell culture ware. Different approaches based on low pressure plasma, electron beam and ultraviolet light techniques (i.e. maleic anhydride plasma reactions; plasma, electron beam and UV immobilization of functional polymer thin films; grafting of functional polymers to plasma activated surfaces) are introduced and briefly illustrated with examples. Results are characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS) and ellipsometry. The different routes are compared in terms of technical feasibility and achievable surface properties.


Three-dimensional shape measurement of non-full-field reflective surfaces.
We describe a technique for the measurement of non-full-field reflective surfaces by using phase-stepping profilometry. We explain the principles of phase demodulation and discuss three-dimensional (3-D) height reconstruction in the case of measuring surfaces with reflective properties such as plain glass and mirrored glass. A number of required calibration algorithms are described to obtain surface slopes and reconstructed 3-D heights of the whole surface. Masking for non-full-field objects and the surface reconstruction procedure are demonstrated mathematically and algorithmically. Several experimental results are given for glass with different shapes and defects. Measurement of a spherical mirror with a known radius has also allowed us to show the performance of the proposed technique. This allows for the possibility to compare 3-D data from the known object with data taken from the measurement system.


A single center comparison of coiling versus stent assisted coiling in 90 consecutive paraophthalmic region aneurysms.
Aneurysm recurrence is a principle limitation of endovascular coiling procedures, with recurrence rates reported of >30%. The adjunct use of self-expandable stents has revolutionized the treatment of intracranial aneurysms, especially for complex morphologies, wide necks or unfavorable dome to neck ratios. However, further investigation into the durability and outcomes of stent assisted coiling procedures is required. The records of a prospective single center aneurysm database were retrospectively reviewed, and 90 consecutive patients with paraophthalmic aneurysms who underwent coil embolization were identified, 30 of which included stent placement. Patient demographics, aneurysm characteristics, coil packing density, angiographic results (initial and follow-up) and complications were analyzed. Complete aneurysm occlusion was obtained on initial angiography in 13/30 (43.3%) stented and 19/60 (31.7%) non-stented patients. At ≤24 months (mean follow-up 12.8±6.2 months for stented and 12.8±6.6 months for non-stented group), aneurysm recurrence occurred in 3/26 (11.5%) stented and 14/39 (35.9%) non-stented patients (p<0.05). At the longest follow-up (mean 14.5±12.5 months for stented and 37.6±35.3 months for non-stented), aneurysm recurrence occurred in 4/26 (15.4%) stented and 17/41 (41.5%) non-stented patients (p<0.03). There was no statistically significant correlation between recurrence and aneurysm size or coiling packing. Following endovascular coil embolization of paraophthalmic region aneurysms, recurrence rates at 2 years were significantly lower in patients who had stent assisted coiling (11.5%) compared with patients who had coiling procedures without the use of a stent (35.9%). Aneurysm size and coiling packing density did not significantly affect recurrence in our study population.


Administering an effective health intervention for smoking cessation online: the international users of Stop-Tabac.
The Internet has opened up new possibilities in public health, yet to date, there are few examples of online health interventions that go beyond information provision. This paper describes the users and return rates of an effective intervention for smoking cessation that has gone online. Open enrollment of smokers via links and search engines with voluntary follow-up for an Internet-based expert system in French and English. Between June 1998 and March 2001, 18,361 people from 112 countries used the program. When compared to the distribution of smokers in the general population in seven main countries, smokers in the action stage (11%) were overrepresented among online program users. Among the 3591 returnees in the study period (20%), we observed a median time to return of 132.5 days. One of the strongest predictors of return was stage of change with smokers in the action stage being most likely to return (28%) and those in the precontemplation stage least likely (14%). The reach of an online public health intervention can be impressive in geographical and numerical terms. Although the quality of behavioral data collected was high, the utility of this medium for science should be refined.


Progress in 13C and 1H solid-state nuclear magnetic resonance for paramagnetic systems under very fast magic angle spinning.
High-resolution solid-state NMR (SSNMR) of paramagnetic systems has been largely unexplored because of various technical difficulties due to large hyperfine shifts, which have limited the success of previous studies through depressed sensitivity/resolution and lack of suitable assignment methods. Our group recently introduced an approach using "very fast" magic angle spinning (VFMAS) for SSNMR of paramagnetic systems, which opened an avenue toward routine analyses of small paramagnetic systems by (13)C and (1)H SSNMR [Y. Ishii et al., J. Am. Chem. Soc. 125, 3438 (2003); N. P. Wickramasinghe et al., ibid. 127, 5796 (2005)]. In this review, we discuss our recent progress in establishing this approach, which offers solutions to a series of problems associated with large hyperfine shifts. First, we demonstrate that MAS at a spinning speed of 20 kHz or higher greatly improves sensitivity and resolution in both (1)H and (13)C SSNMR for paramagnetic systems such as Cu(II)(DL-alanine)(2)H(2)O (Cu(DL-Ala)(2)) and Mn(acac)(3), for which the spectral dispersions due to (1)H hyperfine shifts reach 200 and 700 ppm, respectively. Then, we introduce polarization transfer methods from (1)H spins to (13)C spins with high-power cross polarization and dipolar insensitive nuclei enhanced by polarization transfer (INEPT) in order to attain further sensitivity enhancement and to correlate (1)H and (13)C spins in two-dimensional (2D) SSNMR for the paramagnetic systems. Comparison of (13)C VFMAS SSNMR spectra with (13)C solution NMR spectra revealed superior sensitivity in SSNMR for Cu(DL-Ala)(2), Cu(Gly)(2), and V(acac)(3). We discuss signal assignment methods using one-dimensional (1D) (13)C SSNMR (13)C-(1)H rotational echo double resonance (REDOR) and dipolar INEPT methods and 2D (13)C(1)H correlation SSNMR under VFMAS, which yield reliable assignments of (1)H and (13)C resonances for Cu(Ala-Thr). Based on the excellent sensitivity/resolution and signal assignments attained in the VFMAS approach, we discuss methods of elucidating multiple distance constraints in unlabeled paramagnetic systems by combing simple measurements of (13)C T(1) values and anisotropic hyperfine shifts. Comparison of experimental (13)C hyperfine shifts and ab initio calculated shifts for alpha- and beta-forms of Cu(8-quinolinol)(2) demonstrates that (13)C hyperfine shifts are parameters exceptionally sensitive to small structural difference between the two polymorphs. Finally, we discuss sensitivity enhancement with paramagnetic ion doping in (13)C SSNMR of nonparamagnetic proteins in microcrystals. Fast recycling with exceptionally short recycle delays matched to short (1)H T(1) of approximately 60 ms in the presence of Cu(II) doping accelerated 1D (13)C SSNMR for ubiquitin and lysozyme by a factor of 7.3-8.4 under fast MAS at a spinning speed of 40 kHz. It is likely that the VFMAS approach and use of paramagnetic interactions are applicable to a variety of paramagnetic systems and nonparamagnetic biomolecules.


Determination of subcutaneous tumor size in athymic (nude) mice.
The athymic (nude) mouse is a useful model for studying the biology and response to therapies of human tumors in vivo. A survey of recent literature revealed the use of 19 different formulas for determining the size of subcutaneous tumors grown as xenografts in nude mice (2 for determining tumor area, 3 for tumor diameter, and 14 for calculating tumor volume). We compared the volumes, areas, and diameters predicted by each of the 19 formulas with the actual weights of 50 tumors ranging from 0.46 to 22.0 g established in nude mice as xenografts from human cell lines. In addition to determining how well each formula predicted relative tumor size, we analyzed how well each formula estimated actual tumor mass. The ellipsoid volume formulas (pi/6 x L x W x H and 1/2 x L x W x H) were best for estimating tumor mass (r = 0.93), whereas measurements of diameter correlated poorly with tumor mass (r less than 0.66). Although determination of tumor area correlated well with tumor mass in small tumors (r = 0.89), correlations of area with tumor mass for large tumors were poor (r = 0.41). We conclude that determination of the ellipsoid volume from measurements of three axes consistently yields the most accurate estimations of both relative and actual tumor mass.


Diagnostic accuracy of the Edinburgh Postnatal Depression Scale (EPDS) for detecting major depression in pregnant and postnatal women: protocol for a systematic review and individual patient data meta-analyses.
Studies of the diagnostic accuracy of depression screening tools often used data-driven methods to select optimal cut-offs. Typically, these studies report results from a small range of cut-off points around whatever cut-off score is identified as most accurate. When published data are combined in meta-analyses, estimates of accuracy for different cut-off points may be based on data from different studies, rather than data from all studies for each cut-off point. Thus, traditional meta-analyses may exaggerate accuracy estimates. Individual patient data (IPD) meta-analyses synthesise data from all studies for each cut-off score to obtain accuracy estimates. The 10-item Edinburgh Postnatal Depression Scale (EPDS) is commonly recommended for depression screening in the perinatal period. The primary objective of this IPD meta-analysis is to determine the diagnostic accuracy of the EPDS to detect major depression among women during pregnancy and in the postpartum period across all potentially relevant cut-off scores, accounting for patient factors that may influence accuracy (age, pregnancy vs postpartum). Data sources will include Medline, Medline In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science. Studies that include a diagnosis of major depression based on a validated structured or semistructured clinical interview administered within 2 weeks of (before or after) the administration of the EPDS will be included. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values. Analyses will evaluate data from pregnancy and the postpartum period separately, as well as combining data from all women in a single model. This study does not require ethics approval. Dissemination will include journal articles and presentations to policymakers, healthcare providers and researchers. PROSPERO 2015:CRD42015024785.


Development and application of genomic control methods for genome-wide association studies using non-additive models.
Genome-wide association studies (GWAS) comprise a powerful tool for mapping genes of complex traits. However, an inflation of the test statistic can occur because of population substructure or cryptic relatedness, which could cause spurious associations. If information on a large number of genetic markers is available, adjusting the analysis results by using the method of genomic control (GC) is possible. GC was originally proposed to correct the Cochran-Armitage additive trend test. For non-additive models, correction has been shown to depend on allele frequencies. Therefore, usage of GC is limited to situations where allele frequencies of null markers and candidate markers are matched. In this work, we extended the capabilities of the GC method for non-additive models, which allows us to use null markers with arbitrary allele frequencies for GC. Analytical expressions for the inflation of a test statistic describing its dependency on allele frequency and several population parameters were obtained for recessive, dominant, and over-dominant models of inheritance. We proposed a method to estimate these required population parameters. Furthermore, we suggested a GC method based on approximation of the correction coefficient by a polynomial of allele frequency and described procedures to correct the genotypic (two degrees of freedom) test for cases when the model of inheritance is unknown. Statistical properties of the described methods were investigated using simulated and real data. We demonstrated that all considered methods were effective in controlling type 1 error in the presence of genetic substructure. The proposed GC methods can be applied to statistical tests for GWAS with various models of inheritance. All methods developed and tested in this work were implemented using R language as a part of the GenABEL package.


The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling.
The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.


Extremely low-frequency magnetic fields and risk of childhood leukemia: A risk assessment by the ARIMMORA consortium.
Exposure to extremely low-frequency magnetic fields (ELF-MF) was evaluated in an International Agency for Research on Cancer (IARC) Monographs as "possibly carcinogenic to humans" in 2001, based on increased childhood leukemia risk observed in epidemiological studies. We conducted a hazard assessment using available scientific evidence published before March 2015, with inclusion of new research findings from the Advanced Research on Interaction Mechanisms of electroMagnetic exposures with Organisms for Risk Assessment (ARIMMORA) project. The IARC Monograph evaluation scheme was applied to hazard identification. In ARIMMORA for the first time, a transgenic mouse model was used to mimic the most common childhood leukemia: new pathogenic mechanisms were indicated, but more data are needed to draw definitive conclusions. Although experiments in different animal strains showed exposure-related decreases of CD8+ T-cells, a role in carcinogenesis must be further established. No direct damage of DNA by exposure was observed. Overall in the literature, there is limited evidence of carcinogenicity in humans and inadequate evidence of carcinogenicity in experimental animals, with only weak supporting evidence from mechanistic studies. New exposure data from ARIMMORA confirmed that if the association is nevertheless causal, up to 2% of childhood leukemias in Europe, as previously estimated, may be attributable to ELF-MF. In summary, ARIMMORA concludes that the relationship between ELF-MF and childhood leukemia remains consistent with possible carcinogenicity in humans. While this scientific uncertainty is dissatisfactory for science and public health, new mechanistic insight from ARIMMORA experiments points to future research that could provide a step-change in future assessments. Bioelectromagnetics. 37:183-189, 2016. © 2016 Wiley Periodicals, Inc.


Extraction of Aortic Knuckle Contour in Chest Radiographs Using Deep Learning.
In this paper, we aim to extract the aortic knuckle (AK) contour in chest radiographs, an anatomical structure rarely being addressed in the literature. Since the AK structure is small and thin, simply adopting the deep network methods that are successful for large organ segmentation is inadequate for achieving good pixel-level accuracy and resolving local ambiguities. To address this challenge, we propose a new coarse-to-fine segmentation approach which focuses on global and local information contexts, respectively. Two convolutional networks are used. For the coarse segmentation, we use FasterRCNN; for the fine segmentation, we use U-Net. Our evaluation uses the publicly available JSRT dataset; the results are promising. Besides presenting these results, we analyze issues such as the imprecision of manual contour marking, and automatic generation of the coarse segmentation ground-truth mask used for deep network training. Our approach is general and can be applied to extract other curve-like objects-of-interest.


Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO, and AUA Evidence-Based Guideline.
The aim of this guideline is to present recommendations regarding moderately hypofractionated (240-340 cGy per fraction) and ultrahypofractionated (500 cGy or more per fraction) radiation therapy for localized prostate cancer. The American Society for Radiation Oncology convened a task force to address 8 key questions on appropriate indications and dose-fractionation for moderately and ultrahypofractionated radiation therapy, as well as technical issues, including normal tissue dose constraints, treatment volumes, and use of image guided and intensity modulated radiation therapy. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and Society-approved tools for grading evidence quality and recommendation strength. Based on high-quality evidence, strong consensus was reached for offering moderate hypofractionation across risk groups to patients choosing external beam radiation therapy. The task force conditionally recommends ultrahypofractionated radiation may be offered for low- and intermediate-risk prostate cancer but strongly encourages treatment of intermediate-risk patients on a clinical trial or multi-institutional registry. For high-risk patients, the task force conditionally recommends against routine use of ultrahypofractionated external beam radiation therapy. With any hypofractionated approach, the task force strongly recommends image guided radiation therapy and avoidance of nonmodulated 3-dimensional conformal techniques. Hypofractionated radiation therapy provides important potential advantages in cost and convenience for patients, and these recommendations are intended to provide guidance on moderate hypofractionation and ultrahypofractionation for localized prostate cancer. The limits in the current evidentiary base-especially for ultrahypofractionation-highlight the imperative to support large-scale randomized clinical trials and underscore the importance of shared decision making between clinicians and patients.


AN AGGRESSIVE TEMPORAL BONE SDHC PARAGANGLIOMA ASSOCIATED WITH INCREASED HIF-2α SIGNALING.
To describe a patient with a germline succinate dehydrogenase (SDHC) gene mutation presenting with primary hyperparathyroidism and a large catecholamine-producing temporal bone paraganglioma (PGL). Evaluation of a SDHC mutation-positive PGL tumor biology using staining for tyrosine hydroxylase (TH), hypoxia-inducible factors 1α (HIF-1α) and 2α (HIF-2α). A 66-year-old man was noted to have a lytic skull base mass during work-up for his primary hyperparathyroidism. Biochemical evaluation with 24-hour urine catecholamines and metanephrines revealed marked elevation of norepinephrine and normetanephrine. Genetic testing revealed a germline SDHC mutation. A partial excision of skull base tumor was performed, which upon further examination revealed PGL. Immunohistochemistry of skull base PGL demonstrated heavy expression of TH and HIF-2α but reduced expression of HIF-1α. The remaining skull base PGL was treated with adjuvant radiation therapy. The patient's normetanephrine levels significantly decreased after surgery and radiation. Here, we report an unusual case of a patient presenting with a germline SDHC mutation-related functional PGL along with concomitant primary hyperparathyroidism. The present case illustrates that overexpression of HIF-2α but not of HIF-1α is linked to the pathogenesis of SDHC mutation-related PGL, and it may be responsible for the aggressive clinical behavior of a usually indolent course of SDHC-related PGLs.


A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.
The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.


Acceleration of rare disease therapeutic development: a case study of AGIL-AADC.
Rare-disease drug development is both scientifically and commercially challenging. This case study highlights Agilis Biotherapeutics (Agilis), a small private biotechnology company that has developed the most clinically advanced adeno-associated virus (AAV) gene therapy for the brain. In an international collaboration led by Agilis with National Taiwan University (NTU) Hospital and the Therapeutics for Rare and Neglected Diseases (TRND) program of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health, Agilis' gene therapy for aromatic l-amino acid decarboxylase deficiency (AADC), AGIL-AADC, was granted biologics license application (BLA)-ready status by the FDA in 2018, only 18 months after being licensed from NTU by Agilis. Here, we highlight the factors that enabled this remarkable pace of successful drug development for an ultra-rare disease.


Normal motor adaptation in cervical dystonia: a fundamental cerebellar computation is intact.
The potential role of the cerebellum in the pathophysiology of dystonia has become a focus of recent research. However, direct evidence for a cerebellar contribution in humans with dystonia is difficult to obtain. We examined motor adaptation, a test of cerebellar function, in 20 subjects with primary cervical dystonia and an equal number of aged matched controls. Adaptation to both visuomotor (distorting visual feedback by 30°) and forcefield (applying a velocity-dependent force) conditions were tested. Our hypothesis was that cerebellar abnormalities observed in dystonia research would translate into deficits of cerebellar adaptation. We also examined the relationship between adaptation and dystonic head tremor as many primary tremor models implicate the cerebellothalamocortical network which is specifically tested by this motor paradigm. Rates of adaptation (learning) in cervical dystonia were identical to healthy controls in both visuomotor and forcefield tasks. Furthermore, the ability to adapt was not clearly related to clinical features of dystonic head tremor. We have shown that a key motor control function of the cerebellum is intact in the most common form of primary dystonia. These results have important implications for current anatomical models of the pathophysiology of dystonia. It is important to attempt to progress from general statements that implicate the cerebellum to a more specific evidence-based model. The role of the cerebellum in this enigmatic disease perhaps remains to be proven.


Synthetic peptide arrays for pathway-level protein monitoring by liquid chromatography-tandem mass spectrometry.
Effective methods to detect and quantify functionally linked regulatory proteins in complex biological samples are essential for investigating mammalian signaling pathways. Traditional immunoassays depend on proprietary reagents that are difficult to generate and multiplex, whereas global proteomic profiling can be tedious and can miss low abundance proteins. Here, we report a target-driven liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy for selectively examining the levels of multiple low abundance components of signaling pathways which are refractory to standard shotgun screening procedures and hence appear limited in current MS/MS repositories. Our stepwise approach consists of: (i) synthesizing microscale peptide arrays, including heavy isotope-labeled internal standards, for use as high quality references to (ii) build empirically validated high density LC-MS/MS detection assays with a retention time scheduling system that can be used to (iii) identify and quantify endogenous low abundance protein targets in complex biological mixtures with high accuracy by correlation to a spectral database using new software tools. The method offers a flexible, rapid, and cost-effective means for routine proteomic exploration of biological systems including "label-free" quantification, while minimizing spurious interferences. As proof-of-concept, we have examined the abundance of transcription factors and protein kinases mediating pluripotency and self-renewal in embryonic stem cell populations.


Dynamic thiol/disulphide homeostasis in acute pancreatitis.
The dynamic thiol/disulfide homeostasis plays pivotal roles in many physiological mechanisms in an organism. We aimed to investigate whether dynamic thiol/disulfide homeostasis changes among patients with acute pancreatitis. This prospective trial contained 45 patients with acute pancreatitis and 45 sex-and age-matched healthy volunteers as control group. Thiol/disulfide homeostasis parameters were measured by a novel and automated assay, and detected results were compared between the two groups. Disulfide/total thiol percent ratio and disulfide/native thiol percent ratios were significantly higher in acute pancreatitis group; besides the native thiol, total thiol levels and native thiol/total thiol percent ratios were significantly lower (for all p < 0.001). The thiol/disulfide homeostasis is impaired in acute pancreatitis with a shift toward the oxidative status, and this deficiency might be a pathogenic factor in acute pancreatitis. The correction of this thiol/disulfide imbalance may be a new target in the management of acute pancreatitis.


Development of a System for Studying the Morphology and Dynamics of Agglomerated Flame Particulates by use of Dynamic Light Scattering.
An experimental system for the study of the morphological and dynamic properties of flame-generated agglomerates by use of both polarized (vertical-vertical polarization orientation) and depolarized (vertical-horizontal polarization orientation) dynamic light scattering (DLS) was developed and tested. The system consists of a flame reactor for generating chainlike agglomerates of Fe(2)O(3) in an Fe(CO)(5)-seeded CO-O(2) diffusion flame and a light-scattering spectrometer for performing polarized and depolarized DLS measurements of the agglomerates' dynamic properties. It is demonstrated for the first time that one can successfully obtain depolarized DLS correlation functions from a flame environment by combining the results of a series of measurements obtained using a cross-correlation detection system.


Cumulative effects of exposure to violence on posttraumatic stress in Palestinian and Israeli youth.
We examine cumulative and prospective effects of exposure to conflict and violence across four contexts (ethnic-political, community, family, school) on posttraumatic stress (PTS) symptoms in Palestinian and Israeli youth. Interviews were conducted with 600 Palestinian and 901 Israeli (Jewish and Arab) children (ages 8, 11, and 14) and their parents once a year for 3 consecutive years. Palestinian children, males, and older youth were generally at greatest risk for exposure to conflict/violence across contexts. Regression analysis found unique effects of exposure to ethnic-political (Palestinian sample), school (Palestinian and Israeli Jewish samples), and family conflict/violence (Israeli Arab sample) during the first 2 years on PTS symptoms in Year 3, controlling for prior PTS symptoms. Cumulative exposure to violence in more contexts during the first 2 years predicted higher subsequent PTS symptoms than did exposure to violence in fewer contexts, and this was true regardless of the youth's level of prior PTS symptoms. These results highlight the risk that ongoing exposure to violence across multiple contexts in the social ecology poses for the mental health of children in contexts of ethnic-political violence. Researchers and mental health professionals working with war-exposed youth in a given cultural context must assess both war- and non-war-related stressors affecting youth. Based on this assessment, interventions may not be limited to individual-based, war-trauma-focused approaches but also may include school-based, community-based, and family-level interventions.