High proportion of cactus species threatened with extinction.
A high proportion of plant species is predicted to be threatened with extinction in the near future. However, the threat status of only a small number has been evaluated compared with key animal groups, rendering the magnitude and nature of the risks plants face unclear. Here we report the results of a global species assessment for the largest plant taxon evaluated to date under the International Union for Conservation of Nature (IUCN) Red List Categories and Criteria, the iconic Cactaceae (cacti). We show that cacti are among the most threatened taxonomic groups assessed to date, with 31% of the 1,478 evaluated species threatened, demonstrating the high anthropogenic pressures on biodiversity in arid lands. The distribution of threatened species and the predominant threatening processes and drivers are different to those described for other taxa. The most significant threat processes comprise land conversion to agriculture and aquaculture, collection as biological resources, and residential and commercial development. The dominant drivers of extinction risk are the unscrupulous collection of live plants and seeds for horticultural trade and private ornamental collections, smallholder livestock ranching and smallholder annual agriculture. Our findings demonstrate that global species assessments are readily achievable for major groups of plants with relatively moderate resources, and highlight different conservation priorities and actions to those derived from species assessments of key animal groups.


Acute kidney injury after burn.
Acute kidney injury (AKI) is a common and morbid complication after severe burn, with an incidence and mortality as high as 30% and 80%, respectively. AKI is a broad clinical condition with many etiologies, which makes definition and diagnosis challenging. The most recent Kidney Disease: Improving Global Outcomes (KDIGO) consensus guidelines defined stage and severity of AKI based on changes of serum creatinine and urine output (UOP) across time. Burn-related kidney injury is typically classified as early (0-3days after injury) or late (4-14days after injury). Early burn AKI is typically due to hypovolemia, poor renal perfusion, direct cardiac suppression from TNF-alpha, and precipitation of denatured proteins, while late AKI is often due to sepsis, multi-organ failure, and nephrotoxic drugs. Diagnosis can be difficult as UOP and biochemical markers can be relatively normal even with significant renal injury. A sensitive and specific biomarker for the early diagnosis of AKI is sorely needed, and multiple potential biomarkers are being investigated. For treatment, the reversal of the underlying cause is the first intervention. The advent of renal replacement therapy has significantly improved the mortality of burn patients with AKI and should be initiated early if injury progresses despite initial maneuvers. Unfortunately, no beneficial pharmacologic agents have been identified, despite multiple investigations. Of burn patients who survive AKI, the vast majority do not receive long-term hemodialysis and they are generally thought to have a good renal prognosis although this view is shifting. Preliminary data in the burn population suggest that AKI may confer an increased risk of end-stage renal disease and long-term all-cause mortality, but further research is needed.


In vitro lipid digestion in raw and roasted hazelnut particles and oil bodies.
Previous studies have proved that the physical encapsulation of nutrients by the cell walls of plant foods modulates macronutrient bioaccessibility during human digestion. In this study, we investigated structural factors that modulate lipid hydrolysis during in vitro digestion of raw and roasted hazelnut particles and isolated oil bodies. Isolated oil bodies exhibited a significantly higher lipid hydrolysis compared to hazelnut particles. Moreover, roasting had an impact on the structure of hazelnut cell walls implying a more efficient diffusion of digestive fluids and enzymes into the hazelnut cells. Heat treatment also caused destabilization of oil body interfacial protein membranes, facilitating their proteolysis under gastric conditions, altering the emulsion properties and enhancing fatty acid release during intestinal digestion. This study underlined the barrier role played by the plant cell wall as well as the impact of heat processing on lipid bioaccessibility in hazelnuts.


Does early exercise attenuate muscle atrophy or bone loss after spinal cord injury?
To systematically identify and assess the evidence on the efficacy of exercise initiated early after traumatic spinal cord injury (SCI). A comprehensive search (Any-2014) of eleven databases identified studies evaluating exercise interventions initiated within 12 weeks after SCI on muscle and bone loss in paralyzed limbs and comparing with standard care or immobilization. Two reviewers assessed methodological quality. One reviewer extracted data and critiqued results according to the Spinal Cord Injury Rehabilitation Evidence body of evidence framework. A total of 2811 titles were screened. Eleven studies were included: five randomized controlled trials, four cohort studies and two within-subject control studies. All provided level II evidence with a moderate risk of bias. Two studies found significant positive effects of high-load FES-resisted stance on physiological measures of muscle. Three reported positive effects of 3 months of Functional Electrical Stimulation (FES) on muscle size. Two studies found positive effects of 6-month body-weight supported treadmill training or FES on trabecular bone using pQCT. We found consistent evidence of positive effects of early exercise on muscle, possibly related to load intensity of the protocol. However, the heterogeneity of interventions and outcomes makes this determination speculative. Evidence for the effectiveness of early exercise on bone is scant and confined to measures of trabecular bone mineral density via pQCT. Transparent reporting of methods and variability of data, combined with standardization of valid and sensitive measures of muscle atrophy and bone loss, could facilitate future meta-analysis on this topic.


Recollection in the human hippocampal-entorhinal cell circuitry.
Imagine how flicking through your photo album and seeing a picture of a beach sunset brings back fond memories of a tasty cocktail you had that night. Computational models suggest that upon receiving a partial memory cue ('beach'), neurons in the hippocampus coordinate reinstatement of associated memories ('cocktail') in cortical target sites. Here, using human single neuron recordings, we show that hippocampal firing rates are elevated from ~ 500-1500 ms after cue onset during successful associative retrieval. Concurrently, the retrieved target object can be decoded from population spike patterns in adjacent entorhinal cortex (EC), with hippocampal firing preceding EC spikes and predicting the fidelity of EC object reinstatement. Prior to orchestrating reinstatement, a separate population of hippocampal neurons distinguishes different scene cues (buildings vs. landscapes). These results elucidate the hippocampal-entorhinal circuit dynamics for memory recall and reconcile disparate views on the role of the hippocampus in scene processing vs. associative memory.


Revised international prognostic scoring system for myelodysplastic syndromes.
The International Prognostic Scoring System (IPSS) is an important standard for assessing prognosis of primary untreated adult patients with myelodysplastic syndromes (MDS). To refine the IPSS, MDS patient databases from international institutions were coalesced to assemble a much larger combined database (Revised-IPSS [IPSS-R], n = 7012, IPSS, n = 816) for analysis. Multiple statistically weighted clinical features were used to generate a prognostic categorization model. Bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation. This system comprehensively integrated the numerous known clinical features into a method analyzing MDS patient prognosis more precisely than the initial IPSS. As such, this IPSS-R should prove beneficial for predicting the clinical outcomes of untreated MDS patients and aiding design and analysis of clinical trials in this disease.


Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells.
Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use of xenogeneic tissue transplantation for conditions such as Parkinson's disease. The current study sought to provide insight into the cellular components of donor cell suspensions that are important in stimulating the host rejection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neural stem cell mitogens, epidermal growth factor and fibroblast growth factor-2, have been used to isolate and expand populations of primordial neural precursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised. In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. While equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive projections were present at all time-points, and two large grafts remained even at 60 days. Some grafts appeared to elicit minimal host immune responses at the time-points they were examined, although most did appear to be undergoing a rejection process since a co-ordinated response involving host cytotoxic T-lymphocytes, microglia/macrophages, immunoglobulin M and complement could be demonstrated to varying degrees. Subsequent experiments went on to demonstrate further that expanded precursor populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursors. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations.The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral grafting is reduced when neural stem cell mitogens are used to expand precursor cells. The implications of these findings in the development of novel xenogeneic cellular therapies for neurodegenerative conditions such as Parkinson's disease are discussed.


The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes.
Many cell types undergo apoptosis under conditions of ischemia. Little is known, however, about the molecular pathways that mediate this response. A cellular and biochemical approach to elucidate such signaling pathways was undertaken in primary cultures of cardiac myocytes, a cell type that is especially sensitive to ischemia-induced apoptosis. Deprivation of serum and glucose, components of ischemia in vivo, resulted in myocyte apoptosis, as determined by nuclear fragmentation, internucleosomal cleavage of DNA, and processing of caspase substrates. These manifestations of apoptosis were blocked by zVAD-fmk, a peptide caspase inhibitor, indicating that caspase activity is necessary for the progression of apoptosis in this model. In contrast to control cells, apoptotic myocytes exhibited cytoplasmic accumulation of cytochrome c, indicating release from the mitochondria. Furthermore, both caspase-9 and caspase-3 were processed to their active forms in serum-/glucose-deprived myocytes. Caspase processing, but not cytochrome c release, was inhibited by zVAD-fmk, placing the latter event upstream of caspase activation. This evidence demonstrates that components of ischemia activate the mitochondrial death pathway in cardiac myocytes.


MycDB: an integrated mycobacterial database.
As part of ongoing efforts to investigate the molecular biology of the human pathogens in the genus Mycobacterium, a customized database was developed specifically for these organisms and implemented in ACEDB database manager software. The data loaded include the IMMYC Antigen List, details of reagents available from the CDC/WHO Antibody Bank, more than 1 Mb of sequences of mycobacterial genes and proteins from public databases, the physical maps of Mycobacterium leprae and Mycobacterium tuberculosis developed at the Institut Pasteur, as well as a subset of the references found in MedLine. The ACEDB software allows both quick and intuitive access to the data and to connections between facts by a simple mouse-driven interface, as well as by more powerful query mechanisms.


The Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey: developing hospital-quality indicators of antibiotic prescribing for children.
Previously, web-based tools for cross-sectional antimicrobial point prevalence surveys (PPSs) have been used in adults to develop indicators of quality improvement. We aimed to determine the feasibility of developing similar quality indicators of improved antimicrobial prescribing focusing specifically on hospitalized neonates and children worldwide. A standardized antimicrobial PPS method was employed. Included were all inpatient children and neonates receiving an antimicrobial at 8:00 am on the day of the PPS. Denominators included the total number of inpatients. A web-based application was used for data entry, validation and reporting. We analysed 2012 data from 226 hospitals (H) in 41 countries (C) from Europe (174H; 24C), Africa (6H; 4C), Asia (25H; 8C), Australia (6H), Latin America (11H; 3C) and North America (4H). Of 17,693 admissions, 6499 (36.7%) inpatients received at least one antimicrobial, but this varied considerably between wards and regions. Potential indicators included very high broad-spectrum antibiotic prescribing in children of mainly ceftriaxone (ranked first in Eastern Europe, 31.3%; Asia, 13.0%; Southern Europe, 9.8%), cefepime (ranked third in North America, 7.8%) and meropenem (ranked first in Latin America, 13.1%). The survey identified worryingly high use of critically important antibiotics for hospital-acquired infections in neonates (34.9%; range from 14.2% in Africa to 68.0% in Latin America) compared with children (28.3%; range from 14.5% in Africa to 48.9% in Latin America). Parenteral administration was very common among children in Asia (88%), Latin America (81%) and Europe (67%). Documentation of the reasons for antibiotic prescribing was lowest in Latin America (52%). Prolonged surgical prophylaxis rates ranged from 78% (Europe) to 84% (Latin America). Simple web-based PPS tools provide a feasible method to identify areas for improvement of antibiotic use, to set benchmarks and to monitor future interventions in hospitalized neonates and children. To our knowledge, this study has derived the first global quality indicators for antibiotic use in hospitalized neonates and children.


Effect of Maturing Stages on Bioactive Properties, Fatty Acid Compositions, and Phenolic Compounds of Peanut (Arachis hypogaea L.) Kernels Harvested at Different Harvest Times.
The present study investigated the effects of harvesting time on the physicochemical properties, antioxidant activity, fatty acid composition, and phenolic compounds of peanut kernels. The moisture content (air-dried basis) of peanut kernels was determined between 4.47% (September 15, 2019) and 7.93% (October 6, 2019), whereas the oil contents changed from 45.95% (October 6, 2019) to 49.25% (September 22, 2019). The total carotenoid, chlorophyll, and phenolic contents were low throughout the harvest, showing differences depending on the harvest time. Total phenolic content changed from 0.28 mg GAE/L (September 29, 2019) to 0.43 mg GAE/L (September 8, 2019), whereas the antioxidant activity varied from 4.42% (August 25, 2019) to 4.70% (September 1, 2019). The dominant fatty acids were palmitic, oleic, and linoleic acids, depending on the harvest time, followed by stearic, behenic, arachidic, and linolenic acids. The (+)-catechin content ranged from 2.17 mg/L (September 8, 2019) to 5.15 mg/L (September 1, 2019), whereas 1,2-dihydroxybenzene content changed between 2.67 mg/L (October 6, 2019) and 5.85 mg/L (September 29, 2019). The phenolic compound content fluctuated depending on the harvest time. The results showed that peanut kernel and oil had distinctive phenolic profiles and fatty acid contents. The findings of the present study may provide information for the best time to harvest peanut to achieve its maximum health benefits.


Persistent behavioral alterations in rats neonatally exposed to low doses of the organophosphate pesticide, parathion.
Although developmental exposures of rats to low levels of the organophosphate pesticides (OPs), chlorpyrifos (CPF) or diazinon (DZN), both cause persistent neurobehavioral effects, there are important differences in their neurotoxicity. The current study extended investigation to parathion (PTN), an OP that has higher systemic toxicity than either CPF or DZN. We gave PTN on postnatal days (PND) 1-4 at doses spanning the threshold for systemic toxicity (0, 0.1 or 0.2 mg/kg/day, s.c.) and performed a battery of emotional and cognitive behavioral tests in adolescence through adulthood. The higher PTN dose increased time spent on the open arms and the number of center crossings in the plus maze, indicating greater risk-taking and overall activity. This group also showed a decrease in tactile startle response without altering prepulse inhibition, indicating a blunted acute sensorimotor reaction without alteration in sensorimotor plasticity. T-maze spontaneous alternation, novelty-suppressed feeding, preference for sweetened chocolate milk, and locomotor activity were not significantly affected by neonatal PTN exposure. During radial-arm maze acquisition, rats given the lower PTN dose committed fewer errors compared to controls and displayed lower sensitivity to the amnestic effects of the NMDA receptor blocker, dizocilpine. No PTN effects were observed with regard to the sensitivity to blockade of muscarinic and nicotinic cholinergic receptors, or serotonin 5HT(2) receptors. This study shows that neonatal PTN exposure evokes long-term changes in behavior, but the effects are less severe, and in some incidences opposite in nature, to those seen earlier for CPF or DZN, findings consistent with our neurochemical studies showing different patterns of effects and less neurotoxic damage with PTN. Our results reinforce the conclusion that low dose exposure to different OPs can have quite different neurotoxic effects, obviously unconnected to their shared property as cholinesterase inhibitors.


Union women, the tobacco industry, and excise taxes: a lesson in unintended consequences.
Between 1987 and 1997, the tobacco industry used the issue of cigarette excise tax increases to create a political partnership with the Coalition of Labor Union Women (CLUW), a group representing female trade unionists in the U.S. This paper documents how the industry created this relationship and the lessons tobacco-control advocates can learn from the industry's example, in order to mitigate possible unintended consequences of advocating excise tax increases. In 1998, under the terms of the Master Settlement Agreement, the tobacco industry began making documents produced in litigation available publicly. Currently, approximately 50 million pages are available online, including substantial documentation of the industry-CLUW relationship. For this study, a comprehensive search of these documents was conducted. The tobacco industry encouraged CLUW's opposition to excise tax increases by emphasizing the economic regressivity of these taxes, discussing excise taxes generically to deflect attention from cigarettes, and encouraging opposition to earmarking cigarette taxes to pay for specific programs. In addition, CLUW received at least $221,500 in financial support between 1987 and 1997 and in-kind support for its conferences, membership materials, and other services. Excise tax increases, if pursued without considering the impacts they may have on low-SES populations, may have unintended consequences. In this case, such proposals may have helped to create a relationship between CLUW and the tobacco industry. Because excise taxes are endorsed in the Framework Convention on Tobacco Control, tobacco-control advocates must understand how to build relationships with low-SES populations and mitigate potential alliances with the tobacco industry.


Between two roles - Experiences of newly trained nurse practitioners in surgical care in Sweden: A qualitative study using repeated interviews.
The position of Nurse Practitioner is a new role in Nordic countries. The transition from a registered nurse to the Nurse Practitioner role has been reported to be a personal challenge. This study, guided by the Nordic theoretical model for use in the education of advanced practice nurses, represents a unique opportunity to describe this transition for newly graduated Nurse Practitioners in an interprofessional surgical care team in Sweden. The aim was to explore how the first Nurse Practitioners in surgical care experienced the transition into a new role and what competences they used in the team. Eight new Nurse Practitioners with parallel work in clinical practice were interviewed twice around the time of their graduation. The qualitative analyses show that the participants integrated several central competences, but the focus in this early stage in their new role was on direct clinical praxis, consultation, cooperation, case management, and coaching. Transition from the role of clinical nurse specialist to nurse practitioner was a challenging process in which the positive response from patients was a driving force for the new Nurse Practitioners. The participants felt prepared for and determined to solve the challenging situations they approached working in the interprofessional team.


Theoretical description and experimental simulation of quantum entanglement near open time-like curves via pseudo-density operators.
Closed timelike curves are striking predictions of general relativity allowing for time-travel. They are afflicted by notorious causality issues (e.g. grandfather's paradox). Quantum models where a qubit travels back in time solve these problems, at the cost of violating quantum theory's linearity-leading e.g. to universal quantum cloning. Interestingly, linearity is violated even by open timelike curves (OTCs), where the qubit does not interact with its past copy, but is initially entangled with another qubit. Non-linear dynamics is needed to avoid violating entanglement monogamy. Here we propose an alternative approach to OTCs, allowing for monogamy violations. Specifically, we describe the qubit in the OTC via a pseudo-density operator-a unified descriptor of both temporal and spatial correlations. We also simulate the monogamy violation with polarization-entangled photons, providing a pseudo-density operator quantum tomography. Remarkably, our proposal applies to any space-time correlations violating entanglement monogamy, such as those arising in black holes.


Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals.
Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.


Does Participation in Sports Affect Osteoarthritic Progression After Periacetabular Osteotomy?
Periacetabular osteotomy (PAO) is an effective treatment for symptomatic acetabular dysplasia. However, whether postoperative participation in sports leads to progression of the Kellgren-Lawrence (KL) grade of osteoarthritis (OA) in these patients is unclear. To investigate (1) participation in sports before and after PAO and (2) whether postoperative participation in sports leads to progression of the KL grade. Case-control study; Level of evidence, 3. The authors retrospectively reviewed data on 161 patients (183 hips) who underwent PAO for symptomatic acetabular dysplasia with preoperative KL grade 1 or 2 between 1998 and 2011. The mean age at the time of surgery was 42.0 ± 10.9 years (range, 12-64 years), and the mean follow-up duration was 100 months (range, 13-180 months). Data included participation in sports, the University of California, Los Angeles (UCLA) activity scale score, age at the time of surgery, body mass index, follow-up duration, history of treatment for developmental hip dislocations, Merle d'Aubigné-Postel score, Oxford Hip Score, center-edge angle, and KL grade. Univariate and multivariate analyses were applied to determine which factors were associated with progression to KL grade 3 or 4 after PAO. The number of patients who participated in sports significantly increased from 50 (31.1%) preoperatively to 89 (55.3%) postoperatively. The mean UCLA score significantly increased from 4.7 ± 2.1 preoperatively to 5.5 ± 2.0 postoperatively. The KL grade progressed to grade 3 or 4 in 16 hips, including 4 hips that underwent conversion to total hip arthroplasty. No significant differences were found in postoperative participation in sports (89 hips [53.3%] vs 11 hips [68.8%], respectively; P = .24) and the UCLA score (5.6 ± 2.0 vs 5.1 ± 2.0, respectively; P = .30) between hips with KL grade 1 or 2 and KL grade 3 or 4. A multivariate analysis revealed that no factors, including postoperative participation in sports, were significantly associated with progression to KL grade 3 or 4. Postoperative participation in sports after PAO did not significantly and negatively influence progression of the KL grade at midterm follow-up.


Clinical features of proven basilar artery occlusion.
Our study describes the early symptoms and signs of 85 patients with either basilar artery occlusion or bilateral distal vertebral artery occlusion documented by selective angiography. The most common prodromal symptoms were vertigo, nausea, and headache, which occurred during the 2 weeks before the stroke. Angiographic findings of 49 patients were classified into proximal, middle, and distal basilar artery occlusions. Twenty-two of these patients had additional vertebral artery lesions. A fourth group was composed of 36 patients with bilateral distal vertebral artery occlusion without opacification of the basilar artery through a vertebral artery injection. Onset was sudden in 20 patients; sudden, but preceded by prodromal symptoms in 11 patients; and progressive in 54 patients. Patients with progressive strokes often had bilateral vertebral artery occlusions. Most patients with acute onset had occlusion of the middle and distal basilar artery. An embolic origin of basilar artery occlusion from an arteriosclerotic vertebral artery lesion was assumed to be an important mechanism. An embolus reaching the basilar artery may not necessarily reach the top of the artery, but may also become lodged more proximally.


Dietary Advanced Glycation End Products and Risk Factors for Chronic Disease: A Systematic Review of Randomised Controlled Trials.
Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic reviews indicate that consumption of dietary AGEs may promote inflammation, oxidative stress and insulin resistance. Experimental evidence indicates that dietary AGEs may also induce renal damage, however, this outcome has not been considered in previous systematic reviews. The purpose of this review was to examine the effect of consumption of a high AGE diet on biomarkers of chronic disease, including chronic kidney disease (CKD), in human randomized controlled trials (RCTs). Six databases (SCOPUS, CINHAL, EMBASE, Medline, Biological abstracts and Web of Science) were searched for randomised controlled dietary trials that compared high AGE intake to low AGE intake in adults with and without obesity, diabetes or CKD. Twelve dietary AGE interventions were identified with a total of 293 participants. A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all populations. A high AGE diet increased 8-isoprostanes in healthy adults, and vascular cell adhesion molecule-1 (VCAM-1) in patients with diabetes. Markers of CKD were not widely assessed. The evidence presented indicates that a high AGE diet may contribute to risk factors associated with chronic disease, such as inflammation and oxidative stress, however, due to a lack of high quality randomised trials, more research is required.


Structure and catalytic mechanism of LigI: insight into the amidohydrolase enzymes of cog3618 and lignin degradation.
LigI from Sphingomonas paucimobilis catalyzes the reversible hydrolysis of 2-pyrone-4,6-dicarboxylate (PDC) to 4-oxalomesaconate and 4-carboxy-2-hydroxymuconate in the degradation of lignin. This protein is a member of the amidohydrolase superfamily of enzymes. The protein was expressed in Escherichia coli and then purified to homogeneity. The purified recombinant enzyme does not contain bound metal ions, and the addition of metal chelators or divalent metal ions to the assay mixtures does not affect the rate of product formation. This is the first enzyme from the amidohydrolase superfamily that does not require a divalent metal ion for catalytic activity. The kinetic constants for the hydrolysis of PDC are 340 s(-1) and 9.8 × 10(6) M(-1) s(-1) (k(cat) and k(cat)/K(m), respectively). The pH dependence on the kinetic constants suggests that a single active site residue must be deprotonated for the hydrolysis of PDC. The site of nucleophilic attack was determined by conducting the hydrolysis of PDC in (18)O-labeled water and subsequent (13)C nuclear magnetic resonance analysis. The crystal structures of wild-type LigI and the D248A mutant in the presence of the reaction product were determined to a resolution of 1.9 Å. The C-8 and C-11 carboxylate groups of PDC are coordinated within the active site via ion pair interactions with Arg-130 and Arg-124, respectively. The hydrolytic water molecule is activated by the transfer of a proton to Asp-248. The carbonyl group of the lactone substrate is activated by electrostatic interactions with His-180, His-31, and His-33.


XL647--a multitargeted tyrosine kinase inhibitor: results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib.
Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M. Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA. Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations. The 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.


Exposure to Night-Time Traffic Noise, Melatonin-Regulating Gene Variants and Change in Glycemia in Adults.
Traffic noise has been linked to diabetes, with limited understanding of its mechanisms. We hypothesize that night-time road traffic noise (RTN) may impair glucose homeostasis through circadian rhythm disturbances. We prospectively investigated the relationship between residential night-time RTN and subsequent eight-year change in glycosylated hemoglobin (ΔHbA1c) in 3350 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA), adjusting for diabetes risk factors and air pollution levels. Annual average RTN (Lnight) was assigned to participants in 2001 using validated Swiss noise models. HbA1c was measured in 2002 and 2011 using liquid chromatography. We applied mixed linear models to explore RTN-ΔHbA1c association and its modification by a genetic risk score of six common circadian-related MTNR1B variants (MGRS). A 10 dB difference in RTN was associated with a 0.02% (0.003-0.04%) increase in mean ΔHbA1c in 2142 non-movers. RTN-ΔHbA1c association was modified by MGRS among diabetic participants (Pinteraction = 0.001). A similar trend in non-diabetic participants was non-significant. Among the single variants, we observed strongest interactions with rs10830963, an acknowledged diabetes risk variant also implicated in melatonin profile dysregulation. Night-time RTN may impair glycemic control, especially in diabetic individuals, through circadian rhythm disturbances. Experimental sleep studies are needed to test whether noise control may help individuals to attain optimal glycemic levels.


Civil Society Organizations and the Functions of Global Health Governance: What Role within Intergovernmental Organizations?
Amid discussion of how global health governance should and could be strengthened, the potential role of civil society organizations has been frequently raised. This paper considers the role of Civil Society Organizations (CSOs) in four health governance instruments under the auspices of the World Health Organization - the International Code on the Marketing of Breastmilk Substitutes, Framework Convention on Tobacco Control, International Health Regulations and Codex Alimentarius - and maps the functions they have contributed to. The paper draws conclusions about the opportunities and limitations CSOs represent for strengthening global health governance (GHG).


Primary health clinic toilet/bathroom surface swab sampling can indicate community profile of sexually transmitted infections.
The microbiome of built environment surfaces is impacted by the presence of humans. In this study, we tested the hypothesis that analysis of surface swabs from clinic toilet/bathroom yields results correlated with sexually transmitted infection (STI) notifications from corresponding human populations. We extended a previously reported study in which surfaces in toilet/bathroom facilities in primary health clinics in the Australian Northern Territory (NT) were swabbed then tested for nucleic acid from the STI agents Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis. This was in the context of assessing the potential for such nucleic acid to contaminate specimens collected in such facilities. STIs are notifiable in the NT, thus allowing comparison of swab and notification data. An assumption in the design was that while absolute built environment loads of STI nucleic acids will be a function of patient traffic density and facility cleaning protocols, the relative loads of STI nucleic acids from different species will be largely unaffected by these processes. Another assumption was that the proportion of swabs testing positive for STIs provides a measure of surface contamination. Accordingly, "STI profiles" were calculated. These were the proportions that each of the three STIs of interest contributed to the summed STI positive swabs or notifications. Three comparisons were performed, using swab data from clinics in remote Indigenous communities, clinics in small-medium towns, and a single urban sexual health clinic. These data were compared with time and place-matched STI notifications. There were significant correlations between swab and notifications data for the both the remote Indigenous and regional data. For the remote Indigenous clinics the p values ranged from 0.041 to 0.0089, depending on data transformation and p value inference method. Further, the swab data appeared to strongly indicate known higher relative prevalence of gonorrhoeae in central Australia than in northern Australia. Similarly, the regional clinics yielded p values from 0.0088-0.0022. In contrast, swab and notifications data from the sexual health clinic were not correlated. Strong correlations between swab and notifications were observed. However, there was evidence for limitations of this approach. Despite the correlation observed with the regional clinics data, one clinic yielded zero positive swabs for C. trachomatis, although this STI constituted 25.1% of the corresponding notifications. This could be ascribed to stochastic effects. The lack of correlation observed for sexual health clinic data was also likely due to stochastic effects. It was concluded that toilet/bathroom surface swab sampling has considerable potential for public health surveillance. The approach may be applicable in situations other than primary health clinics, and for targets other than STIs.


Synchrotron-based small-angle X-ray scattering of proteins in solution.
With recent advances in data analysis algorithms, X-ray detectors and synchrotron sources, small-angle X-ray scattering (SAXS) has become much more accessible to the structural biology community. Although limited to ∼10 Å resolution, SAXS can provide a wealth of structural information on biomolecules in solution and is compatible with a wide range of experimental conditions. SAXS is thus an attractive alternative when crystallography is not possible. Moreover, advanced use of SAXS can provide unique insight into biomolecular behavior that can only be observed in solution, such as large conformational changes and transient protein-protein interactions. Unlike crystal diffraction data, however, solution scattering data are subtle in appearance, highly sensitive to sample quality and experimental errors and easily misinterpreted. In addition, synchrotron beamlines that are dedicated to SAXS are often unfamiliar to the nonspecialist. Here we present a series of procedures that can be used for SAXS data collection and basic cross-checks designed to detect and avoid aggregation, concentration effects, radiation damage, buffer mismatch and other common problems. Human serum albumin (HSA) serves as a convenient and easily replicated example of just how subtle these problems can sometimes be, but also of how proper technique can yield pristine data even in problematic cases. Because typical data collection times at a synchrotron are only one to several days, we recommend that the sample purity, homogeneity and solubility be extensively optimized before the experiment.


Far-Forward Blood Donation and Donor Performance.
Fresh whole blood transfusion is advantageous when operating far-forward for both its availability and its physiological advantages over component therapy. However, the far-forward environment may place high physical performance demands on the donor immediately after donation. The aim of this paper was to briefly review the current literature on the effects of whole blood donation on a male donor's immediate physical performance after a standard donation volume of one unit (~450mL). Studies demonstrate reductions in peak volume of oxygen (VO2peak) of ~4% to 15% and time to exhaustion (TTE) of ~10% to 19% in the first 24 to 48 hours after donation. Anaerobic or cognitive performance has not been shown to decrease, but data on these parameters are limited. Donor physical performance decrements after a standard 450mL donation are minimal and may be mitigated through proper exercise training because training status may positively affect many variables that blood donation temporarily attenuates.


O-glycan variability of egg-jelly mucins from Xenopus laevis: characterization of four phenotypes that differ by the terminal glycosylation of their mucins.
Eggs from Xenopus laevis are surrounded by several layers of jelly that are needed for proper fertilization. Jelly coat is composed of high-molecular-mass glycoconjugates to which are bound many globular proteins. O-glycans released from the jelly coat of X. laevis have been partially described in previous studies. In this study, we compared the glycosylation pattern of the egg jelly coat isolated from six specimens of X. laevis. The O-glycans were released from jelly coats by alkali/borohydride treatment. Structural characterization was performed through a combination of one- and two-dimensional (1)H-NMR and methylation analysis. This allowed the description of a new family of sulphated O-glycans present in jelly coats of all X. laevis. However, the jelly O-glycans showed a low extent of polymorphism between specimens. This intra-specific variability was restricted to the terminal substitution of O-linked oligosaccharides. The differential expression of two glycosyltransferase [an alpha-(1-->4) galactosyltransferase and an alpha-(1-->3) fucosyltransferase] activities resulted in the characterization of four phenotypes of X. laevis. Furthermore, electrophoretic analysis suggested that the high-molecular-mass fraction of jelly coat was mostly composed of mucin-type glycoproteins. Blot analysis with lectins confirmed that the glycan variability was borne by these mucin-type components. However, fertilization assays suggested that the glycan polymorphism had no repercussion on egg fertilizability.


Plasmonic Manipulation of DNA using a Combination of Optical and Thermophoretic Forces: Separation of Different-Sized DNA from Mixture Solution.
We demonstrate the size-dependent separation and permanent immobilization of DNA on plasmonic substrates by means of plasmonic optical tweezers. We found that a gold nanopyramidal dimer array enhanced the optical force exerted on the DNA, leading to permanent immobilization of the DNA on the plasmonic substrate. The immobilization was realized by a combination of the plasmon-enhanced optical force and the thermophoretic force induced by a photothermal effect of the plasmons. In this study, we applied this phenomenon to the separation and fixation of size-different DNA. During plasmon excitation, DNA strands of different sizes became permanently immobilized on the plasmonic substrate forming micro-rings of DNA. The diameter of the ring was larger for longer DNA (in base pairs). When we used plasmonic optical tweezers to trap DNA of two different lengths dissolved in solution (φx DNA (5.4 kbp) and λ-DNA (48.5 kbp), or φx DNA and T4 DNA (166 kbp)), the DNA were immobilized, creating a double micro-ring pattern. The DNA were optically separated and immobilized in the double ring, with the shorter sized DNA and the larger one forming the smaller and larger rings, respectively. This phenomenon can be quantitatively explained as being due to a combination of the plasmon-enhanced optical force and the thermophoretic force. Our plasmonic optical tweezers open up a new avenue for the separation and immobilization of DNA, foreshadowing the emergence of optical separation and fixation of biomolecules such as proteins and other ncuelic acids.


Assessing Mental Health for China's Police: Psychometric Features of the Self-Rating Depression Scale and Symptom Checklist 90-Revised.
Police mental health is important because police officers usually encounter stressors that cause high levels of stress. In order to better understand mental health for Chinese police, the Zung Self-Rating Depression Scale (SDS) and Symptom Checklist 90-Revised (SCL-90-R) are commonly used in mainland China. Unfortunately, both the SDS and SCL-90-R lack detailed information on their psychometric properties. More specifically, factor structures of the SDS and SCL-90-R have yet to be confirmed among the police population in mainland China. Therefore, the present study compared several factor structures of the SDS and SCL-90-R proposed by prior research and to determine an appropriate structure for the police population. Utilizing cluster sampling, 1151 traffic police officers (1047 males; mean age = 36.6 years [SD = 6.10]) from 49 traffic police units in Jiangxi Province (China) participated in this study. Confirmatory factor analysis (CFA) with Akaike information criterion (AIC) was used to decide the best fit structure. In the SDS, the three-factor model (first posited by Kitamura et al.) had the smallest AIC and outperformed other models. In the SCL-90-R, the eight-factor model had the smallest AIC and outperformed the one-factor and nine-factor models. CFA fit indices also showed that both the three-factor model in the SDS and the eight-factor model in the SCL-90-R had satisfactory fit. The present study's results support the use of both SDS and SCL-90-R for police officers in mainland China.


Cocaine increases dopaminergic connectivity in the nucleus accumbens.
The development of addictive behavior is associated with functional and structural plasticity in the mesocorticolimbic pathway. Increased connectivity upon cocaine administration has been inferred from increases in dendritic spine density, but without observations of presynaptic elements. Recently, we established a method that enables analyses of both dendritic spines and glutamatergic boutons and presented evidence that cocaine induces changes in striatal connectivity. As the pharmacological and behavioral effects of cocaine directly implicate dopaminergic neurons and their afferents, a remaining question is whether dopaminergic striatal innervations also undergo structural plasticity. To address this issue, we generated transgenic mice in which the fluorophore tdTomato is expressed under the promoter of the dopamine transporter gene. In these mice, specific labeling of dopaminergic boutons was observed in the striatum. Of note, the accordance of our results for control mice with previous electron microscopy studies confirms that our method can be used to decipher the spatial organization of boutons in relation to dendritic elements. Following repeated cocaine administration that led to behavioral locomotor sensitization, an increased density of dopaminergic boutons was observed 1 day later in the nucleus accumbens shell specifically, and not in other striatal regions. Combined labeling of dopaminergic boutons and striatal dendrites showed that cocaine significantly increased the percentage of dendritic spines associated with a dopaminergic bouton. Our results show that chronic cocaine administration induces structural plasticity of dopaminergic boutons that could participate in dopamine-dependent neuronal adaptations in the striatum.


What effect does a structured home-based exercise programme have on people with Huntington's disease? A randomized, controlled pilot study.
The aim of this study was to explore feasibility, safety and outcome of an exercise intervention in people with Huntington's disease. A randomized controlled pilot trial. A home-based exercise programme. A total of 25 subjects with early to mid-stage Huntington's disease. Subjects were randomly allocated to either an exercise intervention (n = 13) or a control group (n = 12). Subjects in the exercise intervention group were asked to perform exercises at home three times a week for eight weeks using an exercise DVD, specifically developed for this purpose. The control group received their usual care. Adherence in the intervention group was calculated from exercise diaries. Measures of gait, balance, function, level of physical activity and quality of life were evaluated. Analysis of covariance was used to compare follow-up scores across groups after adjustment for chance baseline differences. Effect sizes were calculated. Eleven participants from the intervention and ten from the control group completed the study. Mean adherence was 29.4 SD 1.8 for the 32 prescribed sessions. There were no related adverse events. Differences between groups were observed in gait speed, balance, function and level of physical activity, but not quality of life as measured by the SF36. Effect sizes were large (>0.8) for the majority of the outcomes. Short-term structured home exercise programmes are feasible, beneficial and safe for people with early to mid-stage of Huntington's disease. Our findings support the implementation of a larger trial of longer-term home exercise.


Nucleotides regulate secretion of the inflammatory chemokine CCL2 from human macrophages and monocytes.
CCL2 is an important inflammatory chemokine involved in monocyte recruitment to inflamed tissues. The extracellular nucleotide signalling molecules UTP and ATP acting via the P2Y2 receptor are known to induce CCL2 secretion in macrophages. We confirmed this in the human THP-1 monocytic cell line showing that UTP is as efficient as LPS at inducing CCL2 at early time points (2-6 hours). Expression and calcium mobilisation experiments confirmed the presence of functional P2Y2 receptors on THP-1 cells. UTP stimulation of human peripheral CD14+ monocytes showed low responses to LPS (4-hour stimulation) but a significant increase above background following 6 hours of treatment. The response to UTP in human monocytes was variable and required stimulation >6 hours. With such variability in response we looked for single nucleotide polymorphisms in P2RY2 that could affect the functional response. Sequencing of P2RY2 from THP-1 cells revealed the presence of a single nucleotide polymorphism altering amino acid 312 from arginine to serine (rs3741156). This polymorphism is relatively common at a frequency of 0.276 (n = 404 subjects). Finally, we investigated CCL2 secretion in response to LPS or UTP in human macrophages expressing 312Arg-P2Y2 or 312Ser-P2Y2 where only the latter exhibited significant UTP-induced CCL2 secretion (n = 5 donors per group).


Radiographic appearance of the thorax of clinically normal alpaca crias.
To quantitatively and qualitatively assess the radiographic appearance of the thorax of clinically normal alpaca crias. 21 clinically normal alpaca crias. Left-right lateral (LR), right-left lateral (RL), dorsoventral (DV), and ventrodorsal (VD) projections of the thorax were acquired. To account for differences in cria size, measurements of thoracic structures were compared with other anatomic landmarks. Mean ± SD vertebral heart scale was 9.36 ± 0.65 for LR projections, 9.36 ± 0.59 for RL projections, 8.21 ± 0.51 for DV projections, and 8.65 ± 0.57 for VD projections. Dimensions of the heart were compared with the length of the T3 through T5 vertebral bodies, third to fifth rib distance, and thoracic height and width, which provided additional methods of cardiac evaluation. For RL projections, mean ratio of the right cranial pulmonary artery diameter to the third rib width was 0.41 ± 0.10 and mean ratio of the right cranial pulmonary vein to the third rib width was 0.44 ± 0.10. Caudal lobar pulmonary vessels and the caudal vena cava were difficult to quantitatively assess on DV or VD projections. On lateral projections, the trachea was increased in diameter at the origin of the right cranial lobar bronchus. No qualitative differences were found between LR and RL radiographs. The lungs were generally better inflated on VD projections, with more separation of the heart and diaphragm. Establishment of radiographic values for alpaca crias should prove useful in assessment of thoracic disease in this species.


Thermo-responsive polymers and their application as smart biomaterials.
The drastic development of polymeric materials for a wide range of biomedical and biomaterial applications has been explored in the last few decades. Among these materials, a new class of 'smart' or 'intelligent' biomaterial has been developed, and these materials are highly responsive to slight changes in their environments. Due to their dynamically alterable properties, smart materials allow for smart biomaterials to be developed. This review presents smart thermo-responsive polymers and discusses how they may be used as smart biomaterials. We describe typical thermo-responsive polymers that are either lower critical solution temperature-type, upper critical solution temperature-type, or thermo-induced shape-memory polymers. The basic mechanisms of the thermo-response processes will also be described. The applications of smart biomaterials with various forms, such as smart fibres, surfaces and hydrogels, will also be introduced.


Resting-state Amplitude of Low-frequency Fluctuation is a Potentially Useful Prognostic Functional Biomarker in Cervical Myelopathy.
Cervical MRI is the standard diagnostic imaging technique for patients with cervical myelopathy. However, the utility of conventional cervical MRI as a predictive biomarker for surgical recovery remains unclear, partly because of the limited information obtained from this anatomically small area. Brain resting-state functional MRI (rs-fMRI) may help identify candidate predictive biomarkers. Two analytical methods that assess local spontaneous brain activity are widely used for rs-fMRI: functional connectivity between two brain regions and amplitude of low-frequency fluctuation (ALFF). In our previous analysis of functional connectivity, we discovered that brain functional connectivity may be a predictive biomarker for neurologic recovery in patients with cervical myelopathy; however, the functional connectivity analysis identified a correlation with only one clinical outcome (the 10-second test). To establish a comprehensive prediction measure, we need to explore other brain biomarkers that can predict recovery of other clinical outcomes in patients with cervical myelopathy. We aimed to (1) elucidate preoperative ALFF alterations in patients with cervical myelopathy and how ALFF changes after surgery, with a focus on postoperative normalization and (2) establish a predictive model using preoperative ALFF by investigating the correlation between preoperative ALFF and postoperative clinical recovery in patients with cervical myelopathy. Between August 2015 and June 2017, we treated 40 patients with cervical myelopathy. Thirty patients met our prespecified inclusion criteria, all were invited to participate, and 28 patients opted to do so (93%; 14 men and 14 women; mean age: 67 years). The 28 patients and 28 age- and sex-matched controls underwent rs-fMRI (twice for patients with cervical myelopathy: before and 6 months after cervical decompression surgery). We analyzed the same study population that was used in our earlier study investigating functional connectivity. Controls had none of the following abnormalities: neck or arm pain, visual or auditory disorders, cognitive disorder, structural brain disorder, a history of brain surgery, mental and neurologic disorders, and medications for the central nervous system. We performed ALFF comparisons between preoperative patients with cervical myelopathy and controls, analyzed postoperative ALFF changes in patients with cervical myelopathy, and performed a correlation analysis between preoperative ALFF and clinical recovery in these patients. Clinical outcomes in the cervical myelopathy group were assessed using the 10-second test, the Japanese Orthopaedic Association upper-extremity motor (JOA-UEM) score, JOA upper-extremity sensory score (JOA-UES), and Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire for upper-extremity function (JOACMEQ-UEF) score before and 6 months after surgery, which is when we believe these scores generally reach a plateau. A total of 93% of those enrolled (26 of 28 patients) were analyzed both preoperatively and postoperatively; the other two were lost to follow-up. The cervical myelopathy group had an increase in ALFF in the bilateral primary sensorimotor cortices (right, cluster size = 850 voxels, t-value = 6.10; left, cluster size = 370 voxels, t-value = 4.84) and left visual cortex (cluster size = 556 voxels, t-value = 4.21) compared with the control group. The cervical myelopathy group had a decrease in ALFF in the bilateral posterior supramarginal gyrus (right, cluster size = 222 voxels, t-value = 5.09; left, cluster size = 436 voxels, t-value = 5.28). After surgery, the bilateral sensorimotor cortices (right, cluster size = 468 voxels, t-value = 6.74; left, cluster size = 167 voxels, t-value = 5.40) and left visual cortex (cluster size = 3748 voxels, t-value = 6.66) showed decreased ALFF compared with preoperative ALFF, indicating postoperative normalization of spontaneous brain activities in these regions. However, the bilateral posterior supramarginal gyrus did not show an increase in ALFF postoperatively, although ALFF in this region decreased preoperatively. Greater levels of ALFF at the left and right frontal pole and left pars opercularis of the inferior frontal gyrus before surgery in the cervical myelopathy group were correlated with larger improvements in the JOACMEQ-UEF score 6 months after surgery (r = 0.784; p < 0.001, r = 0.734; p < 0.001 and r = 0.770, respectively; p < 0.001). The prediction formula, based on preoperative ALFF values in the left frontal pole, was as follows: the predicted postoperative improvement in the JOACMEQ-UEF score = 34.6 × preoperative ALFF value - 7.0 (r = 0.614; p < 0.001). Our findings suggest that preoperative ALFF may be a biomarker for postoperative recovery in that it predicted postoperative JOACMEQ-UEF scores. To establish a comprehensive prediction measure for neurologic recovery in patients with cervical myelopathy, a multicenter study is underway. Level II, diagnostic study.


Perceptions of the appropriate response to norm violation in 57 societies.
Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate.


Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.
The number of individuals living with dementia is increasing, negatively affecting families, communities, and health-care systems around the world. A successful response to these challenges requires an accurate understanding of the dementia disease burden. We aimed to present the first detailed analysis of the global prevalence, mortality, and overall burden of dementia as captured by the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, and highlight the most important messages for clinicians and neurologists. GBD 2016 obtained data on dementia from vital registration systems, published scientific literature and surveys, and data from health-service encounters on deaths, excess mortality, prevalence, and incidence from 195 countries and territories from 1990 to 2016, through systematic review and additional data-seeking efforts. To correct for differences in cause of death coding across time and locations, we modelled mortality due to dementia using prevalence data and estimates of excess mortality derived from countries that were most likely to code deaths to dementia relative to prevalence. Data were analysed by standardised methods to estimate deaths, prevalence, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs; computed as the sum of YLLs and YLDs), and the fractions of these metrics that were attributable to four risk factors that met GBD criteria for assessment (high body-mass index [BMI], high fasting plasma glucose, smoking, and a diet high in sugar-sweetened beverages). In 2016, the global number of individuals who lived with dementia was 43·8 million (95% uncertainty interval [UI] 37·8-51·0), increased from 20.2 million (17·4-23·5) in 1990. This increase of 117% (95% UI 114-121) contrasted with a minor increase in age-standardised prevalence of 1·7% (1·0-2·4), from 701 cases (95% UI 602-815) per 100 000 population in 1990 to 712 cases (614-828) per 100 000 population in 2016. More women than men had dementia in 2016 (27·0 million, 95% UI 23·3-31·4, vs 16.8 million, 14.4-19.6), and dementia was the fifth leading cause of death globally, accounting for 2·4 million (95% UI 2·1-2·8) deaths. Overall, 28·8 million (95% UI 24·5-34·0) DALYs were attributed to dementia; 6·4 million (95% UI 3·4-10·5) of these could be attributed to the modifiable GBD risk factors of high BMI, high fasting plasma glucose, smoking, and a high intake of sugar-sweetened beverages. The global number of people living with dementia more than doubled from 1990 to 2016, mainly due to increases in population ageing and growth. Although differences in coding for causes of death and the heterogeneity in case-ascertainment methods constitute major challenges to the estimation of the burden of dementia, future analyses should improve on the methods for the correction of these biases. Until breakthroughs are made in prevention or curative treatment, dementia will constitute an increasing challenge to health-care systems worldwide. Bill & Melinda Gates Foundation.


Readmission Rate and Causes at 90-Day after Radical Cystectomy in Patients on Early Recovery after Surgery Protocol.
Background: Radical cystectomy (RC) is associated with high risk of early and late perioperative complications, and readmissions. The Enhanced Recovery After Surgery (ERAS) protocol has been applied to RC showing decreased hospital stay without increased morbidity. Objective: To evaluate the specific causes of hospital readmissions in RC patients treated before and after adoption of an ERAS protocol at our institution. Methods: We retrospectively evaluated the outcome of 207 RC patients on ERAS protocol at the Stanford University Hospital from January 2012 to December 2014. We focused on early (30-day) and late (90-day) postoperative readmission rate and causes. Results were compared with a pre-ERAS consecutive series of 177 RC patients from January 2009 to December 2011. Results: In the post-ERAS time period a total of 56 patients were readmitted, 41 within the first 30 days after surgery (20%) and 15 within the following 60 days (7%). Fever, often associated with dehydration, was the most common reason for presentation to the hospital, accounting for 57% of all readmissions. At 90 days infection accounted for 53% of readmissions. Of all the patients readmitted during the first 90 days after surgery, 32 had positive urine cultures, mostly caused by Enterococcus faecalis isolated in 18 (56%). Readmission rates did not increase since the introduction of the ERAS protocol, with an incidence of 27% in the post-ERAS group versus 30% in the pre-ERAS group. Conclusions: Despite accurate adherence to most recent perioperative antibiotic guidelines, the incidence of readmissions after RC due to infection still remains significant.


Population structure of the primary malaria vector in South America, Anopheles darlingi, using isozyme, random amplified polymorphic DNA, internal transcribed spacer 2, and morphologic markers.
A genetic and morphologic survey of Anopheles darlingi populations collected from seven countries in Central and South America was performed to clarify the taxonomic status of this major malaria vector species in the Americas. Population genetics was based on three techniques including isozyme, random amplified polymorphic DNA-polymerase chain reaction (RAPD-PCR), and internal transcribed spacer 2 (ITS2) markers. The results of the isozyme analysis indicated moderate differences in the allele frequencies of three putative loci (glutamate oxalaoacetate transaminase-1, isocitrate dehydrogenase-1, and phosphoglucomutase) of the 31 analyzed. No fixed electromorphic differences separated the populations of An. darlingi, which showed little genetic divergence (Nei distances = 0.976-0.995). Fragments produced by RAPD-PCR demonstrated evidence of geographic partitioning and showed that all populations were separated by small genetic distances as measured with the 1 - S distance matrix. The ITS2 sequences for all samples were identical except for four individuals from Belize that differed by a three-base deletion (CCC). The morphologic study demonstrated that the Euclidean distances ranged from 0.02 to 0.14, with the highest value observed between populations from Belize and Bolivia. Based on these analyses, all the An. darlingi populations examined demonstrated a genetic similarity that is consistent with the existence of a single species and suggest that gene flow is occurring throughout the species' geographic range.


Family history of alcohol dependence modulates functional neurophysiology in mood/anxiety disorders.
A family history (FH) of alcohol dependence (AD) not only increases the risk for AD, but is also associated with an increased risk for mood and anxiety disorders. However, it is unknown how a FH of AD affects neural substrates in patients with mood and anxiety disorders. In this study we examined the effects of an alcoholic FH on cognitive and emotional functions in these patients using functional magnetic resonance imaging (fMRI). Method In a sample of non-alcoholic patients with depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA) neuroimaging study, patients with a first-degree FH of AD (FH + ; n = 31) were compared with patients without a FH (FH-; n = 77) on performance and brain activation during visuospatial planning and emotional word encoding. Results were compared with those of healthy controls (HCs) without a FH of AD (n = 31). FH+ patients performed slower during planning with increasing task load, coupled with stronger blood oxygen level-dependent responses in dorsal prefrontal areas compared with FH- patients and HCs. FH was not associated with performance differences during word encoding, but right insula activation during positive word encoding was present in FH+ patients, comparable with HCs, but absent in FH- patients. This study demonstrates subtle impairments during planning in FH+ compared with FH- patients and HCs, whereas activation during mood-incongruent stimuli in FH+ patients was similar to HCs but not FH- patients, suggesting that the presence of a FH of AD is a useful marker for the neurophysiological profile in mood/anxiety disorders and possible predictor for treatment success.


Infective endocarditis epidemiology over five decades: a systematic review.
To Assess changes in infective endocarditis (IE) epidemiology over the last 5 decades. We searched the published literature using PubMed, MEDLINE, and EMBASE from inception until December 2011. Einstein Medical Center, Philadelphia, PA were also included. Criteria for inclusion in this systematic review included studies with reported IE microbiology, IE definition, description of population studied, and time frame. Two authors independently extracted data and assessed manuscript quality. One hundred sixty studies (27,083 patients) met inclusion criteria. Among hospital-based studies (n=142; 23,606 patients) staphylococcal IE percentage increased over time, with coagulase-negative staphylococcus (CNS) increasing over each of the last 5 decades (p<0.001) and Staphylococcus aureus (SA) in the last decade (21% to 30%; p<0.05). Streptococcus viridans (SV) and culture negative (CN) IE frequency decreased over time (p<0.001), while enterococcal IE increased in the last decade (p<0.01). Patient age and male predominance increased over time as well. In subgroup analysis, SA frequency increased in North America, but not the rest of the world. This was due, in part, to an increase in intravenous drug abuse IE in North America (p<0.001). Among population-based studies (n=18; 3,477 patients) no significant changes were found. Important changes occurred in IE epidemiology over the last half-century, especially in the last decade. Staphylococcal and enterococcal IE percentage increased while SV and CN IE decreased. Moreover, mean age at diagnosis increased together with male:female ratio. These changes should be considered at the time of decision-making in treatment of and prophylaxis for IE.


Calculation of maximal removal rate of indocyanine green to measure hepatic functional mass in dogs by use of the nine-hour method.
To establish a versatile and reliable procedure for the determination of indocyanine green maximal removal rate (ICG Rmax) to measure hepatic functional mass in dogs within 9 hours (9-hour method). Relation between 9-hour and standard 3-day methods was examined. 101 healthy dogs. On investigation of the optimal technical conditions allowing completion of all procedures in a day, the appropriate IV administered doses of ICG were 0.125, 0.5, and 2.0 mg/kg of body weight, and the best blood sample collection times for obtaining plasma half-life at these 3 doses were before and 3, 6, and 9 minutes after ICG administration. Comparison of the 9-hour with 3-day method yielded a correlation coefficient (r) of 0.84, indicating close (P < 0.01) correlation. In the 9-hour method, mean +/- SD of ICG Rmax in healthy dogs was 0.24 +/- 0.09 mg/kg/min in male (n = 62) and was 0.23 +/- 0.06 mg/kg/min in female (n = 21) Beagles, and was 0.21 +/- 0.10 mg/kg/min in male (n = 11) and 0.20 +/- 0.07 mg/kg/min in female (n = 7) mixed-breed dogs. In Beagles treated orally with carbon tetrachloride (0.1 ml/kg in gelatine capsules) thrice weekly during a 10-week period, plasma alanine transaminase activity plateaued at a high value (> 2,000 IU/L) on day 5, and remained at this value until the end of the study. The ICG Rmax changed accordingly: day 5, 0.17; day 10, 0.11; day 40, 0.05; and day 60, 0.06 mg/kg/min. The 9-hour method for determination of ICG Rmax correlates favorably with the 3-day method. This procedure may be practically applied in veterinary clinics in terms of prediction of hepatic functional mass, and for diagnosis of hepatotoxicosis induced by certain compounds.


Genomics and genetics of Sulfolobus islandicus LAL14/1, a model hyperthermophilic archaeon.
The 2 465 177 bp genome of Sulfolobus islandicus LAL14/1, host of the model rudivirus SIRV2, was sequenced. Exhaustive comparative genomic analysis of S. islandicus LAL14/1 and the nine other completely sequenced S. islandicus strains isolated from Iceland, Russia and USA revealed a highly syntenic common core genome of approximately 2 Mb and a long hyperplastic region containing most of the strain-specific genes. In LAL14/1, the latter region is enriched in insertion sequences, CRISPR (clustered regularly interspaced short palindromic repeats), glycosyl transferase genes, toxin-antitoxin genes and MITE (miniature inverted-repeat transposable elements). The tRNA genes of LAL14/1 are preferential targets for the integration of mobile elements but clusters of atypical genes (CAG) are also integrated elsewhere in the genome. LAL14/1 carries five CRISPR loci with 10 per cent of spacers matching perfectly or imperfectly the genomes of archaeal viruses and plasmids found in the Icelandic hot springs. Strikingly, the CRISPR_2 region of LAL14/1 carries an unusually long 1.9 kb spacer interspersed between two repeat regions and displays a high similarity to pING1-like conjugative plasmids. Finally, we have developed a genetic system for S. islandicus LAL14/1 and created ΔpyrEF and ΔCRISPR_1 mutants using double cross-over and pop-in/pop-out approaches, respectively. Thus, LAL14/1 is a promising model to study virus-host interactions and the CRISPR/Cas defence mechanism in Archaea.


A new family-based association test via a least-squares method.
To test the association between a dichotomous phenotype and genetic marker based on family data, we propose a least-squares method using the vector of phenotypes and their cross products within each family. This new approach allows covariate adjustment and is numerically much simpler to implement compared to likelihood- based methods. The new approach is asymptotically equivalent to the generalized estimating equation approach with a diagonal working covariance matrix, thus avoiding some difficulties with the working covariance matrix reported previously in the literature. When applied to the data from Collaborative Study on the Genetics of Alcoholism, this new method shows a significant association between the marker rs1037475 and alcoholism.


Reverse-engineering the locomotion of a stem amniote.
Reconstructing the locomotion of extinct vertebrates offers insights into their palaeobiology and helps to conceptualize major transitions in vertebrate evolution1-4. However, estimating the locomotor behaviour of a fossil species remains a challenge because of the limited information preserved and the lack of a direct correspondence between form and function5,6. The evolution of advanced locomotion on land-that is, locomotion that is more erect, balanced and mechanically power-saving than is assumed of anamniote early tetrapods-has previously been linked to the terrestrialization and diversification of amniote lineages7. To our knowledge, no reconstructions of the locomotor characteristics of stem amniotes based on multiple quantitative methods have previously been attempted: previous methods have relied on anatomical features alone, ambiguous locomotor information preserved in ichnofossils or unspecific modelling of locomotor dynamics. Here we quantitatively examine plausible gaits of the stem amniote Orobates pabsti, a species that is known from a complete body fossil preserved in association with trackways8. We reconstruct likely gaits that match the footprints, and investigate whether Orobates exhibited locomotor characteristics that have previously been linked to the diversification of crown amniotes. Our integrative methodology uses constraints derived from biomechanically relevant metrics, which also apply to extant tetrapods. The framework uses in vivo assessment of locomotor mechanics in four extant species to guide an anatomically informed kinematic simulation of Orobates, as well as dynamic simulations and robotics to filter the parameter space for plausible gaits. The approach was validated using two extant species that have different morphologies, gaits and footprints. Our metrics indicate that Orobates exhibited more advanced locomotion than has previously been assumed for earlier tetrapods7,9, which suggests that advanced terrestrial locomotion preceded the diversification of crown amniotes. We provide an accompanying website for the exploration of the filters that constrain our simulations, which will allow revision of our approach using new data, assumptions or methods.


Isolation and characterization of PEP3, a gene required for vacuolar biogenesis in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae PEP3 gene was cloned from a wild-type genomic library by complementation of the carboxypeptidase Y deficiency in a pep3-12 strain. Subclone complementation results localized the PEP3 gene to a 3.8-kb DNA fragment. The DNA sequence of the fragment was determined; a 2,754-bp open reading frame predicts that the PEP3 gene product is a hydrophilic, 107-kDa protein that has no significant similarity to any known protein. The PEP3 predicted protein has a zinc finger (CX2CX13CX2C) near its C terminus that has spacing and slight sequence similarity to the adenovirus E1a zinc finger. A radiolabeled PEP3 DNA probe hybridized to an RNA transcript of 3.1 kb in extracts of log-phase and diauxic lag-phase cells. Cells bearing pep3 deletion/disruption alleles were viable, had decreased levels of protease A, protease B, and carboxypeptidase Y antigens, had decreased repressible alkaline phosphatase activity, and contained very few normal vacuolelike organelles by fluorescence microscopy and electron microscopy but had an abundance of extremely small vesicles that stained with carboxyfluorescein diacetate, were severely inhibited for growth at 37 degrees C, and were incapable of sporulating (as homozygotes). Fractionation of cells expressing a bifunctional PEP3::SUC2 fusion protein indicated that the PEP3 gene product is present at low abundance in both log-phase and stationary cells and is a vacuolar peripheral membrane protein. Sequence identity established that PEP3 and VPS18 (J. S. Robinson, T. R. Graham, and S. D. Emr, Mol. Cell. Biol. 11:5813-5824, 1991) are the same gene.


Antiviral treatment of feline immunodeficiency virus-infected cats with (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine.
Feline immunodeficiency virus (FIV), the causative agent of an acquired immunodeficiency syndrome in cats (feline AIDS), is a ubiquitous health threat to the domestic and feral cat population, also triggering disease in wild animals. No registered antiviral compounds are currently available to treat FIV-infected cats. Several human antiviral drugs have been used experimentally in cats, but not without the development of serious adverse effects. Here we report on the treatment of six naturally FIV-infected cats, suffering from moderate to severe disease, with the antiretroviral compound (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine ([R]-PMPDAP), a close analogue of tenofovir, a widely prescribed anti-HIV drug in human medicine. An improvement in the average Karnofsky score (pretreatment 33.2 ± 9.4%, post-treatment 65±12.3%), some laboratory parameters (ie, serum amyloid A and gammaglobulins) and a decrease of FIV viral load in plasma were noted in most cats. The role of concurrent medication in ameliorating the Karnofsky score, as well as the possible development of haematological side effects, are discussed. Side effects, when noted, appeared mild and reversible upon cessation of treatment. Although strong conclusions cannot be drawn owing to the small number of patients and lack of a placebo-treated control group, the activity of (R)-PMPDAP, as observed here, warrants further investigation.


The impact of tourism on municipal solid waste generation: the case of Menorca Island (Spain).
Tourism can sustain high levels of employment and income, but the sector is a source of environmental and health impacts. One of the most important is the generation of municipal solid waste (MSW). However, there is a lack of studies which quantify how much the tourist population engages in total MSW and separately collected recyclables. The aim of this paper is to estimate the impact of the tourist population on MSW, both total and separately collected, for the period 1998-2010, for the Mediterranean island of Menorca (Spain). We use dynamic regressions models, including data for monthly stocks of tourists. The results show that, on average, a 1% increase in the tourist population in Menorca causes an overall MSW increase of 0.282% and one more tourist in Menorca generates 1.31 kg day(-1) (while one more resident generates 1.48 kg day(-1)). This result could be useful to better estimate the seasonal population of different regions, since intrannual fluctuation of MSW is used as a proxy measure of actual population (the sum of residents and tourists). Moreover, an increase of 1% in the tourist population causes an increase of 0.232% in separately collected recyclables and an additional tourist generates 0.160 kg day(-1). One resident selectively collects on average 47.3% more than one tourist. These results can help in the planning of waste infrastructure and waste collection services in tourist areas.


Ranking relations between diseases, drugs and genes for a curation task.
One of the key pieces of information which biomedical text mining systems are expected to extract from the literature are interactions among different types of biomedical entities (proteins, genes, diseases, drugs, etc.). Several large resources of curated relations between biomedical entities are currently available, such as the Pharmacogenomics Knowledge Base (PharmGKB) or the Comparative Toxicogenomics Database (CTD).Biomedical text mining systems, and in particular those which deal with the extraction of relationships among entities, could make better use of the wealth of already curated material. We propose a simple and effective method based on logistic regression (also known as maximum entropy modeling) for an optimized ranking of relation candidates utilizing curated abstracts. Furthermore, we examine the effects and difficulties of using widely available metadata (i.e. MeSH terms and chemical substance index terms) for relation extraction. Cross-validation experiments result in an improvement of the ranking quality in terms of AUCiP/R by 39% (PharmGKB) and 116% (CTD) against a frequency-based baseline of 0.39 (PharmGKB) and 0.21 (CTD). For the TAP-10 metrics, we achieve an improvement of 53% (PharmGKB) and 134% (CTD) against the same baseline system (0.21 PharmGKB and 0.15 CTD). Our experiments with the PharmGKB and the CTD database show a strong positive effect for the ranking of relation candidates utilizing the vast amount of curated relations covered by currently available knowledge databases. The tasks of concept identification and candidate relation generation profit from the adaptation to previously curated material. This presents an effective and practical method suitable for conservative extension and re-validation of biomedical relations from texts that has been successfully used for curation experiments with the PharmGKB and CTD database.


Marine tannins: the importance of a mechanistic framework for predicting ecological roles.
Since chemical ecology emerged as a field of marine science, it has been strongly influenced by studies of chemically mediated interactions in land-based systems. Marine chemical ecologists, like their terrestrial counterparts, initially focused on identifying natural products and evaluating the potential ecological roles of these products as defenses, attractants, or other cues. Now, like our land-based colleagues, we must increase our focus on the physiological and biochemical mechanisms that underlie the chemical interactions, paying particular attention to regulation of biosynthetic pathways, within-plant and between-plant signaling cues, and comparative and functional genomics. Here, we review the current state of knowledge regarding a heterogenous group of macrophyte natural products, the marine tannins and simple phenolics, to illustrate how such information is critical to future attempts to predict their ecological roles.


Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production.
The effects of pentoxifylline (Trental) on human neutrophil CR3 up-modulation, degranulation, and superoxide production were studied. We used the chemotactic peptide fMLP and the phorbol ester PMA as soluble stimuli, and beta-glucan particles as a CR3-specific solid phase stimulus of neutrophil superoxide production. Since neutrophils have adenosine A2 receptors, we compared effects of pentoxifylline to effects of adenosine, and we also looked at the effect of cytochalasin B, which breaks up actin filaments. Pentoxifylline inhibited both CR3 up-modulation and degranulation of myeloperoxidase and lysozyme. Pentoxifylline is a more potent inhibitor of fMLP- compared to PMA-induced degranulation, and is especially potent against superoxide production. While pentoxifylline is less potent than adenosine in its inhibition of fMLP-induced superoxide production, it is more potent in its inhibition of PMA- and beta-glucan particle-stimulated superoxide production. Cytochalasin B, which enhances degranulation and fMLP-stimulated superoxide production, was found to inhibit beta-glucan particle-stimulated superoxide production. These findings are consistent with the hypothesis that pentoxifylline can affect both the cytoskeletal architecture of unstimulated neutrophils and the activation and responses of neutrophils which involve actin polymerization and receptor-cytoskeletal interactions.


Reconceptualizing Anxiety as a Continuum That Ranges From High Calmness to High Anxiety: The Joint Importance of Reducing Distress and Increasing Well-Being.
We first replicate a study by Vautier and Pohl (2009), who used the State-Trait Anxiety Inventory (STAI) to reexamine the structure of anxiety. Using two large samples (N = 4,138 and 1,824), we also find that state and trait anxiety measure continua that range from high calmness to high anxiety. We then significantly extend previous findings and make the clinical importance of this topic more explicit by characterizing the (linear or nonlinear) form of the relationship between the calmness-anxiety continuum and other psychiatric variables for the first time. This form is critical to understanding anxiety problems, as discontinuities in relationships with other psychological conditions could be used to define a natural boundary of problematic anxiety. Baseline levels on the calmness-anxiety continuum are found to have a near linear relationship with changes in depression, aggression, and substance misuse over time. Taken together, these results indicate the joint importance and usefulness of treating anxiety problems and promoting calmness, as doing so may promote resilience from developing other psychiatric conditions. Psychiatric and psychological interventions that are grounded in this continuum conceptualization would logically be stopped when an individual reports experiencing high levels of calmness. Our results point to the usefulness of early intervention and prevention (when people begin to move away from high calmness) and instilling resilience (by providing interventions to move people toward high calmness). (PsycINFO Database Record


Nutrient composition and retention in whole turkeys with and without added solution.
Whole turkeys sold in retail outlets are typically processed with added solutions to improve their taste and tenderness. The purpose of this study was to evaluate the nutrient composition of whole turkeys with and without added solution, and to update the nutrient profile of turkey for the USDA National Nutrient Database for Standard Reference. Eleven pairs of turkeys with added solution were obtained from statistically representative retail outlets using a nationwide sampling plan developed for USDA's National Food and Nutrient Analysis Program; 4 pairs of turkeys without added solution were purchased from local food outlets. Turkeys were roasted to an internal temperature of 165°F (74°C). Values of selected nutrients in light and dark meat, including skin, were determined by USDA approved laboratories using quality assurance protocols. Both raw and cooked turkeys, with and without added solution, were compared by one-way and 2-way factorial ANOVA. The results showed a significant interaction for fat (P < 0.0001) and zinc (P = 0.0070) between turkeys that were raw and cooked and those prepared with or without added solution. Fat was higher in raw turkeys with added solution compared to without added solution. Similarly, sodium, phosphorus, and calcium values were significantly higher in turkeys with added solution (P < 0.05) than in turkeys without added solution. Data from this study will be useful for developing strategies to address sodium-related health issues, nutrition monitoring, consumption surveys, and policy development.


Overexpression and promoter mutation of the TERT gene in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a very aggressive tumor with no known curative treatment. Better knowledge of the molecular mechanisms of mesothelial carcinogenesis is required to develop new therapeutic strategies. MPM, like all cancer cells, needs to maintain telomere length to prevent senescence. Previous studies suggested that the telomere lengthening mechanism in MPM is based mainly on telomerase activity. For this reason, we focused on the key catalytic enzyme, TERT (telomerase reverse transcriptase), by analyzing its gene expression in MPM and by studying the mechanism underlying its upregulation. We used our large collection of MPM composed of 61 MPM in culture and 71 frozen MPM tumor samples. Evaluation of TERT mRNA expression by quantitative RT-PCR showed overexpression in MPM in culture compared with normal mesothelial cells, and in MPM tumor samples compared with normal pleura. We identified a 'hot spot' of mutations in the TERT gene core promoter in both MPM in culture and in MPM tumor samples with an overall frequency of 15%. Furthermore, data clearly identified mutation in the TERT promoter as a mechanism of TERT mRNA upregulation in MPM. In contrast, gene copy number amplification was not associated with TERT overexpression. Then, we analyzed the clinicopathological, etiological and genetic characteristics of MPM with mutations in the TERT promoter. TERT promoter mutations were more frequent in MPM with sarcomatoid histologic subtype (P<0.01), and they were frequently associated with CDKN2A gene inactivation (P=0.03). In conclusion, a subgroup of MPM presents TERT promoter mutations, which lead to TERT mRNA upregulation. This is the first recurrent gain-of-function oncogenic mutations identified in MPM.


Genetics and cytogenetics of multiple myeloma: a workshop report.
Much has been learned regarding the biology and clinical implications of genetic abnormalities in multiple myeloma. Because of recent advances in the field, an International Workshop was held in Paris in february of 2003. This summary describes the consensus recommendations arising from that meeting with special emphasis on novel genetic observations. For instance, it is increasingly clear that translocations involving the immunoglobin heavy-chain locus are important for the pathogenesis of one-half of patients. As a corollary, it also clear that the remaining patients, lacking IgH translocations, have hyperdiploidy as the hallmark of their disease. Several important genetic markers are associated with a shortened survival such as chromosome 13 monosomy, hypodiploidy, and others. The events leading the transformation of the monoclonal gammopathy of undetermined significance (MGUS) to myeloma are still unclear. One of the few differential genetic lesions between myeloma and MGUS is the presence of ras mutations in the latter. Gene expression platforms are capable of detecting many of the genetic aberrations found in the clonal cells of myeloma. Areas in need of further study were identified. The study of the genetic aberrations will likely form the platform for targeted therapy for the disease.


Spatial summation effects on two-component grating thresholds.
Some experimental studies of subthreshold summation between sinusoidal grating components have been interpreted as showing very narrow channel bandwidths in human visions. This paper discusses an alternative interpretation of these experiments based on consideration of probability-summation effects among spatially distributed detectors. We conclude that frequency-selective channels must still be hypothesized in order to fit the data, but the channel bandwidth may be much wider than earlier interpretations suggest.


Associating Type 2 Diabetes Risk Factor Genes and FDG-PET Brain Metabolism in Normal Aging and Alzheimer's Disease.
Background: Several studies have linked type 2 diabetes (T2D) to an increased risk of developing Alzheimer's disease (AD). This has led to an interest in using antidiabetic treatments for the prevention of AD. However, the underlying mechanisms explaining the relationship between T2D and AD have not been completely elucidated. Objective: Our objective was to examine cerebral 18F-fluorodeoxyglucose (FDG) uptake during normal aging and in AD patients in regions associated with diabetes genetic risk factor expression to highlight which genes may serve as potential targets for pharmaceutical intervention. Methods: We calculated regional glucose metabolism differences in units of standardized uptake values (SUVR) for 386 cognitively healthy adults and 335 clinically probable AD patients. We then proceeded to extract gene-expression data from the publicly available Allen Human Brain Atlas (HBA) database. We used the nearest genes to 46 AD- and T2D-associated SNPs previously identified in the literature, and mapped their expression to the same 34 cortical regions in which we calculated SUVRs. SNPs with a donor consistency of 0.40 or greater were selected for further analysis. We evaluated the associations between SUVR and gene-expression across the brain. Results: Of the 46 risk-factor genes, 15 were found to be significantly correlated with FDG-PET brain metabolism in healthy adults and probable AD patients after correction for multiple comparisons. Using multiple regression, we found that five genes explained a total of 72.5% of the SUVR variance across the healthy adult group regions, while four genes explained a total of 79.3% of the SUVR variance across the probable AD group regions. There were significant differences in whole-brain SUVR as a function of allele frequencies for two genes. Conclusions: These results highlight the association between risk factor genes for T2D and regional glucose metabolism during both normal aging and in probable AD. Highlighted genes were associated with mitochondrial stability, vascular maintenance, and glucose intolerance. Pharmacological intervention of these pathways has the potential to improve glucose metabolism during normal again as well as in AD patients.


Hybrid external fixation of distal tibial fractures: new strategy to place pins and wires without penetrating the anterior compartment.
Impalement of the anterior compartment musculature remains a problem in the hybrid external fixation of distal tibial fractures. The purposes of this study were to develop a tensioned wire configuration which does not violate the anterior compartment and to analyze the biomechanical implications of new wire configuration. Thirty-seven adult volunteers without known pathology around either tibia were recruited. Axial computed tomography of the distal tibia was performed at 5-mm slices from the plafond to the upper margin of the syndesmosis. The wire convergence angle was measured at the 1-, 2-, and 2.5-cm levels using the following landmarks: tibialis anterior tendon (TA), tibialis posterior tendon (TP), peroneus brevis tendon (PB), anterolateral border of the lateral malleolus (LM). Two straight lines were drawn by connecting TA and PB and connecting TP and LM. The wire convergence angle was defined as an acute angle between these two lines. Then the orientation of the bisector axis of the wires was measured. As a second part of this study, a validated three-dimensional hybrid external fixator model was developed using finite elements modeling to analyze the stiffness of the frames constructed according to the measured wire convergence angle and orientation. Five simulated configurations were tested. The stiffness of each frame was analyzed under four load conditions: torsion, axial compression, side bending, and anteroposterior bending. The mean convergence angle was 30 degrees irrespective of the level. The bisector axis was oriented towards the anterolateral direction about 20 degrees from the coronal plane. The stiffness of the frame constructed with a wire convergence angle of 30 degrees and an anterolateral wire orientation of 20 degrees was 20-30% less than that of the frame constructed with 60 degrees wires oriented in a coronal plane. The addition of an anteromedial half-pin increased the stiffness significantly. Two tensioned wires may be placed without violating the anterior compartment by using the above four clinically identifiable landmarks. Addition of a half-pin on the anteromedial surface of the distal articular fragment makes the frame markedly stiffer than is possible using the standard wire configuration.