The role of screening, brief intervention, and referral to treatment in the perinatal period.
Substance use during pregnancy is at least as common as many of the medical conditions screened for and managed during pregnancy. While harmful and costly, it is often ignored or managed poorly. Screening, brief intervention, and referral to treatment is an evidence-based approach to manage substance use. In September 2012, the US Centers for Disease Control and Prevention convened an Expert Meeting on Perinatal Illicit Drug Abuse to help address key issues around drug use in pregnancy in the United States. This article reflects the formal conclusions of the expert panel that discussed the use of screening, brief intervention, and referral to treatment during pregnancy. Screening for substance use during pregnancy should be universal. It allows stratification of women into zones of risk given their pattern of use. Low-risk women should receive brief advice, those classified as moderate risk should receive a brief intervention, whereas those who are high risk need referral to specialty care. A brief intervention is a patient-centered form of counseling using the principles of motivational interviewing. Screening, brief intervention, and referral to treatment has the potential to reduce the burden of substance use in pregnancy and should be integrated into prenatal care.


Visible-light promoted fluoroalkylselenolation: toward the reactivity of unsaturated compounds.
The reactivity of fluoroalkylselenotoluenesulfonates with unsaturated substrates is explored herein. The direct activation of these shelf-stable reagents under visible light allows the double functionalisation of alkenes or alkynes efficiently, leading to a wide range of β-fluoroalkylselenolated sulfones. Mechanistic investigations have been undertaken supporting the formation of radical intermediates.


Rapid Prediction of Electron-Ionization Mass Spectrometry Using Neural Networks.
When confronted with a substance of unknown identity, researchers often perform mass spectrometry on the sample and compare the observed spectrum to a library of previously collected spectra to identify the molecule. While popular, this approach will fail to identify molecules that are not in the existing library. In response, we propose to improve the library's coverage by augmenting it with synthetic spectra that are predicted from candidate molecules using machine learning. We contribute a lightweight neural network model that quickly predicts mass spectra for small molecules, averaging 5 ms per molecule with a recall-at-10 accuracy of 91.8%. Achieving high-accuracy predictions requires a novel neural network architecture that is designed to capture typical fragmentation patterns from electron ionization. We analyze the effects of our modeling innovations on library matching performance and compare our models to prior machine-learning-based work on spectrum prediction.


Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations.
Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.


Changes in child mortality over time across the wealth gradient in less-developed countries.
It is unknown whether inequalities in under-5 mortality by wealth in low- and middle-income countries (LMICs) are growing or declining. All Demographic and Health Surveys conducted between 2002 and 2012 were used to measure under-5 mortality trends in 3 wealth tertiles. Two approaches were used to estimate changes in under-5 mortality: within-survey changes from all 54 countries, and between-survey changes for 29 countries with repeated survey waves. The principal outcome measures include annual decline in mortality, and the ratio of mortality between the poorest and least-poor wealth tertiles. Mortality information in 85 surveys from 929 224 households and 1 267 167 women living in 54 countries was used. In the subset of 29 countries with repeat surveys, mortality declined annually by 4.36, 3.36, and 2.06 deaths per 1000 live births among the poorest, middle, and least-poor tertiles, respectively (P = .031 for difference). The mortality ratio declined from 1.68 to 1.48 during the study period (P = .006 for trend). In the complete set of 85 surveys, the mortality ratio declined in 64 surveys (from 2.11 to 1.55), and increased in 21 surveys (from 1.58 to 1.88). Multivariate analyses suggest that convergence was associated with good governance (P ≤ .03 for 4 governance indicators: government effectiveness, rule of law, regulatory quality, and control of corruption). Overall, under-5 mortality in low- and middle-income countries has decreased faster among the poorest compared with the least poor between 1995 and 2012, but progress in some countries has lagged, especially with poor governance.


Evaluation of colon cancer-specific antigen 2 as a potential serum marker for colorectal cancer.
A blood test to detect colon cancer at a preventable stage would represent a major advancement. We have previously identified colon cancer-specific markers using focused proteomics analysis of nuclear structural proteins. Two of these markers, colon cancer-specific antigen (CCSA)-3 and CCSA-4, have been developed into blood-based markers that are able to distinguish individuals with colorectal cancer from those without. CCSA-2 is a distinct novel colon cancer marker identified using focused proteomics. Using an indirect ELISA on serum samples obtained from two institutions, we evaluated CCSA-2 as a serum-based colon cancer marker. A total of 111 serum samples from individuals who underwent colonoscopy and were subsequently diagnosed as either being normal or having hyperplastic polyps, nonadvanced adenomas, advanced adenomas, and colorectal cancer were evaluated. A diverse control population that consisted of 125 serum samples was also included in this study. Receiver operating characteristic analyses were used to measure the sensitivity and specificity of CCSA-2. CCSA-2 at a cutoff of 10.8 mug/mL has overall specificity of 78.4% [95% confidence interval (95% CI), 67.3-87.1%] and sensitivity of 97.3% (95% CI, 85.8-99.5%) in separating individuals with advanced adenomas and colorectal cancer from normal, hyperplastic, and nonadvanced adenoma populations. The receiver operating characteristic curve for CCSA-2 has an area under the curve of 0.90 (95% CI, 0.83-0.95). Our initial study shows that CCSA-2 is a potential serum-based marker for colon cancer detection with high sensitivity and specificity.


Detection of ammonium-oxidizing bacteria of the beta-subclass of the class Proteobacteria in aquatic samples with the PCR.
The PCR was used as the basis for the development of a sensitive and specific assay for the detection of ammonium-oxidizing bacteria belonging to the beta-subclass of the class Proteobacteria. PCR primers were selected on the basis of nucleic acid sequence data available for seven species of nitrifiers in this subclass. The specificity of the ammonium oxidizer primers was evaluated by testing known strains of nitrifiers, several serotyped environmental nitrifier isolates, and other members of the Proteobacteria, including four very closely related, nonnitrifying species (as determined by rRNA sequence analysis). DNA extracts from 19 bacterio-plankton samples collected from Lake Bonney, Antarctica, and the Southern California Bight were assayed for the presence of ammonium oxidizers. By using a two-stage amplification procedure, ammonium oxidizers were detected in samples collected from both sites. Chemical data collected simultaneously support the occurrence of nitrification and the presence of nitrifiers. This is the first report describing PCR primers specific for ammonium-oxidizing bacteria and the successful amplification of nitrifier genes coding for rRNA from DNA extracts from natural samples. This application of PCR is of particular importance for the detection and study of microbes, such as autotrophic nitrifiers, which are difficult or impossible to isolate from indigenous microbial communities.


The Ustilago maydis ubc4 and ubc5 genes encode members of a MAP kinase cascade required for filamentous growth.
Ustilago maydis, the causal agent of corn smut disease, displays dimorphic growth in which it alternates between a budding haploid saprophyte and a filamentous dikaryotic pathogen. We are interested in identifying the genetic determinants of filamentous growth and pathogenicity in U. maydis. To do this we have taken a forward genetic approach. Earlier, we showed that haploid adenylate cyclase (uac1) mutants display a constitutively filamentous phenotype. Mutagenesis of a uac1 disruption strain allowed the isolation of a large number of budding suppressor mutants. These mutants are named ubc, for Ustilago bypass of cyclase, as they no longer require the production of cyclic AMP (cAMP) to grow in the budding morphology. Complementation of a subset of these suppressor mutants led to the identification of the ubc4 and ubc5 genes, which are required for filamentous growth and encode a MAP (mitogen-activated protein) kinase kinase kinase and a MAP kinase kinase, respectively. Evidence suggests that they are important in the pheromone response pathway and in pathogenicity. These results further support an important interplay of the cAMP and MAP kinase signal transduction pathways in the control of morphogenesis and pathogenicity in U. maydis.


The Fourth Industrial Revolution: Will it change pharmacy practice?
The industrial world is at the beginning of a Fourth Industrial Revolution (4IR). This era will radically change the human use of technology, with major implications for the ways people live and work. This commentary asks: will 4IR change pharmacy practice? The first three revolutions created the pharmaceutical industry and gave pharmacists a near-monopoly over drug supply. 4IR could do the opposite and create alternative, non-pharmaceutical means of treating patients as well reducing the involvement in medicines supply. If the pharmacy sector becomes stuck in traditional, linear thinking that assumes the future will be an extension of the past, then the fourth revolution may be less of an opportunity and more of a threat. The sector faces the "innovator's dilemma" when responding to 4IR. Should the pharmacy profession disrupt their current activities in order to: (i) do things better, (ii) do new things, and (iii) deter competition? To maintain its position in the medical marketplace, pharmacy needs to discover how to work with AI, robotics, IoT, autonomous vehicles, 3-D printing, nanotechnology, biotechnology, materials science, energy storage, and quantum computing. If the new game is understood, pharmacists may become the playmaster of tomorrow. If not, then the practice of pharmacy may be replaced by innovative new ways of meeting patient pharmaceutical needs.


Influence of neighboring plants on the dynamics of an ant-acacia protection mutualism.
Ant-plant protection symbioses, in which plants provide food and/or shelter for ants in exchange for protection from herbivory, are model systems for understanding the ecology of mutualism. While interactions between ants, host plants, and herbivores have been intensively studied, we know little about how plant-plant interactions influence the dynamics of these mutualisms, despite strong evidence that plants compete for resources, that hosting ants can be costly, and that host-plant provisioning to ants can therefore be constrained by resource availability. We used field experiments in a semiarid Kenyan savanna to examine interactions between the ant-plant Acacia drepanolobium, neighboring grasses, and two species of symbiotic acacia-ants with divergent behaviors: Crematogaster mimosae, an aggressive symbiont that imposes high costs to host trees via consumption of extrafloral nectar, and Tetraponera penzigi, a less-protective symbiont that imposes lower costs because it does not consume nectar. We hypothesized that by competing with acacias for resources, neighboring grasses (1) reduce hosts' ability to support costly C. mimosae, while having little or no effect on the ability of hosts to support low-cost T. penzigi, and (2) reduce sapling growth rates irrespective of ant occupant. We factorially manipulated the presence/absence of grasses and the identity of ant occupants on saplings and evaluated effects on colony survivorship and sapling growth rates over 40 weeks. Contrary to prediction, the high-cost/high-reward nectar-dependent mutualist C. mimosae had higher colony-survival rates on saplings with grass neighbors present. Grasses appear to have indirectly facilitated the survival of C. mimosae by reducing water stress on host plants; soils under saplings shaded by grasses had higher moisture content, and these saplings produced more active nectaries than grass-removal saplings. Consistent with prediction, survival of low-cost/low-reward T. penzigi did not differ significantly between grass-removal treatments. Saplings occupied by low-cost/low-reward T. penzigi grew 100% more on average than saplings occupied by high-cost/high-reward C. mimosae, demonstrating that mutualist-partner identity strongly and differentially influences demographic rates of young plants. In contrast, contrary to prediction, grass neighbors had no significant net impact on sapling growth rates. Our results suggest that neighboring plants can exert strong and counterintuitive effects on ant-plant protection symbioses, highlighting the need to integrate plant-plant interactions into our understanding of these mutualisms.


Spatial and temporal dynamics of irrigation water quality under drought conditions in a large reservoir in Southern Portugal.
Water is a scarce resource in the Mediterranean region where adverse climatic conditions promoting water shortages tend to increase with climate change. Under water scarcity conditions and high atmosphere evaporative demand, the risks of decreased water quality, and land salinization are major threats to the sustainability of irrigated agriculture in this region. The assessment of the quality of irrigation water is increasingly important to ensure the maintenance of long-term salt balance at a crop, farm, and regional scale. This study is focused on the spatial and temporal variability of water quality for irrigation in the Alqueva reservoir (Southern Portugal). The assessment was performed every 2 months during a distinctive drought year (2017) and included inorganic ions (Na+, Ca2+, Mg2+, K+, NH4+, Cl-, F-, SO42-, NO3-, and NO2-), pH, and electric conductivity (ECW) of water. Sodium adsorption ratio (SAR) was calculated, and potential soil permeability problems were estimated. The assessment showed significantly higher values of the physicochemical parameters in the most upstream sites, located near tributaries inflows, and an upward trend in ion concentrations throughout the year, with significantly higher concentrations of Na+, Mg2+, Cl-, and SO42, registered through May to November, reflecting the severe drought felt in the summer, autumn, and winter. The evaluation of water quality for irrigation indicated a slight to moderate risk of reduced infiltration rates, which should be considered whenever sprinkler irrigation is used, mainly in fine-textured soils, which are prevalent in the irrigated area. The multivariate statistical approach, using principal component analysis and factor analysis, identified two principal components related to salinity and nutrient concentrations. The cluster analysis revealed three groups of similarity between samples pointing to a more time- than space-controlled pattern. Overall, the temporal dynamics of the water physicochemical parameters could indicate that an abnormal annual distribution of precipitation and temperature may distort seasonal differences. To prevent water and soil degradation, a more frequent assessment of the water quality should be considered, allowing for the selection of appropriate soil and water management measures in irrigated areas.


Describing the genetic architecture of epilepsy through heritability analysis.
Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.


Brief communication: a proposed method for the assessment of pubertal stage in human skeletal remains using cervical vertebrae maturation.
The assessment of age-at-death in non-adult skeletal remains is under constant review. However, in many past societies an individual's physical maturation may have been more important in social terms than their exact age, particularly during the period of adolescence. In a recent article (Shapland and Lewis: Am J Phys Anthropol 151 (2013) 302-310) highlighted a set of dental and skeletal indicators that may be useful in mapping the progress of the pubertal growth spurt. This article presents a further skeletal indicator of adolescent development commonly used by modern clinicians: cervical vertebrae maturation (CVM). This method is applied to a collection of 594 adolescents from the medieval cemetery of St. Mary Spital, London. Analysis reveals a potential delay in ages of attainment of the later CVM stages compared with modern adolescents, presumably reflecting negative environmental conditions for growth and development. The data gathered on CVM is compared to other skeletal indicators of pubertal maturity and long bone growth from this site to ascertain the usefulness of this method on archaeological collections.


The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress.
Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated & FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.


Isolation and characterisation of the mating-type (MAT) locus from Rhynchosporium secalis.
The mating-type ( MAT) genes from Rhynchosporium secalis were isolated using PCR-based methods. Characterisation of the MAT idiomorphs suggests that R. secalis is closely related to the discomycetes Pyrenopeziza brassicae and Tapesia yallundae in terms of sequence and MAT locus gene composition. The MAT1-2 idiomorph contains a single gene encoding a protein with a high-mobility group (HMG) DNA-binding domain. The MAT1-1 idiomorph contains two genes, one encoding a protein with a HMG domain and the other encoding an alpha box domain. A second, previously undescribed, intron was identified within the P. brassicae MAT1-2-1 gene. Two introns were also present in the corresponding gene in R. secalis and this showed the similarity between these genes at the discomycete MAT1-2 locus. Using PCR, we identified isolates of both mating types from barley crops in different parts of the UK and showed that the composition of the MAT idiomorphs is conserved in these isolates. These findings support the hypothesis that R. secalis is a heterothallic discomycete which has an as yet unidentified teleomorph.


Statins as Pleiotropic Modifiers of Vascular Oxidative Stress and Inflammation.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world and in the future is expected to be the number one killer worldwide. The main cause underlying CVD is atherosclerosis. A key event in atherosclerosis initiation and progression is oxidative stress through the production of reactive oxygen species as well as endothelial dysfunction. Several pro- inflammatory and anti-inflammatory cytokines and proteins are involved in this process, complemented by activation of adhesion molecules that promote leukocyte rolling, tethering and infiltration into the sub-endothelial space. Statins represent the agent of choice since numerous clinical trials have verified that their pharmacological action extends beyond lipid lowering. Statins demonstrate direct anti-oxidant effects by scavenging free radicals and stimulating anti-oxidant enzymes while acting as regulators for cytokine, protein and adhesion molecule expression, all of which are involved in the atherosclerotic process. Statin use is considered one of the most efficient currently used interventions in managing CVD with the likely hood of remaining so in the near future.


[Accuracy, precision and clinically acceptable level of complete blood cell count by an automated multichannel hematology analyzer].
Measurement of complete blood cell count (CBC) is one of the essential laboratory tests. In this study, the accuracy of CBC was high, when measured by six different automated blood cell counters, including SE-9000/RAM-1, CELL-DYN 4000, ADVIA 120, VEGA RETIC-LC141 or GEN*S. The correlations of CBC counts among these instruments were also good. In contrast, the accuracy in abnormal samples depended on matching the instrument and type of clinical conditions. Internal quality control of automated multichannel hematology analyzers was recommended by the NCCLS H26-A in 1996. However, actual external quality control of the CBC count was poorly understood. We surveyed three samples from healthy volunteers for CBC values in 1997. Among six different instruments, the inter-assay of the red blood cell count (RBC), hemoglobin, hematocrit and MCV was fairly good, shown as < 4.2%, < 3.0%, < 4.4% and < 3.4%, respectively. In contrast, the inter-assay of the white blood cell count (WBC) and platelet (PLT) was not good, shown as < 11.4% and < 9.6%, respectively. The clinically acceptable levels for the blood cell count were reported to be 4% for RBC, 3% for hemoglobin, 4% for MCV, 5% for WBC and 7% for PLT, by JCCLS in 1994. The clinically acceptable CBC by hematologists at Keio University resembled those by councilors of The Japanese Society of Clinical Hematology, whereas, residents at Keio University and general physicians required more precise clinical CBC counts. These results indicate that a larger study is needed to clarify the accuracy, clinically acceptable level, and performance of different automated blood cell counters.


Interactions between xenoestrogens and ketoconazole on hepatic CYP1A and CYP3A, in juvenile Atlantic cod (Gadus morhua).
BACKGROUND: Xenoestrogens and antifungal azoles probably share a common route of metabolism, through hepatic cytochrome P450 (CYP) enzymes. Chemical interactions with metabolic pathways may affect clearance of both xenobiotics and endobiotics. This study was carried out to identify possible chemical interactions by those substances on CYP1A and CYP3A, in Atlantic cod liver. We investigated effects of two xenoestrogens (nonylphenol and ethynylestradiol) and of the model imidazole ketoconazole, alone and in combination. RESULTS: Treatment with ketoconazole resulted in 60% increase in CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity. Treatment with nonylphenol resulted in 40% reduction of CYP1A activity. Combined exposure to ketoconazole and nonylphenol resulted in 70% induction of CYP1A activities and 93% increase in CYP1A protein levels. Ketoconazole and nonylphenol alone or in combination had no effect on CYP3A expression, as analyzed by western blots. However, 2-dimensional (2D) gel electrophoresis revealed the presence of two CYP3A-immunoreactive proteins, with a more basic isoform induced by ketoconazole. Treatment with ketoconazole and nonylphenol alone resulted in 54% and 35% reduction of the CYP3A-mediated benzyloxy-4-[trifluoromethyl]-coumarin-O-debenzyloxylase (BFCOD) activity. Combined exposure of ketoconazole and nonylphenol resulted in 98% decrease in CYP3A activity. This decrease was greater than the additive effect of each compound alone. In vitro studies revealed that ketoconazole was a potent non-competitive inhibitor of both CYP1A and CYP3A activities and that nonylphenol selectively non-competitively inhibited CYP1A activity. Treatment with ethynylestradiol resulted in 46% decrease in CYP3A activity and 22% decrease in protein expression in vivo. In vitro inhibition studies in liver microsomes showed that ethynylestradiol acted as a non-competitive inhibitor of CYP1A activity and as an uncompetitive inhibitor of CYP3A activity. CONCLUSIONS: Ketoconazole, nonylphenol and ethynylestradiol all interacted with CYP1A and CYP3A activities and protein expression in Atlantic cod. However, mechanisms of interactions on CYP1A and CYP3A differ between theses substances and combined exposure had different effects than exposure to single compounds. Thus, CYP1A and CYP3A mediated clearance may be impaired in situations of mixed exposure to those types of compounds.


Manipulation and mobilisation for neck pain contrasted against an inactive control or another active treatment.
Manipulation and mobilisation are commonly used to treat neck pain. This is an update of a Cochrane review first published in 2003, and previously updated in 2010. To assess the effects of manipulation or mobilisation alone compared wiith those of an inactive control or another active treatment on pain, function, disability, patient satisfaction, quality of life and global perceived effect in adults experiencing neck pain with or without radicular symptoms and cervicogenic headache (CGH) at immediate- to long-term follow-up. When appropriate, to assess the influence of treatment characteristics (i.e. technique, dosage), methodological quality, symptom duration and subtypes of neck disorder on treatment outcomes. Review authors searched the following computerised databases to November 2014 to identify additional studies: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched ClinicalTrials.gov, checked references, searched citations and contacted study authors to find relevant studies. We updated this search in June 2015, but these results have not yet been incorporated. Randomised controlled trials (RCTs) undertaken to assess whether manipulation or mobilisation improves clinical outcomes for adults with acute/subacute/chronic neck pain. Two review authors independently selected studies, abstracted data, assessed risk of bias and applied Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods (very low, low, moderate, high quality). We calculated pooled risk ratios (RRs) and standardised mean differences (SMDs). We included 51 trials (2920 participants, 18 trials of manipulation/mobilisation versus control; 34 trials of manipulation/mobilisation versus another treatment, 1 trial had two comparisons). Cervical manipulation versus inactive control: For subacute and chronic neck pain, a single manipulation (three trials, no meta-analysis, 154 participants, ranged from very low to low quality) relieved pain at immediate- but not short-term follow-up. Cervical manipulation versus another active treatment: For acute and chronic neck pain, multiple sessions of cervical manipulation (two trials, 446 participants, ranged from moderate to high quality) produced similar changes in pain, function, quality of life (QoL), global perceived effect (GPE) and patient satisfaction when compared with multiple sessions of cervical mobilisation at immediate-, short- and intermediate-term follow-up. For acute and subacute neck pain, multiple sessions of cervical manipulation were more effective than certain medications in improving pain and function at immediate- (one trial, 182 participants, moderate quality) and long-term follow-up (one trial, 181 participants, moderate quality). These findings are consistent for function at intermediate-term follow-up (one trial, 182 participants, moderate quality). For chronic CGH, multiple sessions of cervical manipulation (two trials, 125 participants, low quality) may be more effective than massage in improving pain and function at short/intermediate-term follow-up. Multiple sessions of cervical manipulation (one trial, 65 participants, very low quality) may be favoured over transcutaneous electrical nerve stimulation (TENS) for pain reduction at short-term follow-up. For acute neck pain, multiple sessions of cervical manipulation (one trial, 20 participants, very low quality) may be more effective than thoracic manipulation in improving pain and function at short/intermediate-term follow-up. Thoracic manipulation versus inactive control: Three trials (150 participants) using a single session were assessed at immediate-, short- and intermediate-term follow-up. At short-term follow-up, manipulation improved pain in participants with acute and subacute neck pain (five trials, 346 participants, moderate quality, pooled SMD -1.26, 95% confidence interval (CI) -1.86 to -0.66) and improved function (four trials, 258 participants, moderate quality, pooled SMD -1.40, 95% CI -2.24 to -0.55) in participants with acute and chronic neck pain. A funnel plot of these data suggests publication bias. These findings were consistent at intermediate follow-up for pain/function/quality of life (one trial, 111 participants, low quality). Thoracic manipulation versus another active treatment: No studies provided sufficient data for statistical analyses. A single session of thoracic manipulation (one trial, 100 participants, moderate quality) was comparable with thoracic mobilisation for pain relief at immediate-term follow-up for chronic neck pain. Mobilisation versus inactive control: Mobilisation as a stand-alone intervention (two trials, 57 participants, ranged from very low to low quality) may not reduce pain more than an inactive control. Mobilisation versus another active treatment: For acute and subacute neck pain, anterior-posterior mobilisation (one trial, 95 participants, very low quality) may favour pain reduction over rotatory or transverse mobilisations at immediate-term follow-up. For chronic CGH with temporomandibular joint (TMJ) dysfunction, multiple sessions of TMJ manual therapy (one trial, 38 participants, very low quality) may be more effective than cervical mobilisation in improving pain/function at immediate- and intermediate-term follow-up. For subacute and chronic neck pain, cervical mobilisation alone (four trials, 165 participants, ranged from low to very low quality) may not be different from ultrasound, TENS, acupuncture and massage in improving pain, function, QoL and participant satisfaction at immediate- and intermediate-term follow-up. Additionally, combining laser with manipulation may be superior to using manipulation or laser alone (one trial, 56 participants, very low quality). Although support can be found for use of thoracic manipulation versus control for neck pain, function and QoL, results for cervical manipulation and mobilisation versus control are few and diverse. Publication bias cannot be ruled out. Research designed to protect against various biases is needed. Findings suggest that manipulation and mobilisation present similar results for every outcome at immediate/short/intermediate-term follow-up. Multiple cervical manipulation sessions may provide better pain relief and functional improvement than certain medications at immediate/intermediate/long-term follow-up. Since the risk of rare but serious adverse events for manipulation exists, further high-quality research focusing on mobilisation and comparing mobilisation or manipulation versus other treatment options is needed to guide clinicians in their optimal treatment choices.


The effect of in-hospital acquired thrombocytopenia on the outcome of patients with acute coronary syndromes: A systematic review and meta-analysis.
In-hospital acquired thrombocytopenia (TP) is relatively common among patients hospitalized with acute coronary syndromes (ACS). However, its effect on short-term and long-term outcomes has yet to be reviewed systematically. We conducted a systematic review and meta-analysis of clinical studies assessing the relationship between new-onset in-hospital TP and adverse outcomes among ACS patients. MEDLINE, Scopus and the Cochrane Library were searched for eligible studies published before March 20, 2016. Ten studies reporting on a total of 142,161 ACS patients were identified. 8133 patients showed evidence of new-onset TP during the course of their hospitalization. Compared with patients with normal platelet counts, patients with new-onset TP had a prolonged in-hospital stay, significantly higher risk of both short-term mortality (<30days) (Odds ratio (OR) [95% confidence interval (CI)]: 5.58 [3.63-8.57]) and late death (6months to 1year) (OR [95% CI]: 3.45 [2.35-5.07]), as well as a significantly higher risk of major bleeding events in the first 30days (OR [95% CI]: 6.93 [5.13-9.38]). In addition, risk for other secondary cardiovascular endpoints, including recurrent myocardial infarction, stroke, in-hospital heart failure, stent thrombosis and unplanned revascularization was also significantly higher in the TP versus the no TP group. Development of TP during the in-hospital management of ACS patients is a significant predictor of both short- and long-term adverse events, including mortality. In the light of this evidence, clinicians should be cautious and closely monitor abnormal platelet counts that present early following an ACS.


Labral base refixation in the hip: rationale and technique for an anatomic approach to labral repair.
Recent literature has defined the importance of anatomic repair in shoulder and knee arthroscopy. New advances in hip arthroscopy have created opportunities to apply the principle of anatomic repair to the hip. To address the obstacles in the restoration of labral anatomy, we describe an anatomic approach to labral refixation. We reviewed the literature on biomechanics of the labrum to identify the factors that are essential to the function of the labrum. Existing techniques for arthroscopic labral repair and potential challenges in restoration of labral anatomy were reviewed. A list of criteria for anatomic labral repair was created, and a technique for anatomic labral base refixation was developed. The technique incorporates the understanding of the function and biomechanical role of the labrum and builds on existing techniques to fulfill the criteria for restoration of anatomy. Our purpose was to review the anatomy, biomechanics, and existing repair techniques of the labrum, as well as to describe the rationale and surgical steps for anatomic labral base refixation in the hip.


Response of Acidithiobacillus caldus toward suboptimal pH conditions.
Maintenance of a circumneutral intracellular pH is important for any organism. Acidophilic microorganisms thrive at low pH while maintaining their intracellular pH around 6.5. However, the mechanisms contributing to acidophile pH homeostasis are not well characterized. The authors investigated the proteomic response and cytoplasmic membrane fatty acid profiles of Acidithiobacillus caldus toward three pH values: 1.1, 2.5, and 4.0. Major rearrangements were observed but lower pH elicited larger changes. Differentially expressed transcription factors suggested tight transcriptional control of pH induced genes. Enzymes involved in sulfur metabolism were up-regulated at pH 1.1 suggesting either that: (1) cells required more energy for maintenance or (2) increased metabolic activity was a specific acid stress response to export intracellular protons via 1° electron transport proton pumps. Furthermore, glutamate decarboxylase, an important enzyme in Escherichia coli acid resistance, was uniquely expressed at pH 1.1. Other proteins previously shown to be involved in neutrophilic acid response, such as spermidine synthase, PspA, and toluene tolerance protein, were differentially expressed in At. caldus but require further investigation to show a direct link to pH homeostasis. Their roles in acidophilic organisms are discussed. Active modulation of fatty acid profiles was detected and suggested a more rigid membrane at low pH.


Contribution to the study of acoustic communication in two Belgian river bullheads (Cottus rhenanus and C. perifretum) with further insight into the sound-producing mechanism.
The freshwater sculpins (genus Cottus) are small, bottom-living fishes widely distributed in North America and Europe. The taxonomy of European species has remained unresolved for a long time due to the overlap of morphological characters. Sound production has already been documented in some cottid representatives, with sounds being involved in courtship and agonistic interactions. Although the movements associated with sound production have been observed, the underlying mechanism remains incomplete. Here, we focus on two closely related species from Belgium: C. rhenanus and C. perifretum. This study aims 1) to record and to compare acoustic communication in both species, 2) to give further insight into the sound-producing mechanism and 3) to look for new morphological traits allowing species differentiation. Both Cottus species produce multiple-pulsed agonistic sounds using a similar acoustic pattern: the first interpulse duration is always longer, making the first pulse unit distinct from the others. Recording sound production and hearing abilities showed a clear relationship between the sound spectra and auditory thresholds in both species: the peak frequencies of calls are around 150 Hz, which corresponds to their best hearing sensitivity. However, it appears that these fishes could not hear acoustic signals produced by conspecifics in their noisy habitat considering their hearing threshold expressed as sound pressure (~ 125 dB re 1 μPa). High-speed video recordings highlighted that each sound is produced during a complete back and forth movement of the pectoral girdle. Both Cottus species use an acoustic pattern that remained conserved during species diversification. Surprisingly, calls do not seem to have a communicative function. On the other hand, fish could detect substrate vibrations resulting from movements carried out during sound production. Similarities in temporal and spectral characteristics also suggest that both species share a common sound-producing mechanism, likely based on pectoral girdle vibrations. From a morphological point of view, only the shape of the spinelike scales covering the body allows species differentiation.


The sialic acid residue of exogenous GM1 ganglioside is recycled for biosynthesis of sialoglycoconjugates in rat liver.
In order to assess metabolic recycling of sialic acid, GM1 ganglioside [nomenclature of Svennerholm (1964) J. Lipid. Res. 5, 145-155; IUPAC-IUB Recommendations (1977) Lipids 12, 455-468], 14C-radiolabelled at the acetyl group of sialic acid, was intravenously injected into Wistar rats, and the presence of radioactive sialic acid in liver sialoglycolipids (gangliosides) and sialoglycoproteins was ascertained. A time-course study (20 min-72 h) showed that the radioactivity present in the liver distributed in the following fractions, with reciprocal proportion varying with time: the protein (glycoprotein) fraction, the ganglioside fraction and the diffusible fraction, which contained low-Mr compounds, including sialic acid. Ganglioside-linked radioactivity gradually decreased with time; protein-linked radioactivity appeared soon after injection (20 min), reached a maximum around 20 h, then slowly diminished; diffusible radioactivity provided a sharp peak at 4 h, then rapidly decreased till disappearing after 40 h. The behaviour of bound radioactivity in the individual liver gangliosides was as follows: (a) rapid diminution with time in GM1, although with a lower rate at the longer times after injection; (b) early appearance (20 min) with a peak at 1 h, followed by continuous diminution, in GM2; (c) early appearance (20 min), peak at 1 h, diminution till 4 h, followed by a plateau, in GM3; (d) appearance at 60 min, maximum around 40 h and slow diminution thereafter, in GD1a, GD1b and GT1b. A detailed study, accomplished at 40 h after injection, demonstrated that almost all radioactivity present in the protein fraction was released by mild acid treatment and recovered in purified sialic acid; most of radioactive glycoprotein-bound sialic acid was releasable by sialidase action. In addition, the radioactivity present in the different gangliosides was exclusively carried by sialic acid and present in both sialidase-resistant and sialidase-labile residues. Only in the case of GD1a was the specific radioactivity of sialidase-resistant sialic acid superior to that of sialidase-releasable sialic acid. The results obtained lead to the following conclusions: (a) radioactive GM3 and GM2 were produced by degradation of GM1 taken up; GM3 originated partly by a process of neosynthesis; (b) radioactive GM1 consisted in part of residual exogenous GM1 and in part of a neosynthetized product; (c) radioactive GD1a originated in part by direct sialylation of GM1 taken up and in part by a neosynthetic process; (d) radioactive GD1b and GT1b resulted only from neosynthesis.(ABSTRACT TRUNCATED AT 400 WORDS)


Placental vascularisation requires the AP-1 component fra1.
Fra1 is an immediate-early gene encoding a member of the AP-1 transcription factor family, which has diverse roles in development and oncogenesis. To determine the function of Fra1 in mouse development, the gene was inactivated by gene targeting. Foetuses lacking Fra1 were severely growth retarded and died between E10.0 and E10.5, owing to defects in extra-embryonic tissues. The placental labyrinth layer, where X-gal staining revealed expression of Fra1, was reduced in size and largely avascular, owing to a marked decrease in the number of vascular endothelial cells, as shown by the lack of Flk1 expression. In contrast, the spongiotrophoblast layer was unaffected and expressed the marker genes 4311 (Tpbp) and Flt1. Furthermore, mutant foetuses exhibited yolk-sac defects that may contribute to their growth retardation and lethality. Importantly, when the placental defect was rescued by injection of Fra1(-)(/)(-) ES cells into tetraploid wild-type blastocysts, Fra1(-)(/)(-) pups were obtained that were no longer growth retarded and survived up to 2 days after birth without apparent phenotypic defects. These data indicate that a defect in the extra-embryonic compartment is causal to the observed lethality, and suggest that Fra1 plays a crucial role in establishing normal vascularisation of the placenta.


Longer breastfeeding is associated with increased lower body explosive strength during adolescence.
Our aim in this study was to examine the association between breastfeeding duration and cardiorespiratory fitness, isometric strength, and explosive strength during adolescence. A total of 2567 adolescents (1426 girls) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study aged 12.5-17.5 y were included. Information about duration of any and exclusive breastfeeding was obtained retrospectively by means of a parental questionnaire. The 20-m shuttle run, handgrip strength, and standing long jump tests were used to assess physical fitness. Significant differences among the categories of breastfeeding duration were tested using ANCOVA after adjusting for a set of potential confounders: gestational and current age, birth weight, sexual maturation, fat mass, fat-free mass, maternal education, parental weight status, country, smoking behavior, and days of vigorous physical activity. Longer breastfeeding (either any or exclusive) was associated with a higher performance in the standing long jump test in both boys and girls (P < 0.001), regardless of fat mass, fat-free mass, and the rest of potential confounders. In adolescents who were breastfed for 3-5 mo or ≥6 mo, the risk of having a standing long jump performance below the 5th percentile was reduced by half compared with those who were never breastfed [odds ratio (OR) = 0.54, 95% CI = 0.30-0.96, P < 0.05; and OR = 0.40, 95% CI = 0.22-0.74, P < 0.01, respectively). These findings suggest a role of breastfeeding in determining lower body explosive strength during adolescence.


Decreased hydrodynamic resistance in the two-phase flow of blood through small vertical tubes at low flow rates.
The aggregation of red blood cells in blood flowing through small tubes at very low shear rates leads to the two-phase flow of an inner core of rouleaux surrounded by a cell-depleted peripheral layer. The formation of this layer is known to be accompanied by a decrease in hydrodynamic resistance to flow. To quantitate this effect, we measured the pressure gradient, flow rate, and the radius of the red blood cell core in suspensions flowing through tubes of 172-microns radius at mean linear flow rates (U) from 50 to 0.15 tube diameters.sec-1. Washed red blood cells were suspended in 1.5% buffered dextran 110 at hematocrits of 34-52%. Using syringe pumps, blood flowed from a stirred reservoir through a vertical 12-cm length of tube in either the upward or downward direction. The pressure drop was measured with transducers. Mean values in distributions in the core radius were obtained by analyzing cine films of flow taken through a microscope with flow in the upward direction, measuring the core radius at five equally spaced axial positions of the tube in each of 100 frames. At 34% and 46% hematocrit, the hydrodynamic resistance increased as U decreased from 50 sec-1, reaching a maximum at U-2 sec-1. It then decreased to a minimum at U less than 0.5 sec-1 as the red blood cell core formed in the tube, and the mean core radius/tube radius ratio decreased from 0.98 to 0.74 with marked axial fluctuations at the lower U. At higher hematocrits, both the increase and decrease in hydrodynamic resistance were greater. In a red blood cell albumin-saline suspension, where there is no aggregation of red blood cells and no two-phase flow, hydrodynamic resistance increases linearly with decreasing U. The experimental results were compared with the predictions of a two-phase steady-flow model, assuming axisymmetric flow of a core surrounded by cell-free suspending medium. Two models were considered, one in which the core is solid, the other in which the rheological properties of the suspension in the core are given by the Quemada equation. The effects of sedimentation of the core resulting in a zero net flow pressure gradient were taken into account. Provided that an experimentally extrapolated value for the zero pressure gradient was used, the Quemada-fluid model gave good agreement with the experimentally observed core radius as a function of U and hematocrit.


Regulation of RAW 264.7 cell-mediated immunity by polysaccharides from Agaricus blazei Murill via the MAPK signal transduction pathway.
Agaricus blazei Murill (ABM) is a common anticancer folk remedy. Its active ingredients, i.e., polysaccharides, have been isolated and exhibit indirect tumor-suppressing activity via immunological activation. The effects of polysaccharides derived from A. blazei Murill (ABMP) on RAW 264.7 cells were examined by western blotting and real-time reverse transcription polymerase chain reaction (RT-PCR). The effects of 500, 1000, and 2000 μg mL-1 ABMP on the growth of RAW 264.7 cells were evaluated by measuring the OD490 value; the optimum concentration was found to be 1000 μg mL-1. Based on the RT-PCR results, the expression levels of JNK, ERK, and p38 decreased substantially in lipopolysaccharide (LPS)-induced RAW 264.7 cells treated with ABMP. In RAW 264.7 cells treated with LPS, the protein expression levels of JNK, ERK, and p38 were decreased, as were the levels of phosphorylated JNK, ERK, and p38. These results indicate that the MAPK signal transduction pathway is a potential mechanism by which ABMP regulates the cell-mediated immunity of RAW 264.7 cells.


Transcriptional initiation under conditions of anoxia-induced quiescence in mitochondria from Artemia franciscana embryos.
In response to anoxia, embryos of the brine shrimp Artemia franciscana are able coordinately to downregulate metabolism to levels low enough to permit survival for several years at room temperature. In addition to dramatic decreases in free ATP levels and heat production, intracellular pH drops from 7.8 to 6.3 overnight. Use of isolated mitochondria to study transcriptional responses to anoxia offers several advantages: (1). the localized nature of transcript initiation, processing and degradation, all of which may be followed in organello; (2). the relatively simple cis- and trans-machinery involved and (3). the ability to provide relevant physiological treatments in vitro. In response to anoxic incubation of embryos in vivo for 4 h followed by anoxic mitochondrial isolation and anoxic transcription assay at pH 6.4, a significant decrease in overall UTP incorporation (77%) was seen after 30 min relative to normoxic, pH 7.9 controls. A less severe inhibition of transcription under anoxia (52%) was observed compared with controls when pH was raised to 7.9. Similarly, under normoxia, the incubation at low pH (6.4) reduced transcription by 59%. Ribonuclease protection assays showed that the contribution of in vitro initiation during the assay fell from 78% at pH 7.9 to approximately 32% at pH 6.4 under either normoxic or anoxic conditions. DNA footprinting of putative transcriptional promoters revealed proteins at regular intervals upstream of the 12S rRNA in the control region, which previously had been indirectly inferred to contain promoters for H-strand transcription. The area between 1230 and 12065 contains a sequence in the tRNA(leu) gene believed to bind the transcription termination factor mTERF or TERM, and we provide the first evidence that this sequence is protein-bound in A. franciscana. However, our hypothesis that initiation is reduced at low pH because of a change in DNA binding by mitochondrial transcription factors was not confirmed. We propose that regulation of initiation may be mediated by covalent modification or by protein-protein interactions not detected by footprinting.


Functional magnetic resonance imaging based on changes in vascular space occupancy.
During brain activation, local control of oxygen delivery is facilitated through microvascular dilatation and constriction. A new functional MRI (fMRI) methodology is reported that is sensitive to these microvascular adjustments. This contrast is accomplished by eliminating the blood signal in a manner that is independent of blood oxygenation and flow. As a consequence, changes in cerebral blood volume (CBV) can be assessed through changes in the remaining extravascular water signal (i.e., that of parenchymal tissue) without need for exogenous contrast agents or any other invasive procedures. The feasibility of this vascular space occupancy (VASO)-dependent functional MRI (fMRI) approach is demonstrated for visual stimulation, breath-hold (hypercapnia), and hyperventilation (hypocapnia). During visual stimulation and breath-hold, the VASO signal shows an inverse correlation with the stimulus paradigm, consistent with local vasodilatation. This effect is reversed during hyperventilation. Comparison of the hemodynamic responses of VASO-fMRI, cerebral blood flow (CBF)-based fMRI, and blood oxygenation level-dependent (BOLD) fMRI indicates both arteriolar and venular temporal characteristics in VASO. The effect of changes in water exchange rate and partial volume contamination with CSF were calculated to be negligible. At the commonly-used fMRI resolution of 3.75 x 3.75 x 5 mm(3), the contrast-to-noise-ratio (CNR) of VASO-fMRI was comparable to that of CBF-based fMRI, but a factor of 3 lower than for BOLD-fMRI. Arguments supporting a better gray matter localization for the VASO-fMRI approach compared to BOLD are provided.


Dynamic moment analysis of the extracellular electric field of a biologically realistic spiking neuron.
Based on the membrane currents generated by an action potential in a biologically realistic model of a pyramidal, hippocampal cell within rat CA1, we perform a moment expansion of the extracellular field potential. We decompose the potential into both inverse and classical moments and show that this method is a rapid and efficient way to calculate the extracellular field both near and far from the cell body. The action potential gives rise to a large quadrupole moment that contributes to the extracellular field up to distances of almost 1 cm. This method will serve as a starting point in connecting the microscopic generation of electric fields at the level of neurons to macroscopic observables such as the local field potential.


The Kallisti Limnes, carbon dioxide-accumulating subsea pools.
Natural CO2 releases from shallow marine hydrothermal vents are assumed to mix into the water column, and not accumulate into stratified seafloor pools. We present newly discovered shallow subsea pools located within the Santorini volcanic caldera of the Southern Aegean Sea, Greece, that accumulate CO2 emissions from geologic reservoirs. This type of hydrothermal seafloor pool, containing highly concentrated CO2, provides direct evidence of shallow benthic CO2 accumulations originating from sub-seafloor releases. Samples taken from within these acidic pools are devoid of calcifying organisms, and channel structures among the pools indicate gravity driven flow, suggesting that seafloor release of CO2 at this site may preferentially impact benthic ecosystems. These naturally occurring seafloor pools may provide a diagnostic indicator of incipient volcanic activity and can serve as an analog for studying CO2 leakage and benthic accumulations from subsea carbon capture and storage sites.


The causal role of elevated uric acid and waist circumference on the risk of metabolic syndrome components.
Hyperuricemia has been found to cluster with multiple components of metabolic syndrome (MetS). It is unclear whether hyperuricemia is a downstream result of MetS or may play an upstream role in MetS development. Using the Mendelian randomization (MR) method, we examined the causal relationship between elevated uric acid and the various components of MetS with waist circumference as a positive control. Data from 10k participants of Taiwan Biobank was used to carry out MR analysis with uric acid risk score (wGRS) and waist circumference wGRS as instrumental variables and components of MetS as the outcomes. We found that genetically increased serum uric acid corresponds to a significant increment of triglyceride (β = 0.065, p < 0.0001), systolic blood pressure (β = 1.047, p = 0.0005), diastolic blood pressure (β = 0.857, p < 0.0001), and mean arterial pressure (β = 0.920, p < 0.0001), but a significant reduction of high-density lipoprotein cholesterol (β = -0.020, p = 0.0014). Uric acid wGRS was not associated with fasting serum glucose, HbA1C, waist circumference, or BMI. On the other hand, waist circumference was causally associated with all the components of MetS including uric acid. Our MR investigation shows that uric acid increment may augment the risk of MetS through increasing blood pressure and triglyceride levels and lowering HDL-C value but not through accumulating fat or hyperglycemia. High waist circumference may be a causal agent for all the components of MetS including hyperuricemia.


Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia.
Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.


Metabolism and disposition of naltrexone in man after oral and intravenous administration.
The metabolism and elimination of [15, 16,-3H2]naltrexone was studied in man after oral and intravenous administration. The same metabolites, although in varying proportions, were observed in both cases; conjugated naltrexone and conjugated and unconjugated 6 beta-naltrexol were the major metabolites observed in plasma, urine, and feces. 2-Hydroxy-3-O-methyl-6 beta-naltrexol was found in minor quantities. Naltrexone was almost completely absorbed after oral administration. After oral and intravenous administration of naltrexone, about 60% of the dose was recovered in the urine in 48 and 72 hr, respectively. The route of administration did not significantly affect urinary clearance values obtained for unconjugated or conjugated naltrexone and 6 beta-naltrexol. The route of administration significantly affected terminal plasma half-life values obtained for unconjugated naltrexone (2.7 hr, iv; 8.9 hr, oral), but had little effect on comparable values obtained for total drug, conjugated naltrexone, and unconjugated and conjugated 6 beta-naltrexol. Combined gas chromatography-mass spectrometry was used to validate the presence of naltrexone, 6 beta-naltrexol, and 2-hydroxy-3-O-methyl-6 beta-naltrexol in urine.


Assessment of coronary arterial restenosis with phase-contrast magnetic resonance imaging measurements of coronary flow reserve.
After successful percutaneous coronary arterial revascularization, 25% to 60% of subjects have restenosis, a recurrent coronary arterial narrowing at the site of the intervention. At present, restenosis is usually detected invasively with contrast coronary angiography. This study was performed to determine if phase-contrast MRI (PC-MRI) could be used to detect restenosis noninvasively in patients with recurrent chest pain after percutaneous revascularization. Seventeen patients (15 men, 2 women, age 36 to 77 years) with recurrent chest pain >3 months after successful percutaneous intervention underwent PC-MRI measurements of coronary artery flow reserve followed by assessments of stenosis severity with computer-assisted quantitative coronary angiography. The intervention was performed in the left anterior descending coronary artery in 15 patients, one of its diagonal branches in 2 patients, and the right coronary artery in 1 patient. A PC-MRI coronary flow reserve value </=2.0 was 100% and 82% sensitive and 89% and 100% specific for detecting a luminal diameter narrowing of >/=70% and >/=50%, respectively. Assessments of coronary flow reserve with PC-MRI can be used to identify flow-limiting stenoses (luminal diameter narrowings >70%) in patients with recurrent chest pain in the months after a successful percutaneous intervention.


Antenatal and delivery care in rural western Kenya: the effect of training health care workers to provide "focused antenatal care".
Maternal mortality remains high in developing countries and data to monitor indicators of progress in maternal care is needed. We examined the status of maternal care before and after health care worker (HCW) training in WHO recommended Focused Antenatal Care. An initial cross-sectional survey was conducted in 2002 in Asembo and Gem in western Kenya among a representative sample of women with a recent birth. HCW training was performed in 2003 in Asembo, and a repeat survey was conducted in 2005 in both areas. Antenatal clinic (ANC) attendance was similar in both areas (86%) in 2005 and not significantly different from 2002 (90%). There was no difference in place of delivery between the areas or over time. However, in 2005, more women in Asembo were delivered by a skilled assistant compared to Gem (30% vs.23%, P = 0.04), and this proportion increased compared to 2002 (17.6% and 16.1%, respectively). Provision of iron (82.4%), folic acid (72.0%), sulfadoxine-pyrimethamine (61.7%), and anthelminths (12.7%) had increased in Asembo compared to 2002 (2002: 53.3%, 52.8%, 20.3%, and 4.6%, respectively), and was significantly higher than in Gem in 2005 (Gem 2005: 69.7%, 47.8%, 19.8%, and 4.1%, respectively) (P < 0.05 for all). Offering of tests for sexually transmitted diseases and providing information related to maternal health was overall low (<20%) and did not differ by area. In 2005, more women rated the quality of the antenatal service in Asembo as very satisfactory compared to Gem (17% vs. 6.5%, P < 0.05). We observed improvements in some ANC services in the area where HCWs were trained. However, since our evaluation was carried out 2 years after three-day training, we consider any significant, sustained improvement to be remarkable.


Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg(2+) at 2.0-A resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, R1441 and I1371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD.


Validation of a brachial cuff-based method for estimating central systolic blood pressure.
The prognostic value of central systolic blood pressure has been established recently. At present, its noninvasive assessment is limited by the need of dedicated equipment and trained operators. Moreover, ambulatory and home blood pressure monitoring of central pressures are not feasible. An algorithm enabling conventional automated oscillometric blood pressure monitors to assess central systolic pressure could be of value. We compared central systolic pressure, calculated with a transfer-function like method (ARCSolver algorithm), using waveforms recorded with a regular oscillometric cuff suitable for ambulatory measurements, with simultaneous high-fidelity invasive recordings, and with noninvasive estimations using a validated device, operating with radial tonometry and a generalized transfer function. Both studies revealed a good agreement between the oscillometric cuff-based central systolic pressure and the comparator. In the invasive study, composed of 30 patients, mean difference between oscillometric cuff/ARCSolver-based and invasive central systolic pressures was 3.0 mm Hg (SD: 6.0 mm Hg) with invasive calibration of brachial waveforms and -3.0 mm Hg (SD: 9.5 mm Hg) with noninvasive calibration of brachial waveforms. Results were similar when the reference method (radial tonometry/transfer function) was compared with invasive measurements. In the noninvasive study, composed of 111 patients, mean difference between oscillometric cuff/ARCSolver-derived and radial tonometry/transfer function-derived central systolic pressures was -0.5 mm Hg (SD: 4.7 mm Hg). In conclusion, a novel transfer function-like algorithm, using brachial cuff-based waveform recordings, is suited to provide a realistic estimation of central systolic pressure.


FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ(2) = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.


The phylogeny of Little Red Riding Hood.
Researchers have long been fascinated by the strong continuities evident in the oral traditions associated with different cultures. According to the 'historic-geographic' school, it is possible to classify similar tales into "international types" and trace them back to their original archetypes. However, critics argue that folktale traditions are fundamentally fluid, and that most international types are artificial constructs. Here, these issues are addressed using phylogenetic methods that were originally developed to reconstruct evolutionary relationships among biological species, and which have been recently applied to a range of cultural phenomena. The study focuses on one of the most debated international types in the literature: ATU 333, 'Little Red Riding Hood'. A number of variants of ATU 333 have been recorded in European oral traditions, and it has been suggested that the group may include tales from other regions, including Africa and East Asia. However, in many of these cases, it is difficult to differentiate ATU 333 from another widespread international folktale, ATU 123, 'The Wolf and the Kids'. To shed more light on these relationships, data on 58 folktales were analysed using cladistic, Bayesian and phylogenetic network-based methods. The results demonstrate that, contrary to the claims made by critics of the historic-geographic approach, it is possible to identify ATU 333 and ATU 123 as distinct international types. They further suggest that most of the African tales can be classified as variants of ATU 123, while the East Asian tales probably evolved by blending together elements of both ATU 333 and ATU 123. These findings demonstrate that phylogenetic methods provide a powerful set of tools for testing hypotheses about cross-cultural relationships among folktales, and point towards exciting new directions for research into the transmission and evolution of oral narratives.


Pyogenic variant of primary cutaneous anaplastic large-cell lymphoma: a lymphoproliferative disorder with a predilection for the immunocompromized and the young.
Cutaneous anaplastic large-cell lymphoma belongs to the class of primary cutaneous CD30-positive lymphoproliferative disorders. The pyogenic variant is marked by a neutrophil rich inflammatory background. We describe 2 cases (one which clinically presented as cellulitis, and another arising in a patient with Hodgkin lymphoma) and review the clinicopathologic features of cases reported in the literature. In all cases, the male to female ratio is 1.2:1. The average age at presentation for patients with this variant is 47 years old with 15% of patients being 25 years old or younger. Thirteen percent of patients are immunocompromized. Ten percent of patients experience extracutaneous disease progression and 18% of patients are dead at 10 months. Immunophenotypically, the anaplastic large cells demonstrate loss of pan-T cell antigens, CD2, CD3, CD5, and CD7, with 65% of cases expressing CD4 and 29% of cases expressing CD8. Epithelial membrane antigen expression is reported in over half of the cases. In the clinical context of a progressive ulcerating lesion in younger or immunocompromized patients, it is important for the pathologist when presented with a skin specimen demonstrating a neutrophil-rich inflammatory background to include the pyogenic variant of anaplastic large-cell lymphoma. We hope to increase awareness of this rare CD30-positive lymphoproliferative disorder subtype by better defining the clinical spectrum in which this entity can present.


IGF-1 and insulin exert opposite actions on ClC-K2 activity in the cortical collecting ducts.
Despite similar stimulatory actions on the epithelial sodium channel (ENaC)-mediated sodium reabsorption in the distal tubule, insulin promotes kaliuresis, whereas insulin-like growth factor-1 (IGF-1) causes a reduction in urinary potassium levels. The factors contributing to this phenomenon remain elusive. Electrogenic distal nephron ENaC-mediated Na(+) transport establishes driving force for Cl(-) reabsorption and K(+) secretion. Using patch-clamp electrophysiology, we document that a Cl(-) channel is highly abundant on the basolateral plasma membrane of intercalated cells in freshly isolated mouse cortical collecting duct (CCD) cells. The channel has characteristics attributable to the ClC-K2: slow gating kinetics, conductance ∼10 pS, voltage independence, Cl(-)>NO3 (-) anion selectivity, and inhibition/activation by low/high pH, respectively. IGF-1 (100 and 500 nM) acutely stimulates ClC-K2 activity in a reversible manner. Inhibition of PI3-kinase (PI3-K) with LY294002 (20 μM) abrogates activation of ClC-K2 by IGF-1. Interestingly, insulin (100 nM) reversibly decreases ClC-K2 activity in CCD cells. This inhibitory action is independent of PI3-K and is mediated by stimulation of a mitogen-activated protein kinase-dependent cascade. We propose that IGF-1, by stimulating ClC-K2 channels, promotes net Na(+) and Cl(-) reabsorption, thus reducing driving force for potassium secretion by the CCD. In contrast, inhibition of ClC-K2 by insulin favors coupling of Na(+) reabsorption with K(+) secretion at the apical membrane contributing to kaliuresis.


Bone marrow concentrate: a novel strategy for bone defect treatment.
Although strong efforts have been made over the last decade to introduce stem cell and tissue engineering treatment strategies to the field of orthopaedics, only few clinical applications are currently available. The clinical outcomes of ten patients with volumetric bone deficiencies treated with mesenchymal stem cells and bone marrow aspirate are presented in this case series. Results were evaluated with radiographs. In addition to the in vivo data, we also presented in vitro data of BMC cultivated onto a porous collagen I scaffold and the technique of bone marrow aspiration via a commercially available system. Our results demonstrated that there is a rationale for a clinical application of BMC / bone aspirate in the treatment of osseous defects. The intraoperative harvest procedure is a safe method and does not significantly prolong the time of surgery. In addition, MSC isolated from the aspirate was able to adhere and proliferate onto a collagen scaffold in significant numbers after a 15 min incubation period. These cells were then able to allow osteogenic differentiation in vitro without any osteogenic stimuli. The local application of BMC / bone aspirate in the treatment of bone deficiencies may be a promising alternative to autogenous bone grafting and help reduce donor site morbidity.


Health-related quality of life in inflammatory bowel disease. Functional status and patient worries and concerns.
The assessment of health-related quality of life may be an adjunct to understanding the chronic illness experience and its effects on health outcomes. In this study, we evaluated health-related quality of life of 150 patients with inflammatory bowel disease (63 ulcerative colitis, 87 Crohn's disease). We used a standardized measure, the Sickness Impact Profile, and a questionnaire we developed that elicits and prioritizes the disease-related worries and concerns of patients with IBD. Our preliminary data indicate that: (1) IBD patients experience moderate functional impairment more in the social and psychological than in the physical dimensions; (2) Crohn's disease patients report psychosocial dysfunction to a greater degree than ulcerative colitis patients; (3) IBD patients report greatest concerns about having surgery, degree of energy, and body image issues such as having an ostomy bag; and (4) functional status and patient concerns correlate better with other measures of health status and previous health care utilization than the physician's rating of disease activity. We believe that questionnaires measuring health-related quality of life (HRQOL) can be used in research and patient care to extend the clinical assessment of patients with IBD. Further work is needed to determine the role of HRQOL relative to disease activity and other physician-based assessments in predicting health outcomes.


Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study.
There is no study that has compared, in a randomized manner, which vasopressor is most suitable in optimizing both systemic and regional hemodynamics in cardiogenic shock patients. Hence, the present study was designed to compare epinephrine and norepinephrine-dobutamine in dopamine-resistant cardiogenic shock. Open, randomized interventional human study. Medical intensive care unit in a university hospital. Thirty patients with a cardiac index of <2.2 L/min/m and a mean arterial pressure of <60 mm Hg resistant to combined dopamine-dobutamine treatment and signs of shock. Patients were not included in cases of cardiogenic shock secondary to acute ischemic events such as myocardial infarction. Noninclusion criteria also included immediate indication of mechanical assistance. Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain a mean arterial pressure of between 65 and 70 mm Hg with a stable or increased cardiac index. Both regimens increased cardiac index and oxygen-derived parameters in a similar manner. Patients in the norepinephrine-dobutamine group demonstrated heart rates lower (p<.05) than those in the epinephrine group. Epinephrine infusion was associated with new arrhythmias in three patients. When compared to baseline values, after 6 hrs, epinephrine infusion was associated with an increase in lactate level (p<.01), whereas this level decreased in the norepinephrine-dobutamine group. Tonometered PCO2 gap, a surrogate for splanchnic perfusion adequacy, increased in the epinephrine-treated group (p<.01) while decreasing in the norepinephrine group (p<.01). Diuresis increased in both groups but significantly more so in the norepinephrine-dobutamine group, whereas plasma creatinine decreased in both groups. When considering global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, epinephrine is associated with a transient lactic acidosis, higher heart rate and arrhythmia, and inadequate gastric mucosa perfusion. Thus, the combination norepinephrine-dobutamine appears to be a more reliable and safer strategy.


A programmable lipid-polymer hybrid nanoparticle system for localized, sustained antibiotic delivery to Gram-positive and Gram-negative bacterial biofilms.
Bacteria enmeshed in an extracellular matrix, biofilms, exhibit enhanced antibiotic tolerance. Coupled with the rapid emergence of multidrug-resistant strains, the current cohorts of antibiotics are becoming ineffective. Alternative antimicrobial approaches are therefore urgently needed to overcome recalcitrant biofilm infections. Here, we propose the use of a non-toxic lipid-polymer hybrid nanoparticle (LPN) system composed of a solid polymer core (i.e. PLGA; poly lactic-co-glycolic acid) and a cationic lipid shell (i.e. DOTAP) for localized, sustained release of antimicrobial agents to bacterial biofilms. LPNs were synthesized through a simple, robust self-assembly approach. LPNs of uniform particle size (i.e. 100-130 nm), efficiently encapsulated (up to 95%) bioimaging molecules or antibiotics and provided controlled release of the latter. The cationic lipid coating enabled the LPN to anchor onto surfaces of a diverse range of Gram-positive and Gram-negative bacterial pathogens, either in the planktonic or biofilm form. Consistently, the LPN formulations reduced more than 95% of biofilm activity at concentrations that were 8 to 32-fold lower than free antibiotics. These data clearly indicate that these novel formulations could be a useful strategy to enhance the efficacy of antimicrobials against planktonic cells and biofilms of diverse species.


Turning back from the brink: detecting an impending regime shift in time to avert it.
Ecological regime shifts are large, abrupt, long-lasting changes in ecosystems that often have considerable impacts on human economies and societies. Avoiding unintentional regime shifts is widely regarded as desirable, but prediction of ecological regime shifts is notoriously difficult. Recent research indicates that changes in ecological time series (e.g., increased variability and autocorrelation) could potentially serve as early warning indicators of impending shifts. A critical question, however, is whether such indicators provide sufficient warning to adapt management to avert regime shifts. We examine this question using a fisheries model, with regime shifts driven by angling (amenable to rapid reduction) or shoreline development (only gradual restoration is possible). The model represents key features of a broad class of ecological regime shifts. We find that if drivers can only be manipulated gradually management action is needed substantially before a regime shift to avert it; if drivers can be rapidly altered aversive action may be delayed until a shift is underway. Large increases in the indicators only occur once a regime shift is initiated, often too late for management to avert a shift. To improve usefulness in averting regime shifts, we suggest that research focus on defining critical indicator levels rather than detecting change in the indicators. Ideally, critical indicator levels should be related to switches in ecosystem attractors; we present a new spectral density ratio indicator to this end. Averting ecological regime shifts is also dependent on developing policy processes that enable society to respond more rapidly to information about impending regime shifts.


The Roles of Parasitoid Foraging for Hosts, Food and Mates in the Augmentative Control of Tephritidae.
Ultimately, the success of augmentative fruit fly biological control depends upon the survival, dispersal, attack rate and multi-generational persistence of mass-reared parasitoids in the field. Foraging for hosts, food and mates is fundamental to the above and, at an operational level, the choice of the parasitoid best suited to control a particular tephritid in a certain environment, release rate estimates and subsequent monitoring of effectiveness. In the following we review landscape-level and microhabitat foraging preferences, host/fruit ranges, orientation through environmental cues, host vulnerabilities/ovipositor structures, and inter and intraspecific competition. We also consider tephritid parasitoid mating systems and sexual signals, and suggest the directions of future research.


Evaluation of oxidative markers in women with invasive cervical cancer in Lagos, Nigeria.
Epidemiological studies have showed that low levels of antioxidants induce the generation of free radicals leading to DNA damage and further mutations seen in cancer. This study evaluated the effects of oxidative markers on the occurrence and severity of cervical cancer at the Lagos University Teaching Hospital. This was an analytical cross-sectional study carried out among women with histological diagnosis of invasive cervical cancer and their healthy cancer-free comparison group. Venous blood samples were collected from each participant for measurements of antioxidants (erythrocyte glutathione and vitamin C) and malondialdehyde (a marker of lipid peroxidation). Descriptive statistics were carried out for relevant demographic and clinical data. Associations between continuous variables were tested using the independent sample t-test or the analysis of variance for normally distributed data or the Mann-Whitney U test for skewed data, whereas categorical variables were compared using the χ2 test. p < 0.05 was considered statistically significant. The mean level of malondialdehyde (MDA) was statistically higher in women with cervical cancer than in their cancer-free counterparts (p = 0.032). However, the mean glutathione (32.6 ± 6.2 versus 14.2 ± 6.1 mg/dL; p = 0.019) and vitamin C (12.4 ± 2.3 versus 14.6 ± 2.4 µmol/L; p = 0.001) levels were significantly lower in the case group compared to the cancer-free group. There are statistically increasing mean levels of MDA (p = 0.017) and decreasing mean levels of vitamin C (p = 0.004) with increasing stages of the disease. This study showed that women with cervical cancer have low levels of antioxidants and an increased level of the oxidative marker. The levels of these markers become more pronounced as the disease progresses. This will, therefore, form the basis for the conduct of future randomised controlled trials of antioxidant supplementations among cervical cancer patients in sub-Saharan Africa.


Cannabis coadministration potentiates the effects of "ecstasy" on heart rate and temperature in humans.
This study assessed the acute physiologic effects over time of (co)administration of Delta9-tetrahydrocannabinol (Delta9-THC) (the main psychoactive compound of cannabis) and 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") in 16 healthy volunteers. Pharmacokinetics and cardiovascular, temperature, and catecholamine responses were assessed over time. Both single-drug conditions robustly increased heart rate, and coadministration showed additive effects. MDMA increased epinephrine and norepinephrine concentrations, whereas THC did not affect the catecholamine response. Coadministration of MDMA and THC attenuated the increase of norepinephrine concentrations relative to administration of MDMA alone. These results show that THC mediates heart rate increase independent of sympathetic (catecholaminergic) activity, probably through direct cannabinoid receptor type 1 (CB(1)) agonism in cardiac tissue. Furthermore, THC coadministration did not prevent MDMA-induced temperature increase, but it delayed the onset and prolonged the duration of temperature elevation. These effects may be of particular relevance for the cardiovascular safety of ecstasy users who participate in energetic dancing in nightclubs with high ambient temperature.


Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction.
The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.


Signal-to-noise performance of a short-wave infrared nanoinjection imager.
We report on the signal-to-noise performance of a nanoinjection imager, which is based on a short-wave IR InGaAs/GaAsSb/InP detector with an internal avalanche-free amplification mechanism. Test pixels in the imager show responsivity values reaching 250 A/W at 1550 nm, -75 degrees C, and 1.5V due to an internal charge amplification mechanism in the detector. In the imager, the measured imager noise was 28 electrons (e(-)) rms at a frame rate of 1950 frames/s. Additionally, compared to a high-end short-wave IR imager, the nanoinjection camera shows 2 orders of magnitude improved signal-to-noise ratio at thermoelectric cooling temperatures primarily due to the small excess noise at high amplification.


Synergistic Effect of Honey and Propolis on Cutaneous Wound Healing in Rats.
Accelerating wound healing is now considered as a principle clinical treatment and increasing the quality and speed of healing which has always been emphasized by the scientists. Propolis and honey are natural bee products with wide range of biological and medicinal properties. This study was aimed to determine the synergistic effect of honey and propolis in wound healing of rat skin. A total of 75 Wistar rats weighing 200-250 gr were placed under general anesthesia and sterile conditions. Then a square shape wound with 1.5*1.5 mm dimension was made on the back of the neck. Animals were randomly divided into control, honey, propolis, combined honey propolis and phenytoin 1% groups, respectively. Rats were randomly divided into the following groups: 4th, 7th and, 14th days of treatment in each period of study. Wound area in the experimental group was covered once daily with a fixed amount of thyme honey, propolis, propolis and honey and phenytoin cream (1%), the control group did not receive any treatment. For histological studies, during the fourth, seventh and fourteenth day's rats were sacrificed and samples were taken from the wound and adjacent skin. After histological staining fibroblast, neutrophils, macrophages and vascular sections were counted in the wound bed. The macroscopic and microscopic evaluations showed that the percentage of wound healing on different days in the experimental and control groups were significant (P<0.05). The macroscopic and microscopic evaluation showed that the percentage of wound healing on different days in combined propolis and honey experimental group was significantly different from the control group (Multivariate ANOVA test) (P<0.05). Combined application of propolis and honey on the open wound healing in rats has a synergistic effect.


Suppression of the antiferromagnetic pseudogap in the electron-doped high-temperature superconductor by protect annealing.
In the hole-doped cuprates, a small number of carriers suppresses antiferromagnetism and induces superconductivity. In the electron-doped cuprates, on the other hand, superconductivity appears only in a narrow window of high-doped Ce concentration after reduction annealing, and strong antiferromagnetic correlation persists in the superconducting phase. Recently, Pr(1.3-x)La0.7Ce(x)CuO4 (PLCCO) bulk single crystals annealed by a protect annealing method showed a high critical temperature of around 27 K for small Ce content down to 0.05. Here, by angle-resolved photoemission spectroscopy measurements of PLCCO crystals, we observed a sharp quasi-particle peak on the entire Fermi surface without signature of an antiferromagnetic pseudogap unlike all the previous work, indicating a dramatic reduction of antiferromagnetic correlation length and/or of magnetic moments. The superconducting state was found to extend over a wide electron concentration range. The present results fundamentally challenge the long-standing picture on the electronic structure in the electron-doped regime.


Vascular endothelial growth factor: an essential component of angiogenesis and fracture healing.
Fractures require adequate stability and blood supply to heal. The vascular supply to long bones is compromised in a fracture, and the ability to heal hinges on the ability of new blood vessels to proliferate from surrounding vessels in a process known as angiogenesis. This process is largely driven by the growth factor, vascular endothelial growth factor (VEGF), whose levels are increased locally and systemically during fracture healing. VEGF is involved in many steps throughout the fracture healing cascade, from initially being concentrated in fracture hematoma, to the promotion of bone turnover during the final remodeling phase. This article reviews the current literature surrounding the role of VEGF and other growth factors in reestablishing vascular supply to fractured bone, as well as medications and surgical techniques that may inhibit this process.


Ultra-tough injectable cytocompatible hydrogel for 3D cell culture and cartilage repair.
In this work, we developed a very facile strategy, i.e. dual dynamic crosslinking, to prepare a high performance injectable hydrogel. Poly(vinyl alcohol) (PVA) was crosslinked by 4-carboxyphenylboronic acid (CPBA) through the generation of borate bonding and ionic interaction to bridge the polymer chains in the presence of calcium ions. The dynamic gathering of CPBA could induce a self-reinforcing effect inside the hydrogel matrix, leading to high tensile and compressive moduli of the hydrogel over 1.0 MPa including the highest compressive modulus up to 5.6 MPa. Meanwhile, the mechanical properties of the hydrogel can be broadly and accurately tuned. And owing to the flexible PVA network, the hydrogel is ultra-tough, showing maximum tensile strain, tensile and compressive fracture energies up to 1600%, 600 kJ m-2 and 25 kJ m-2, respectively. Besides, the dynamic bonding overcomes the barriers to forming an injected strong hydrogel, e.g. to obtain a modulus and a fracture energy exceeding 1.0 MPa and 40 kJ m-2, by using a commercial dual-syringe kit under physiological conditions. Such a mild gelation procedure benefits the administration, 3D encapsulation and proliferation of cells of the hydrogels. The application of the PVA hydrogel was demonstrated by effective cartilage repair.


Adult soft-tissue sarcomas of the head and neck.
Head and neck sarcomas are relatively rare tumors, accounting for only about 2% of all head and neck malignancies and for 4 to 10% of all soft tissue sarcomas. The rarity and more over the heterogeneity of these tumors make rigorous study of their clinical behavior difficult. We analyzed our single center experience of adult soft tissue sarcomas of the head and neck. Our study included 27 patients of adult soft-tissue sarcomas of the head and neck who presented to our center between January 1996 and December 2005. Patient characteristics, clinical features, treatment modalities, clinical course, and long-term outcomes and its determinants were analyzed. Surgery in the form of wide excision aimed at achieving negative margins was the main modality of treatment and adjuvant radiation was used in selected patients. The five-year disease-free survival was 64.5% and overall survival (OS) was 68%. Of the multiple potential factors analyzed, univariate analysis showed grade, margin status, and adjuvant radiation to be the important prognostic factors for the survival. The multivariate analysis however only showed margin status and adjuvant radiation to be prognostic. Surgery with negative margins is a key to long-term survival. Complete resection with adjuvant radiation in selected cases potentially decreases local recurrences and improves OS.


Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage.
DNA double-strand breaks (DSBs) are common lesions that continually threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including cell death. Misrepair is also fraught with danger, especially inappropriate end-joining events, which commonly underlie oncogenic transformation and can scramble the genome. Canonically, cells employ two basic mechanisms to repair DSBs: homologous recombination (HR) and the classical nonhomologous end-joining pathway (cNHEJ). More recent experiments identified a highly error-prone NHEJ pathway, termed alternative NHEJ (aNHEJ), which operates in both cNHEJ-proficient and cNHEJ-deficient cells. aNHEJ is now recognized to catalyze many genome rearrangements, some leading to oncogenic transformation. Here, we review the mechanisms of cNHEJ and aNHEJ, their interconnections with the DNA damage response (DDR), and the mechanisms used to determine which of the three DSB repair pathways is used to heal a particular DSB. We briefly review recent clinical applications involving NHEJ and NHEJ inhibitors.