Abnormal Changes of Brain Cortical Anatomy and the Association with Plasma MicroRNA107 Level in Amnestic Mild Cognitive Impairment.
MicroRNA107 (Mir107) has been thought to relate to the brain structure phenotype of Alzheimer's disease. In this study, we evaluated the cortical anatomy in amnestic mild cognitive impairment (aMCI) and the relation between cortical anatomy and plasma levels of Mir107 and beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Twenty aMCI (20 aMCI) and 24 cognitively normal control (NC) subjects were recruited, and T1-weighted MR images were acquired. Cortical anatomical measurements, including cortical thickness (CT), surface area (SA), and local gyrification index (LGI), were assessed. Quantitative RT-PCR was used to examine plasma expression of Mir107, BACE1 mRNA. Thinner cortex was found in aMCI in areas associated with episodic memory and language, but with thicker cortex in other areas. SA decreased in aMCI in the areas associated with working memory and emotion. LGI showed a significant reduction in aMCI in the areas involved in language function. Changes in Mir107 and BACE1 messenger RNA plasma expression were correlated with changes in CT and SA. We found alterations in key left brain regions associated with memory, language, and emotion in aMCI that were significantly correlated with plasma expression of Mir107 and BACE1 mRNA. This combination study of brain anatomical alterations and gene information may shed lights on our understanding of the pathology of AD. http://www.ClinicalTrials.gov, identifier NCT01819545.


Comparison between direct contact and extract exposure methods for PFO cytotoxicity evaluation.
A series of recent acute blindness cases following non-complicated retinal detachment surgery caused the release of several health alerts in Spain. The blindness was attributed to certain lots of perfluoro-octane (PFO; a volatile and transient medical device). Similar cases have been reported in other countries. This has raised questions regarding the validity of cytotoxicity test methods currently used to certify the safety of PFO lots. The tests were performed according to the International Organization for Standardization (ISO) norms, using the extract dilution method or the indirect contact method as applied to L929 cells, a line derived from mouse fibroblasts. The limitations of those methods have been resolved in this study by proposing a new cytotoxicity test method for volatile substances. The new method requires direct contact of the tested substance with cells that are similar to those exposed to the substance in the clinical setting. This approach includes a few new technical steps that are crucial for detecting cytotoxicity. Our new method detected toxic PFO lots that corresponded to the lots producing clinical blindness, which previous methods failed to detect. The study suggests applying this new method to avoid occurrence of such cases of blindness.


Dystrophin-deficient dogs with reduced myostatin have unequal muscle growth and greater joint contractures.
Myostatin (Mstn) is a negative regulator of muscle growth whose inhibition promotes muscle growth and regeneration. Dystrophin-deficient mdx mice in which myostatin is knocked out or inhibited postnatally have a less severe phenotype with greater total mass and strength and less fibrosis and fatty replacement of muscles than mdx mice with wild-type myostatin expression. Dogs with golden retriever muscular dystrophy (GRMD) have previously been noted to have increased muscle mass and reduced fibrosis after systemic postnatal myostatin inhibition. Based partly on these results, myostatin inhibitors are in development for use in human muscular dystrophies. However, persisting concerns regarding the effects of long-term and profound myostatin inhibition will not be easily or imminently answered in clinical trials. To address these concerns, we developed a canine (GRippet) model by crossbreeding dystrophin-deficient GRMD dogs with Mstn-heterozygous (Mstn (+/-)) whippets. A total of four GRippets (dystrophic and Mstn (+/-)), three GRMD (dystrophic and Mstn wild-type) dogs, and three non-dystrophic controls from two litters were evaluated. Myostatin messenger ribonucleic acid (mRNA) and protein levels were downregulated in both GRMD and GRippet dogs. GRippets had more severe postural changes and larger (more restricted) maximal joint flexion angles, apparently due to further exaggeration of disproportionate effects on muscle size. Flexors such as the cranial sartorius were more hypertrophied on magnetic resonance imaging (MRI) in the GRippets, while extensors, including the quadriceps femoris, underwent greater atrophy. Myostatin protein levels negatively correlated with relative cranial sartorius muscle cross-sectional area on MRI, supporting a role in disproportionate muscle size. Activin receptor type IIB (ActRIIB) expression was higher in dystrophic versus control dogs, consistent with physiologic feedback between myostatin and ActRIIB. However, there was no differential expression between GRMD and GRippet dogs. Satellite cell exhaustion was not observed in GRippets up to 3 years of age. Partial myostatin loss may exaggerate selective muscle hypertrophy or atrophy/hypoplasia in GRMD dogs and worsen contractures. While muscle imbalance is not a feature of myostatin inhibition in mdx mice, findings in a larger animal model could translate to human experience with myostatin inhibitors.


The phenology of Rubus fruticosus in Ireland: herbarium specimens provide evidence for the response of phenophases to temperature, with implications for climate warming.
To date, phenological research has provided evidence that climate warming is impacting both animals and plants, evidenced by the altered timing of phenophases. Much of the evidence supporting these findings has been provided by analysis of historic records and present-day fieldwork; herbaria have been identified recently as an alternative source of phenological data. Here, we used Rubus specimens to evaluate herbaria as potential sources of phenological data for use in climate change research and to develop the methodology for using herbaria specimens in phenological studies. Data relevant to phenology (collection date) were recorded from the information cards of over 600 herbarium specimens at Ireland's National Herbarium in Dublin. Each specimen was assigned a score (0-5) corresponding to its phenophase. Temperature data for the study period (1852 - 2007) were obtained from the University of East Anglia's Climate Research Unit (CRU); relationships between temperature and the dates of first flower, full flower, first fruit and full fruit were assessed using weighted linear regression. Of the five species of Rubus examined in this study, specimens of only one (R. fruticosus) were sufficiently abundant to yield statistically significant relationships with temperature. The results revealed a trend towards earlier dates of first flower, full flower and first fruit phenophases with increasing temperature. Through its multi-phenophase approach, this research serves to extend the most recent work-which validated the use of herbaria through use of a single phenophase-to confirm herbarium-based research as a robust methodology for use in future phenological studies.


Parametrization of the contribution of mono- and bidentate ligands on the symmetric C[triple bond]O stretching frequency of fac-[Re(CO)(3)](+) complexes.
A ligand parameter, IR(P)(L), is introduced in order to evaluate the effect that different monodentate and bidentate ligands have on the symmetric C[triple bond]O stretching frequency of octahedral d(6) fac-[Re(CO)(3)L(3)] complexes (L = mono- or bidentate ligand). The parameter is empirically derived by assuming that the electronic effect, or contribution, that any given ligand L will add to the fac-[ReCO(3)](+) core, in terms of the total observed energy of symmetric C[triple bond]O stretching frequency (nu(CO(obs))), is additive. The IR(P)(CO) (i.e., the IR(P) of carbon monoxide) is first defined as one-sixth that of the observed C[triple bond]O frequency (nu(CO(obs))) of [Re(CO)(6)](+). All subsequent IR(P)(L) parameters of fac-[Re(CO)(3)L(3)] complexes are derived from IR(P)(L) = (1)/(3)[nu(CO(obs)) - 3IR(P)(CO)]. The symmetric C[triple bond]O stretching frequency was selected for analysis by assuming that it alone describes the "average electronic environment" in the IR spectra of the complexes. The IR(P)(L) values for over 150 ligands are listed, and the validity of the model is tested against other octahedral d(6) fac-[M(CO)(3)L(3)] complexes (M = Mn, (99)Tc, and Ru) and cis-[Re(CO)(2)L(4)](+) species and by calculations at the density functional level of theory. The predicted symmetric C[triple bond]O stretching frequency (nu(CO(cal))) is given by nu(CO(cal)) = S(R)[ sum IR(P)(L)] + I(R), where S(R) and I(R) are constants that depend upon the metal, its oxidation state, and the number of CO ligands in its primary coordination sphere. A linear relationship between IR(P) values and the well-established ligand electrochemical parameter E(L) is found. From a purely thermodynamic point of view, it is suggested that ligands with high IR(P)(L) values should weaken the M-CO bond to a greater extent than ligands with low IR(P)(L) values. The significance of the results and the limitations of the model are discussed.


Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma.
Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway.Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962-73. ©2016 AACR.


Baicalein induces apoptosis in SCC-4 human tongue cancer cells via a Ca2+-dependent mitochondrial pathway.
The effects of baicalein on SCC-4 human tongue cancer cells were examined to better understand its effect on apoptosis and associated possible signal pathways in vitro. Apoptosis induction, reactive oxygen species (ROS), cytoplasmic Ca2+, mitochondrial membrane potential (MMP) and caspase-3 activity were analyzed using the flow cytometric assay. Apoptosis-associated proteins, such as p53, BAX, BCL-2, cytochrome c, caspase-3 and -9, EndoG and AIF were determined by Western blotting. Our results showed that baicalein promoted the levels of p53, BAX, cytochrome c, capase-3 and -9 and reduced the level of BCL-2, which were associated with the induction of apoptotic cell death of SCC-4 cells. A release of cytochrome c from mitochondria into cytosol was demonstrated and an activation of caspase-3, which led to the occurrence of apoptosis in SCC-4 cells treated with baicalein as determined by Western blot. In order to understand the role of Ca2+ in the induction of apoptosis, cells were pre-treated with BAPTA (intracellular calcium chelator) and baicalein. It was shown that the MMP was restored, and the level of cytoplasmic Ca2+ suppressed, the proportion of cells undergoing apoptosis was also markedly diminished. Our data suggest that cellular Ca2+ modulates baicalein-induced cell death via a Ca2+-dependent mitochondrial death pathway in SCC-4 cells.


The magnitude of the intrinsic rate constant: How deep can association reactions be in the diffusion limited regime?
Intrinsic and effective rate constants have an important role in the theory of diffusion-limited reactions. In a previous paper, we provide detailed microscopic expressions for these intrinsic rates [A. Vijaykumar, P. G. Bolhuis, and P. R. ten Wolde, Faraday Discuss. 195, 421 (2016)], which are usually considered as abstract quantities and assumed to be implicitly known. Using these microscopic expressions, we investigate how the rate of association depends on the strength and the range of the isotropic potential and the strength of the non-specific attraction in case of the anisotropic potential. In addition, we determine the location of the interface where these expressions become valid for anisotropic potentials. In particular, by investigating the particles' orientational distributions, we verify whether the interface at which these distributions become isotropic agrees with the interface predicted by the effective association rate constant. Finally, we discuss how large the intrinsic association rate can become, and what are the consequences for the existence of the diffusion limited regime.


Loss of self-understanding: a behavior-oriented model of depression.
A new model of depression is proposed which is biological and explanatory on the behavioral level. It is hypothesized that a patient suffering from a depressive disorder loses the ability to produce one or more modes of behavior at a given time and simultaneously has the urge to produce one or more other modes of behavior constantly. The patient is also unable to interpret his behavioral disorder ("loss of self-understanding"). The authors developed the Salzburg Subjective Behavioral Analysis (SSBA) self-assessment questionnaire asking subjects to elaborate on changes in 35 modes of behavior and to interpret the behavioral disorder, if possible. The study was conducted using this questionnaire and the Hamilton Depression Scale on 30 inpatients with depressive disorders and this questionnaire on 30 healthy controls. Extreme positions in the SSBA were found in all 30 patients, compared with 2 in the 30 healthy controls. Significant correlation between the occurrence of extreme positions and the Hamilton scores was found (r=0.44, p=0.02) and correlation between the Hamilton scores and the inability of the patients to interpret the behavioral disorder was nearly significant (r=-0.35, p=0.06). The occurrence of extreme positions in the SSBA increased with depressive mood. In addition, the likelihood that subjects could explain their extreme positions in behavior decreased with increasing depression. The SSBA questionnaire assesses the self-evaluation of modes of behavior. As a diagnostic instrument, DSM-IV does not have criteria for modes of behavior. Thus, behavioral analysis should be considered in diagnosing depression.


B-type natriuretic peptide levels are decreased by reducing dietary salt intake in patients with compensated heart failure with preserved ejection fraction.
Dietary salt restriction is believed to be a mainstay in the management of patients with heart failure. However, the effect of salt intake on heart failure has not been well evaluated in outpatient medical practice. The aim of the present study was to assess the hypothesis that B-type natriuretic peptide (BNP) level, as an objective marker of heart failure, is associated with salt intake in patients with heart failure. One hundred and thirteen consecutive patients with mild compensated heart failure (77 ± 10 years old, 51 female) were included. We estimated dietary salt intake by the concentration of sodium and creatinine in spot urine. We measured BNP at the time of urine sampling and assessed the relationship between the % changes in BNP levels (%ΔBNP) and the changes in the estimated daily salt excretion (ΔNaCl) during the follow-up period. The baseline median BNP level was 150 (interquartile range: 83-263) pg/mL and the estimated daily salt excretion was 162 ± 45 mmol/day. There was a positive correlation between %ΔBNP and ΔNaCl (r = 0.61, P < 0.01). Multiple regression analysis revealed that %ΔBNP was associated with ΔNaCl (P < 0.01), but not with changes in systolic blood pressure and bodyweight. Changes in BNP levels were associated with changes in the estimated daily salt excretion in outpatients with compensated heart failure. Salt restriction may be beneficial for the management of patients with heart failure.


BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins.
AZD6244 (ARRY 142886) is a potent and selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor currently in early clinical trials. We examined the activity of AZD6244 in a panel of non-small cell lung cancer and a panel of cell lines representing many cancer types using in vitro growth assays. AZD6244 induced G(0)-G(1) cell cycle arrest in sensitive cell lines that primarily included cells containing the BRAF V600E mutation. In these cells, G(0)-G(1) arrest is accompanied by the up-regulation of the cell cycle inhibitors p21(WAF1) and p27(Kip1) and down-regulation of cyclin D1. In the majority of cell lines tested, including those with K-ras or non-V600E BRAF mutations, AZD6244 induced the accumulation of phospho-MEK, an effect not observed in the most sensitive BRAF V600E-containing cells. Accumulation of phospho-MEK in non-V600E-containing cell lines is due to abrogation of negative feedback pathways. BRAF V600E disrupts negative feedback signaling, which results in enhanced baseline phospho-MEK expression. Exogenous expression of BRAF V600E disrupts feedback inhibition but does not sensitize cells to AZD6244. Specific suppression of endogenous BRAF V600E does not confer resistance to AZD6244 but enhances sensitivity to AZD6244. Thus, our findings show that BRAF V600E marks cells with an in vitro requirement for MAPK signaling to support proliferation. These cells are exquisitely sensitive to AZD6244 (IC(50), <100 nmol/L), have high baseline levels of phospho-MEK, and lack feedback inhibition between ERK and Raf. These data suggest an approach to identifying cells that may be sensitive to AZD6244 and other MEK inhibitors.


Comparing robotic surgery with conventional laparoscopy and laparotomy for cervical cancer management.
The aim of this study was to compare the outcomes of robotic surgery, laparoscopy, and laparotomy for the surgical treatment of stage IA to IIB cervical cancer. This retrospective study was carried out in a university-affiliated teaching hospital. A total of 100 women with an initial diagnosis of stage IA to IIB cervical cancer, without preoperative brachytherapy or chemotherapy, were included in this study. With selection of the cases, 44 patients received laparotomy surgery, 32 patients received laparoscopic surgery, and 24 patients received robotic surgery. The perioperative parameters measured included operation time, blood loss, transfusion rate, lymph node yield, adhesion score, laparotomy conversion rate, postoperative and 24-hour pain scores, time to full diet resumption, and hospital stay. The perioperative complication and disease-free survival were also evaluated. The robotic group showed a shorter operation time, less blood loss, lower transfusion rate, and lower laparotomy conversion rate than the laparoscopic or laparotomy group. As for the postoperative parameters, the robotic group showed reduced postoperative and 24-hour pain scores, shortened length of hospital stay, and decreased time to full diet resumption compared with the other 2 surgical groups. No significant differences were found between the groups in perioperative complication rate or disease-free survival. The data suggested that robotic surgery is a feasible and potentially optimal option for the treatment of stage IA to IIB cervical cancer with favorable short-term surgical outcomes.


Antifungal use in the surgical ICU patient.
The successful treatment of surgical fungal infections depends of a timely and adequate source control alongside with the use of prompt systemic antifungals. The main challenge of antifungal use in critically ill surgical patients is to find a balance between rational versus indiscriminate use in order to accomplish an antifungal stewardship program. Surgical fungal infections represent an important burden in the daily clinical activity in many ICUs. The efficacy of the available antifungal drugs has not been adequately assessed in randomized controlled trials with surgical fungal infections in ICU patients. Most clinical experience is limited to case reports or uncontrolled case series. Due to the lack of adequate scientific evidence to assess the role of the different antifungals in surgical ICU patients, it is usually suggested to follow the recommendations for invasive candidiasis and candidemia. Antifungal use in the surgical patients admitted to an ICU is a complex matter and there are several elements to consider like the presence of septic shock and multiorgan failure, local epidemiology and antifungal resistance, among others. The proper use of antifungals alongside early recognition and prompt source control, are critical factors for improved outcomes.


Genetic diversity and introgression in the Scottish wildcat.
This paper describes a genetic analysis of wild-living cats in Scotland. Samples from 230 wild-living Scottish cats (including 13 museum skins) and 74 house cats from England and Scotland were surveyed for nine microsatellite loci. Pelage characteristics of the wild-living cats were recorded, and the cats were then grouped into five separate categories depending on the degree to which they conformed to the characteristics attributed to Felis silvestris Schreber, 1775. Allele frequency differences between the morphological groups are greater than those among the three house cat samples. Analysis of genetic distances suggests that more of the differences between individuals can be explained by pelage than geographical proximity, and that pelage and geographical location are not confounded. Ordination of the genetic distances suggests two main groups of wild-living cats, with intermediates, and one group is genetically very similar to the house cats, while the other group contains all cats taxonomically identified as wildcat based on morphology. A genetic mixture analysis gives similar results to the ordination, but also suggests that the genotypes of a substantial number of cats in the wildcat group are drawn from a gene pool with genotypes in approximately equilibrium proportions. We argue that this is evidence that these cats do not have very recent domestic ancestry. However, from the morphological data it is highly likely that this gene pool also contains a contribution from earlier introgression of domestic cat genes.


Effects of applied voltage on water at a gold electrode interface from ab initio molecular dynamics.
Electrode-water interfaces under voltage bias demonstrate anomalous electrostatic and structural properties that are influential in their catalytic and technological applications. Mean-field and empirical models of the electrical double layer (EDL) that forms in response to an applied potential do not capture the heterogeneity that polarizable, liquid-phase water molecules engender. To illustrate the inhomogeneous nature of the electrochemical interface, Born-Oppenheimer ab initio molecular dynamics calculations of electrified Au(111) slabs interfaced with liquid water were performed using a combined explicit-implicit solvent approach. The excess charges localized on the model electrode were held constant and the electrode potentials were computed at frequent simulation times. The electrode potential in each trajectory fluctuated with changes in the atomic structure, and the trajectory-averaged potentials converged and yielded a physically reasonable differential capacitance for the system. The effects of the average applied voltages, both positive and negative, on the structural, hydrogen bonding, dynamical, and vibrational properties of water were characterized and compared to literature where applicable. Controlled-potential simulations of the interfacial solvent dynamics provide a framework for further investigation of more complex or reactive species in the EDL and broadly for understanding electrochemical interfaces in situ.


Endometriosis of extra-pelvic round ligament, a diagnostic dilemma for physicians.
A 49-year-old multiparous woman presented with a swelling in the left groin of 6 months duration. The swelling was associated with a dull aching pain. The patient reported increase in size of the swelling during lifting of heavy weights. Menstrual history was normal and there was no increase in pain over the swelling during menstruation. She underwent a caesarean section 20 years ago and the scar had healed by primary intention. She was provisionally diagnosed to have a left-sided inguinal hernia. Ultrasonography showed a multiloculated cyst measuring 5.3×1.5×5.2 cm within the inguinal canal. The patient had excision of the cyst under spinal anaesthesia. Intraoperatively the cyst was found to arise from the left round ligament. It measured 7×6 cm extending to the left lateral vaginal wall. Histopathology revealed endometriosis of the round ligament. Her gynaecological assessment was normal and they recommended no further treatment. On follow-up the patient was asymptomatic and wound had healed well.


Lamellar zirconium phosphates to host metals for catalytic purposes.
In the present study a porous lamellar zirconium phosphate heterostructure (PPH) formed from zirconium(iv) phosphate expanded with silica galleries (P/Zr molar ratio equal to 2 and (Si + Zr)/P equal to 3) was prepared to host noble metals. Textural and structural characterization of PPH-noble metal materials was carried out in order to elucidate the location and dispersion of the metallic particles and the properties of the resulting material to be used in catalytic processes. In the present paper, their activity in the catalytic hydrodeoxygenation (HDO) reaction of dibenzofuran (DBF) was evaluated. X-ray diffraction (XRD), solid state nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) evidenced that the structure of the pillared zirconium phosphate material was not modified by the incorporation of Pt and Pd. Moreover, transmission electron microscopy (TEM) showed a different dispersion of the noble metal. The acidity of the resulting PPH-noble metal materials also changed, although in all cases the acidity was of weak nature, and the incorporation of noble metals affected Brønsted acid sites as observed from 31P NMR spectra. In general, the textural, structural and acidic properties of the resulting materials suggest that PPH can be considered a good candidate to be used as a catalytic support. Thus, the catalytic results of the PPH-noble metal samples indicated that the Pd sample showed a stable behavior probably ascribed to a high dispersion of the active phase. However, the Pt sample suffered from fast deactivation. The selectivity to the reaction products was strongly dependent on the noble metal employed.


Making Management Skills a Core Component of Medical Education.
Physicians are being called upon to engage in greater leadership and management in increasingly complex and dynamic health care organizations. Yet, management skills are largely undeveloped in medical education. Without formal management training in the medical curriculum, physicians are left to cultivate their leadership and management abilities through a haphazard array of training programs or simply through trial and error, with consequences that may range from frustration among staff to reduced quality of care and increased risk of patient harm. To address this issue, the authors posit that medical education needs a more systematic focus on topics related to management and organization, such as individual decision making, interpersonal communication, team knowledge sharing, and organizational culture. They encourage medical schools to partner with business school faculty or other organizational scholars to offer a "Management 101" course in the medical curriculum to provide physicians-in-training with an understanding of these topics and raise the quality of physician leadership and management in modern health care organizations.


Functional outcomes of kinesio taping versus standard orthotics in the management of shin splint.
Exercise-related or lower-limb overuse injury characterized by pain located between the knee and the ankle that occurs during activity is commonly referred to as shin splint. Hyperpronation is considered the ultimate culprit in the development of overuse injuries such as shin splint. This study endeavors to compare the functional outcomes of the most commonly used anti-pronation techniques, kinesio taping and standard orthotics. A total of 40 subjects (mean age, 24.16±2.6 years) with symptoms of shin splint participated in the current study. These subjects were randomly allocated to two groups (N.=20) and underwent anti-pronation kinesio taping and standard orthotics, respectively. The functional outcomes were assessed using the navicular drop test, visual analog scale, and hop distance. The kinesio taping intervention group showed significant improvements in pain and hop distance compared to the standard orthotics intervention group, whereas an insignificant intergroup difference was observed for the navicular drop test. Patients in both groups benefited, but the response to kinesio taping was better than that to orthotics. Kinesio taping played a vital role in improving functional outcomes compared to orthotics by reducing pain and improving functional activity in patients with shin splint; however, navicular drop correction did not occur using either intervention.


Child-parent agreement on reports of disease, injury and pain.
Studies on school students are indicating that somatic complaints and pain have increased during the past decades. Throughout this period there has been a change in methodology from proxy reports by parents to having the students themselves act as the respondents, possible explaining some of the increase in prevalence. The aim of this study was to compare the agreement of answers from students with answers given by their parents regarding the students' medical background and subjective rating of perceived health with specific focus on frequency of headache, musculoskeletal pain and tiredness. The participating students came from eleven different schools in Sweden. The schools were a sub sample of randomly selected schools originally participating in a larger multidisciplinary base study. Those 8th grade students present at school on the test date became the subjects of the investigation. A total of 232 students answered, assisted by the test leader, a specially designed self-complete questionnaire at school. Their parents were, at the same time, contacted and 200 answered a similar mailed-out questionnaire. One hundred and eighty-six (186) corresponding student-same parent questionnaires were registered for which comparisons of answers could be made and analysis conducted. When a child is in good health, in absence of diseases, pain and injuries, his or her assessment matches up with their parent. Children and parents also showed agreement in cases of severe injuries and frequent (daily) complaints of knee pain. Less frequent headaches, back- and musculoskeletal pain and other complaints of minor injuries and less wellbeing, such as students' tiredness, were all under-reported and under-rated by their parents. When assessing the perceived health and wellbeing of students, their own expressions should be the basis for the data collection and analysis rather than relying entirely on parental reports.


Why do We Find It so Hard to Discuss Spirituality? A Qualitative Exploration of Attitudinal Barriers.
Despite known health benefits of spiritual care and high patient interest in discussing spirituality with their physicians, the frequency of spiritual discussions in the medical consultation is low. We investigated spiritual conversations for doctors caring for patients with advanced cancer; why these conversations so difficult; and what the underlying challenges are for discussing spirituality with patients; Participants were contacted through the Australian and New Zealand Society of Palliative Medicine and the Medical Oncology Group of Australia, including physicians from two secular countries. Semi-structured interviews were taped and transcribed verbatim. The text was analyzed using thematic analysis; Thematic saturation was reached after 23 participants had been interviewed. The following themes were identified: (1) confusing spirituality with religion; (2) peer pressure; (3) personal spirituality; (4) institutional factors; (5) historical factors; This study explored the underlying attitudes contributing to the reluctance doctors have to discuss spirituality in the medical consultation. Underlying confusion regarding the differences between religion and spirituality, and the current suspicion with which religion is regarded in medicine needs to be addressed if discussion of spirituality in the medical consultation is to become routine. Historical opposition to a biopsychosocial-spiritual model of the human being is problematic.


A novel G-quadruplex-forming GGA repeat region in the c-myb promoter is a critical regulator of promoter activity.
The c-myb promoter contains multiple GGA repeats beginning 17 bp downstream of the transcription initiation site. GGA repeats have been previously shown to form unusual DNA structures in solution. Results from chemical footprinting, circular dichroism and RNA and DNA polymerase arrest assays on oligonucleotides representing the GGA repeat region of the c-myb promoter demonstrate that the element is able to form tetrad:heptad:heptad:tetrad (T:H:H:T) G-quadruplex structures by stacking two tetrad:heptad G-quadruplexes formed by two of the three (GGA)(4) repeats. Deletion of one or two (GGA)(4) motifs destabilizes this secondary structure and increases c-myb promoter activity, indicating that the G-quadruplexes formed in the c-myb GGA repeat region may act as a negative regulator of the c-myb promoter. Complete deletion of the c-myb GGA repeat region abolishes c-myb promoter activity, indicating dual roles of the c-myb GGA repeat element as both a transcriptional repressor and an activator. Furthermore, we demonstrated that Myc-associated zinc finger protein (MAZ) represses c-myb promoter activity and binds to the c-myb T:H:H:T G-quadruplexes. Our findings show that the T:H:H:T G-quadruplex-forming region in the c-myb promoter is a critical cis-acting element and may repress c-myb promoter activity through MAZ interaction with G-quadruplexes in the c-myb promoter.


Management of focal cartilage defects in the knee - Is ACI the answer?
Injuries to the articular cartilage of the knee are common. They alter the normal distribution of weightbearing forces and predispose patients to the development of degenerative joint disease. The management of focal chondral lesions continues to be problematic for the treating orthopaedic surgeon. Although many treatment options are currently available, none fulfill the criteria for an ideal repair solution: a hyaline repair tissue that completely fills the defect and integrates well with the surrounding normal cartilage. Autologous chondrocyte implantation (ACI) is a relatively new cell-based treatment method for full-thickness cartilage injuries that in recent years has increased in popularity, with early studies showing promising results. The current article reviews the nature of cartilage lesions in the knee and the treatment modalities utilized in their management, focusing on the role ACI plays in the surgical treatment of these complex injuries.


Growth of Western Australian corals in the anthropocene.
Anthropogenic increases of atmospheric carbon dioxide lead to warmer sea surface temperatures and altered ocean chemistry. Experimental evidence suggests that coral calcification decreases as aragonite saturation drops but increases as temperatures rise toward thresholds optimal for coral growth. In situ studies have documented alarming recent declines in calcification rates on several tropical coral reef ecosystems. We show there is no widespread pattern of consistent decline in calcification rates of massive Porites during the 20th century on reefs spanning an 11° latitudinal range in the southeast Indian Ocean off Western Australia. Increasing calcification rates on the high-latitude reefs contrast with the downward trajectory reported for corals on Australia's Great Barrier Reef and provide additional evidence that recent changes in coral calcification are responses to temperature rather than ocean acidification.


Incubation during laser ablation with bursts of femtosecond pulses with picosecond delays.
We report on an experimental investigation of the incubation effect during irradiation of stainless steel with bursts of ultrashort laser pulses. A series of birefringent crystals was used to split the pristine 650-fs pulses into bursts of up to 32 sub-pulses with time separations of 1.5 ps and 3 ps, respectively. The number of selected bursts was varied between 50 and 1600. The threshold fluence was measured in case of Burst Mode (BM) processing depending on the burst features, i.e. the number of sub-pulses and their separation time, and on the number of bursts. We found as many values of threshold fluence as the combinations of the number of bursts and of sub-pulses constituting the bursts set to give the same total number of impinging sub-pulses. However, existing incubation models developed for Normal Pulse Mode (NPM) return, for a given number of impinging pulses, a constant value of threshold fluence. Therefore, a dependence of the incubation coefficient with the burst features was hypothesized and experimentally investigated. Numerical solutions of the Two Temperature Model (TTM) in case of irradiation with single bursts of up to 4 sub-pulses have been performed to interpret the experimental results.


Phytochemical studies and cytotoxicity evaluations of Colchicum tunicatum Feinbr and Colchicum hierosolymitanum Feinbr (Colchicaceae): two native Jordanian meadow saffrons.
As a part of our continuing investigation of Jordanian Colchicum species, the biologically active components of Colchicum hierosolymitanum Feinbr and Colchicum tunicatum Feinbr (Colchicaceae) were pursued. The brine shrimp lethality test (BSLT) was used to direct the fractionation and isolation of active components. Five and four known colchicinoids were isolated and characterized from C. tunicatum and C. hierosolymitanum, respectively. The known colchicinoids, reported for the first time from these two species are: (-)-colchicine (I), 3-demethyl-(-)-colchicine (II), (-)-cornigerine (III), beta-lumicolchicine (IV), and (-)-androbiphenyline (V) from C. tunicatum, and (-)-colchicine (I), 2-demethyl-(-)-colchicine (VI), (-)-cornigerine (III), and beta-lumicolchicine (IV) from C. hierosolymitanum. The chemical structures of the isolated compounds have been elucidated using a series of spectroscopic and spectrometric techniques principally; 1D-NMR (1H and 13C) and low resolution EI-MS and APCIMS. All pure compounds were evaluated for cytotoxicity against three human cancer cell lines; MCF-7 human breast carcinoma, NCI-H460 human large cell lung carcinoma, and SF-268 human astrocytoma. (-)-Colchicine (I) and (-)-cornigerine (III) were found to be the most bioactive of the identified compounds with EC50 values in the range of 0.016-0.097 microM.


Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion.
Glioblastomas are the most aggressive primary brain tumors in humans. Microglia/brain macrophage accumulation in and around the tumor correlates with malignancy and poor clinical prognosis of these tumors. We have previously shown that microglia promote glioma expansion through upregulation of membrane type 1 matrix metalloprotease (MT1-MMP). This upregulation depends on signaling via the Toll-like receptor (TLR) adaptor molecule myeloid differentiation primary response gene 88 (MyD88). Using in vitro, ex vivo, and in vivo techniques, we identified TLR2 as the main TLR controlling microglial MT1-MMP expression and promoting microglia-assisted glioma expansion. The implantation of mouse GL261 glioma cells into TLR2 knockout mice resulted in significantly smaller tumors, reduced MT1-MMP expression, and enhanced survival rates compared with wild-type control mice. Tumor expansion studied in organotypic brain slices depended on both parenchymal TLR2 expression and the presence of microglia. Glioma-derived soluble factors and synthetic TLR2 specific ligands induced MT1-MMP expression in microglia from wild-type mice, but no such change in MT1-MMP gene expression was observed in microglia from TLR2 knockout mice. We also found evidence that TLR1 and TLR6 cofunction with TLR2 as heterodimers in regulating MT1-MMP expression in vitro. Our results thus show that activation of TLR2 along with TLRs 1 and/or 6 converts microglia into a glioma supportive phenotype.


Machine learning for decoding listeners' attention from electroencephalography evoked by continuous speech.
Previous research has shown that it is possible to predict which speaker is attended in a multispeaker scene by analyzing a listener's electroencephalography (EEG) activity. In this study, existing linear models that learn the mapping from neural activity to an attended speech envelope are replaced by a non-linear neural network (NN). The proposed architecture takes into account the temporal context of the estimated envelope and is evaluated using EEG data obtained from 20 normal-hearing listeners who focused on one speaker in a two-speaker setting. The network is optimized with respect to the frequency range and the temporal segmentation of the EEG input, as well as the cost function used to estimate the model parameters. To identify the salient cues involved in auditory attention, a relevance algorithm is applied that highlights the electrode signals most important for attention decoding. In contrast to linear approaches, the NN profits from a wider EEG frequency range (1-32 Hz) and achieves a performance seven times higher than the linear baseline. Relevant EEG activations following the speech stimulus after 170 ms at physiologically plausible locations were found. This was not observed when the model was trained on the unattended speaker. Our findings therefore indicate that non-linear NNs can provide insight into physiological processes by analyzing EEG activity.


Multiple Introductions and Antigenic Mismatch with Vaccines May Contribute to Increased Predominance of G12P[8] Rotaviruses in the United States.
Rotavirus is the leading global cause of diarrheal mortality for unvaccinated children under 5 years of age. The outer capsid of rotavirus virions consists of VP7 and VP4 proteins, which determine viral G and P types, respectively, and are primary targets of neutralizing antibodies. Successful vaccination depends upon generating broadly protective immune responses following exposure to rotaviruses presenting a limited number of G- and P-type antigens. Vaccine introduction resulted in decreased rotavirus disease burden but also coincided with the emergence of uncommon G and P genotypes, including G12. To gain insight into the recent predominance of G12P[8] rotaviruses in the United States, we evaluated 142 complete rotavirus genome sequences and metadata from 151 clinical specimens collected in Nashville, TN, from 2011 to 2013 through the New Vaccine Surveillance Network. Circulating G12P[8] strains were found to share many segments with other locally circulating strains but to have distinct constellations. Phylogenetic analyses of G12 sequences and their geographic sources provided evidence for multiple separate introductions of G12 segments into Nashville, TN. Antigenic epitopes of VP7 proteins of G12P[8] strains circulating in Nashville, TN, differ markedly from those of vaccine strains. Fully vaccinated children were found to be infected with G12P[8] strains more frequently than with other rotavirus genotypes. Multiple introductions and significant antigenic mismatch may in part explain the recent predominance of G12P[8] strains in the United States and emphasize the need for continued monitoring of rotavirus vaccine efficacy against emerging rotavirus genotypes.IMPORTANCE Rotavirus is an important cause of childhood diarrheal disease worldwide. Two immunodominant proteins of rotavirus, VP7 and VP4, determine G and P genotypes, respectively. Recently, G12P[8] rotaviruses have become increasingly predominant. By analyzing rotavirus genome sequences from stool specimens obtained in Nashville, TN, from 2011 to 2013 and globally circulating rotaviruses, we found evidence of multiple introductions of G12 genes into the area. Based on sequence polymorphisms, VP7 proteins of these viruses are predicted to present themselves to the immune system very differently than those of vaccine strains. Many of the sick children with G12P[8] rotavirus in their diarrheal stools also were fully vaccinated. Our findings emphasize the need for continued monitoring of circulating rotaviruses and the effectiveness of the vaccines against strains with emerging G and P genotypes.


Human hyolaryngeal movements show adaptive motor learning during swallowing.
The hyoid bone and larynx elevate to protect the airway during swallowing. However, it is unknown whether hyolaryngeal movements during swallowing can adjust and adapt to predict the presence of a persistent perturbation in a feed-forward manner (adaptive motor learning). We investigated adaptive motor learning in nine healthy adults. Electrical stimulation was administered to the anterior neck to reduce hyolaryngeal elevation, requiring more strength to swallow during the perturbation period of this study. We assessed peak hyoid bone and laryngeal movements using videofluoroscopy across thirty-five 5-ml water swallows. Evidence of adaptive motor learning of hyolaryngeal movements was found when (1) participants showed systematic gradual increases in elevation against the force of electrical stimulation and (2) hyolaryngeal elevation overshot the baseline (preperturbation) range of motion, showing behavioral aftereffects, when the perturbation was unexpectedly removed. Hyolaryngeal kinematics demonstrates adaptive, error-reducing movements in the presence of changing and unexpected demands. This is significant because individuals with dysphagia often aspirate due to disordered hyolaryngeal movements. Thus, if rapid motor learning is accessible during swallowing in healthy adults, patients may be taught to predict the presence of perturbations and reduce errors in swallowing before they occur.


Precise role of H pylori in duodenal ulceration.
The facts that H pylori infection is commoner in duodenal ulcer (DU) patients than in the normal population, and that eradication results in most cases being cured, have led to the belief that it causes DU. However, early cases of DU are less likely than established ones to be infected. H pylori-negative cases are usually ascribed to specific associated factors such as non-steroidal anti-inflammatory drugs (NSAIDs), Crohn's disease, and hypergastrinaemia, but even after excluding these, several H pylori-negative cases remain and are particularly common in areas of low prevalence of H pylori infection. Moreover, this incidence of H pylori negative DU is not associated with a fall in overall DU prevalence when compared with countries with a higher H pylori prevalence. In countries with a high H pylori prevalence there are regional differences in DU prevalence, but no evidence of an overall higher prevalence of DU than in countries with a low H pylori prevalence. There is no evidence that virulence factors are predictive of clinical outcome. After healing following eradication of H pylori infection DU can still recur. Medical or surgical measures to reduce acid output can lead to long-term healing despite persistence of H pylori infection. Up to half of cases of acute DU perforation are H pylori negative. These findings lead to the conclusion that H pylori infection does not itself cause DU, but leads to resistance to healing, i.e., chronicity. This conclusion is shown not to be incompatible with the universally high prevalence of DU compared with controls.


Adamts18 deletion results in distinct developmental defects and provides a model for congenital disorders of lens, lung, and female reproductive tract development.
The ADAMTS family comprises 19 secreted metalloproteinases that cleave extracellular matrix components and have diverse functions in numerous disease and physiological contexts. A number of them remain 'orphan' proteases and among them is ADAMTS18, which has been implicated in developmental eye disorders, platelet function and various malignancies. To assess in vivo function of ADAMTS18, we generated a mouse strain with inactivated Adamts18 alleles. In the C57Bl6/Ola background, Adamts18-deficient mice are born in a normal Mendelian ratio, and are viable but show a transient growth delay. Histological examination revealed a 100% penetrant eye defect resulting from leakage of lens material through the lens capsule occurring at embryonic day (E)13.5, when the lens grows rapidly. Adamts18-deficient lungs showed altered bronchiolar branching. Fifty percent of mutant females are infertile because of vaginal obstruction due to either a dorsoventral vaginal septum or imperforate vagina. The incidence of ovarian rete is increased in the mutant mouse strain. Thus, Adamts18 is essential in the development of distinct tissues and the new mouse strain is likely to be useful for investigating ADAMTS18 function in human disease, particularly in the contexts of infertility and carcinogenesis.


A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa.
To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified. Homozygosity mapping, amplification-refractory mutation system (ARMS) analysis, and Sanger sequencing were performed to identify mutations in FAM161A. Microsatellite and SNP markers were genotyped for haplotype analysis. Patients with biallelic mutations underwent detailed ophthalmologic examinations, including measuring best-corrected visual acuity, extensive fundus photography with reflectance and autofluorescence imaging, and optical coherence tomography. Homozygosity mapping in 230 Dutch individuals with suspected arRP yielded five individuals with a homozygous region harboring FAM161A. Sanger sequencing revealed a homozygous nonsense mutation (c.1309A>T; p.[Arg437*]) in one individual. Subsequent ARMS analysis and Sanger sequencing in Dutch and Belgian arRP patients resulted in the identification of seven additional individuals carrying the p.(Arg437*) mutation, either homozygously or compound heterozygously with another mutation. Haplotype analysis identified a shared haplotype block of 409 kb surrounding the p.(Arg437*) mutation in all patients, suggesting a founder effect. Although the age of onset was variable among patients, all eight developed pronounced outer retinal loss with severe visual field defects and a bull's eye-like maculopathy, followed by loss of central vision within 2 decades after the initial diagnosis in five subjects. A founder mutation in FAM161A p.(Arg437*) underlies approximately 2% of arRP cases in the Dutch and Belgian populations. The age of onset of the retinal dystrophy appears variable, but progression can be steep, with almost complete loss of central vision later in life.


Morel-Lavallee Lesions-Review of Pathophysiology, Clinical Findings, Imaging Findings and Management.
Morel-Lavallee lesion is a post-traumatic soft tissue degloving injury. This is commonly associated with sports injury caused by a shearing force resulting in separation of the hypodermis from the deeper fascia. Most common at the greater trochanter, these injuries also occur at flank, buttock, lumbar spine, scapula and the knee. Separation of the tissue planes result in a complex serosanguinous fluid collection with areas of fat within it. The imaging appearance is variable and non specific, potentially mimicking simple soft tissue haematoma, superficial bursitis or necrotic soft tissue neoplasms. If not treated in the acute or early sub acute settings, these collections are at risk for superinfection, overlying tissue necrosis and continued expansion. In this review article, we discuss the clinical presentation, pathophysiology, imaging features and differential diagnostic considerations of Morel-Lavallee lesions. Role of imaging in guiding prompt and appropriate treatment has also been discussed.


DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine.
Transitions of cytosine to thymine in CpG dinucleotides are the most frequent type of mutations observed in cancer. This increased mutability is commonly explained by the presence of 5-methylcytosine (5mC) and its spontaneous hydrolytic deamination into thymine. Here, we describe observations that question whether spontaneous deamination alone causes the elevated mutagenicity of 5mC. Tumours with somatic mutations in DNA mismatch-repair genes or in the proofreading domain of DNA polymerase ε (Pol ε) exhibit more 5mC to T transitions than would be expected, given the kinetics of hydrolytic deamination. This enrichment is asymmetrical around replication origins with a preference for the leading strand template, in particular in methylated cytosines flanked by guanines (GCG). Notably, GCG to GTG mutations also exhibit strand asymmetry in mismatch-repair and Pol ε wild-type tumours. Together, these findings suggest that mis-incorporation of A opposite 5mC during replication of the leading strand might be a contributing factor in the mutagenesis of methylated cytosine.


Contributions of signal analysis to the interpretation of spirometry.
Chronic Obstructive Pulmonary Disease (COPD) is taking on catastrophic proportions. However, there is still a need for more objective and quantitative methods for its diagnosis and stratification. The present study explores the effectiveness of signal analysis methodologies as the means to increase the effectiveness of spirometry in diagnosing and stratifying COPD. Since expiratory flow at the mouth results from converging airflows, it is possible to use signal analysis to identify changes in the characteristics of airflow along the respiratory tree. This was achieved by non-invasively identifying alterations in the frequency spectrum of the Forced Expiratory Flow (FEF) curve of 108 patients (49 men and 59 women, 12-75 yrs of age) presenting with (a) clinically and spirometrically normal respiratory profile, (b) COPD, (c) restrictive lung disease and (d) interstitial fibrosis. Fundamental to the study design was the notion that the characteristics of the expiratory output of the respiratory system are determined by the bronchial tree and the upper respiratory tract. A number of quantitative measures for the power spectrum of the FEF curve were identified, which permit the definition of specific rules and allow for the accurate classification of, at least, the basic types of respiratory disease. (a) It is for the first time that airflow resonances are identified in the sub-audible (<20 Hz) range of the power spectrum of the FEF curve. (b) COPD patients present with FEF curves which have different power spectral characteristics from those of healthy individuals (p<0.01), at frequencies lower than 3.66 Hz. (c) In COPD, in restrictive lung disease and in interstitial fibrosis, the lower resonant frequencies of the spectrum of the FEF curve predominate.


Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by Galpha13.
Signaling pathways that link extracellular factors to activation of the monomeric guanosine triphosphatase (GTPase) Rho control cytoskeletal rearrangements and cell growth. Heterotrimeric guanine nucleotide-binding proteins (G proteins) participate in several of these pathways, although their mechanisms are unclear. The GTPase activities of two G protein alpha subunits, Galpha12 and Galpha13, are stimulated by the Rho guanine nucleotide exchange factor p115 RhoGEF. Activated Galpha13 bound tightly to p115 RhoGEF and stimulated its capacity to catalyze nucleotide exchange on Rho. In contrast, activated Galpha12 inhibited stimulation by Galpha13. Thus, p115 RhoGEF can directly link heterotrimeric G protein alpha subunits to regulation of Rho.


Performance Limitations in Sensorimotor Control: Trade-Offs Between Neural Computation and Accuracy in Tracking Fast Movements.
The ability to move fast and accurately track moving objects is fundamentally constrained by the biophysics of neurons and dynamics of the muscles involved. Yet the corresponding trade-offs between these factors and tracking motor commands have not been rigorously quantified. We use feedback control principles to quantify performance limitations of the sensorimotor control system (SCS) to track fast periodic movements. We show that (1) linear models of the SCS fail to predict known undesirable phenomena, including skipped cycles, overshoot and undershoot, produced when tracking signals in the "fast regime," while nonlinear pulsatile control models can predict such undesirable phenomena, and (2) tools from nonlinear control theory allow us to characterize fundamental limitations in this fast regime. Using a validated and tractable nonlinear model of the SCS, we derive an analytical upper bound on frequencies that the SCS model can reliably track before producing such undesirable phenomena as a function of the neurons' biophysical constraints and muscle dynamics. The performance limitations derived here have important implications in sensorimotor control. For example, if the primary motor cortex is compromised due to disease or damage, the theory suggests ways to manipulate muscle dynamics by adding the necessary compensatory forces using an assistive neuroprosthetic device to restore motor performance and, more important, fast and agile movements. Just how one should compensate can be informed by our SCS model and the theory developed here.


CSF/plasma HIV-1 RNA discordance even at low levels is associated with up-regulation of host inflammatory mediators in CSF.
HIV-1 RNA can be found at higher levels in cerebrospinal fluid (CSF) than in plasma, termed CSF/plasma discordance. The clinical significance of CSF/plasma discordance is not known and the degree of discordance considered important varies. We aimed to determine whether a panel of CSF cytokines, chemokines and associated mediators were raised in patients with CSF/plasma discordance at different levels. A nested case-control study of 40 CSF samples from the PARTITION study. We used a cytometric bead array to measure CSF mediator concentrations in 19 discordant and 21 non-discordant samples matched for plasma HIV-1 RNA. Discordant samples were subdivided into 'high discordance' (>1log10) and 'low discordance' (0.5-1log10, or ultrasensitive discordance). CSF mediators significant in univariate analysis went forward to two-way unsupervised hierarchical clustering based on the patterns of relative mediator concentrations. In univariate analysis 19 of 21 CSF mediators were significantly higher in discordant than non-discordant samples. There were no significant differences between samples with high versus low discordance. The samples grouped into two clusters which corresponded to CSF/plasma discordance (p<0.0001). In cluster one all mediators had relatively high abundance; this included 18 discordant samples and three non-discordant samples. In cluster two all mediators had relatively low abundance; this included 18 non-discordant samples and one non-discordant sample with ultrasensitive discordance only. CSF/plasma discordance is associated with potentially damaging neuroinflammatory process. Patients with discordance at lower levels (ie. 0.5-1log10) should also be investigated as mediator profiles were similar to those with discordance >1log10. Sensitive testing may have a role to determine whether ultrasensitive discordance is present in those with low level CSF escape.


Impact of hydraulic retention time on community assembly and function of photogranules for wastewater treatment.
Photogranules are dense, spherical agglomerates of cyanobacteria, microalgae and non-phototrophic microorganisms that have considerable advantages in terms of harvesting and nutrient removal rates for light driven wastewater treatment processes. This ecosystem is poorly understood in terms of the microbial community structure and the response of the community to changing abiotic conditions. To get a better understanding, we investigated the effect of hydraulic retention time (HRT) on photogranule formation and community assembly over a period of 148 days. Three laboratory bioreactors were inoculated with field samples from various locations in the Netherlands and operated in sequencing batch mode. The bioreactors were operated at four different HRTs (2.00, 1.00, 0.67, 0.33 days), while retaining the same solid retention time of 7 days. A microbial community with excellent settling characteristics (95-99% separation efficiency) was established within 2-5 weeks. The observed nutrient uptake rates ranged from 24 to 90 mgN L-1 day-1 and from 3.1 to 5.4 mgP L-1 day-1 depending on the applied HRT. The transition from single-cell suspension culture to floccular agglomeration to granular sludge was monitored by microscopy and 16S/18S sequencing. In particular, two important variables for driving aggregation and granulation, and for the structural integrity of photogranules were identified: 1. Extracellular polymeric substances (EPS) with high protein to polysaccharide ratio and 2. specific microorganisms. The key players were found to be the cyanobacteria Limnothrix and Cephalothrix, the colony forming photosynthetic eukaryotes within Chlamydomonadaceae, and the biofilm producing bacteria Zoogloea and Thauera. Knowing the makeup of the microbial community and the operational conditions influencing granulation and bioreactor function is crucial for successful operation of photogranular systems.


Saccharomyces cerevisiae C-type cyclin Ume3p/Srb11p is required for efficient induction and execution of meiotic development.
The yeast C-type cyclin Ume3p/Srb11p and its cyclin-dependent kinase partner Ume5p/Srb10p repress the transcription of several genes required for meiotic recombination or meiosis I nuclear division. To relieve this repression, Srbllp is destroyed early in meiosis, prior to the first meiotic division. This report identifies two roles for Srb11p in regulating meiotic development. First, SRB11 is required for the normal exit from the mitotic cell cycle prior to meiotic induction. Specifically, mutants lacking SRB11 (srb11delta) uncouple bud growth from chromosome segregation, producing small buds with nuclei. The bud growth defect is most likely due to the failure of srb11delta mutants to reestablish polarized actin fibers at the bud tip following exposure to sporulation medium. Second, Srb11p is required for the efficient execution of meiosis I. srb11delta mutants either exhibited a delay in performing meiosis I and meiosis II or skipped meiosis I entirely. This meiotic defect is not due to the activation of the recombination or spindle assembly checkpoint pathways. However, the expression of several meiotic genes is delayed and reduced in the mutant strains. These results suggest a positive role for Srb10-Srb11p in regulating the transcription program. This model is supported by the finding that overexpression of the meiotic inducer IME2 partially restored the ability of srb11 mutants to perform meiosis I. In conclusion, these findings indicate that Srb11p is required for both entry into and execution of the meiotic program, thus describing multiple roles for a C-type cyclin in the regulation of a developmental pathway.


Incrementally Corrected Periodic Local MP2 Calculations: I. The Cohesive Energy of Molecular Crystals.
A method for accurate calculations of the cohesive energy of molecular crystals is presented. The cohesive energy is evaluated as a sum of several components. The major contribution is captured by periodic Hartree-Fock (HF) coupled with the local Møller-Plesset perturbation theory of second order (LMP2) with a triple-ζ basis set. Post-MP2 corrections and corrections for the basis set incompleteness are calculated from inexpensive incremental calculations with finite clusters. This is an essential improvement with respect to the periodic LMP2 method and allows for results of benchmark quality for crystalline systems. The proposed technique is superior to the standard incremental scheme as concerns the cluster size and basis set convergence of the results. In contrast to the total energy or electron correlation energy, which are evaluated in standard incremental calculations, post-MP2 and basis set corrections are rather insensitive to approximations and converge quickly both in terms of the order of the increments and the number of terms at a given order. Evaluation of the incremental corrections within the sub-kJ/mol precision requires computing very few of the most compact two-center and three-center non-embedded clusters, making the whole correction scheme computationally inexpensive. This method as well as alternative routes to compute the cohesive energy via the incremental scheme are tested on two molecular crystals: carbon dioxide (CO2) and hydrogen cyanide (HCN).


Social Support and Exclusive Breast feeding among Canadian Women.
The World Health Organization recommendation for exclusive breast feeding for 6 months has been endorsed by Health Canada, the Canadian Pediatric Society, Dietitians of Canada, and the Breastfeeding Committee for Canada as of 2012. This study examines whether social support is associated with exclusive breast feeding up to 6 months among Canadian mothers. We utilised data from the Canadian Community Health Survey and limited our sample to mothers who gave birth in the 5 years prior to the 2009-2010 survey (n = 2133). Multivariable logistic regression was used to examine the relationship between exclusive breast feeding and four dimensions of social support: (i) tangible, (ii) affectionate, (iii) positive social interaction, and (iv) emotional and informational, based on the Medical Outcomes Study Social Support Scale. Absolute and relative differences in the probability of breast feeding exclusively and their 95% confidence intervals were calculated. In adjusted models, differences in the probability of exclusive breast feeding for 6 months were not different among women with high vs. low social support. The association between social support and breastfeeding exclusively was modified by education level, with significantly higher probability of breast feeding exclusively among women with lower education and high vs. low levels of tangible and affectionate support. Among women with education below a high school level, high tangible and affectionate support significantly increased probability of exclusive breast feeding for 6 months in this study. Efforts to encourage exclusive breast feeding need to address social support for mothers, especially those with lower education.


A Role for Auditory Corticothalamic Feedback in the Perception of Complex Sounds.
Feedback signals from the primary auditory cortex (A1) can shape the receptive field properties of neurons in the ventral division of the medial geniculate body (MGBv). However, the behavioral significance of corticothalamic modulation is unknown. The aim of this study was to elucidate the role of this descending pathway in the perception of complex sounds. We tested the ability of adult female ferrets to detect the presence of a mistuned harmonic in a complex tone using a positive conditioned go/no-go behavioral paradigm before and after the input from layer VI in A1 to MGBv was bilaterally and selectively eliminated using chromophore-targeted laser photolysis. MGBv neurons were identified by their short latencies and sharp tuning curves. They responded robustly to harmonic complex tones and exhibited an increase in firing rate and temporal pattern changes when one frequency component in the complex tone was mistuned. Injections of fluorescent microbeads conjugated with a light-sensitive chromophore were made in MGBv, and, following retrograde transport to the cortical cell bodies, apoptosis was induced by infrared laser illumination of A1. This resulted in a selective loss of ∼60% of layer VI A1-MGBv neurons. After the lesion, mistuning detection was impaired, as indicated by decreased d' values, a shift of the psychometric curves toward higher mistuning values, and increased thresholds, whereas discrimination performance was unaffected when level cues were also available. Our results suggest that A1-MGBv corticothalamic feedback contributes to the detection of harmonicity, one of the most important grouping cues in the perception of complex sounds.SIGNIFICANCE STATEMENT Perception of a complex auditory scene is based on the ability of the brain to group those sound components that belong to the same source and to segregate them from those belonging to different sources. Because two people talking simultaneously may differ in their voice pitch, perceiving the harmonic structure of sounds is very important for auditory scene analysis. Here we demonstrate mistuning sensitivity in the thalamus and that feedback from the primary auditory cortex is required for the normal ability of ferrets to detect a mistuned harmonic within a complex sound. These results provide novel insight into the function of descending sensory pathways in the brain and suggest that this corticothalamic circuit plays an important role in scene analysis.


Incidence, clearance and predictors of human papillomavirus infection in women.
Persistent infection with carcinogenic human papillomavirus (HPV) is linked to high-grade lesions and cervical cancer. To better understand the natural history of HPV, we sought to determine the rates of incident and cleared carcinogenic HPV infection, by age, among women aged 15-49 years and to explore risk factors for incident infection. Women enrolled in an earlier HPV prevalence survey (500 of 800 who were HPV-negative and all 121 who were HPV-positive) were invited to participate in follow-up HPV testing at their periodic health examination one year later. A cervical soft-brush specimen for HPV testing and a smear for cytologic examination were obtained, and participants completed a questionnaire on their demographic characteristics and sexual history. Two hundred and fifty-three (50.6%) previously HPV-negative women and 54 (44.6%) previously HPV-positive women were retested. The mean interval between visits was 14.0 (standard deviation 2.0, median 13.5, range 9.0-21.3) months. Incident HPV infection occurred in 11.1% (28/253) of the women overall, with the highest rate, 25.0% (6/24), in the 15-19-year age group. In the univariate analyses, risk factors for incident HPV were the median number of sexual partners in the past year (< or = 1 v. > or = 2: odds ratio [OR] 8.2, 95% confidence interval [CI] 3.0-22.2; p < 0.001) and the median number of sexual partners over a lifetime (> 3 v. < or = 3: OR 3.0, 95% CI 1.2-7.2; p = 0.014). In multivariate logistic regression modelling adjusted for age, median number of sexual partners in the past year, median number of sexual partners over a lifetime, marital status, current smoking and current use of oral contraceptives, only the median number of sexual partners in the past year remained significantly associated with incidence (OR 6.2, 95% CI 1.6-24.5; p = 0.009). Of the previously HPV-positive women, 51.9% (28/54) had cleared the infection. Incident infection with carcinogenic HPV was highest in women aged 15-19 years, and risk factors were consistent with a sexually transmitted infection. A large proportion of the women who were HPV-positive appeared to have cleared the infection after one year.


Children's emotion understanding in relation to attachment to mother and father.
Although attachment plays a key role in children's socio-emotional development, little attention has been paid to the role of children's attachment to their father. This study examined whether insecure attachment to each parent was associated with reduced emotion understanding in children and whether children showed consistent attachments to their mother and father. We measured children's attachment to each parent using the Manchester Child Attachment Story Task and child emotion understanding using the Test of Emotion Comprehension (children's Mage = 5.64 years, SD = 0.84). The results indicated that insecure father-child attachment and insecure mother-child attachment were each associated with lower emotion understanding in children after controlling for parent's depressive symptoms and children's age. There was significant concordance of child attachment to mother and father. The findings provide support for convergence of children's attachment across parents and suggest that father-child attachment is an important factor to consider when examining children's emotion understanding. Statement of contribution What is already known on this subject Secure mother-child attachment is positively associated with children's emotional competence. Children form similar representations of attachment to their mother and father. What the present study adds Both mother-child and father-child attachment are associated with children's emotion understanding. The study's findings highlight the importance of father-child attachment in their children's emotion understanding. The study provides support for concordance of children's attachment across parents.


Effect of annealing on the mechanical properties and the degradation of electrospun polydioxanone filaments.
Annealing, or heat treatment, has traditionally been used as a treatment to improve the strength and stiffness of electrospun materials. Understanding the extent to which annealing can improve the mechanical properties and alter the degradation rate of electrospun polydioxanone filaments could influence the range of its potential clinical applications. In this study, we investigated the effect of annealing electrospun polydioxanone filaments at varying times and temperatures and subsequently subjecting them to in vitro degradation in phosphate buffer saline for up to 6 weeks. Fibre alignment, tensile strength and thermal properties were assessed. It was determined that annealing at 65°C for 3h only marginally improved the tensile strength (9±2%) but had a significant effect on reducing strain and rate of degradation, as well as maintaining fibre alignment within the filament. The filament retained significantly more of its force at failure after 4 weeks (82±15%, compared to 61±20% for non annealed filaments) and after 6 weeks of degradation (81±9%, compared to 55±13% for non annealed filaments). Conversely, annealing filaments at 75°C improved the initial tensile strength of the filament (17±6%), but over 6 weeks, both samples annealed at 75°C and 85°C otherwise performed similarly or mechanically worse than those not annealed. These findings suggest that annealing at low temperatures is more useful as a method to tailor degradation rate than to improve mechanical properties. The ability to modulate the degradation profile with annealing may become useful to tailor the properties of electrospun materials without altering the chemistry of the polymer used. This might better match the degradation of the implant and gradual loss of mechanical properties with the new matrix deposition within the structure, enabling multiple regenerative strategies within a single biomaterial system.


Tetrachlorobenzoquinone exhibits neurotoxicity by inducing inflammatory responses through ROS-mediated IKK/IκB/NF-κB signaling.
Tetrachlorobenzoquinone (TCBQ) is a joint metabolite of persistent organic pollutants (POPs), hexachlorobenzene (HCB) and pentachlorophenol (PCP). Previous studies have been reported that TCBQ contributes to acute hepatic damage due to its pro-oxidative nature. In the current study, TCBQ showed the highest capacity on the cytotoxicity, ROS formation and inflammatory cytokines release among four compounds, i.e., HCB, PCP, tetrachlorohydroquinone (TCHQ, reduced form of TCBQ) and TCBQ, in PC 12 cells. Further mechanistic study illustrated TCBQ activates nuclear factor-kappa B (NF-κB) signaling. The activation of NF-κB was identified by measuring the protein expressions of inhibitor of nuclear factor kappa-B kinase (IKK) α/β, p-IKKα/β, an inhibitor of NF-κB (IκB) α, p-IκBα, NF-κB (p65) and p-p65. The translocation of NF-κB was assessed by Western blotting of p65 in nuclear/cytosolic fractions, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. In addition, TCBQ significantly induced protein and mRNA expressions of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and the production of nitric oxide (NO) and prostaglandin E2 (PGE2). Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor inhibited these effects efficiently, further suggested TCBQ-induced inflammatory responses involve NF-κB signaling. Moreover, antioxidants, i.e., N-acetyl-l-cysteine (NAC), Vitamin E and curcumin, ameliorated TCBQ-induced ROS generation as well as the activation of NF-κB, which implied that ROS serve as the upstream molecule of NF-κB signaling. In summary, TCBQ exhibits a neurotoxic effect by inducing oxidative stress-mediated inflammatory responses via the activation of IKK/IκB/NF-κB pathway in PC12 cells.


Report of a WHO workshop on the standardization and control of antivenoms.
A workshop to discuss progress in the standardization and control of antivenoms, organized by the Quality Assurance and Safety of Biologicals Unit of WHO, was held at the National Institute for Biological Standards and Control, Potters Bar, England, 7-9 February 2001. This was the first meeting convened by the WHO on this subject since 1979 and it brought together experts from academic institutions, antivenom manufacturers and national regulatory authorities from 21 countries. The meeting reviewed antivenom production and quality control measures and special consideration was given to the current crisis in antivenom production and supply in sub-Saharan Africa. The importance of snake bite and scorpion stings as public health issues was re-emphasised. The majority of commercial antivenoms are raised against snake or scorpion venoms.The review of antivenom production methods indicated that the vast majority of commercial antivenoms were still produced by traditional technology in horses, although some antisera were raised in sheep and rabbits. Methods used for plasma fractionation included salt and heat coagulation, caprylic acid stabilization or ion exchange chromatography, as well as immunoglobulin digestion with pepsin to produce F(ab')(2) or with papain to produce Fab fragments. The meeting agreed that there was much room for improving the production, quality control and safety profile of these products and that lessons could be learnt from the experience gained with the preparation of human immunoglobulins. Many basic assumptions, such as the need to remove Fc fragments by enzyme digestion and to freeze-dry antivenom preparations, required critical re-examination and more attention should be given to clinical trials as a means of assessing efficacy and safety and of defining the average initial dose. The Workshop also discussed concerns about the risks of transmitting infectious agents to humans via animal blood products, especially those posed by viruses or prions and it was agreed that this aspect needed attention. However, there was no documented or even suspected example of this ever having occurred in the case of antivenom treatment. Current WHO Requirements for the production and control of antivenoms and for immune sera of animal origin date from the late 1960s. The Workshop recommended that these be updated to take account of the progress that had taken place in the production and quality control of biologicals in recent years. In addition, the Workshop discussed the need for better standardization of both the venoms and antivenoms, but concluded that international standards and reference materials were not appropriate in the antivenom field due to the considerable variation in venom characteristics from the same species from region to region. Instead, it was recommended that national or regional standards be prepared and used.


Pregnant women's preference for cesarean section and subsequent mode of birth - a six-country cohort study.
The rate of cesarean section (CS) for non-medical reasons has risen and it is a concern for health care. Women's preferences may vary across countries for psychosocial or obstetric reasons. A prospective cohort study of 6549 women in routine antenatal care giving birth in Belgium, Iceland, Denmark, Estonia, Norway or Sweden. Preference for mode of birth was self-reported in mid-pregnancy. Birth outcome data were collected from hospital records. A CS was preferred by 3.5% of primiparous women and 8.7% of the multiparous women. Preference for CS was associated with severe fear of childbirth (FOC), with a negative birth experience in multiparous women and with depressive symptoms in the primiparous. Women were somewhat more prone to prefer a cesarean in Iceland, odd ratio (OR) 1.70 (1.02-2.83), adjusted for age, education, depression, FOC, history of abuse, previous cesarean and negative birth experience. Out of the 404 women who preferred CS during pregnancy, 286 (70.8%) delivered by CS, mostly for a medical indication. A total of 9% of the cesareans in the cohort had a non-medical indication only. Women's preference for CS often seems to be due to health concerns. Both medical and psychological factors need to be addressed in antenatal counseling. Obstetricians need to convey accurately to women the risks and benefits of CS in her specific case. Maternity professionals should identify and explore psychosocial reasons for women's preferences.


Partial exchange of Fe(III) montmorillonite with hexadecyltrimethylammonium cation increases catalytic activity for hydrophobic substrates.
Fe(III) montmorillonite clay that was partially exchanged with hexadecyltrimethylammonium (HDTMA(+)) cations achieved increased catalytic activity for the oxidative coupling of hydrophobic organic substrates. A series of mixed-cation organoclays were produced, where the organic cation content ranged from 6 to 50% relative to the cation-exchange capacity (CEC) of the clay, and were tested for catalytic activity using different Fe(III)-mediated oxidative coupling reactions. Enhanced catalytic activity by Fe(3+)/HDTMA(+) montmorillonite for coupling hydrophobic substrates was observed, with maximum catalytic activity in the oxidative coupling of 2-naphthol observed at 6% HDTMA(+) coverage. However, maximum catalytic activity with a more hydrophobic substrate, anthrone, was achieved with 50% HDTMA(+) coverage, indicating that matching levels of organic modification to substrate hydrophobicity improves catalytic activity. The organization of the organic cations at the clay surfaces proved to be heterogeneous, as determined by scanning transmission X-ray microscopy (STXM) and powder X-ray diffraction. Results from molecular dynamics simulations supported the heterogeneous nature of the catalysts but also pointed toward large regions within the interlayers that may be filled with nonreactive hydrated Fe oxides resulting from the organic cation treatment. The exchangeable Fe content of the organic treated clays, as determined by AAS and ICP measurements, was observed to be higher than expected relative to that of Fe-saturated clay, substantiating this hypothesis. These findings have implications for the development of substrate-specific clay catalysts, where the composition and configuration of exchangeable cations can be matched to a particular substrate or reaction.


Fundamentally Distributed Information Processing Integrates the Motor Network into the Mental Workspace during Mental Rotation.
The manipulation of mental representations in the human brain appears to share similarities with the physical manipulation of real-world objects. In particular, some neuroimaging studies have found increased activity in motor regions during mental rotation, suggesting that mental and physical operations may involve overlapping neural populations. Does the motor network contribute information processing to mental rotation? If so, does it play a similar computational role in both mental and manual rotation, and how does it communicate with the wider network of areas involved in the mental workspace? Here we used multivariate methods and fMRI to study 24 participants as they mentally rotated 3-D objects or manually rotated their hands in one of four directions. We find that information processing related to mental rotations is distributed widely among many cortical and subcortical regions, that the motor network becomes tightly integrated into a wider mental workspace network during mental rotation, and that motor network activity during mental rotation only partially resembles that involved in manual rotation. Additionally, these findings provide evidence that the mental workspace is organized as a distributed core network that dynamically recruits specialized subnetworks for specific tasks as needed.


Evidence for anion-binding of all-cis hexafluorocyclohexane in solution and solid state.
We report a solution NMR and X-ray crystallographic study on the anion affinity of all-cis 1,2,3,4,5,6-hexafluorocyclohexane, which has only recently become synthetically accessible. Our results suggest that the interaction exhibits preferential 1 : 1 stoichiometry, while its strength is only moderate (e.g. Ka = 400 M-1 in acetone for Cl-) and depends mainly on the size of the anion and the dielectric constant of the solvent.


Re-exploring the early relationship between teenage cigarette and e-cigarette use using price and tax changes.
In 2016, the Surgeon General used longitudinal cohort studies to conclude that youth e-cigarette use is strongly associated with cigarette use. We re-evaluate data from the period of time before the writing of the Surgeon General report, using quasi-experimental methods, and reach the opposite conclusion. We study contemporaneous and intertemporal effects of e-cigarette and cigarette price and tax changes. Our price variation comes from 35,000 retailers participating in the Nielsen Retail Scanner data system. We match price and tax variation to survey data on current use of e-cigarettes and cigarettes for over 94,000 students between grades 6 and 12 in the National Youth Tobacco Survey (NYTS) for years 2011-2015. We find evidence that e-cigarettes and cigarettes are same-period economic substitutes. Coefficient estimates (while imprecisely estimated) also suggest potentially large positive effects of past e-cigarette prices on current cigarette use, indicating intertemporal economic substitution. Our findings raise doubts about the conclusion of government-sponsored reports that e-cigarettes and cigarettes are strongly positively associated. We recommend revisiting and possibly amending this conclusion.


Cooperative effects of Janus and Aurora kinase inhibition by CEP701 in cells expressing Jak2V617F.
The Janus kinase 2 mutant V617F occurs with high frequency in myeloproliferative neoplasms. Further mutations affecting the Janus kinase family have been discovered mostly in leukaemias and in myeloproliferative neoplasms. Owing to their involvement in neoplasia, inflammatory diseases and in the immune response, Janus kinases are promising targets for kinase inhibitor therapy in these disease settings. Various quantitative assays including two newly developed screening assays were used to characterize the function of different small-molecule compounds in cells expressing Jak2V617F. A detailed comparative analysis of different Janus kinase inhibitors in our quantitative assays and the subsequent characterization of additional activities demonstrated for the first time that the most potent Jak2 inhibitor in our study, CEP701, also targets Aurora kinases. CEP701 shows a unique combination of both activities which is not found in other compounds also targeting Jak2. Furthermore, colony forming cell assays showed that Janus kinase 2 inhibitors preferentially suppressed the growth of erythroid colonies, whereas inhibitors of Aurora kinases preferentially blocked myeloid colony growth. CEP701 demonstrated a combined suppression of both colony types. Moreover, we show that combined application of a Janus and an Aurora kinase inhibitor recapitulated the effect observed for CEP701 but might allow for more flexibility in combining both activities in clinical settings, e.g. in the treatment of myeloproliferative neoplasms. The newly developed screening assays are high throughput compatible and allow an easy detection of new compounds with Janus kinase 2 inhibitory activity.


Atypical Anxiety-Related Amygdala Reactivity and Functional Connectivity in Sant Mat Meditation.
While meditation has drawn much attention in cognitive neuroscience, the neural mechanisms underlying its emotional processing remains elusive. Sant Mat meditators were recruited, who adopt a loving-kindness mode of meditation along with a vegetarian diet and an alcohol-restricted lifestyle and novices. We assessed their State-Trait Anxiety Inventory (STAI) and scanned their amygdala reactivity in response to an explicit and implicit (backward masked) perception of fearful and happy faces. In contrast with novices, meditators reported lower STAI scores. Meditators showed stronger amygdala reactivity to explicit happiness than to fear, whereas novices exhibited the opposite pattern. The amygdala reactivity was reduced in meditators regardless of implicit fear or happiness. Those who had more lifetime practice in meditation reported lower STAI and showed a weaker amygdala response to fear. Furthermore, the amygdala in meditators, relative to novices, had a stronger positive functional connectivity with the ventrolateral prefrontal cortex (PFC) to explicit happiness, but a more negative connectivity with the insula and medial orbitofrontal cortex (OFC) to explicit fear. Mediation analysis indicated the amygdala reactivity as the mediator for the linkage between meditation experience and trait anxiety. The findings demonstrate the neural correlates that underpin the beneficial effects of meditation in Sant Mat. Long-term meditation could be functionally coupled with the amygdala reactivity to explicit and implicit emotional processing, which would help reduce anxiety and potentially enhance well-being.


Comparison of equine platelet function and survival in whole blood collected in acid-citrate-dextrose solution or citrate-phosphate-dextrose-adenine solution.
Equine whole blood collection and storage methods have been evaluated to assess red blood cell viability; however, platelet (PLT) viability has not been comprehensively assessed. The purpose of the study was to compare viability of PLTs collected in whole blood into 2 different anticoagulants. Whole blood from 6 healthy adult Thoroughbred horses was collected into citrate-phosphate-dextrose-adenine (CPDA) or acid-citrate-dextrose (ACD). Platelet count, pH, and concentrations of glucose, lactate, carbon dioxide, oxygen, bicarbonate, sodium, potassium, and chloride were measured within 10 minutes of collection and then again one hour later at which time PLT aggregometry was performed to assess PLT function. Aggregometry mean amplitudes were significantly higher in CPDA compared to ACD. Blood glucose, pH, bicarbonate, sodium, and lactate concentrations were significantly higher in CPDA compared to ACD. Lactate concentration was higher following one hour in either anticoagulant. Potassium, oxygen, and carbon dioxide concentrations were significantly higher in ACD compared to CPDA at collection. Platelet aggregometry results suggest that CPDA is superior to ACD for maintaining PLT viability following whole blood collection. This may be associated with the higher, more neutral pH as well as an increase in glucose available for metabolism. Although lactate was increased in the CPDA samples it was not high enough to decrease pH and therefore may not have been high enough to cause morphologic lesions and loss of PLT viability.


Contesting facts about wind farms in Australia and the legitimacy of adverse health effects.
The development of wind energy in Australia has been subject to ongoing public debate and has been characterised by concerns over the health impacts of wind turbines. Using discursive psychology, we examine 'wind turbine syndrome' as a contested illness and analyse how people build and undermine divergent arguments about wind-farm health effects. This article explores two facets of the dispute. First, we consider how participants construct 'facts' about the health effects of wind farms. We examine rhetorical resources used to construct wind farms as harmful or benign. Second, we examine the local negotiation of the legitimacy of health complaints. In the research interviews examined, even though interviewees treat those who report experiencing symptoms from wind farms as having primary rights to narrate their own experience, this epistemic primacy does not extend to the ability to 'correctly' identify symptoms' cause. As a result, the legitimacy of health complaints is undermined. Wind turbine syndrome is an example of a contested illness that is politically controversial. We show how stake, interest and legitimacy are particularly relevant for participants' competing descriptions about the 'facts' of wind turbine health effects.


Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle.
Opitz syndrome (OS) is a multiple congenital anomaly manifested by abnormal closure of midline structures. The gene responsible for the X-linked form of this disease, MID1, encodes a protein (midin) that contains a RING, two B-boxes, a coiled-coil (the so-called tripartite motif) and an RFP-like domain. The tripartite motif is characteristic of a family of proteins, named the B-box family, involved in cell proliferation and development. Since the subcellular compartmentalization and the ability to form multiprotein structures both appear to be crucial for the function of this family of proteins, we have studied these properties on the wild-type and mutated forms of midin. We found that endogenous midin is associated with microtubules throughout the cell cycle, co-localizing with cytoplasmic fibres in interphase and with the mitotic spindle and midbodies during mitosis and cytokinesis. Immunoprecipitation experiments demonstrated the ability of the tripartite motif to mediate midin homodimerization, consistent with the evidence, obtained by gel filtration analysis, that midin exists in the form of large protein complexes. Functional characterization of altered forms of midin, resulting from mutations found in OS patients, revealed that association with microtubules is compromised, while the ability to homodimerize and form multiprotein complexes is retained. We suggest that midin is involved in the formation of multiprotein structures acting as anchor points to microtubules and that impaired association with these cytoskeletal structures causes OS developmental defects.


Effect of amphetamine on adult male and female rats prenatally exposed to methamphetamine.
The aim of the present study was to examine the cross-sensitization induced by prenatal methamphetamine (MA) exposure to adult amphetamine (AMP) treatment in male and female rats. Rat mothers received a daily injection of MA (5 mg/kg) or saline throughout the gestation period. Adult male and female offspring (prenatally MA- or saline-exposed) were administered with AMP (5 mg/kg) or saline (1 ml/kg) in adulthood. Behaviour in unknown environment was examined in open field test (Laboras), active drug-seeking behaviour in conditioned place preference test (CPP), spatial memory in the Morris water maze (MWM), and levels of corticosterone (CORT) were analyzed by enzyme immunoassay (EIA). Our data demonstrate that in Laboras test, AMP treatment in adulthood increased general locomotion (time and distance travelled) regardless of the prenatal exposure and sex, while AMP increased exploratory activity (rearing) only in prenatally MA-exposed animals. AMP induced sensitization only in male rats, but not in females when tested drug-seeking behaviour in the CPP test. In the spatial memory MWM test, AMP worsened the performance only in females, but not in males. On the other hand, males swam faster after chronic AMP treatment regardless of the prenatal drug exposure. EIA analysis of CORT levels demonstrated higher level in females in all measurement settings. In males, prenatal MA exposure and chronic adult AMP treatment decreased CORT levels. Thus, our data demonstrated that adult AMP treatment affects behaviour of adult rats, their spatial memory and stress response in sex-specific manner. The effect is also influenced by prenatal drug exposure.