50-GHz repetition-rate, 280-fs pulse generation at 100-mW average power from a mode-locked laser diode externally compressed in a pedestal-free pulse compressor.
280-fs pedestal-free pulses are generated at average output powers exceeding 100 mW at a repetition rate of 50 GHz by compression of the output of a mode-locked laser diode (MLLD) by use of a pedestal-free pulse compressor (PFPC). The MLLD consists of a monolithically integrated chirped distributed Bragg reflector, a gain section, and an electroabsorption modulator. The PFPC is composed of a dispersion-flattened dispersion-decreasing fiber and a dispersion-flattened dispersion-imbalanced nonlinear optical loop mirror. Frequency modulation for linewidth broadening is used to overcome the power limitation imposed by stimulated Brillouin scattering.


APP mutations in the Aβ coding region are associated with abundant cerebral deposition of Aβ38.
Aβ is the main component of amyloid deposits in Alzheimer disease (AD) and its aggregation into oligomers, protofibrils and fibrils is considered a seminal event in the pathogenesis of AD. Aβ with C-terminus at residue 42 is the most abundant species in parenchymal deposits, whereas Aβ with C-terminus at residue 40 predominates in the amyloid of the walls of large vessels. Aβ peptides with other C-termini have not yet been thoroughly investigated. We analysed Aβ38 in the brains of patients with Aβ deposition linked to sporadic and familial AD, hereditary cerebral haemorrhage with amyloidosis, or Down syndrome. Immunohistochemistry, confocal microscopy, immunoelectron microscopy, immunoprecipitation and the electrophoresis separation of low molecular weight aggregates revealed that Aβ38 accumulates consistently in the brains of patients carrying APP mutations in the Aβ coding region, but was not detected in the patients with APP mutations outside the Aβ domain, in the patients with presenilin mutations or in subjects with Down syndrome. In the patients with sporadic AD, Aβ38 was absent in the senile plaques, but it was detected only in the vessel walls of a small subset of patients with severe cerebral amyloid angiopathy. Our results suggest that APP mutations in the Aβ coding region favour Aβ38 accumulation in the brain and that the molecular mechanisms of Aβ deposition in these patients may be different from those active in patients with familial AD associated with other genetic defects and sporadic AD.


Defoliation and arbuscular mycorrhizal fungi shape plant communities in overgrazed semiarid grasslands.
Overgrazing substantially contributes to global grassland degradation by decreasing plant community productivity and diversity through trampling, defoliation, and removal of nutrients. Arbuscular mycorrhizal (AM) fungi also play a critical role in plant community diversity, composition, and primary productivity, maintaining ecosystem functions. However, interactions between grazing disturbances, such as trampling and defoliation, and AM fungi in grassland communities are not well known. We examined influences of trampling, defoliation, and AM fungi on semiarid grassland plant community composition for 3 yr, by comparing all combinations of these factors. Benomyl fungicide was applied to reduce AM fungal abundance. Overgrazing typically resulted in reduced dominance of Stipa Krylovii, contributing to degradation of typical steppe grasslands. Our results indicated trampling generally had little effect on plant community composition, unless combined with defoliation or AM fungal suppression. Defoliation was the main component of grazing that promoted dominance of Potentilla acaulis over Stipa krylovii and Artemisia frigida, presumably by alleviating light limitation. In non-defoliated plots, AM fungi promoted A. frigida, with a concomitant reduction in S. krylovii growth compared to corresponding AM suppressed plots. Our results indicate AM fungi and defoliation jointly suppress S. krylovii biomass; however, prolonged defoliation weakens mycorrhizal influence on plant community composition. These findings give new insight into dominant plant species shifts in degraded semiarid grasslands.


Outcomes analysis of revision total shoulder replacement.
The number of total shoulder arthroplasties has increased exponentially over the last ten years, creating a more prominent role for revision shoulder arthroplasty in the future. The main reasons for failure of shoulder arthroplasty can be classified as soft-tissue deficiencies, osseous deficiencies, component wear, or infection. We hypothesized that, despite appropriate surgical techniques, the outcome of revision total shoulder replacement can be predicted on the basis of the indication for the revision procedure. We conducted a retrospective review of seventy-eight shoulders that had undergone revision shoulder arthroplasty. The shoulders were divided into two categories: (1) those with osseous or component-related problems and (2) those with soft-tissue deficiency. Category 1 consisted of four cohorts of shoulders: twenty-two treated with revision of the glenoid component, sixteen treated with conversion of a hemiarthroplasty to a total shoulder arthroplasty because of glenoid arthrosis, eight treated with revision of the humeral stem, and four treated for a periprosthetic fracture. Category 2 consisted of five cohorts of shoulders: ten treated with rotator cuff repair following total shoulder replacement, four with a failed tuberosity reconstruction, four with cuff tear arthropathy, five with instability, and five with infection. Patients were evaluated with the UCLA subjective outcome instrument, the L'Insalata shoulder questionnaire, and a subjective satisfaction scale (maximum score of 5 points). The average UCLA score was 21.4 points and the average L'Insalata score was 68.73 points for the seventy-eight shoulders that were analyzed. The average score on the subjective satisfaction questionnaire was 2.91 points. According to the UCLA scores, twenty-four revisions were considered to have had an excellent result; fifteen, a good result; twenty-four, a fair result; and fifteen, a poor result. The average scores for the category-1 shoulders were significantly better than those for the category-2 shoulders (p < 0.05). Of the different types of operations, revision or implantation of a glenoid component and open reduction and internal fixation of a periprosthetic fracture provided the best outcomes. Tuberosity reconstruction, hemiarthroplasty for treatment of cuff tear arthropathy, and revision due to infection had uniformly poor outcomes. In general, these results indicate that the outcome of revision shoulder arthroplasty can be predicted on the basis of the indication for the procedure. Component revisions, excluding humeral head revision for salvage, provide the best results, whereas soft-tissue reconstructions can be expected to yield poorer results overall. Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.


Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.
To investigate the prevalence of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) among outpatients presenting with recurrent fevers and clinical features consistent with TRAPS. Mutational screening was performed in affected members of 18 families in which multiple members had symptoms compatible with TRAPS and in 176 consecutive subjects with sporadic (nonfamilial) "TRAPS-like" symptoms. Plasma concentrations of soluble tumor necrosis factor receptor superfamily 1A (sTNFRSF1A) were measured, and fluorescence-activated cell sorter analysis was used to measure TNFRSF1A shedding from monocytes. Eight novel and 3 previously reported TNFRSF1A missense mutations were identified, including an amino acid deletion (Delta D42) in a Northern Irish family and a C70S mutation in a Japanese family, both reported for the first time. Only 3 TNFRSF1A variants were found in patients with sporadic TRAPS (4 of 176 patients). Evidence for nonallelic heterogeneity in TRAPS-like conditions was found: 3 members of the "prototype familial Hibernian fever" family did not possess C33Y, present in 9 other affected members. Plasma sTNFRSF1A levels were low in TRAPS patients in whom renal amyloidosis had not developed, but also in mutation-negative symptomatic subjects in 4 families, and in 14 patients (8%) with sporadic TRAPS. Reduced shedding of TNFRSF1A from monocytes was demonstrated in vitro in patients with the T50M and T50K variants, but not in those with other variants. The presence of TNFRSF1A shedding defects and low sTNFRSF1A levels in 3 families without a TNFRSF1A mutation indicates that the genetic basis among patients with "TRAPS-like" features is heterogeneous. TNFRSF1A mutations are not commonly associated with nonfamilial recurrent fevers of unknown etiology.


Localization of human immunoglobulin kappa light chain variable region genes to the short arm of chromosome 2 by in situ hybridization.
The genes for human immunoglobulin kappa light chains have been localized in normal lymphocyte and fibroblast chromosomes by in situ hybridization of probes from cloned DNA fragments of the kappa variable region locus. The localization was achieved by counting grains (after autoradiography) over chromosomes in a number of karyotypes. The variable region gene probes hybridized in a cluster on a region of the chromosome 2 short arm close to the centromere (2cen leads to p12). This location was confirmed in lymphocytes from a balanced translocation carrier 46XXt (2; 16) (q13; q22). Our results show that human kappa light chain genes are located in the region of the break point observed in specific chromosomal translocations associated with Burkitt lymphoma.


Sudden visual loss associated with sexual activity.
To characterize the ocular fundus findings of patients who suffered sudden visual loss associated with sexual activity. Case series. Outpatient ophthalmic practice. Six patients presented with a precipitous decrease in vision in one eye with no apparent predisposing factors. After obtaining a careful history, each patient revealed that he or she had been engaging in rigorous sexual activity immediately before experiencing the visual loss. Five of the six patients were followed up without intervention. One patient required prophylactic laser photocoagulation of a retinal tear to decrease the risk of retinal detachment. Six patients aged 24 to 53 years suffered sudden loss of vision secondary to intraretinal, preretinal, or vitreous hemorrhaging. Visual acuity in the affected eyes ranged from a mild decrease (20/40) to profound visual loss (counting fingers at 6 in). Five of the six patients were followed up for at least 1 month and showed spontaneous improvement in vision as the blood cleared. Those who returned for long-term follow-up enjoyed complete visual recovery without any sequelae. Sudden debilitating visual loss may occur during sexual activity from the rupture of retinal blood vessels in the macular region or from the development of vitreous bleeding from an induced retinal tear. The long-term prognosis after such hemorrhaging appears to be excellent, with good visual recovery occurring as the blood resorbs spontaneously.


Calculated photonic structures for infrared emittance control.
Using an available program package based on the transfer-matrix method, we calculated the photonic band structure for two different structures: a quasi-three-dimensional crystal of square air rods in a high-index matrix and an opal structure of high-index spheres in a matrix of low index, epsilon = 1.5. The high index used is representative of gallium arsenide in the thermal infrared range. The geometric parameters of the rod dimension, sphere radius, and lattice constants were chosen to give total reflectance for normal incidence, i.e., minimum thermal emittance, in either one of the two infrared atmospheric windows. For these four photonic crystals, the bulk reflectance spectra and the wavelength-averaged thermal emittance as a function of crystal thickness were calculated. The results reveal that potentially useful thermal signature suppression is obtained for crystals as thin as 20-50 microm, i.e., comparable with that of a paint layer.


The high resolution crystal structure of rat liver AKR7A1: understanding the substrate specificites of the AKR7 family.
The structure of the rat liver aflatoxin dialdehyde reductase (AKR7A1) has been solved to 1.38 A resolution. The crystal structure reveals details of the ternary complex as one subunit of the dimer contains NADP+ and the inhibitor citrate. The underlying catalytic mechanism appears similar to other aldo-keto reductases (AKR), whilst the substrate-binding pocket contains several positively charged amino acids (Arg-231 and Arg-327) which distinguishes it from the well characterised AKR1 family of enzymes. These differences account for the substrate specificity for 4-carbon acid-aldehydes such as succinic semialdehyde (SSA) and 2-carboxybenzaldehyde, as well as for the idiosyncratic substrate aflatoxin B1 dialdehyde of this subfamily of enzymes. The AKR7 enzymes seem to be subdivided into two subgroups based on their sequence and kinetic properties. Modelling of the rat AKR7A4 highlights important structural differences localised within the active site of the two isoenzymes.


Novel regulation of protein kinase C-η.
Protein kinase C (PKC) is the receptor for tumor promoting phorbol esters, which are potent activators of conventional and novel PKCs, but persistent treatment with phorbol esters leads to downregulation of these PKCs. However, PKCη, a novel PKC isozyme, resists downregulation by tumor-promoting phorbol esters, but little is known about how PKCη level is regulated. Phosphorylation and dephosphorylation play an important role in regulating activity and stability of PKCs. In the present study, we have investigated the molecular mechanism of PKCη regulation. Several PKC activators, including phorbol 12,13-dibutyrate, 12-O-tetradecanoylphorbol-13-acetate and indolactam V caused upregulation of PKCη, whereas the general PKC inhibitor Gö 6983, but not the conventional PKC inhibitor Gö 6976 led to the downregulation of PKCη. Upregulation of PKCη was associated with an increase in phosphorylation of PKCη. Silencing of phosphoinositide-dependent kinase-1, which phosphorylates PKCη at the activation loop, failed to prevent PKC activator-induced upregulation of PKCη. Knockdown of PKCε but not PKCα inhibited PKC activator-induced upregulation of PKCη. Thus, our results suggest that the regulation of PKCη is unique and PKCε is required for the PKC activator-induced upregulation of PKCη.


Spontaneous electrical activity in sheep mesenteric lymphatics.
It has recently become apparent that the lymph pump is an electrical entity that rivals the heart in complexity. Many interesting currents have been demonstrated by voltage clamping isolated lymphatic smooth muscle cells, but until now the role of these currents in the intact syncitium has not been studied. Intracellular microelectrode recordings were made from smooth muscle of sheep mesenteric lymphatics to investigate the electrophysiological basis of lymphatic pumping. Approximately 50% of the vessels exhibited spontaneous electrical activity, varying from regular oscillations in membrane potential to spike complexes. Spike complexes generally consisted of one or more action potentials superimposed on a slower depolarization or 'plateau' phase and were often preceded by a slow diastolic depolarization or 'pre-potential'. Norepinephrine (5 microM) induced depolarizing events in quiescent preparations. Both agonist-induced oscillations and spike complexes were attenuated or completely abolished by 2-aminoethoxydiphenyl borate (2-APB); 10-100 microM). Cesium (1 mM) reduced the frequency of spontaneous firing by approximately 30% by flattening the pre-potential phase. In addition to having a negative inotropic effect, 10 mM Cs(+) also caused gradual membrane depolarization and prolonged the plateau. 1 microM nifedipine abolished spontaneous events while tetrodotoxin (TTX; 0.5-1 muM) decreased the amplitude and maximum dV/dt of the spike upstroke or stopped activity completely. Spontaneously active segments of lymphatic vessel were inhibited by the chloride channel blocker, anthracene-9-carboxylic acid (9-AC; 250 microM - 1 mM) suggesting that I(Cl(Ca)) plays a significant role in the generation of spontaneous activity in this tissue. Penitrem-A (0.1 microM) did not affect resting membrane potential but increased action potential amplitude and prolonged the plateau, suggesting that calcium-activated potassium current does not make a significant contribution to resting membrane conductance but is important in membrane repolarization following calcium influx during the action potential. In contrast 4-aminopyridine (4-AP; 5 microM) caused significant membrane depolarization, suggesting the existence of an active 4-AP-sensitive current at rest. These results demonstrate that the currents found in isolated voltage-clamped cells from sheep mesenteric lymphatics do play a significant role in the shaping of spontaneous electrical activity of the intact syncitium.


Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.
Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively. The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.


Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1.
Morphine produces analgesia by activating mu opioid receptors encoded by the MOR-1 gene. Although morphine-6 beta-glucuronide (M6G), heroin and 6-acetylmorphine also are considered mu opioids, recent evidence suggests that they act through a distinct receptor mechanism. We examined this question in knockout mice containing disruptions of either the first or second coding exon of MOR-1. Mice homozygous for either MOR-1 mutation were insensitive to morphine. Heroin, 6-acetylmorphine and M6G still elicited analgesia in the exon-1 MOR-1 mutant, which also showed specific M6G binding, whereas M6G and 6-acetylmorphine were inactive in the exon-2 MOR-1 mutant. These results provide genetic evidence for a unique receptor site for M6G and heroin analgesia.


Religious-Ethnic Differences in Prevalence and Correlates of Suicidal Ideation and Attempts Among Israeli Vocational Education Students.
The current study is the first to examine serious suicidal ideation, suicide attempts and psychological distress among students belonging to different religious-ethnic groups attending VET high schools. 3,553 students studying in the VET high schools completed a self-report survey. The survey evaluated serious suicidal ideation, suicide attempts, depression, anxiety, somatization, self-efficacy, belonging and sociodemographic variables. Students coming from minority groups (Arab Muslim, Bedouin Arab Muslim, Druze) are more likely to have seriously considered suicide or attempted suicide compared to their Jewish counterparts, with the exception of Christian Arabs. Bedouin Arab Muslim students were more susceptible to suicide ideation and attempts upon high depression levels. Minority youth at VET schools are at greater risk of experiencing suicidal ideation and attempting suicide compared to non-minority students. The education system must be highly alert to depressive symptoms among Bedouin Arab Muslim students since they may pose a greater risk to develop into suicidal ideation and attempt.


Transfer learning by feature-space transformation: A method for Hippocampus segmentation across scanners.
Many successful approaches in MR brain segmentation use supervised voxel classification, which requires manually labeled training images that are representative of the test images to segment. However, the performance of such methods often deteriorates if training and test images are acquired with different scanners or scanning parameters, since this leads to differences in feature representations between training and test data. In this paper we propose a feature-space transformation (FST) to overcome such differences in feature representations. The proposed FST is derived from unlabeled images of a subject that was scanned with both the source and the target scan protocol. After an affine registration, these images give a mapping between source and target voxels in the feature space. This mapping is then used to map all training samples to the feature representation of the test samples. We evaluated the benefit of the proposed FST on hippocampus segmentation. Experiments were performed on two datasets: one with relatively small differences between training and test images and one with large differences. In both cases, the FST significantly improved the performance compared to using only image normalization. Additionally, we showed that our FST can be used to improve the performance of a state-of-the-art patch-based-atlas-fusion technique in case of large differences between scanners.


Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance.
The Cancer Target Discovery and Development (CTD(2)) Network was established to accelerate the transformation of "Big Data" into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges. The Network implemented a multi-tier framework designed to substantiate the biological and biomedical relevance as well as the reproducibility of data and insights resulting from its collaborative activities. The same approach can be used by the broad scientific community to drive development of novel therapeutic and biomarker strategies for cancer. Mol Cancer Res; 14(8); 675-82. ©2016 AACR.


Functional brain imaging of nicotinic effects on higher cognitive processes.
Significant advances in human functional brain imaging offer new opportunities for direct observation of the effects of nicotine, novel nicotinic agonists and nicotinic antagonists on human cognitive and behavioral performance. Careful research over the last decade has enabled investigators to explore the role of nicotinic systems on the functional neuroanatomy and neural circuitry of cognitive tasks in domains such as selective attention, working memory, episodic memory, cognitive control, and emotional processing. In addition, recent progress in understanding functional connectivity between brain regions utilized during cognitive and emotional processes offers new opportunities for examining drug effects on network-related activity. This review will critically summarize available nicotinic functional brain imaging studies focusing on the specific cognitive domains of attention, memory, behavioral control, and emotional processing. Generally speaking, nicotine appears to increase task-related activity in non-smokers and deprived smokers, but not active smokers. By contrast, nicotine or nicotinic stimulation decreases the activity of structures associated with the default mode network. These particular patterns of activation and/or deactivation may be useful for early drug development and may be an efficient and cost-effective method of screening potential nicotinic agents. Further studies will have to be done to clarify whether such activity changes correlate with cognitive or affective outcomes that are clinically relevant. The use of functional brain imaging will be a key tool for probing pathologic changes related to brain illness and for nicotinic drug development.


Decreased mitochondrial DNA content in posttreatment salivary rinses from head and neck cancer patients.
Alterations in mitochondrial DNA (mtDNA) sequence and content have been described in human tissues and tumors in association with smoking exposure. We did quantitative PCR analysis of cytochrome c oxidase (Cox) I and Cox II genes to measure changes in mtDNA content in pretreatment and posttreatment salivary rinses obtained from 76 patients undergoing surgical resection for primary head and neck squamous cell carcinoma. We also examined the relationship between changes in mtDNA content and postoperative radiation therapy, smoking exposure, alcohol intake, and other clinical characteristics. Overall, mtDNA content in posttreatment saliva was significantly decreased. The mean change for Cox I was -0.21 [95% confidence interval (95% CI), -0.44 to 0.01, P = 0.06] and for Cox II was -0.31 (95% CI, -0.55 to -0.08, P = 0.01). Patients in the radiation therapy group exhibited a significant decrease compared with the nonradiated group (P = 0.03 for Cox I; P = 0.05 for Cox II). In addition, significant decreases in Cox I (-0.71; 95% CI, -1.17 to -0.25, P = 0.005) and Cox II (-0.65; 95% CI, -1.17 to -0.13, P = 0.02) were found in never-smoking patients but not in former or current smokers. Our data suggest that salivary mtDNA content is decreased in never smokers and in response to radiation therapy after primary surgical resection.


The role of cell lineage in development.
Studies of the role of cell lineage in development began in the latter part of the 19th century, fell into decline in the early part of the 20th, and were revived about 20 years ago. This recent revival was accompanied by the introduction of new and powerful analytical techniques. Concepts of importance for cell lineage studies include the principal division modes by which a cell may give rise to its descendant clone (proliferative, stem cell and diversifying); developmental determinacy, or indeterminacy, which refer to the degree to which the normal cleavage pattern of the early embryo and the developmental fate of its individual cells is, or is not, the same in specimen after specimen; commitment, which refers to the restriction of the developmental potential of a pluripotent embryonic cell; and equivalence group, which refers to two or more equivalently pluripotent cell clones that normally take on different fates but of which under abnormal conditions one clone can take on the fate of another. Cell lineage can be inferred to have a causative role in developmental cell fate in embryos in which induced changes in cell division patterns lead to changes in cell fate. Moreover, such a causative role of cell lineage is suggested by cases where homologous cell types characteristic of a symmetrical and longitudinally metameric body plan arise via homologous cell lineages. The developmental pathways of commitment to particular cell fates proceed according to a mixed typologic and topographic hierarchy, which appears to reflect an evolutionary compromise between maximizing the ease of ordering the spatial distribution of the determinants of commitment and minimizing the need for migration of differentially committed embryonic cells. Comparison of the developmental cell lineages in leeches and insects indicates that the early course of embryogenesis is radically different in these phyletically related taxa. This evolutionary divergence of the course of early embryogenesis appears to be attributable to an increasing prevalence of polyclonal rather than monoclonal commitment in the phylogenetic line leading from an annelid-like ancestor to insects.


Barriers to the Use of Breast Cancer Risk Reduction Therapies.
Evidence from randomized clinical trials supports the use of tamoxifen, raloxifene, exemestane, and anastrozole for the reduction of risk of invasive breast cancer, predominately estrogen receptor-positive tumors. Revised clinical guidelines now strongly recommend that physicians offer high-risk women medication for breast cancer risk reduction. Although only a small portion of eligible women receive risk reduction medication, evidence suggests higher acceptance among women with atypical hyperplasia or lobular carcinoma in situ. Among physicians, barriers for prescribing risk reduction medications include inadequate training in risk assessment, lack of reimbursement for prevention counseling, and the unavailability of easily accessible and user-friendly prediction tools for estimating risk/benefit profiles. Strategies to improve uptake among women have focused on providing education about breast cancer risk and information that accurately conveys the risks and benefits of risk reduction medications. Priority areas of research that have been identified to improve the use of risk reduction medications are the (1) development of risk assessment tools that more accurately identify women most likely to benefit, (2) identification of circulating or tissue biomarkers that can predict and monitor responsiveness of treatment, and (3) better understanding of patient-related barriers, including patients' subjective beliefs and experiences.


A classroom-based physical activity intervention for urban kindergarten and first-grade students: a feasibility study.
Urban elementary schools in minority communities with high obesity prevalence may have limited resources for physical education (PE) to achieve daily activity recommendations. Little is known whether integrating physical activity (PA) into classrooms can increase activity levels of students attending such schools. We conducted a cluster randomized, controlled trial among kindergarten and first-grade students from four Bronx, New York, schools to determine feasibility and impact of a classroom-based intervention on students' PA levels. Students in two intervention schools received the Children's Hospital at Montefiore Joining Academics and Movement (CHAM JAM), an audio CD consisting of 10-minute, education-focused aerobic activities led by teachers three times a day. PA was objectively measured by pedometer. Each subject wore a sealed pedometer during the 6-hour school day for 5 consecutive days at baseline (Time 1) and 8 weeks postintervention (Time 2). Hierarchical linear models were fit to evaluate differences in mean number of steps between the two groups. A total of 988 students participated (intervention group, n=500; control group, n=488). There was no significant difference at baseline between the two groups on mean number of steps (2581 [standard deviation (SD), 1284] vs. 2476 [SD, 1180]; P=0.71). Eight weeks post-CHAM JAM, intervention group students took significantly greater mean number of steps than controls (2839 [SD, 1262] vs. 2545 [SD, 1153]; P=0.0048) after adjusting for baseline number of steps and other covariates (grade, gender, recess, and PE class). CHAM JAM was equally effective in gender, grade level, and BMI subgroups. CHAM JAM significantly increased school-based PA among kindergarten and first-grade students in inner-city schools. This approach holds promise as a cost-effective means to integrate the physical and cognitive benefits of PA into high-risk schools.


Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride.
Mesolimbic dopamine is thought to play a role in the processing of rewards. However, animal studies also demonstrate dopamine release in response to aversive stressful stimuli. Also, in animal studies, disruptions of the mother-infant relationship have been shown to have long-lasting effects on the mesolimbic dopamine system and the hypothalamic-pituitary adrenal axis. We therefore investigated dopamine release in response to stress in human subjects, considering the relationship to early life parental care. We screened 120 healthy young college students for parental care in early life using a combination of telephone interviews and questionnaires. Five students from the top end and five students from the bottom end of the parental care distribution were then invited for a positron emission tomography study using [11C]raclopride and a psychosocial stress task. The psychosocial stressor caused a significant release of dopamine in the ventral striatum as indicated by a reduction in [11C]raclopride binding potential in the stress versus resting condition in subjects reporting low parental care. Moreover, the magnitude of the salivary cortisol response to stress was significantly correlated with the reduction in [11C]raclopride binding in the ventral striatum (r = 0.78), consistent with a facilitating effect of cortisol on dopamine neuron firing. These data suggest that aversive stressful events can be associated with mesolimbic dopamine release in humans, and that the method presented here may be useful to study the effects of early life events on neurobiological stress systems.


Evaluation of a new pediatric positive airway pressure mask.
The choice and variety of pediatric masks for continuous positive airway pressure (CPAP) is limited in the US. Therefore, clinicians often prescribe modified adult masks. Until recently a mask for children aged < 7 years was not available. This study evaluated apnea-hypopnea index (AHI) equivalence and acceptability of a new pediatric CPAP mask for children aged 2-7 years (Pixi; ResMed Ltd, Sydney, Australia). Patients aged 2-7 years were enrolled and underwent in-lab baseline polysomnography (PSG) using their previous mask, then used their previous mask and the VPAP III ST-A flow generator for ≥ 10 nights at home. Thereafter, patients switched to the Pixi mask for ≥ 2 nights before returning for a PSG during PAP therapy via the Pixi mask. Patients then used the Pixi mask at home for ≥ 21 nights. Patients and their parents/guardians returned to the clinic for follow-up and provided feedback on the Pixi mask versus their previous mask. AHI with the Pixi mask was 1.1 ± 1.5/h vs 2.6 ± 5.4/h with the previous mask (p = 0.3538). Parents rated the Pixi mask positively for: restfulness of the child's sleep, trouble in getting the child to sleep, and trouble in having the child stay asleep. The Pixi mask was also rated highly for leaving fewer or no marks on the upper lip and under the child's ears, and being easy to remove. The Pixi mask is suitable for children aged 2-7 years and provides an alternative to other masks available for PAP therapy in this age group.


Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression.
Aberrant Notch signaling contributes to more than half of all human T-cell leukemias, and accumulating evidence indicates Notch involvement in other human neoplasms. We developed a tetracycline-inducible mouse model (Top-Notch(ic)) to examine the genetic interactions underlying the development of Notch-induced neoplastic disease. Using this model, we show that Notch suppresses p53 in lymphomagenesis through repression of the ARF-mdm2-p53 tumor surveillance network. Attenuation of Notch expression resulted in a dramatic increase in p53 levels that led to tumor regression by an apoptotic program. This shows that continued Notch activity is required to maintain the disease state. However, all tumors relapsed with rapid kinetics, most of which, by reactivation of Notch expression. Furthermore, by directly inhibiting the mdm2-p53 interaction by using either ionizing radiation or the novel small molecule therapeutic Nutlin, p53 can be activated and cause tumor cell death, even in the presence of sustained Notch activity. Therefore, it is the suppression of p53 that provides the Achilles heel for Notch-induced tumors, as activation of p53 in the presence of Notch signaling drives tumor regression. Our study provides proof-of-principle for the rational targeting of therapeutics against the mdm2-p53 pathway in Notch-induced neoplasms. Furthermore, we propose that suppression of p53 by Notch is a key mechanism underlying the initiation of T-cell lymphoma.


On-line monitoring for control of a pilot-scale sequencing batch reactor using a submersible UV/VIS spectrometer.
A submersible UV/VIS spectrometer was used to monitor a pilot-scale sequencing batch reactor (SBR). The instrument utilises the whole UV/VIS range between 200 and 750 nm. With just one single instrument nitrate, organic matter and suspended solids can be measured simultaneously. The spectrometer is installed directly in the reactor, measures in real-time, and is equipped with an auto-cleaning system using pressured air. The paper shows the calibration results for measurements in the SBR tank, time series for typical SBR cycles, and proposes possible ways for optimisation of the operation by using these measurements.


Population origins in Mongolia: genetic structure analysis of ancient and modern DNA.
In the present study, nuclear (autosomal and Y-chromosome short tandem repeats) and mitochondrial (hypervariable region I) ancient DNA data previously obtained from a 2,300-year-old Xiongnu population of the Egyin Gol Valley (south of Lake Baikal in northern Mongolia) (Keyser-Tracqui et al. 2003 Am. J. Hum. Genet. 73:247-260) were compared with data from two contemporary Mongolian populations: one from the same location (Egyin Gol Valley plus a perimeter of less than 100 km around the valley), and one from the whole of Mongolia. The principal objective of this comparative analysis was to assess the likelihood that genetic continuity exists between ancient and present-day Mongolian populations. Since the ancient Xiongnu sample might have been composed of some of the ancestors of the present-day Yakuts, data from a present-day Yakut population, as well as published data from Turkish populations, were also included in the comparative analysis. The main result of our study was the genetic similarity observed among Mongolian samples from different periods and geographic areas. This result supports the hypothesis that the succession over time of different Turkic and Mongolian tribes in the current territory of Mongolia resulted in cultural rather than genetic exchanges. Furthermore, it appears that the Yakuts probably did not find their origin among the Xiongnu tribes, as we previously hypothesized.


Subunit organization of Mcm2-7 and the unequal role of active sites in ATP hydrolysis and viability.
The Mcm2-7 (minichromosome maintenance) complex is a toroidal AAA(+) ATPase and the putative eukaryotic replicative helicase. Unlike a typical homohexameric helicase, Mcm2-7 contains six distinct, essential, and evolutionarily conserved subunits. Precedence to other AAA(+) proteins suggests that Mcm ATPase active sites are formed combinatorially, with Walker A and B motifs contributed by one subunit and a catalytically essential arginine (arginine finger) contributed by the adjacent subunit. To test this prediction, we used copurification experiments to identify five distinct and stable Mcm dimer combinations as potential active sites; these subunit associations predict the architecture of the Mcm2-7 complex. Through the use of mutant subunits, we establish that at least three sites are active for ATP hydrolysis and have a canonical AAA(+) configuration. In isolation, these five active-site dimers have a wide range of ATPase activities. Using Walker B and arginine finger mutations in defined Mcm subunits, we demonstrate that these sites similarly make differential contributions toward viability and ATP hydrolysis within the intact hexamer. Our conclusions predict a structural discontinuity between Mcm2 and Mcm5 and demonstrate that in contrast to other hexameric helicases, the six Mcm2-7 active sites are functionally distinct.


Virus-specific T lymphocytes home to the skin during natural dengue infection.
Dengue, which is the most prevalent mosquito-borne viral disease afflicting human populations, causes a spectrum of clinical symptoms that include fever, muscle and joint pain, maculopapular skin rash, and hemorrhagic manifestations. Patients infected with dengue develop a broad antigen-specific T lymphocyte response, but the phenotype and functional properties of these cells are only partially understood. We show that natural infection induces dengue-specific CD8(+) T lymphocytes that are highly activated and proliferating, exhibit antiviral effector functions, and express CXCR3, CCR5, and the skin-homing marker cutaneous lymphocyte-associated antigen (CLA). In the same patients, bystander human cytomegalovirus -specific CD8(+) T cells are also activated during acute dengue infection but do not express the same tissue-homing phenotype. We show that CLA expression by circulating dengue-specific CD4(+) and CD8(+) T cells correlates with their in vivo ability to traffic to the skin during dengue infection. The juxtaposition of dengue-specific T cells with virus-permissive cell types at sites of possible dengue exposure represents a previously uncharacterized form of immune surveillance for this virus. These findings suggest that vaccination strategies may need to induce dengue-specific T cells with similar homing properties to provide durable protection against dengue viruses.


Although DR3-DQB1*0201 may be associated with multiple component diseases of the autoimmune polyglandular syndromes, the human leukocyte antigen DR4-DQB1*0302 haplotype is implicated only in beta-cell autoimmunity.
Human leukocyte antigen (HLA)-DRB1 and -DQB1 alleles were analyzed using a PCR-based sequence-specific priming technique in 16 patients with autoimmune polyglandular syndrome type I (APS-I), 31 patients with APS-II, and 110 patients with component diseases of APS-II, including 9 patients with isolated Addison's disease, 43 patients with Hashimoto's thyroiditis, 22 patients with Graves' disease, and 36 patients with vitiligo. No significant associations was observed between HLA and APS-I patients in our data set, nor was sharing of HLA haplotypes by sibling pairs affected by APS I significantly different from the random expectation. Thus, HLA-DRB1 and -DQB1 genes are probably not involved in APS-I. To delineate the associations between HLA-DRB1, DQB1, and APS-II, we analyzed APS-II patients with or without beta-cell autoimmunity [i.e. insulin-dependent diabetes (IDD) and/or islet cell or glutamic acid decarboxylase autoantibodies]. Our results suggest that the association between DR4-DQB1*0302 and APS-II was entirely due to the presence of pancreatic beta-cell autoimmunity, since this haplotype was otherwise not significantly associated with APS-II or with any other of its component diseases. In contrast, the DR3-DQB1*0201 haplotype was associated not only with IDD, but also with APS-II in the absence of pancreatic beta-cell autoimmunity, as were several its component diseases, including isolated Addison's disease, Graves' disease, and Hashimoto's thyroiditis. Interestingly, the frequency of DQB1*0602, a dominantly protective allele against IDD, was not significantly decreased in the APS-II patients with IDD or beta-cell autoimmunity, albeit the patient numbers were small. This phenomenon may suggest that the development of autoimmunity to nonpancreatic endocrine glands may predispose autoimmunity to the pancreatic beta-cells and involve genes other than those of the MHC.


Rates and types of hospitalisations for children who have subsequent contact with the child protection system: a population based case-control study.
To determine whether children who have child maltreatment allegation or substantiation have a higher rate of general hospital admissions and injury related admissions when compared to other children and to investigate other types of admissions, such as mental health, infections and admissions due to external causes. A prospective matched case-control study of children born in Western Australia between 1990 and 2005 using de-identified record linked Child Protection and Hospital Morbidity data. Rates of prior hospital admissions for cases versus controls were calculated, and conditional logistic regression was used to estimate the effect of hospital admission rate on the risk of child maltreatment allegation and substantiated allegation. Children with child maltreatment allegations and substantiations had higher mean prior admission rates compared to controls. Higher rates of general admissions and admissions for injuries, infections, mental and behavioural disorders, and external causes of morbidity, were associated with a markedly increased risk of child maltreatment allegations and substantiation. The hospital system plays not only an important role both in the surveillance of maltreatment-related injuries and conditions but also in the role of prevention in the referral of families who may need support and assistance in ensuring the health and safety of their children. This research highlights the importance of moving to electronic patient records in identifying children who have high rates of admissions and the types of conditions they have previously presented with, particularly for injuries, mental and behavioural disorders and external causes of admissions.


Severe iron deficiency anemia and anasarca edema due to excessive cow`s milk intake.
Mantadakis E, Zikidou P, Tsouvala E, Thomaidis S, Chatzimichael A. Severe iron deficiency anemia and anasarca edema due to excessive cow`s milk intake. Turk J Pediatr 2019; 61: 102-106. The authors describe a 13-month-old girl who presented with progressively worsening anasarca edema that developed over the last three weeks along with increasing fatigue. Over the last several months she was consuming progressively increasing amounts of fresh cow`s milk. Laboratory examinations on admission showed severe microcytic and hypochromic anemia (hemoglobin 3.8 g/dl) and hypoferritenemia indicative of iron deficiency, while urinalyses showed no proteinuria. The child was transfused with 13ml/kg packed red blood cells and approximately 2g/kg intravenous albumin. On the second and fourth hospital days, she received 100 mg of iron sucrose intravenously that she tolerated well. Eight months after the described events, she is healthy with normal hemoglobin for age, while she has no laboratory evidence of cow`s milk protein allergy. Pediatricians should be aware of the association of severe iron deficiency anemia (IDA) and anasarca edema, and should screen infants in their practice for anemia at the age of 12 months or sooner, if risk factors are present.


Escherichia coli sequence type 131 is a dominant, antimicrobial-resistant clonal group associated with healthcare and elderly hosts.
To determine prevalence, predictors, and outcomes of infection due to Escherichia coli sequence type ST131. Retrospective cohort. All healthcare settings in Olmsted County, Minnesota (eg, community hospital, tertiary care center, long-term care facilities, and ambulatory clinics). Ambulatory and hospitalized children and adults with extraintestinal E. coli isolates. We analyzed 299 consecutive, nonduplicate extraintestinal E. coli isolates submitted to Olmsted County laboratories in February and March 2011. ST131 was identified using single-nucleotide polymorphism polymerase chain reaction and further evaluated through pulsed-field gel electrophoresis. Associated clinical data were abstracted through medical record review. Most isolates were from urine specimens (90%), outpatients (68%), and community-associated infections (61%). ST131 accounted for 27% of isolates overall and for a larger proportion of those isolates resistant to fluoroquinolones (81%), trimethoprim-sulfamethoxazole (42%), gentamicin (79%), and ceftriaxone (50%). The prevalence of ST131 increased with age (accounting for 5% of isolates from those 11-20 years of age, 26% of isolates from those 51-60 years of age, and 50% of isolates from those 91-100 years of age). ST131 accounted for a greater proportion of healthcare-associated isolates (49%) than community-associated isolates (15%) and for fully 76% of E. coli isolates from long-term care facility (LTCF) residents. Multivariable predictors of ST131 carriage included older age, LTCF residence, previous urinary tract infection, high-complexity infection, and previous use of fluoroquinolones, macrolides, and extended-spectrum cephalosporins. With multivariable adjustment, ST131-associated infection outcomes included receipt of more than 1 antibiotic (odds ratio [OR], 2.54 [95% confidence interval (CI), 1.25-5.17]) and persistent or recurrent symptoms (OR, 2.53 [95% CI, 1.08-5.96]). Two globally predominant ST131 pulsotypes accounted for 45% of ST131 isolates. ST131 is a dominant, antimicrobial-resistant clonal group associated with healthcare settings, elderly hosts, and persistent or recurrent symptoms.


Acupuncture for posttraumatic stress disorder: a systematic review of randomized controlled trials and prospective clinical trials.
To evaluate the current evidence for effectiveness of acupuncture for posttraumatic stress disorder (PTSD) in the form of a systematic review, a systematic literature search was conducted in 23 electronic databases. Grey literature was also searched. The key search terms were "acupuncture" and "PTSD." No language restrictions were imposed. We included all randomized or prospective clinical trials that evaluated acupuncture and its variants against a waitlist, sham acupuncture, conventional therapy control for PTSD, or without control. Four randomized controlled trials (RCTs) and 2 uncontrolled clinical trials (UCTs) out of 136 articles in total were systematically reviewed. One high-quality RCT reported that acupuncture was superior to waitlist control and therapeutic effects of acupuncture and cognitive-behavioral therapy (CBT) were similar based on the effect sizes. One RCT showed no statistical difference between acupuncture and selective serotonin reuptake inhibitors (SSRIs). One RCT reported a favorable effect of acupoint stimulation plus CBT against CBT alone. A meta-analysis of acupuncture plus moxibustion versus SSRI favored acupuncture plus moxibustion in three outcomes. This systematic review and meta-analysis suggest that the evidence of effectiveness of acupuncture for PTSD is encouraging but not cogent. Further qualified trials are needed to confirm whether acupuncture is effective for PTSD.


Ionothermal synthesis of novel Pb-OH-Cu-X (X = Cl, Br and I) quaternary heterometallic frameworks with tunable optical properties.
Reported herein is the new application of ionothermal synthesis for inorganic optical materials. Under ionothermal conditions with different imidazolium ionic liquids, novel quaternary heterometallic frameworks based on [Pb4(OH)4] cubane and [CuCl4] or [CuBr4] chains and [Cu2I6] binuclear clusters have been successfully produced. Simple chlorine, bromine and iodine replacement leads to not only the space group change (tetragonal I41/acd for 1 and 2, and orthorhombic Fddd for 3) but also the topological net transformation (8,12-net for 1 and 2, and 6,6-net for 3). Notably, compounds 1, 2 and 3 all show tunable solid-state semiconducting and luminescence properties.


Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury.
Traumatic brain injury (TBI) is a devastating condition, often leading to life-long consequences for patients. Even though modern neurointensive care has improved functional and cognitive outcomes, efficient pharmacological therapies are still lacking. Targeting peripherally derived, or resident inflammatory, cells that are rapid responders to brain injury is promising, but complex, given that the contribution of inflammation to exacerbation versus improved recovery varies with time post-injury. The injury-induced inflammatory response is triggered by release of alarmins, and in the present study we asked whether interleukin-33 (IL-33), an injury-associated nuclear alarmin, is involved in TBI. Here, we used samples from human TBI microdialysate, tissue sections from human TBI, and mouse models of central nervous system injury and found that expression of IL-33 in the brain was elevated from nondetectable levels, reaching a maximum after 72 h in both human samples and mouse models. Astrocytes and oligodendrocytes were the main producers of IL-33. Post-TBI, brains of mice deficient in the IL-33 receptor, ST2, contained fewer microglia/macrophages in the injured region than wild-type mice and had an altered cytokine/chemokine profile in response to injury. These observations indicate that IL-33 plays a role in neuroinflammation with microglia/macrophages being cellular targets for this interleukin post-TBI.


Identifying patients with physician-diagnosed asthma in health administrative databases.
Asthma imposes a heavy and expensive burden on individuals and populations. A population-based surveillance and research program based on health administrative data could measure and study the burden of asthma; however, the validity of a health administrative data diagnosis of asthma must first be confirmed. To evaluate the accuracy of population-based provincial health administrative data in identifying adult patients with asthma for ongoing surveillance and research. Patients from randomly selected primary care practices were assigned to four categories according to their previous diagnoses: asthma, chronic obstructive pulmonary disease, related respiratory conditions and nonasthma conditions. In each practice, 10 charts from each category were randomly selected, abstracted, then reviewed by a blinded expert panel who identified them as asthma or nonasthma. These reference standard diagnoses were then linked to the patients' provincial records and compared with health administrative algorithms designed to identify asthma. Analyses were performed using the concepts of diagnostic test evaluation. A total of 518 charts, including 160 from individuals with asthma, were reviewed. The algorithm of two or more ambulatory care visits and/or one or more hospitalization(s) for asthma in two years had a sensitivity of 83.8% (95% CI 77.1% to 89.1%) and a specificity of 76.5% (95% CI 71.8% to 80.8%). Definitions of adult asthma using health administrative data are sensitive and specific for identifying adults with asthma. Using these definitions, cohorts of adults with asthma for ongoing population-based surveillance and research can be developed.


Developing generalism in the South African context.
The largest impact on the South African burden of disease will be made in community-based and primary healthcare (PHC) settings and not in referral hospitals. Medical generalism is an approach to the delivery of healthcare that routinely applies a broad and holistic perspective to the patient's problems and is a feature of PHC. A multi-professional team of generalists, who share similar values and principles, is needed to make this a reality. Ward-based outreach teams include community health workers and nurses with essential support from doctors. Expert generalists - family physicians - are required to support PHC as well as provide care at the district hospital. All require sufficient training, at scale, with greater collaboration and integration between training programmes. District clinical specialist teams are both an opportunity and a threat. The value of medical generalism needs to be explained, advocated and communicated more actively.


Omega-3 fatty acids and inflammation.
Dietary omega-3 (n-3) fatty acids have a variety of anti-inflammatory and immune-modulating effects that may be of relevance to atherosclerosis and its clinical manifestations of myocardial infarction, sudden death, and stroke. The n-3 fatty acids that appear to be most potent in this respect are the long-chain polyunsaturates derived from marine oils, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and this review is restricted to these substances. A variety of biologic effects of EPA and DHA have been demonstrated from feeding studies with fish or fish oil supplements in humans and animals. These include effects on triglycerides, high-density lipoprotein cholesterol, platelet function, endothelial and vascular function, blood pressure, cardiac excitability, measures of oxidative stress, pro- and anti-inflammatory cytokines, and immune function. Epidemiologic studies provide evidence for a beneficial effect of n-3 fatty acids on manifestations of coronary heart disease and ischemic stroke, whereas randomized, controlled, clinical feeding trials support this, particularly with respect to sudden cardiac death in patients with established disease. Clinically important anti-inflammatory effects in man are further suggested by trials demonstrating benefits of n-3 fatty acids in rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disorders. Given the evidence relating progression of atherosclerosis to chronic inflammation, the n-3 fatty acids may play an important role via modulation of the inflammatory processes.


Two-year prospective naturalistic study of remission from major depressive disorder as a function of personality disorder comorbidity.
In this study, the authors examined prospectively the 24-month natural course of remission from major depressive disorder (MDD) as a function of personality disorder (PD) comorbidity. In 302 participants (196 women, 106 men), psychiatric and PDs were assessed at baseline with diagnostic interviews, and the course of MDD was assessed with the Longitudinal Interval Follow-Up Evaluation at 6-, 12-, and 24-month follow-ups. Survival analyses revealed an overall 24-month remission rate of 73.5% for MDD that differed little by gender. Participants with MDD who had certain forms of coexisting PD psychopathology (schizotypal, borderline, or avoidant) as their primary PD diagnoses had a significantly longer time to remission from MDD than did patients with MDD without any PD. These PDs emerged as robust predictors of slowed remission from MDD even when controlling for other negative prognostic predictors.


The Servant Leadership Survey: Development and Validation of a Multidimensional Measure.
PURPOSE: The purpose of this paper is to describe the development and validation of a multi-dimensional instrument to measure servant leadership. DESIGN/METHODOLOGY/APPROACH: Based on an extensive literature review and expert judgment, 99 items were formulated. In three steps, using eight samples totaling 1571 persons from The Netherlands and the UK with a diverse occupational background, a combined exploratory and confirmatory factor analysis approach was used. This was followed by an analysis of the criterion-related validity. FINDINGS: The final result is an eight-dimensional measure of 30 items: the eight dimensions being: standing back, forgiveness, courage, empowerment, accountability, authenticity, humility, and stewardship. The internal consistency of the subscales is good. The results show that the Servant Leadership Survey (SLS) has convergent validity with other leadership measures, and also adds unique elements to the leadership field. Evidence for criterion-related validity came from studies relating the eight dimensions to well-being and performance. IMPLICATIONS: With this survey, a valid and reliable instrument to measure the essential elements of servant leadership has been introduced. ORIGINALITY/VALUE: The SLS is the first measure where the underlying factor structure was developed and confirmed across several field studies in two countries. It can be used in future studies to test the underlying premises of servant leadership theory. The SLS provides a clear picture of the key servant leadership qualities and shows where improvements can be made on the individual and organizational level; as such, it may also offer a valuable starting point for training and leadership development.


Second generation sequencing and morphological faecal analysis reveal unexpected foraging behaviour by Myotis nattereri (Chiroptera, Vespertilionidae) in winter.
Temperate winters produce extreme energetic challenges for small insectivorous mammals. Some bat species inhabiting locations with mild temperate winters forage during brief inter-torpor normothermic periods of activity. However, the winter diet of bats in mild temperate locations is studied infrequently. Although microscopic analyses of faeces have traditionally been used to characterise bat diet, recently the coupling of PCR with second generation sequencing has offered the potential to further advance our understanding of animal dietary composition and foraging behaviour by allowing identification of a much greater proportion of prey items often with increased taxonomic resolution. We used morphological analysis and Illumina-based second generation sequencing to study the winter diet of Natterer's bat (Myotis nattereri) and compared the results obtained from these two approaches. For the first time, we demonstrate the applicability of the Illumina MiSeq platform as a data generation source for bat dietary analyses. Faecal pellets collected from a hibernation site in southern England during two winters (December-March 2009-10 and 2010-11), indicated that M. nattereri forages throughout winter at least in a location with a mild winter climate. Through morphological analysis, arthropod fragments from seven taxonomic orders were identified. A high proportion of these was non-volant (67.9% of faecal pellets) and unexpectedly included many lepidopteran larvae. Molecular analysis identified 43 prey species from six taxonomic orders and confirmed the frequent presence of lepidopteran species that overwinter as larvae. The winter diet of M. nattereri is substantially different from other times of the year confirming that this species has a wide and adaptable dietary niche. Comparison of DNA derived from the prey to an extensive reference dataset of potential prey barcode sequences permitted fine scale taxonomic resolution of prey species. The high occurrence of non-volant prey suggests that gleaning allows prey capture at low ambient temperatures when the abundance of flying insects may be substantially reduced. Interesting questions arise as to how M. nattereri might successfully locate and capture some of the non-volant prey species encountered in its faeces. The consumption of lepidopteran larvae such as cutworms suggests that M. nattereri eats agricultural pest species.


Identification and pharmacokinetics of novel alkylresorcinol metabolites in human urine, new candidate biomarkers for whole-grain wheat and rye intake.
Biomarkers of dietary intake are prominent tools in nutritional research. The alkylresorcinol metabolites 3,5-dihydroxybenzoic acid (3,5-DHBA) and 3-(3,5-dihydroxyphenyl)propanoic acid (3,5-DHPPA) have been proposed as exposure biomarkers of whole-grain (WG) wheat and rye intake. However, the profile of alkylresorcinol metabolites is not fully understood. The aim of this study was to investigate the metabolism of alkylresorcinols in mice and in humans, while further determining urinary pharmacokinetics of the novel alkylresorcinol metabolites to explore their potential as biomarkers of WG wheat intake. Utilization of the liquid chromatography-mass spectrometry approach resulted in 10 alkylresorcinol metabolites identified in mice and in humans, including 3 phenolic acids and 7 of their phase II conjugates. Among them, 2 novel metabolites were discovered: 5-(3,5-dihydroxyphenyl)pentanoic acid (3,5-DHPPTA) and 2-(3,5-dihydroxybenzamido)acetic acid (3,5-DHBA glycine). The structures of these 2 metabolites were confirmed by comparing with authentic standards synthesized in-house. In the pharmacokinetic study, a group of 12 volunteers consumed a polyphenolic-restricted diet for 4 d before ingesting WG wheat bread containing 61 mg of alkylresorcinols. Urine samples were collected for 32 h, and alkylresorcinol metabolites were quantified with HPLC-coulometric electrode array detection. The mean urinary excretion rates and mean apparent half-life of 3,5-DHPPTA, 3,5-DHBA glycine, 3,5-DHBA, and 3,5-DHPPA at each time point were determined. Our results suggest that 3,5-DHPPTA and 3,5-DHBA glycine may be used in combination with 3,5-DHBA and 3,5-DHPPA as potential biomarkers to increase the accuracy of recording WG wheat and rye intake in epidemiologic studies. Further validation of 3,5-DHPPTA and 3,5-DHBA glycine as potential biomarkers is warranted.


First case of confirmed congenital Zika syndrome in continental Africa.
Zika virus has been responsible for recent outbreaks in the western hemisphere with known neurological complications such as microcephaly. This complication has not been previously documented in continental Africa. Neurological evaluation of the newborn was performed after birth, at one and two months of age. The mother and the newborn sera samples were tested by immunofluorescent assay (IFA; immunoglobulin G [IgG] and IgM) for Zika virus and the presence of Zika virus ribonucleic acid (RNA) was checked by qualitative real-time reverse transcription polymerase chain reaction (RT-PCR) in placenta, blood and urine samples. We report on a newborn, born in Portugal, with microcephaly with confirmed congenital Zika virus infection (Asian lineage) imported from Angola with typical clinical and imaging findings. To our knowledge this is the first report that shows the circulation of the Asian lineage in Angola and the first report of a congenital Zika syndrome in continental Africa.


Measurements of blood flow to individual glomeruli in the ophidian kidney.
Continuous measurements of the instantaneous rate of blood flow to individual glomeruli in a normal vertebrate kidney were made in the garter snake Thamnophis sirtalis. Epifluorescence video microscopy was used to visualize and record blood flow in the afferent arterioles of superficial nephrons. The dual-slit method was used for the determination of red blood cell (RBC) velocity from the video replay. Simultaneous measurements of the vessel diameter allowed the continuous determination of the instantaneous rate of blood flow. A total of 100 glomeruli was surveyed in 12 animals. These glomeruli displayed both constant and highly variable rates of blood flow, with 21% of all nephrons displaying intermittent glomerular perfusion. The mean single-nephron blood flow rate (SNBFR) for all individuals was 23.9 +/- 10.3 (SD) nl/min (n = 12). The percentage of nephrons with intermittent flow for an individual animal increased significantly with increasing plasma osmolality. Intermittency was associated with low SNBFR values; SNBFR averaged 13.5 +/- 10.2 (SD) nl/min (n = 21) in intermittent nephrons and 29.2 +/- 19.0 (SD) nl/min (n = 79) in continuous flow nephrons, the difference being significant (P less than 0.001). Nephrons with continuous perfusion displayed a much greater range of SNBFR values than intermittent nephrons. This suggests that, although changes in whole kidney glomerular filtration rate (GFR) in reptiles need not involve glomerular intermittency, intermittency may lower GFR.


Family level phylogenies reveal modes of macroevolution in RNA viruses.
Despite advances in understanding the patterns and processes of microevolution in RNA viruses, little is known about the determinants of viral diversification at the macroevolutionary scale. In particular, the processes by which viral lineages assigned as different "species" are generated remain largely uncharacterized. To address this issue, we use a robust phylogenetic approach to analyze patterns of lineage diversification in five representative families of RNA viruses. We ask whether the process of lineage diversification primarily occurs when viruses infect new host species, either through cross-species transmission or codivergence, and which are defined here as analogous to allopatric speciation in animals, or by acquiring new niches within the same host species, analogous to sympatric speciation. By mapping probable primary host species onto family level viral phylogenies, we reveal a strong clustering among viral lineages that infect groups of closely related host species. Although this is consistent with lineage diversification within individual hosts, we argue that this pattern more likely represents strong biases in our knowledge of viral biodiversity, because we also find that better-sampled human viruses rarely cluster together. Hence, although closely related viruses tend to infect related host species, it is unlikely that they often infect the same host species, such that evolutionary constraints hinder lineage diversification within individual host species. We conclude that the colonization of new but related host species may represent the principle mode of macroevolution in RNA viruses.


Clinical effectiveness and cost-effectiveness of surgical options for the management of anterior and/or posterior vaginal wall prolapse: two randomised controlled trials within a comprehensive cohort study - results from the PROSPECT Study.
The use of mesh in prolapse surgery is controversial, leading to a number of enquiries into its safety and efficacy. To compare synthetic non-absorbable mesh inlay, biological graft and mesh kit with a standard repair in terms of clinical effectiveness, adverse effects, quality of life (QoL), costs and cost-effectiveness. Two randomised controlled trials within a comprehensive cohort (CC) study. Allocation was by a remote web-based randomisation system in a 1 :1 : 1 ratio (Primary trial) or 1 : 1 : 2 ratio (Secondary trial), and was minimised on age, type of prolapse repair planned, need for a concomitant continence procedure, need for a concomitant upper vaginal prolapse procedure and surgeon. Participants and outcome assessors were blinded to randomisation; participants were unblinded if they requested the information. Surgeons were not blinded to allocated procedure. Thirty-five UK hospitals. Primary study: 2474 women in the analysis (including 1348 randomised) having primary anterior or posterior prolapse surgery. Secondary study: 398 in the analysis (including 154 randomised) having repeat anterior or posterior prolapse surgery. CC3: 215 women having either uterine or vault prolapse repair. Anterior or posterior repair alone, or with mesh inlay, biological graft or mesh kit. Prolapse symptoms [Pelvic Organ Prolapse Symptom Score (POP-SS)]; prolapse-specific QoL; cost-effectiveness [incremental cost per quality-adjusted life-year (QALY)]. Primary trials: adjusting for baseline and minimisation covariates, mean POP-SS was similar for each comparison {standard 5.4 [standard deviation (SD) 5.5] vs. mesh 5.5 (SD 5.1), mean difference (MD) 0.00, 95% confidence interval (CI) -0.70 to 0.71; standard 5.5 (SD 5.6) vs. graft 5.6 (SD 5.6), MD -0.15, 95% CI -0.93 to 0.63}. Serious non-mesh adverse effects rates were similar between the groups in year 1 [standard 7.2% vs. mesh 7.8%, risk ratio (RR) 1.08, 95% CI 0.68 to 1.72; standard 6.3% vs. graft 9.8%, RR 1.57, 95% CI 0.95 to 2.59]. There were no statistically significant differences between groups in any other outcome measure. The cumulative mesh complication rates over 2 years were 2 of 430 (0.5%) for standard repair (trial 1), 46 of 435 (10.6%) for mesh inlay and 2 of 368 (0.5%) for biological graft. The CC findings were comparable. Incremental costs were £363 (95% CI -£32 to £758) and £565 (95% CI £180 to £950) for mesh and graft vs. standard, respectively. Incremental QALYs were 0.071 (95% CI -0.004 to 0.145) and 0.039 (95% CI -0.041 to 0.120) for mesh and graft vs. standard, respectively. A Markov decision model extrapolating trial results over 5 years showed standard repair had the highest probability of cost-effectiveness, but results were surrounded by considerable uncertainty. Secondary trials: there were no statistically significant differences between the randomised groups in any outcome measure, but the sample size was too small to be conclusive. The cumulative mesh complication rates over 2 years were 7 of 52 (13.5%) for mesh inlay and 4 of 46 (8.7%) for mesh kit, with no mesh exposures for standard repair. In women who were having primary repairs, there was evidence of no benefit from the use of mesh inlay or biological graft compared with standard repair in terms of efficacy, QoL or adverse effects (other than mesh complications) in the short term. The Secondary trials were too small to provide conclusive results. Women in the Primary trials included some with a previous repair in another compartment. Follow-up is vital to identify any long-term potential benefits and serious adverse effects. Long-term follow-up to at least 6 years after surgery is ongoing to identify recurrence rates, need for further prolapse surgery, adverse effects and cost-effectiveness. Current Controlled Trials ISRCTN60695184. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 95. See the NIHR Journals Library website for further project information.


IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity.
IL-6 is secreted from muscles to the circulation during high-intensity and long-duration exercise, where muscle-derived IL-6 works as an energy sensor to increase release of energy substrates from liver and adipose tissues. We investigated the mechanism involved in the exercise-mediated surge in IL-6 during exercise. Using interval-based cycling in healthy young men, swimming exercise in mice, and electrical stimulation of primary human muscle cells, we explored the role of lactate production in muscular IL-6 release during exercise. First, we observed a tight correlation between lactate production and IL-6 release during both strenuous bicycling and electrically stimulated muscle cell cultures. In mice, intramuscular injection of lactate mimicked the exercise-dependent release of IL-6, and pH buffering of lactate production during exercise attenuated IL-6 secretion. Next, we used in vivo bioimaging to demonstrate that intrinsic intramuscular proteases were activated in mice during swimming, and that blockade of protease activity blunted swimming-induced IL-6 release in mice. Last, intramuscular injection of the protease hyaluronidase resulted in dramatic increases in serum IL-6 in mice, and immunohistochemical analyses showed that intramuscular lactate and hyaluronidase injections led to release of IL-6-containing intramyocellular vesicles. We identified a pool of IL-6 located within vesicles of skeletal muscle fibers, which could be readily secreted upon protease activity. This protease-dependent release of IL-6 was initiated by lactate production, linking training intensity and lactate production to IL-6 release during strenuous exercise.


The applicability of hepatocellular carcinoma risk prediction scores in a North American patient population with chronic hepatitis B infection.
Patients with chronic hepatitis B (CHB) infection are at an increased risk of developing hepatocellular carcinoma (HCC). Risk scores have been developed in Asian populations to predict HCC risk over time. To assess the performance of HCC risk prediction models in a heterogeneous population of patients with CHB. Scores were calculated at baseline using CU-HCC, REACH-B, NGM1-HCC, NGM2-HCC and GAG-HCC models and the incidence of HCC was determined. The predictive ability of each score was evaluated using the area under the receiver operating characteristic curve (AUROC), Cox regression and plots of observed versus predicted HCC. The predictive value of the scores was compared between Asian and non-Asian patients and between cirrhotic versus non-cirrhotic with and without treatment. Of 2105 patients, 70 developed HCC. Increasing risk score was associated with HCC in all models. The CU-HCC model had the highest AUROC in Asian (0.85) and non-Asian (0.91) patients. Patients identified as low risk by any model had a very low incidence of HCC (0-0.15 per year), with the highest proportion of patients identified as low risk using CU-HCC (67%) or GAG-HCC (78%). The risk of HCC was similar to predicted for low-risk and medium-risk patients but was lower than predicted for high-risk patients. Treated patients had a lower than predicted risk of HCC, particularly in non-cirrhotic high-risk patients with longer follow-up. Although all models predicted the risk of HCC, models that incorporated parameters of liver function or cirrhosis (CU-HCC/GAG-HCC) were most accurate. Low-risk patients likely require reduced HCC surveillance.


Diagnostic specificity and nonspecificity in the dimensions of preschool psychopathology.
The appropriateness of the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) nosology for classifying preschool mental health disturbances continues to be debated. To inform this debate, we investigate whether preschool psychopathology shows differentiation along diagnostically specific lines when DSM-IV symptoms are aggregated statistically. One thousand seventy-three parents of preschoolers aged 2-5 years attending a large pediatric clinic completed the Child Behavior Checklist 1.5-5. A stratified probability sample of 193 parents of high scorers and 114 parents of low scorers were interviewed with the Preschool Age Psychiatric Assessment (PAPA). Confirmatory factor analysis was performed on symptoms from seven DSM disorders. Comparison of competing models supported the differentiation of emotional syndromes into three factors: social phobia (SOC), separation anxiety (SAD), and depression/generalized anxiety (MDD/GAD), and the differentiation of disruptive syndromes into three factors: oppositional defiant/conduct syndrome (ODD/CD), hyperactivity/impulsivity, and inattention. Latent syndrome correlations were moderately high after accounting for symptom overlap and measurement error. Psychopathology appears to be differentiated among preschoolers much as it is among older children, and adolescents. We conclude that it is as reasonable to apply the DSM-IV nosology to preschoolers as it is to apply it to older individuals.


The HIV cytopathic effect: potential target for therapy?
HIV kills activated infected CD4+ T cells after a burst of replication and the release of large numbers of virions. From a review of the literature on HIV regulatory genes and from preliminary mathematical models of HIV dynamics at four levels (host population epidemiology, the immune system, gene regulation within infected cells, and selection of mutants) we have arrived at the theory that in the etiology of HIV the HIV cytopathic effect may actively be caused by a viral regulatory gene product. The most likely candidate is the rev regulatory protein. Rev and the analogous rex protein from HTLV-I (human T cell leukemia virus) both have two active sites with similar function: one site locates the protein in the nucleus/nucleolus, and the other site interacts with viral mRNAs, facilitating their export from the nucleus to the cytoplasm. Rev seems to have a third functional site near the 3' end. We conjecture that this site may be responsible for the cytopathic effect. We think that rev acts on cellular genes that normally induce senescence and cell death during development, or T-cell maturation, or on terminal differentiation. We propose that mathematical and computer models of the immune system could be used to explore whether suppression of the cytopathic action of the rev protein could be of therapeutic benefit in restoring the ability of the immune system to clear HIV or at least to extend latency. We also suggest how immune deficiency disease might be created as laboratory artifact in animal populations.


The structure of human thrombospondin, an adhesive glycoprotein with multiple calcium-binding sites and homologies with several different proteins.
Thrombospondin is one of a class of adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. We have used two monoclonal antibodies to isolate cDNA clones of thrombospondin from a human endothelial cell cDNA library and have determined the complete nucleotide sequence of the coding region. Three regions of known amino acid sequence of human platelet thrombospondin confirm that the clones are authentic. Three types of repeating amino acid sequence are present in thrombospondin. The first is 57 amino acids long and shows homology with circumsporozoite protein from Plasmodium falciparum. The second is 50-60 amino acids long and shows homology with epidermal growth factor precursor. The third occurs as a continuous eightfold repeat of a 38-residue sequence; structural homology with parvalbumin and calmodulin indicates that these repeats constitute the multiple calcium-binding sites of thrombospondin. The amino acid sequence arg-gly-asp-ala is included in the last type 3 repeat. This sequence is probably the site for the association of thrombospondin with cells. In addition, localized homologies with procollagen, fibronectin, and von Willebrand factor are present in one region of the thrombospondin molecule.


Bifunctional crosslinking ligands for transthyretin.
Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR-ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.


Confident phylogenetic identification of uncultured prokaryotes through long read amplicon sequencing of the 16S-ITS-23S rRNA operon.
Amplicon sequencing of the 16S rRNA gene is the predominant method to quantify microbial compositions and to discover novel lineages. However, traditional short amplicons often do not contain enough information to confidently resolve their phylogeny. Here we present a cost-effective protocol that amplifies a large part of the rRNA operon and sequences the amplicons with PacBio technology. We tested our method on a mock community and developed a read-curation pipeline that reduces the overall read error rate to 0.18%. Applying our method on four environmental samples, we captured near full-length rRNA operon amplicons from a large diversity of prokaryotes. The method operated at moderately high-throughput (22286-37,850 raw ccs reads) and generated a large amount of putative novel archaeal 23S rRNA gene sequences compared to the archaeal SILVA database. These long amplicons allowed for higher resolution during taxonomic classification by means of long (∼1000 bp) 16S rRNA gene fragments and for substantially more confident phylogenies by means of combined near full-length 16S and 23S rRNA gene sequences, compared to shorter traditional amplicons (250 bp of the 16S rRNA gene). We recommend our method to those who wish to cost-effectively and confidently estimate the phylogenetic diversity of prokaryotes in environmental samples at high throughput.


Effect of ON pathway blockade on directional selectivity in the rabbit retina.
1. In this report we describe extracellular recordings made from directionally selective (DS) ganglion cells in the rabbit retina during perfusion with 2-amino-4-phosphonobutyric acid (APB) to block ON channels through the retina. 2. Application of 100 microM APB selectively and reversibly abolished the responses of ON ganglion cells in the rabbit retina. In addition, 100 microM APB completely and reversibly blocked ON component responses of ON-OFF DS ganglion cells to both stationary and moving stimuli. These results are consistent with the idea that APB blocks ON pathways through the retina. 3. Under ON pathway blockade with APB, OFF component responses of ON-OFF DS ganglion cells remained DS. DS OFF responses retained the same preferred direction as the pre-APB ON-OFF responses and could be driven using either normal or reversed contrast stimuli. 4. Extracellular responses of ON DS ganglion cells were completely blocked by APB. Under APB, these cells showed no response to stationary or moving stimuli. 5. Application of the gamma-aminobutyric acid-A (GABAA) antagonist 2-(3-Carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide (SR95531) reversibly abolished directional selectivity of ON DS and ON-OFF DS ganglion cells in the rabbit retina. This finding is consistent with previous data for picrotoxin. 6. Application of SR95531 during ON channel blockade by APB caused OFF component responses of ON-OFF DS ganglion cells to lose their directional selectivity. Under these conditions, OFF responses to movement in the preferred and null directions became virtually identical. 7. These results indicate that simultaneous ON and OFF layer input is not required to generate directional responses in ON-OFF DS ganglion cells. In addition, it appears that a GABAA-dependent mechanism for directional selectivity may operate independently in the two separate dendritic layers of the ON-OFF DS ganglion cell.


Crystal structure of the Bacillus subtilis phosphodiesterase PhoD reveals an iron and calcium-containing active site.
The PhoD family of extra-cytoplasmic phosphodiesterases are among the most commonly occurring bacterial phosphatases. The exemplars for this family are the PhoD protein of Bacillus subtilis and the phospholipase D of Streptomyces chromofuscus. We present the crystal structure of B. subtilis PhoD. PhoD is most closely related to purple acid phosphatases (PAPs) with both types of enzyme containing a tyrosinate-ligated Fe(3+) ion. However, the PhoD active site diverges from that found in PAPs and uses two Ca(2+) ions instead of the single extra Fe(2+), Mn(2+), or Zn(2+) ion present in PAPs. The PhoD crystals contain a phosphate molecule that coordinates all three active site metal ions and that is proposed to represent a product complex. A C-terminal helix lies over the active site and controls access to the catalytic center. The structure of PhoD defines a new phosphatase active site architecture based on Fe(3+) and Ca(2+) ions.


Giant Rashba Splitting in CH_{3}NH_{3}PbBr_{3} Organic-Inorganic Perovskite.
As they combine decent mobilities with extremely long carrier lifetimes, organic-inorganic perovskites open a whole new field in optoelectronics. Measurements of their underlying electronic structure, however, are still lacking. Using angle-resolved photoelectron spectroscopy, we measure the valence band dispersion of single-crystal CH_{3}NH_{3}PbBr_{3}. The dispersion of the highest energy band is extracted applying a modified leading edge method, which accounts for the particular density of states of organic-inorganic perovskites. The surface Brillouin zone is consistent with bulk-terminated surfaces both in the low-temperature orthorhombic and the high-temperature cubic phase. In the low-temperature phase, we find a ring-shaped valence band maximum with a radius of 0.043 Å^{-1}, centered around a 0.16 eV deep local minimum in the dispersion of the valence band at the high-symmetry point. Intense circular dichroism is observed. This dispersion is the result of strong spin-orbit coupling. Spin-orbit coupling is also present in the room-temperature phase. The coupling strength is one of the largest ones reported so far.


Formulation and evaluation of effervescent floating tablets of tizanidine hydrochloride.
Tizanidine hydrochloride is an orally administered prokinetic agent that facilitates or restores motility through-out the length of the gastrointestinal tract. The objective of the present investigation was to develop effervescent floating matrix tablets of tizanidine hydrochloride for prolongation of gastric residence time in order to overcome its low bioavailability (34-40 %) and short biological half life (4.2 h). Tablets were prepared by the direct compression method, using different viscosity grades of hydroxypropyl methylcellulose (HPMC K4M, K15M and K100M). Tablets were evaluated for various physical parameters and floating properties. Further, tablets were studied for in vitro drug release characteristics in 12 hours. Drug release from effervescent floating matrix tablets was sustained over 12 h with buoyant properties. DSC study revealed that there is no drug excipient interaction. Based on the release kinetics, all formulations best fitted the Higuchi, first-order model and non-Fickian as the mechanism of drug release. Optimized formulation (F9) was selected based on the similarity factor (f2) (74.2), dissolution efficiency at 2, 6 and 8 h, and t50 (5.4 h) and was used in radiographic studies by incorporating BaSO4. In vivo X-ray studies in human volunteers showed that the mean gastric residence time was 6.2 ± 0.2 h.


Sleep Quality and Quantity of International Rugby Sevens Players During Pre-season.
Leduc, C, Jones, B, Robineau, J, Piscione, J, and Lacome, M. Sleep quality and quantity of international rugby sevens players during pre-season. J Strength Cond Res 33(7): 1878-1886, 2019-The aim of this study was to investigate the influence of training load on objective and subjective sleep measures among elite rugby sevens players during pre-season. Nine international male rugby sevens players participated in this study. Actigraphic and subjective sleep assessment were performed on a daily basis to measure sleep parameters. Training load was measured during the entire pre-season period, and sleep data from the highest and lowest training load week were used in the analysis through magnitude-based inferences. During the highest training load, likely to possibly small, moderate decreases in time in bed (effect sizes; ±90% confidence limits: -0.42; ±0.44 for session rating of perceived exertion [sRPE], -0.69; ±0.71 for total distance covered [TDC]) and total sleep time (-0.20; ±0.37 for sRPE, -0.23; ±0.35 for TDC) were found. Possibly small (-0.21; ±0.35 for high-speed distance, -0.52; ±0.73 for acceleration/deceleration [A/D]) and likely moderate (-074; ±0.67 for TDC) decreases were observed in subjective sleep quality. Possibly small to very likely moderate changes in sleep schedule were observed. Sleep quantity and subjective quality seem to be deteriorated during higher loads of training. This study highlights the necessity to monitor and improve sleep among elite rugby sevens players, especially for the intense period of training.


Umbilical Cord-derived Mesenchymal Stem Cells with Surfactant Protein B Alleviates Inflammatory Response in Acute Respiratory Distress Syndrome by Regulating Macrophage Polarization.
Acute respiratory distress syndrome (ARDS) is a severe disorder that is related to a high mortality. Mesenchymal stem cells (MSCs) have shown strong effects in relieving lung injury. To determine the role of umbilical cord-derived MSCs (UC-MSCs) together with surfactant protein B (SP-B) in ARDS. Animal experimentation. Immunophenotypic characteristics of UC-MSCs were identified. BALB/c mice were intratracheally administrated with lipopolysaccharide (LPS) and received UC-MSCs or UC-MSCs transfected with SP-B (UC-MSCs-SP-B). Pathological changes and lung injury degrees after transplantation were assessed by histological and biochemical analyses. Inflammatory chemokine and cytokine production in the bronchoalveolar lavage fluid (BALF) was measured using enzyme-linked immunoassay. Flow cytometry was used to examine macrophage phenotypes and differentiation of T-helper 17 (Th17) and T-regulatory (Treg) in the BALF. Our results showed that isolated UC-MSCs possessed multilineage differentiation potential. SP-B transfection into UC-MSCs strengthened the effects of UC-MSCs on lung function repair in LPS-induced ARDS. UC-MSCs and UC-MSCs-SP-B attenuated cellular infiltration. Additionally, UC-MSCs and UC-MSCs-SP-B inhibited the inflammatory response by promoting M2-like polarization, as well as reduced Th17 differentiation and promoted Treg differentiation. UC-MSCs in combination with SP-B, alleviates inflammatory reaction in ARDS by regulating macrophage polarization.


Exhaled single-breath nitric oxide measurements are reproducible, repeatable and reflect levels of nitric oxide found in the lower airways.
Measurement of exhaled nitric oxide (NO) may allow noninvasive assessment of inflammatory disease in the lung. We determined immediate and day-to-day reproducibility of single-breath NO measurements at different points on the exhaled test, and whether levels recorded reflect levels of NO in the lower airways. Using a rapid chemiluminescence analyser, 55 healthy control subjects performed three sequential tests on each of two days. NO levels were compared at the level corresponding with: 1) the time the mouth pressure fell below 4 cmH2O (MP); 2) the plateau of end-exhaled CO2 (CO2); and 3) the NO plateau (NOp). NO levels were measured directly from the lower airways of 15 lung transplant recipients and compared with NO levels from a single-breath test performed in the same cohort. For measurements performed at MP, CO2 and NOp, the mean +/- SD differences between the two closest levels performed on the same day were 0.11+/-0.18, 0.095+/-0.16 and 0.094+/-0.13 parts per billion (ppb), respectively, and between days were 0.18+/-0.76, 0.19+/-0.78 and 0.17+/-0.8 ppb, respectively. End-expiratory levels recorded at the mouth from a single-breath test and in the lower airways were highly correlated (mouth versus trachea r2=0.95, p<0.0001, mouth versus bronchus r2=0.92, p<0.0001). Single-breath exhaled nitric oxide levels are a simple, reproducible and valid measure of nitric oxide production from the lower respiratory tract.


Islands within islands: Diversification of tailless whip spiders (Amblypygi, Phrynus) in Caribbean caves.
Islands have played a key role in understanding species formation ever since Darwin's work on the Galapagos and Wallace's work in the Malay Archipelago. Like oceanic islands, habitat 'islands', such as mountaintops and caves similarly may drive diversification. Here we examine patterns of diversification in the tailless whip spider genus Phrynus Larmarck, 1809 (Amblypygida: Phrynidae) a system that shows evidence of diversification under the influence of 'islands within islands'. We estimate phylogeographic history and measure genetic diversity among representatives of three nominal Phrynus species from epigean and cave systems of Puerto Rico and nearby islands. Data from five loci (mitochondrial 12S, 16S, Cox1; nuclear H3, 28S) were used to generate phylogenetic hypotheses and to assess species monophyly and phylogeographic relationships. Genetic divergences and population limits were estimated and assessed using the Geneious barcoding plugin and the genealogical sorting index. We find that mtDNA sequence divergences within each of the three Phrynus species range between 15% and 20%. Genetic divergence is structured at three spatial scales: among islands in a manner consistent with the GAARlandia hypothesis, among bedrock formations within Puerto Rico, and among caves within these formations. Every isolated cave system contains a unique mtDNA genetic lineage of Phrynus, with divergence among cave systems far exceeding that within. In some localities epigean specimens nest among cave taxa, in others caves are monophyletic. Remarkably, clades that show up to 20% mtDNA sequence divergence show little or no variation in the nuclear markers. We interpret this pattern as resulting from extreme conservation of our nuclear markers rather than male sex-biased dispersal, based on high conservation of 28S and H3 between our individuals and other amblypygid genera that are restricted to Africa. While this study includes but a tiny fraction of Caribbean caves, our findings suggest Phrynus may be much more diverse than hitherto thought, at least in terms of mtDNA diversity, and that the arthropod fauna of caves may represent a dimension of biodiversity that is yet to be discovered in the Caribbean biodiversity hotspot.