Schistosomiasis Control: Leave No Age Group Behind.
Despite accelerating progress towards schistosomiasis control in sub-Saharan Africa, several age groups have been eclipsed by current treatment and monitoring strategies that mainly focus on school-aged children. As schistosomiasis poses a threat to people of all ages, unfortunate gaps exist in current treatment coverage and associated monitoring efforts, preventing subsequent health benefits to preschool-aged children as well as certain adolescents and adults. Expanding access to younger ages through the forthcoming pediatric praziquantel formulation and improving treatment coverage in older ages is essential. This should occur alongside formal inclusion of these groups in large-scale monitoring and evaluation activities. Current omission of these age groups from treatment and monitoring exacerbates health inequities and has long-term consequences for sustainable schistosomiasis control.


"Remotion" total wrist arthroplasty: preliminary results of a prospective international multicenter study of 215 cases.
This study reports the current results of an international multicenter study of one last generation total wrist arthroplasty (TWA) ("ReMotion," Small Bone Innovation, Morristown, PA). The two first authors (G.H. and M.B.) built a Web-based prospective database including clinical and radiological preoperative and postoperative reports of "ReMotion" TWA at regular intervals. The cases of 7 centers with more than 15 inclusions were considered for this article. A total of 215 wrists were included. In the rheumatoid arthritis (RA; 129 wrists) and nonrheumatoid arthritis (non-RA; 86 wrists) groups, there were respectively 5 and 6% complications requiring implant revision with a survival rate of 96 and 92%, respectively, at an average follow-up of 4 years. Within the whole series, only one dislocation was observed in one non-RA wrist. A total of 112 wrists (75 rheumatoid and 37 nonrheumatoid) had more than 2 years of follow-up (minimum: 2 years, maximum: 8 years). In rheumatoid and non-RA group, visual analog scale (VAS) pain score improved by 48 and 54 points, respectively, and QuickDASH score improved by 20 and 21 points, respectively, with no statistical differences. Average postoperative arc of wrist flexion-extension was 58 degrees in rheumatoid wrists (loss of 1 degree) compared with 63 degrees in non-RA wrists (loss of 9 degrees) with no statistical differences. Grip strength improved respectively by 40 and 19% in rheumatoid and non-RA groups (p = 0.033). Implant loosening was observed in 4% of the rheumatoid wrists and 3% of the non-RA wrists with no statistical differences. A Web-based TWA international registry was presented. Our results suggest that the use of the "ReMotion" TWA is feasible in the midterm both for rheumatoid and non-RA patients. This is a significant improvement compared with the previous generation TWA. The level of evidence for this study is IV.


A metal-mediated hydride shift mechanism for xylose isomerase based on the 1.6 A Streptomyces rubiginosus structures with xylitol and D-xylose.
The crystal structure of recombinant Streptomyces rubiginosus D-xylose isomerase (D-xylose keto-isomerase, EC 126.96.36.199) solved by the multiple isomorphous replacement technique has been refined to R = 0.16 at 1.64 A resolution. As observed in an earlier study at 4.0 A (Carrell et al., J. Biol. Chem. 259: 3230-3236, 1984), xylose isomerase is a tetramer composed of four identical subunits. The monomer consists of an eight-stranded parallel beta-barrel surrounded by eight helices with an extended C-terminal tail that provides extensive contacts with a neighboring monomer. The active site pocket is defined by an opening in the barrel whose entrance is lined with hydrophobic residues while the bottom of the pocket consists mainly of glutamate, aspartate, and histidine residues coordinated to two manganese ions. The structures of the enzyme in the presence of MnCl2, the inhibitor xylitol, and the substrate D-xylose in the presence and absence of MnCl2 have also been refined to R = 0.14 at 1.60 A, R = 0.15 at 1.71 A, R = 0.15 at 1.60 A, and R = 0.14 at 1.60 A, respectively. Both the ring oxygen of the cyclic alpha-D-xylose and its C1 hydroxyl are within hydrogen bonding distance of NE2 of His-54 in the structure crystallized in the presence of D-xylose. Both the inhibitor, xylitol, and the extended form of the substrate, D-xylose, bind such that the C2 and C4 OH groups interact with one of the two divalent cations found in the active site and the C1 OH with the other cation. The remainder of the OH groups hydrogen bond with neighboring amino acid side chains. A detailed mechanism for D-xylose isomerase is proposed. Upon binding of cyclic alpha-D-xylose to xylose isomerase, His-54 acts as the catalytic base in a ring opening reaction. The ring opening step is followed by binding of D-xylose, involving two divalent cations, in an extended conformation. The isomerization of D-xylose to D-xylulose involves a metal-mediated 1,2-hydride shift. The final step in the mechanism is a ring closure to produce alpha-D-xylulose. The ring closing is the reverse of the ring opening step. This mechanism accounts for the majority of xylose isomerase's biochemical properties, including (1) the lack of solvent exchange between the 2-position of D-xylose and the 1-pro-R position of D-xylulose, (2) the chemical modification of histidine and lysine, (3) the pH vs. activity profile, and (4) the requirement for two divalent cations in the mechanism.


Clinical Management of Ebola Virus Disease in the United States and Europe.
Available data on the characteristics of patients with Ebola virus disease (EVD) and clinical management of EVD in settings outside West Africa, as well as the complications observed in those patients, are limited. We reviewed available clinical, laboratory, and virologic data from all patients with laboratory-confirmed Ebola virus infection who received care in U.S. and European hospitals from August 2014 through December 2015. A total of 27 patients (median age, 36 years [range, 25 to 75]) with EVD received care; 19 patients (70%) were male, 9 of 26 patients (35%) had coexisting conditions, and 22 (81%) were health care personnel. Of the 27 patients, 24 (89%) were medically evacuated from West Africa or were exposed to and infected with Ebola virus in West Africa and had onset of illness and laboratory confirmation of Ebola virus infection in Europe or the United States, and 3 (11%) acquired EVD in the United States or Europe. At the onset of illness, the most common signs and symptoms were fatigue (20 patients [80%]) and fever or feverishness (17 patients [68%]). During the clinical course, the predominant findings included diarrhea, hypoalbuminemia, hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia; 14 patients (52%) had hypoxemia, and 9 (33%) had oliguria, of whom 5 had anuria. Aminotransferase levels peaked at a median of 9 days after the onset of illness. Nearly all the patients received intravenous fluids and electrolyte supplementation; 9 (33%) received noninvasive or invasive mechanical ventilation; 5 (19%) received continuous renal-replacement therapy; 22 (81%) received empirical antibiotics; and 23 (85%) received investigational therapies (19 [70%] received at least two experimental interventions). Ebola viral RNA levels in blood peaked at a median of 7 days after the onset of illness, and the median time from the onset of symptoms to clearance of viremia was 17.5 days. A total of 5 patients died, including 3 who had respiratory and renal failure, for a mortality of 18.5%. Among the patients with EVD who were cared for in the United States or Europe, close monitoring and aggressive supportive care that included intravenous fluid hydration, correction of electrolyte abnormalities, nutritional support, and critical care management for respiratory and renal failure were needed; 81.5% of these patients who received this care survived.


Remote neurodegeneration: multiple actors for one play.
Remote neurodegeneration significantly influences the clinical outcome in many central nervous system (CNS) pathologies, such as stroke, multiple sclerosis, and traumatic brain and spinal cord injuries. Because these processes develop days or months after injury, they are accompanied by a therapeutic window of opportunity. The complexity and clinical significance of remote damage is prompting many groups to examine the factors of remote degeneration. This research is providing insights into key unanswered questions, opening new avenues for innovative neuroprotective therapies. In this review, we evaluate data from various remote degeneration models to describe the complexity of the systems that are involved and the importance of their interactions in reducing damage and promoting recovery after brain lesions. Specifically, we recapitulate the current data on remote neuronal degeneration, focusing on molecular and cellular events, as studied in stroke and brain and spinal cord injury models. Remote damage is a multifactorial phenomenon in which many components become active in specific time frames. Days, weeks, or months after injury onset, the interplay between key effectors differentially affects neuronal survival and functional outcomes. In particular, we discuss apoptosis, inflammation, oxidative damage, and autophagy-all of which mediate remote degeneration at specific times. We also review current findings on the pharmacological manipulation of remote degeneration mechanisms in reducing damage and sustaining outcomes. These novel treatments differ from those that have been proposed to limit primary lesion site damage, representing new perspectives on neuroprotection.


Predictors of uncontrolled hypertension in the Stroke Belt.
Inadequate control of high systolic blood pressure in older adults has been largely attributable to poor control of overall hypertension (HTN). The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines emphasize the importance of controlling isolated systolic HTN in older adults. The study examined demographics, self-reported health information, and clinical measures as predictors of uncontrolled HTN among individuals taking antihypertensive medications. The Community Initiative to Eliminate Stroke, a stroke risk factor screening and prevention project, collected data in two North Carolina counties. Statistical modeling of predictors included odds ratios (ORs) and logistic regression analyses. Of the 2663 participants, 43.5% and 22.8% had uncontrolled systolic and diastolic HTN, respectively. African Americans were more likely to have uncontrolled systolic (60%) or diastolic HTN (70.9%) compared with whites (40% and 29.1%, respectively). Participants 55 years and older were more likely to have uncontrolled systolic HTN compared with younger individuals. Regression analyses showed that race (OR, 1.239; P=.00), age (OR, 1.683; P=.00), and nonadherence with medications (OR, 2.593; P=.00) were significant predictors of uncontrolled systolic HTN. Future interventions should focus on improving management of isolated systolic HTN in older adults and African Americans to increase overall control of HTN.


CD27 cooperates with the pre-T cell receptor in the regulation of murine T cell development.
CD27 is a lymphocyte-specific member of the TNF receptor family and has a TNF-related transmembrane ligand, CD70. The CD27/CD70 receptor-ligand pair cooperates with the TCR in the regulation of the peripheral T cell response. The study presented here reveals that CD27 may play a similar role in thymic pre-T cell development. We have previously cloned the cDNA encoding murine CD27, prepared specific mAbs and observed that murine CD27 is expressed on virtually all thymocytes, with the exception of a subpopulation of CD4-8- precursor T cells. It is shown here that induction of murine CD27 expression occurs at the transition from the CD4-8-25+ to the CD4-8-25- precursor T cell stage and is regulated by the pre-TCR. Therefore, we investigated whether CD27 contributes to pre-TCR-mediated thymocyte development. Pre-TCR function was mimicked by the induction of CD3 signaling in thymocytes of recombination activating gene (RAG)-deficient mice. This in vivo anti-CD3 epsilon mAb treatment induces an about fifty fold numerical expansion of CD4-8-25+ thymocytes and their differentiation to the CD4+8+25- stage. Co-injection of anti-CD27 mAb inhibited the CD3-mediated expansion and differentiation of the CD4-8-25+ precursor population. Also, injection of anti-CD27 mAb in TCR alpha-/- mutant mice led to a reduction in the absolute number of CD4+8+25- thymocytes. We present evidence that in these in vivo systems, anti-CD27 mAb inhibits CD27-ligand interaction. Therefore, we conclude that CD27 may contribute to normal murine T cell development by synergizing with the pre-TCR-mediated signal.


Comparative mRNA analysis of behavioral and genetic mouse models of aggression.
Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially regulated in a stress (behavioral) mouse model of aggression with those from a recent genetic mouse model aggression. The study used a discovery-replication design using two independent mRNA studies from mouse brain tissue. The discovery study identified strain (BALB/cJ and C57BL/6J) × stress (chronic mild stress or control) interactions. Probe sets differentially regulated in the discovery set were intersected with those uncovered in the replication study, which evaluated differences between high and low aggressive animals from three strains specifically bred to study aggression. Network analysis was conducted on overlapping genes uncovered across both studies. A significant overlap was found with the genetic mouse study sharing 1,916 probe sets with the stress model. Fifty-one probe sets were found to be strongly dysregulated across both studies mapping to 50 known genes. Network analysis revealed two plausible pathways including one centered on the UBC gene hub which encodes ubiquitin, a protein well-known for protein degradation, and another on P38 MAPK. Findings from this study support the stress model of aggression, which showed remarkable molecular overlap with a genetic model. The study uncovered a set of candidate genes including the Erg2 gene, which has previously been implicated in different psychopathologies. The gene networks uncovered points at a Redox pathway as potentially being implicated in aggressive related behaviors.


Recovery from supraspinal fatigue is slowed in old adults after fatiguing maximal isometric contractions.
This study compared the contribution of supraspinal fatigue to muscle fatigue in old and young adults. Transcranial magnetic stimulation (TMS) of motor cortex was used to assess voluntary activation during maximal voluntary contractions (MVCs) of elbow flexor muscles in 17 young adults (25.5 +/- 3.6 yr; mean +/- SD) and 7 old adults (73.0 +/- 3.3 yr). Subjects performed a fatigue task involving six sustained MVCs (22-s duration, separated by 10 s). Young adults exhibited greater reductions in maximal voluntary torque (67 +/- 15% of baseline) than the old (37 +/- 6%; P < 0.001). Increments in torque (superimposed twitch) generated by TMS during sustained MVCs increased for the young and old (P < 0.001) but were larger for the old adults at the start of the sustained contractions and during recovery (P < 0.05). Voluntary activation was less for the old adults at the start of some sustained contractions and during recovery (P = 0.02). Motor-evoked potential area increased similarly with age during the fatiguing task but was greater for the old adults than young during recovery. Silent period duration lengthened less for the old adults during the fatigue task. At the end of the fatiguing task, peak relaxation rate of muscle fibers had declined more in the young than the old adults. The greater endurance with age is largely due to a difference in mechanisms located within the muscle. However, recovery from the fatiguing exercise is impaired for old adults because of greater supraspinal fatigue than in the young.


General Aviation Pilots Over 70 Years Old.
Currently it is not unusual for general aviation pilots in the United States to continue to fly beyond the age of 70, even into their 80s and 90s. Pilots have regular examinations according to protocols which do not specify special or additional requirements for pilots over 70 yr of age. Additionally, the third class medical reforms passed by the U.S. Senate on 15 July 2016 could potentially result in even less stringent medical certification requirements for general aviation pilots. Accident rates, medical parameters, autopsy findings, and toxicological findings from the U.S. National Transportation Safety Board (NTSB) general aviation (GA) accident database were analyzed to assess potential risk factors with accident outcomes. During 2003-2012, there were 114 (113 men, 1 woman) general aviation fatal accidents involving pilots ages 70 to 92 yr. A combination of 3 or more drugs were found in 13 (13%) of deceased pilots. The most frequent drugs were first generation antihistamines and antidepressants represented the next highest proportion of possible performance-affecting medications. This study indicates that there are critical medical factors that may contribute to fatal accidents among elderly pilots. Polypharmacy use should be taken into consideration, especially during periodic health examinations and fatal aviation investigations involving elderly pilots.Vuorio A, Asmayawati S, Budowle B, Griffiths R, Strandberg T, Kuoppala J, Sajantila A. General aviation pilots over 70 years old. Aerosp Med Hum Perform. 2017; 88(2):142-145.


Effect of pH on cardiorespiratory and metabolic responses to exercise.
Five male subjects performed exercise at 33, 66, and 95% of their maximum power output on three occasions in random order. Each study was preceded by a 3-h period in which capsules were taken by mouth, containing either CaCO3 (control, NH4Cl (acidosis), or NaHCO3 (alkalosis) in a dose of 0.3 g/kg body wt; preexercise blood pH was 7.38 +/- 0.015, 7.21 +/- 0.033, and 7.43 +/- 0.029, respectively. Exercise was continuous and maintained for 20 min at the two lower power outputs and for as long as possible at the highest. Compared with control (270 +/- 13 s), endurance time at the highest power output was reduced in acidosis (160 +/- 22 s) and increased in alkalosis (438 +/- 120 s). No differences were observed for central cardiovascular changes in exercise (cardiac output, frequency, or stroke volume). The respiratory changes expected from changes in blood pH were observed, with a higher alveolar ventilation in acidosis. At all power outputs arterialized venous lactate was lowest in acidosis and highest in alkalosis. Plasma glycerol and free fatty acids were lowest in acidosis. Changes in blood [HCO3-] and pH were shown to have major effects on metabolism in exercise which presumably were responsible for impaired endurance.


Monoclonal antibodies against surface antigens of Bacteroides gingivalis.
Monoclonal antibodies against the various surface antigens of Bacteroides gingivalis were obtained by the fusion of murine myeloma cells (SP2/0-Ag14) with spleen cells of BALB/c mice immunized with the whole cells. Two monoclonal antibodies reacted with lipopolysaccharide, and the other two reacted strongly with capsule antigen. One showed reactivity with the hemagglutinin of the cells. The five monoclonal antibodies reacted with sonicated antigen from all B. gingivalis strains tested. No cross-reactivity of the monoclonal antibodies with antigens from nine species of other black-pigmented Bacteroids strains was observed. An immunoblotting test involving the use of these monoclonal antibodies indicated that the epitope of B. gingivalis lipopolysaccharide was polysaccharide with a high molecular weight of 40,000 to 60,000. The immunoblotting test also demonstrated that the epitopes of capsule antigen and of hemagglutinin were 27,000- and 40,000-molecular-weight proteins, respectively.


Molecular Links between Alcohol and Tobacco Induced DNA Damage, Gene Polymorphisms and Patho-physiological Consequences: A Systematic Review of Hepatic Carcinogenesis.
Chronic alcohol and tobacco abuse plays a crucial role in the development of different liver associated disorders. Intake promotes the generation of reactive oxygen species within hepatic cells exposing their DNA to continuous oxidative stress which finally leads to DNA damage. However in response to such damage an entangled protective repair machinery comprising different repair proteins like ATM, ATR, H2AX, MRN complex becomes activated. Under abnormal conditions the excessive reactive oxygen species generation results in genetic predisposition of various genes (as ADH, ALDH, CYP2E1, GSTT1, GSTP1 and GSTM1) involved in xenobiotic metabolic pathways, associated with susceptibility to different liver related diseases such as fibrosis, cirrhosis and hepatocellular carcinoma. There is increasing evidence that the inflammatory process is inherently associated with many different cancer types, including hepatocellular carcinomas. The generated reactive oxygen species can also activate or repress epigenetic elements such as chromatin remodeling, non-coding RNAs (micro-RNAs), DNA (de) methylation and histone modification that affect gene expression, hence leading to various disorders. The present review provides comprehensive knowledge of different molecular mechanisms involved in gene polymorphism and their possible association with alcohol and tobacco consumption. The article also showcases the necessity of identifying novel diagnostic biomarkers for early cancer risk assessment among alcohol and tobacco users.


Full-Length Transcriptome Analysis of the Genes Involved in Tocopherol Biosynthesis in Torreya grandis.
The seeds of Torreya grandis (Cephalotaxaceae) are rich in tocopherols, which are essential components of the human diet as a result of their function in scavenging reactive oxygen and free radicals. Different T. grandis cultivars (10 cultivars selected in this study were researched, and their information is shown in Table S1 of the Supporting Information) vary enormously in their tocopherol contents (0.28-11.98 mg/100 g). However, little is known about the molecular basis and regulatory mechanisms of tocopherol biosynthesis in T. grandis kernels. Here, we applied single-molecule real-time (SMRT) sequencing to T. grandis (X08 cultivar) for the first time and obtained a total of 97 211 full-length transcripts. We proposed the biosynthetic pathway of tocopherol and identified eight full-length transcripts encoding enzymes potentially involved in tocopherol biosynthesis in T. grandis. The results of the correlation analysis between the tocopherol content and gene expression level in the 10 selected cultivars and different kernel developmental stages of the X08 cultivar suggested that homogentisate phytyltransferase coding gene ( TgVTE2b) and γ-tocopherol methyltransferase coding gene ( TgVTE4) may be key players in tocopherol accumulation in the kernels of T. grandis. Subcellular localization assays showed that both TgVTE2b and TgVTE4 were localized to the chloroplast. We also identified candidate regulatory genes similar to WRI1 and DGAT1 in Arabidopsis that may be involved in the regulation of tocopherol biosynthesis. Our findings provide valuable genetic information for T. grandis using full-length transcriptomic analysis, elucidating the candidate genes and key regulatory genes involved in tocopherol biosynthesis. This information will be critical for further molecular-assisted screening and breeding of T. grandis genotypes with high tocopherol contents.


Convergent and discriminant validity of the ImPACT with traditional neuropsychological measures.
Neuropsychological assessment of cognitive sequelae secondary to sports concussion is limited by lengthy administration times and lack of readily available neuropsychologists. Brief computerized test batteries are now under development to address this, but the validity of these measures is not yet established. The validity of one such computerized test battery, the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), was administered to 93 healthy NCAA Division I athletes, aged 18-24, along with a battery of traditional, well-described neuropsychological tests. Convergent and discriminant validity between the ImPACT and traditional measures was investigated using multitrait-multimethod matrix (MTMM) analysis. As an example, the ImPACT Visual Motor Speed composite demonstrated reasonably good convergent validity secondary to moderate correlations with traditional measures of processing speed, but it demonstrated relatively poor discriminant validity as it significantly correlated with the Reaction Time composite score. MTMM results were variable across ImPACT composites and data for each are presented. The ImPACT composite's validity was further investigated using exploratory factor analysis (EFA). Six principal components were termed processing speed, visual memory, verbal memory, attention & working memory, and verbal fluency, based upon traditional test loadings, and a sixth loaded only on the ImPACT Reaction Time composite. EFA indicated content validity of moderate strength for the Visual Motor Speed and Visual Memory composites, but revealed problems with specificity for the other composites. Based upon the present findings, validity problems render the interpretability of the ImPACT composites somewhat questionable, and more research is necessary prior to using the ImPACT for assessment of clinical populations.


Study progress, recreational activities, and loneliness in young adult carers: a national student survey.
Young adults (18-25 years) with informal care responsibilities have received limited attention in the research literature, and little is known on how caring responsibilities are related to functioning across different life domains. In the present study we examine associations between care responsibilities and study progress, recreational life, and loneliness in young adults in higher education. A national survey was conducted among Norwegian students in higher education (the SHoT2018-study). The response rate was 30.8%. The current sample is a subsample of the respondents, including young adults 18 to 25 years old, comprising 40.205 participants (70.2% women, mean age 22.0 years, SD = 1.7). Participants reported whether they had regular care responsibility for someone with physical or mental illness, disabilities, or substance misuse. They also answered questions on study progress, number of hours studying, physical exercise, involvement in organized volunteer student activities, number of close friends, and feelings of loneliness. Data were analyzed by Chi-square tests and logistic regression analyses, adjusting for age, sex, and chronic illness. Compared to students without care responsibility, young adult carers (n = 2228, 5.5% of study sample) were more likely to report delayed study progress (OR 1.20, p < .001), higher average number of failed exams (e.g., having failed three times or more, OR 1.31, p = .002), more feelings of loneliness (OR 1.26, p < .001), and slightly fewer friends. Those with limited care responsibility (≤ 1 h daily) were more likely to participate in organized volunteer student activities, whereas students with 2 h or more of caring per day were less likely to participate in leisure student activities. Both study progress and feelings of loneliness were related to care responsibility in a response-dose pattern, with worse outcomes for those with 2 h or more of daily caring responsibility. All comparisons were adjusted for age, sex, and chronic illness. Study progress, recreational activities, and loneliness among young adults are associated with informal caring responsibilities. Professionals in the educational system as well as health personnel should be sensitized to the needs of young adult carers and necessary support made available.


Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial.
Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.


Translating person-centred care: a case study of preceptor nurses and their teaching practices in acute care areas.
The research aims to explore how preceptors interpret, operationalize, document and teach person-centred care as they guide students within an acute surgical environment. Person-centred care is a term that is widely used in the nursing literature; however, its interpretation in nursing practice remains virtually unexplored. This is of great significance to nurses in general but to Irish nurses in particular on whom this study is focused. As preceptor nurses have been identified as key people in the education of clinical students, it was considered important to explore how clinical preceptors promote person-centred care to current undergraduate nursing students. Using a case study design and a qualitative approach, six preceptors were chosen to participate in this study. Data were collected by means of participant observation, review of nursing care records and semi-structured interviews. Data were analysed in two stages. The first stage involved the identification of themes. In the second stage data were analysed using a number of propositions to examine and explain what was gleaned from the data in the context of what was originally identified in the literature. Findings highlighted that preceptors had a limited conception of person-centred care. Measures of care reflected the medical model of nursing. Beyond that, preceptors expressed care in terms of good manners or respectful etiquette. Preceptors also had limited appreciation of what learning entails and were sceptical about classroom theory other than what they considered essential for safe practice. This study highlights that preceptors need both internal and external support to implement the changes advocated by the Commission in Nursing in 1998, the Nursing Education Forum in 2000, the Department of Health and Children in 2001 and An Bord Altranais in 2003. Person-centred care is a relatively new concept in nursing and recommended for practice. Preceptors need facilitation with its implementation. In an effort to promote changes in the delivery of health care, it is suggested that university-based lecturers empower students to practice evidence-based nursing as students and subsequently as qualified nurses.


Linked selection and recombination rate variation drive the evolution of the genomic landscape of differentiation across the speciation continuum of Ficedula flycatchers.
Speciation is a continuous process during which genetic changes gradually accumulate in the genomes of diverging species. Recent studies have documented highly heterogeneous differentiation landscapes, with distinct regions of elevated differentiation ("differentiation islands") widespread across genomes. However, it remains unclear which processes drive the evolution of differentiation islands; how the differentiation landscape evolves as speciation advances; and ultimately, how differentiation islands are related to speciation. Here, we addressed these questions based on population genetic analyses of 200 resequenced genomes from 10 populations of four Ficedula flycatcher sister species. We show that a heterogeneous differentiation landscape starts emerging among populations within species, and differentiation islands evolve recurrently in the very same genomic regions among independent lineages. Contrary to expectations from models that interpret differentiation islands as genomic regions involved in reproductive isolation that are shielded from gene flow, patterns of sequence divergence (d(xy) and relative node depth) do not support a major role of gene flow in the evolution of the differentiation landscape in these species. Instead, as predicted by models of linked selection, genome-wide variation in diversity and differentiation can be explained by variation in recombination rate and the density of targets for selection. We thus conclude that the heterogeneous landscape of differentiation in Ficedula flycatchers evolves mainly as the result of background selection and selective sweeps in genomic regions of low recombination. Our results emphasize the necessity of incorporating linked selection as a null model to identify genome regions involved in adaptation and speciation.


Management of children with autism spectrum disorders.
Pediatricians have an important role not only in early recognition and evaluation of autism spectrum disorders but also in chronic management of these disorders. The primary goals of treatment are to maximize the child's ultimate functional independence and quality of life by minimizing the core autism spectrum disorder features, facilitating development and learning, promoting socialization, reducing maladaptive behaviors, and educating and supporting families. To assist pediatricians in educating families and guiding them toward empirically supported interventions for their children, this report reviews the educational strategies and associated therapies that are the primary treatments for children with autism spectrum disorders. Optimization of health care is likely to have a positive effect on habilitative progress, functional outcome, and quality of life; therefore, important issues, such as management of associated medical problems, pharmacologic and nonpharmacologic intervention for challenging behaviors or coexisting mental health conditions, and use of complementary and alternative medical treatments, are also addressed.


Conserving the abundance of nonthreatened species.
Human modification of the environment is driving declines in population size and distributional extent of much of the world's biota. These declines extend to many of the most abundant and widespread species, for which proportionally small declines can result in the loss of vast numbers of individuals, biomass, and interactions. These losses could have major localized effects on ecological and cultural processes and services without elevating a species' global extinction risk. Although most conservation effort is directed at species threatened with extinction in the very near term, the value of retaining abundance regardless of global extinction risk is justifiable based on many biodiversity or ecosystem service metrics, including cultural services, at scales from local to global. The challenges of identifying conservation priorities for widespread and abundant species include quantifying the effects of species' abundance on services and understanding how these effects are realized as populations decline. Negative effects of population declines may be disconnected from the threat processes driving declines because of species movements and environment flows (e.g., hydrology). Conservation prioritization for these species shares greater similarity with invasive species risk assessments than extinction risk assessments because of the importance of local context and per capita effects of abundance on other species. Because conservation priorities usually focus on preventing the extinction of threatened species, the rationale and objectives for incorporating declines of nonthreatened species must be clearly articulated, going beyond extinction risk to encompass the range of likely harmful effects (e.g., secondary extinctions, loss of ecosystem services) if declines persist or are not reversed. Research should focus on characterizing the effects of local declines in species that are not threatened globally across a range of ecosystem services and quantifying the spatial distribution of these effects through the distribution of abundance. The case for conserving abundance in nonthreatened species can be made most powerfully when the costs of losing this abundance are better understood.


Rejuvenation of the aging neck.
Patients seeking rejuvenation of the face are influenced by youthful faces commonly seen in the media and entertainment world. Although standards of beauty evolve over time, classical facial features such as symmetry, high cheek bones, and an angular jaw-neck line remain as ideals. As the human face ages, a relatively consistent series of anatomic events occurs. Although the rate of change varies from person to person, the process of facial aging is predictable. This process involves a loss of tone of the elastic fibers of the face, resulting in sagging of the skin and soft tissues of the face and neck. Additionally, aging of the lower face often includes ptosis of the soft tissues of the chin and banding or cording of the muscles of the anterior neck. Aesthetic rejuvenation of the face and neck involves repositioning of poorly supported soft tissues. To accurately treat facial aging, an individualized diagnosis and anatomically based problem list is compiled. This should include analysis of the skin quality, bone structure, amount and distribution of subcutaneous fat, and relationship of the superficial muscles to the overlying skin. After a detailed diagnosis is made, a surgical treatment plan is outlined to improve the face and restore a youthful appearance. This article describes the applied anatomy associated with facial aging and explains the author's specific techniques to obtain a natural postoperative appearance. Avoidance of common problems associated with aging face surgery is emphasized.


Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis.
Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen-positive slides were analyzed by PCR for VZV DNA. VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen-positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen-positive TAs, in 6/10 (60%) VZV antigen-positive skeletal muscles, and in one VZV antigen-positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.


Nursing Staff Factors Contributing to Seclusion in Acute Mental Health Care - An Explorative Cohort Study.
Seclusion is a controversial intervention. Efficacy with regard to aggressive behaviour has not been demonstrated, and seclusion is only justified for preventing safety hazards. Previous studies indicate that nursing staff factors may be predictors for seclusion, although methodological issues may have led to equivocal results. To perform a prospective cohort study to determine whether nursing staff characteristics are associated with seclusion of adult inpatients admitted to a closed psychiatric ward. We studied the association between nurses' demographics and incidence of seclusion during every shift. Data were collected during five months in 2013. Multiple logistic regression was used for analysis. In univariable analysis, we found a non-significant association between seclusion and female gender, odds ratio (OR) = 5.27 (0.98-28.49) and a significant association between seclusion and nurses' large physical stature, OR = 0.21 (0.06-0.72). We found that physical stature is the most substantial factor, although not significant: ORadjusted = 0.27 (0.07-1.04). Nurses' gender may be a predictor for seclusion, but it seems to be mediated by the effect of physical stature. We used a rigorous, census-based, prospective design to collect data on a highly detailed level and found a large effect of physical stature of nurses on seclusion. We found nurses' physical stature to be the most substantial predictor for seclusion. These and other factors need to be explored in further research with larger sample size.


Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity.
The anti-human immunodeficiency virus (-HIV) nucleoside analogs azidothymidine (AZT), dideoxycytidine (ddC), dideoxyinosine (ddl), dideoxydidehydrothymidine (D4T), and dideoxydidehydrocytidine (D4C) and the anticancer drug cytosine arabinoside (AraC) were compared for their effects on the mitochondrial DNA (mtDNA) content in a human lymphoblastoid cell line, CEM. The potency of these compounds in reducing mtDNA content was in the order of ddC greater than D4C greater than D4T greater than AZT greater than ddl. AraC did not have a significant effect on mtDNA content. All of the compounds tested, except AraC, stimulated lactic acid production at concentrations that inhibited mtDNA synthesis. The action of ddC and ddl occurred at concentrations that did not affect cell growth significantly in 4 days but retarded cell growth by day 6. D4T and D4C decreased mtDNA content by 50% at doses lower than those that inhibited cell growth by 50% in 4 days (ID50). However, AZT required a dose higher than the ID50 to exert similar effects on mtDNA content. The decrease of mtDNA content caused by ddC also occurred in nerve growth factor-treated PC12 cells, which differentiate to neuron-like cells upon treatment with nerve growth factor. The preferential inhibition of mtDNA, compared with cell growth, by some of these anti-HIV nucleoside analogs correlates well with their ability to cause drug-limiting delayed toxicity, such as peripheral neuropathy, in patients. These data suggest that the selective mitochondrial toxicity could be responsible for the delayed toxicity caused by these anti-HIV analogs.


Inhibition of human pulpal gelatinases (MMP-2 and MMP-9) by zinc oxide cements.
The interaction between metal ions and the oral environment is a major subject matter in dental research. Matrix metalloproteinases (MMPs) have been implicated in several pathological and physiological processes such as, periodontal tissue destruction, root caries, dentin calcification and pulpal inflammation. The aim of this work was to test the effect of zinc released from zinc oxide-eugenol (ZOE) cements, on the activity of the major pulpal gelatinolytic MMPs. Pulpal explants were cultured overnight in Dulbecco's Modified Eagle Medium and the activity of secreted enzymes was analysed by gelatin zymography in buffer conditioned with diverse ZOE cements. Phenanthroline, a zinc chelator, was used to revert the inhibition of MMPs caused by zinc. The major gelatinolytic proteinases present in the conditioned media were characterized as MMP-2 and MMP-9 by immunoprecipitation. All ZOE cements inhibited MMPs activity, whereas phenanthroline could partially revert the inhibition caused by plain ZOE and Intermediate Restorative Material (IRM).


Role of intestinal microbiota and metabolites on gut homeostasis and human diseases.
A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health. This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA). In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction. A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.


Elevation of Vernier thresholds during image motion depends on target configuration.
Previously we showed that thresholds for abutting Vernier targets are unaffected by motion, as long as the targets are processed by the same spatial-frequency channel at each velocity and remain equally detectable [Invest. Ophthalmol. Visual Sci. (Suppl.) 37, S734 (1996)]. In this study we compared Vernier thresholds for stationary and moving abutting and nonabutting targets (gaps = 0, 18, and 36 arc min) for velocities of 0-16 deg/s. The Vernier targets were spatially filtered vertical lines (peak spatial frequency = 3.3 or 6.6 c/deg), presented at contrast levels of two, four, and eight times the detection threshold of each component line. Unlike the results for abutting targets, Vernier thresholds for nonabutting targets worsen with velocity as well as gap size. The results for abutting Vernier targets are consistent with the hypothesis that thresholds are mediated by oriented spatial filters, whose responses increase proportionally with the stimulus contrast. The velocity-dependent thresholds found for nonabutting Vernier targets can be explained on the basis of local-sign comparisons if the comparison process is assumed to include a small amount of temporal noise.


First-year results of routine alpha-fetoprotein testing on prenatal patients in a family practice.
For one year all pregnant women presenting to a family practice clinic for prenatal care were routinely tested for maternal serum alpha-fetoprotein levels (MSAFP). Unexpectedly, 14 (15.7 percent) of 89 tested patients had low MSAFP levels. All 14 pregnant women underwent appropriate diagnostic workups because of the low MSAFP level and were subsequently followed until delivery. Although the literature reports that low MSAFP levels are associated with chromosomal anomalies, none of the 14 women were delivered of infants with anomalies. Reasons for the unexpectedly high rate of abnormal MSAFP levels were investigated. Investigation revealed that normal values for MSAFP tests had been derived from testing performed on high-risk pregnant women who had an inherently higher rate of abnormal pregnancies and, apparently, a different range for normal MSAFP levels than a population of unselected family practice patients. The results of this study demonstrate that it may not be appropriate to apply diagnostic algorithms based on data derived in high-risk subspecialty clinics to unselected patients in a family practice.


SLC2A9 is a high-capacity urate transporter in humans.
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man. We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 microM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 microM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82). This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.


Comparison of host immune responses to homologous and heterologous type II porcine reproductive and respiratory syndrome virus (PRRSV) challenge in vaccinated and unvaccinated pigs.
Porcine reproductive and respiratory syndrome (PRRS) is a high-consequence animal disease with current vaccines providing limited protection from infection due to the high degree of genetic variation of field PRRS virus. Therefore, understanding host immune responses elicited by different PRRSV strains will facilitate the development of more effective vaccines. Using IngelVac modified live PRRSV vaccine (MLV), its parental strain VR-2332, and the heterologous KS-06-72109 strain (a Kansas isolate of PRRSV), we compared immune responses induced by vaccination and/or PRRSV infection. Our results showed that MLV can provide complete protection from homologous virus (VR-2332) and partial protection from heterologous (KS-06) challenge. The protection was associated with the levels of PRRSV neutralizing antibodies at the time of challenge, with vaccinated pigs having higher titers to VR-2332 compared to KS-06 strain. Challenge strain did not alter the cytokine expression profiles in the serum of vaccinated pigs or subpopulations of T cells. However, higher frequencies of IFN-γ-secreting PBMCs were generated from pigs challenged with heterologous PRRSV in a recall response when PBMCs were re-stimulated with PRRSV. Thus, this study indicates that serum neutralizing antibody titers are associated with PRRSV vaccination-induced protection against homologous and heterologous challenge.


Fabrication and characterization of large numerical aperture, high-resolution optical fiber bundles based on high-contrast pairs of soft glasses for fluorescence imaging.
Fabrication and characterization of flexible optical fiber bundles (FBs) with in-house synthesized high-index and low-index thermally matched glasses are presented. The FBs composed of around 15000 single-core fibers with pixel sizes between 1.1 and 10 μm are fabricated using the stack-and-draw technique from sets of thermally matched zirconium-silicate ZR3, borosilicate SK222, sodium-silicate K209, and F2 glasses. With high refractive index contrast pair of glasses ZR3/SK222 and K209/F2, FBs with numerical apertures (NAs) of 0.53 and 0.59 are obtained, respectively. Among the studied glass materials, ZR3, SK222, and K209 are in-house synthesized, while F2 is commercially acquired. Seven different FBs with varying pixel sizes and bundle diameters are characterized. Brightfield imaging of a micro-ruler and a Convallaria majalis sample and fluorescence imaging of a dye-stained paper tissue and a cirrhotic mice liver tissue are demonstrated using these FBs, demonstrating their good potential for microendoscopic imaging. Brightfield and fluorescence imaging performance of the studied FBs are compared. For both sets of glass compositions, good imaging performance is observed for FBs, with core diameter and core-to-core distance values larger than 1.6 μm and 2.3 μm, respectively. FBs fabricated with K209/F2 glass pairs revealed better performance in fluorescence imaging due to their higher NA of 0.59.


The impact of early stroke on identity: A discourse analytic study.
This article examines the ways in which sufferers talk about early stroke and the effects this chronic condition has on identity. Traditional research into chronic illness has largely used medical, psychiatric or cognitive models. We adopt a social constructionist perspective and use a discourse analytic methodology to study data collected via focus group interaction. Analysis of the data collected shows that participants displayed sensitivity about having acquired a potentially 'damaged' sense of self by mitigating negative features of their experiences. Participants also attended to the issue of whether their accounts were persuasive or believable. Some carers were present in these discussions. As a consequence, participants who had suffered a stroke displayed sensitivity to the way that carers might respond to mitigation of the negative aspects of stroke.


SmedGD: the Schmidtea mediterranea genome database.
The planarian Schmidtea mediterranea is rapidly emerging as a model organism for the study of regeneration, tissue homeostasis and stem cell biology. The recent sequencing, assembly and annotation of its genome are expected to further buoy the biomedical importance of this organism. In order to make the extensive data associated with the genome sequence accessible to the biomedical and planarian communities, we have created the Schmidtea mediterranea Genome Database (SmedGD). SmedGD integrates in a single web-accessible portal all available data associated with the planarian genome, including predicted and annotated genes, ESTs, protein homologies, gene expression patterns and RNAi phenotypes. Moreover, SmedGD was designed using tools provided by the Generic Model Organism Database (GMOD) project, thus making its data structure compatible with other model organism databases. Because of the unique phylogenetic position of planarians, SmedGD (http://smedgd.neuro.utah.edu) will prove useful not only to the planarian research community, but also to those engaged in developmental and evolutionary biology, comparative genomics, stem cell research and regeneration.


Coalescent Simulation with msprime.
Coalescent simulation is a fundamental tool in modern population genetics. The msprime library provides unprecedented scalability in terms of both the simulations that can be performed and the efficiency with which the results can be processed. We show how coalescent models for population structure and demography can be constructed using a simple Python API, as well as how we can process the results of such simulations to efficiently calculate statistics of interest. We illustrate msprime's flexibility by implementing a simple (but functional) approximate Bayesian computation inference method in just a few tens of lines of code.


[Formaldehyde in electronic cigarettes and in heat-not-burn products: let's make the point].
The spread of electronic cigarettes (e-cigs) and of the so-called heat-not-burn (HnB), also known as heated tobacco products, presented as a less harmful alternative to traditional cigarettes, required further in-depth studies to demonstrate the real benefits or possible risks linked to this type of habit among smokers and possible new smokers. There are numerous harmful substances produced by these devices, such as metals, organic compounds, and aldehydes. The presence of formaldehyde is particularly worrying: its indoor concentration is 2.7, 1.2, and 40 µg/m3 for HnB, e-cigs, and traditional cigarettes, respectively. The evidence of this substance, which numerous epidemiological studies have already shown to be harmful to health (in particular, the International Agency for Research on Cancer classified it as a group 1 carcinogen), would lead to the need to modify the legislation with more restrictive rules on the use of these devices in public environment and in particular in the presence of more susceptible subjects, such as minors and pregnant women.


Protection of dried probiotic bacteria from bile using bile adsorbent resins.
Enteric coated oral tablets or capsules can deliver dried live cells directly into the intestine. Previously, we found that a live attenuated bacterial vaccine acquired sensitivity to intestinal bile when dried, raising the possibility that although gastric acid can be bypassed, significant loss of viability might occur on release from an enteric coated oral formulations. Here we demonstrate that some food-grade lyophilised preparations of Lactobacillus casei and Lactobacillus salivarius also show temporary bile sensitivity that can be rapidly reversed by rehydration. To protect dried bacterial cells from temporary bile sensitivity, we propose using bile acid adsorbing resins, such as cholestyramine, which are bile acid binding agents, historically used to lower cholesterol levels. Vcaps™ HPMC capsules alone provided up to 830-fold protection from bile. The inclusion of 50% w/w cholestyramine in Vcaps™ HPMC capsules resulted in release of up to 1700-fold more live Lactobacillus casei into simulated intestinal fluid containing 1% bile, when compared to dried cells added directly to bile. We conclude that delivery of dried live probiotic organisms to the intestine may be improved by providing protection from bile by addition of bile adsorbing resins and the use of HPMC capsules.


Phosphoproteomic analysis of mammalian infective Trypanosoma brucei subjected to heat shock suggests atypical mechanisms for thermotolerance.
The symptoms of African sleeping sickness, caused by the parasite Trypanosoma brucei, can include periods of fever as high as 41 °C which triggers a heat shock response in the parasite. To capture events involved in sensing and responding to heat shock in the mammalian infective form we have conducted a SILAC-based quantitative proteomic and phosphoproteomic analysis of T. brucei cells treated at 41 °C for 1h. Our analysis identified 193 heat shock responsive phosphorylation sites with an average of 5-fold change in abundance, but only 20 heat shock responsive proteins with average of 1.5-fold change. These data indicate that protein abundance does not rapidly respond (≤1 h) to heat shock, and that the changes observed in phosphorylation site abundance are larger and more widespread. The heat shock responsive phosphorylation sites showed enrichment of RNA binding proteins with putative roles in heat shock response included P-body / stress granules and the eukaryotic translation initiation 4F complex. The ZC3H11-MKT1 complex, which stabilises mRNAs of thermotolerance proteins, appears to represent a key signal integration node in the heat shock response. SIGNIFICANCE: We report the first quantitative study of changes in protein and phosphorylation site abundance in response to heat shock in the clinically relevant form of the human parasite Trypanosoma brucei. The identification of heat shock responsive phosphorylation sites on proteins with putative roles in thermotolerance including the ZC3H11-MKT1 complex provides evidence of the role dynamic phosphorylation of RNA binding proteins in co-ordinating heat shock. Temperature changes in the host are a major physiological challenge to parasites and factors conferring tolerance to heat shock constitute overlooked virulence factors. A better understanding of these virulence factors will pave the way for the development of novel drug therapies which selectively target T. brucei.


Irreversible Shear-Activated Gelation of a Liquid Crystalline Polyelectrolyte.
We report irreversible, shear-activated gelation in liquid crystalline solutions of a rigid polyelectrolyte that forms rodlike assemblies (rods) in salt-free solution. At rest, the liquid crystalline solutions are kinetically stable against gelation and exhibit low viscosities. Under steady shear at, or above, a critical shear rate, a physically cross-linked, nematic gel network forms due to linear growth and branching of the rods. Above a critical shear rate, the time scale of gelation can be tuned from hours to nearly instantaneously by varying the shear rate and solution concentration. The shear-activated gels are distinct in their structure and rheological properties from thermoreversible gels. At a fixed concentration, the induction time prior to gelation decreases exponentially with the shear rate. This result indicates that shear-activated thermalization of the electrostatically stabilized rods overcomes the energy barrier for rod-rod contact, enabling rod fusion and subsequent irreversible network formation.


Identifying persistent negative symptoms in first episode psychosis.
Although persistent negative symptoms (PNS) are known to contribute significantly to poor functional outcome, they remain poorly understood. We examined the heuristic value of various PNS definitions and their respective prevalence in patients with first episode psychosis (FEP). We also contrasted those definitions to the Proxy for the Deficit Syndrome (PDS) to identify deficit syndrome (DS) in the same FEP cohort. One hundred and fifty-eight FEP patients were separated into PNS and non-PNS groups based on ratings from the Scale for Assessment of Negative Symptoms (SANS). PNS was defined in the following ways: 1) having a score of 3 or greater on at least 1 global subscale of the SANS (PNS_1); 2) having a score of 3 or more on at least 2 global subscales of the SANS (PNS_2); and 3) having a score of 3 or more on a combination of specific SANS subscales and items (PNS_H). For all three definitions, symptoms had to be present for a minimum of six consecutive months. Negative symptoms were measured upon entry to the program and subsequently at 1,2,3,6,9 and 12 months. Functional outcome was quantified at first assessment and month 12. PNS prevalence: PNS_1 (27%); PNS_2 (13.2%); PNS_H (13.2%). The prevalence of DS was found to be 3% when applying the PDS. Regardless of the definition being applied, when compared to non-PNS, patients in the PNS group were shown to have significantly worse functioning at month 12. All three PNS definitions showed similar associations with functional outcome at month 12. Persistent negative symptoms are present in about 27% of FEP patients with both affective and non-affective psychosis. Although there has previously been doubt as to whether PNS represents a separate subdomain of negative symptoms, the current study suggests that PNS may be more applicable to FEP when compared to DS. Although all three PNS definitions were comparable in predicting functional outcome, we suggest that the PNS definition employed is dependent on the clinical or research objective at hand.


Deep learning from phylogenies to uncover the epidemiological dynamics of outbreaks.
Widely applicable, accurate and fast inference methods in phylodynamics are needed to fully profit from the richness of genetic data in uncovering the dynamics of epidemics. Standard methods, including maximum-likelihood and Bayesian approaches, generally rely on complex mathematical formulae and approximations, and do not scale with dataset size. We develop a likelihood-free, simulation-based approach, which combines deep learning with (1) a large set of summary statistics measured on phylogenies or (2) a complete and compact representation of trees, which avoids potential limitations of summary statistics and applies to any phylodynamics model. Our method enables both model selection and estimation of epidemiological parameters from very large phylogenies. We demonstrate its speed and accuracy on simulated data, where it performs better than the state-of-the-art methods. To illustrate its applicability, we assess the dynamics induced by superspreading individuals in an HIV dataset of men-having-sex-with-men in Zurich. Our tool PhyloDeep is available on github.com/evolbioinfo/phylodeep .


Transcriptomic analysis of Rhizobium leguminosarum bacteroids in determinate and indeterminate nodules.
Two common classes of nitrogen-fixing legume root nodules are those that have determinate or indeterminate meristems, as in Phaseolus bean and pea, respectively. In indeterminate nodules, rhizobia terminally differentiate into bacteroids with endoreduplicated genomes, whereas bacteroids from determinate nodules are less differentiated and can regrow. We used RNA sequencing to compare bacteroid gene expression in determinate and indeterminate nodules using two Rhizobium leguminosarum strains whose genomes differ due to replacement of the symbiosis (Sym) plasmid pRP2 (strain Rlp4292) with pRL1 (strain RlvA34), thereby switching symbiosis hosts from Phaseolus bean (determinate nodules) to pea (indeterminate nodules). Both bacteroid types have gene expression patterns typical of a stringent response, a stressful environment and catabolism of dicarboxylates, formate, amino acids and quaternary amines. Gene expression patterns were indicative that bean bacteroids were more limited for phosphate, sulphate and iron than pea bacteroids. Bean bacteroids had higher levels of expression of genes whose products are predicted to be associated with metabolite detoxification or export. Pea bacteroids had increased expression of genes associated with DNA replication, membrane synthesis and the TCA (tricarboxylic acid) cycle. Analysis of bacteroid-specific transporter genes was indicative of distinct differences in sugars and other compounds in the two nodule environments. Cell division genes were down-regulated in pea but not bean bacteroids, while DNA synthesis was increased in pea bacteroids. This is consistent with endoreduplication of pea bacteroids and their failure to regrow once nodules senesce.


Coincident tick infestations in the nostrils of wild chimpanzees and a human in Uganda.
Ticks in the nostrils of humans visiting equatorial African forests have been reported sporadically for decades, but their taxonomy and natural history have remained obscure. We report human infestation with a nostril tick in Kibale National Park, Uganda, coincident with infestation of chimpanzees in the same location with nostril ticks, as shown by high-resolution digital photography. The human-derived nostril tick was identified morphologically and genetically as a nymph of the genus Amblyomma, but the mitochondrial 12S ribosomal RNA or the nuclear intergenic transcribed spacer 2 DNA sequences of the specimen were not represented in GenBank. These ticks may represent a previously uncharacterized species that is adapted to infesting chimpanzee nostrils as a defense against grooming. Ticks that feed upon apes and humans may facilitate cross-species transmission of pathogens, and the risk of exposure is likely elevated for persons who frequent ape habitats.


Quality of physiotherapy services for injured workers compensated by workers' compensation in Quebec: a focus group study of physiotherapy professionals.
Musculoskeletal disorders are among the leading causes of work-related physical disability in the province of Quebec in Canada. The authors conducted a focus group study with physiotherapists and physical rehabilitation therapists working with patients whose treatments are compensated by the Quebec Workers' Compensation Board with the goal of exploring quality of care and ethical issues. Three main themes were identified: (1) systemic factors, (2) complexity in treatment decisions and (3) inequality of care. Although physiotherapy professionals strive to give these patients the best possible care, patients might not always be provided with optimal or equal treatment. When compared with other patients, there appear to be differences with respect to access to care and types of services offered to injured workers, raising equity concerns. Factors that shape and constrain quality of physiotherapy services for injured workers need to be addressed to improve care for these patients.


A Bayesian method and its variational approximation for prediction of genomic breeding values in multiple traits.
Genomic selection is an effective tool for animal and plant breeding, allowing effective individual selection without phenotypic records through the prediction of genomic breeding value (GBV). To date, genomic selection has focused on a single trait. However, actual breeding often targets multiple correlated traits, and, therefore, joint analysis taking into consideration the correlation between traits, which might result in more accurate GBV prediction than analyzing each trait separately, is suitable for multi-trait genomic selection. This would require an extension of the prediction model for single-trait GBV to multi-trait case. As the computational burden of multi-trait analysis is even higher than that of single-trait analysis, an effective computational method for constructing a multi-trait prediction model is also needed. We described a Bayesian regression model incorporating variable selection for jointly predicting GBVs of multiple traits and devised both an MCMC iteration and variational approximation for Bayesian estimation of parameters in this multi-trait model. The proposed Bayesian procedures with MCMC iteration and variational approximation were referred to as MCBayes and varBayes, respectively. Using simulated datasets of SNP genotypes and phenotypes for three traits with high and low heritabilities, we compared the accuracy in predicting GBVs between multi-trait and single-trait analyses as well as between MCBayes and varBayes. The results showed that, compared to single-trait analysis, multi-trait analysis enabled much more accurate GBV prediction for low-heritability traits correlated with high-heritability traits, by utilizing the correlation structure between traits, while the prediction accuracy for uncorrelated low-heritability traits was comparable or less with multi-trait analysis in comparison with single-trait analysis depending on the setting for prior probability that a SNP has zero effect. Although the prediction accuracy with varBayes was generally lower than with MCBayes, the loss in accuracy was slight. The computational time was greatly reduced with varBayes. In genomic selection for multiple correlated traits, multi-trait analysis was more beneficial than single-trait analysis and varBayes was much advantageous over MCBayes in computational time, which would outweigh the loss of prediction accuracy caused by the approximation procedure, and is thus considered a practical method of choice.


Efficacy and safety of honey based formulation of Nigella sativa seed oil in functional dyspepsia: A double blind randomized controlled clinical trial.
A honey based formulation from Nigella sativa L. (N. sativa) has been used in Traditional Persian Medicine for upper gastrointestinal symptoms. Considering the traditional use of this formulation and its ingredients known pharmacologic effects, this study aimed to evaluate the efficacy and safety of N. sativa seed oil mixed with honey in treatment of patients with functional dyspepsia. Seventy patients diagnosed with functional dyspepsia according to ROME III criteria and confirmed by upper gastrointestinal endoscopy were selected to receive a traditional honey based formulation of N. sativa (5 ml N. sativa oil orally daily) or placebo for 8 weeks in a double-blind randomized placebo-controlled clinical trial using a parallel design with a 1:1 allocation ratio. Patients were evaluated prior to and following 8 weeks of the intervention in terms of the Hong Kong index of dyspepsia severity, presence of Helicobacter pylori infection based on urease test, scores in different domains of short form (SF-36) health survey, and any observed adverse events. The mean scores of Hong Kong index of dyspepsia severity sores and the rate of H. pylori infection were significantly lower in the N. sativa group comparing the placebo group after the intervention (P<0.001). No serious adverse event was reported. This study showed that adjuvant supplementation of honey based formulation of N. sativa can cause significant symptomatic improvement of patients with functional dyspepsia whom received the standard anti-secretory therapy. The results should be investigated further in studies with longer duration and larger sample size.


Progressive resistance training improving gait performance and mobility in acute and chronic stroke patients.
Stroke, a neurological disorder, leads to long-term disability thereby greatly affecting gait and mobility. The purpose of the current study was to investigate the effects of progressive resistance training in both acute and chronic stroke patients. A quasi interventional study was designed and 46 stroke patients were recruited through convenience sampling technique. Sample size was calculated using epi-tool. Patients who had cognitive problems, balance impairments and contractures were excluded from the study. The study was conducted from January to June 2018, at Rafsan Rehab & Research Centre, Peshawar. Progressive resistance exercises starting at 50 % of one repetition maximum (RM) were performed three days/week and for a total duration of nine weeks. Blind assessor measured readings at baseline and after nine weeks. Gait dynamic index (GDI), Six-Meter Walk Test (SMWT) and Five Times Sit-to-Stand (FTSTS) tools were used to collect the required data. The data was analysed at baseline and after nine weeks on SPSS-20. After nine weeks of intervention significant improvement was recorded in patients on GDI (p<0.001), SMWT score (P<0.001) and FTSTS (p<0.001). Progressive resistance training improves mobility limitations and gait in both acute and chronic stroke patients.


Metabolomics-based profiles predictive of low bone mass in menopausal women.
Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. Low bone mass and/or pre-existing bone fragility fractures serve as diagnostic criteria in deciding when to start medication for osteoporosis. Although osteoporosis is a metabolic disorder, metabolic markers to predict reduced bone mass are unknown. Here, we show serum metabolomics profiles of women grouped as pre-menopausal with normal bone mineral density (BMD) (normal estrogen and normal BMD; NN), post-menopausal with normal BMD (low estrogen and normal BMD; LN) or post-menopausal with low BMD (low estrogen and low BMD; LL) using comprehensive metabolomics analysis. To do so, we enrolled healthy volunteer and osteoporosis patient female subjects, surveyed them with a questionnaire, measured their BMD, and then undertook a comprehensive metabolomics analysis of sera of the three groups named above. We identified 24 metabolites whose levels differed significantly between NN/LN and NN/LL groups, as well as 18 or 10 metabolites whose levels differed significantly between NN/LN and LN/LL, or LN/LL and NN/LN groups, respectively. Our data shows metabolomics changes represent useful markers to predict estrogen deficiency and/or bone loss.


Thin and strong! The bioengineering dilemma in the structural and functional design of the blood-gas barrier.
In gas exchangers, the tissue barrier, the partition that separates the respiratory media (water/air and hemolymph/blood), is exceptional for its remarkable thinness, striking strength, and vast surface area. These properties formed to meet conflicting roles: thinness was essential for efficient flux of oxygen by passive diffusion, and strength was crucial for maintaining structural integrity. What we have designated as "three-ply" or "laminated tripartite" architecture of the barrier appeared very early in the evolution of the vertebrate gas exchanger. The design is conspicuous in the water-blood barrier of the fish gills through the lungs of air-breathing vertebrates, where the plan first appeared in lungfishes (Dipnoi) some 400 million years ago. The similarity of the structural design of the barrier in respiratory organs of animals that remarkably differ phylogenetically, behaviorally, and ecologically shows that the construction has been highly conserved both vertically and horizontally, i.e., along and across the evolutionary continuum. It is conceivable that the blueprint may have been the only practical construction that could simultaneously grant satisfactory strength and promote gas exchange. In view of the very narrow allometric range of the thickness of the blood-gas barrier in the lungs of different-sized vertebrate groups, the measurement has seemingly been optimized. There is convincing, though indirect, evidence that the extracellular matrix and particularly the type IV collagen in the lamina densa of the basement membrane is the main stress-bearing component of the blood-gas barrier. Under extreme conditions of operation and in some disease states, the barrier fails with serious consequences. The lamina densa which in many parts of the blood-gas barrier is <50 nm thin is a lifeline in the true sense of the word.


The use of oral misoprostol as a cervical ripening agent in operative hysteroscopy: a double-blind, placebo-controlled trial.
The purpose of this study was to assess the effectiveness of oral misoprostol as a cervical ripening agent when used in operative hysteroscopy. This was a double-blind, placebo-controlled trial. Any patient undergoing an operative hysteroscopy (with a 9-mm to 10-mm hysteroscope) was considered eligible for the trial. Patients were randomly allocated, by means of computer-generated numbers, to receive either placebo or 400 microg of misoprostol 12 and 24 hours before surgery. The primary outcome measure in this study was the ease of cervical dilatation as measured by the largest-number Hegar dilator that could be inserted into the cervix without resistance. A subjective assessment of the ease of dilatation was also recorded on a Likert scale. Other demographic data including age, menopausal status, parity, and use of gonadotropin-releasing hormone (GnRH) analogues were also recorded. Adverse effects experienced and any other adverse outcomes were also recorded for each group. Logistic regression analysis was used to compare the two groups. Two hundred four patients were recruited into the study. There were no differences between the two groups in demographic variables. The misoprostol group demonstrated an increased ease of cervical dilatation (odds ratio [OR] 2.6; CI 1.28-5.29; P =.008). This was also demonstrated in the subgroup of patients who were menopausal or who had been pretreated with a gonadotropin-releasing hormone analog (OR 2.49; CI 1.11-5.58; P =.026), as well as in those who were premenopausal (OR 2.15; CI 1.04 4.45; P =.04). There were no differences between the two groups in the time required for dilatation (P =.08) or ease of dilatation (P =.12). Adverse effects were greater in the treatment group: diarrhea (28% vs 4%; P <.001), cramps (27% vs 1%; P <.0001), and bleeding (26% vs 1.3%; P <.001). Misoprostol demonstrates a benefit over placebo in the ease of cervical dilatation in premenopausal and postmenopausal women and in those pretreated with a gonadotropin-releasing hormone analog. Adverse effects were more common in the treatment group but did not preclude the patients from taking the medication.


Design of optical metamaterial mirror with metallic nanoparticles for floating-gate graphene optoelectronic devices.
The purpose of this work is to conceive the idea for using the gate dielectrics of floating-gate memory device (i.e., Au nanoparticle (AuNP) monolayer embedded within polymeric matrix) as a magnetic mirror, so as to harness the broadband light absorption of thin film optoelectronics. In particular, we systematically examined whether the versatile assembly of spherical AuNP monolayer can be indeed treated as the effective magnetic mirror for floating-gate graphene optoelectronic device. High amenability of the AuNP assembly with the large-area device fabrication procedures may make this strategy widely applicable to various thin film optoelectronic devices. Our study thereby advances the design of mirror for thin film optoelectronics.


The novel activated microglia/macrophage WAP domain protein, AMWAP, acts as a counter-regulator of proinflammatory response.
Microgliosis is a common phenomenon in neurodegenerative disorders, including retinal dystrophies. To identify candidate genes involved in microglial activation, we used DNA-microarray analysis of retinal microglia from wild-type and retinoschisin-deficient (Rs1h(-/Y)) mice, a prototypic model for inherited retinal degeneration. Thereby, we cloned a novel 76 aa protein encoding a microglia/macrophage-restricted whey acidic protein (WAP) termed activated microglia/macrophage WAP domain protein (AMWAP). The gene consists of three exons and is located on mouse chromosome 11 in proximity to a chemokine gene cluster. mRNA expression of AMWAP was detected in microglia from Rs1h(-/Y) retinas, brain microglia, and other tissue macrophages. AMWAP transcription was rapidly induced in BV-2 microglia upon stimulation with multiple TLR ligands and IFN-gamma. The TLR-dependent expression of AMWAP was dependent on NF-kappaB, whereas its microglia/macrophage-specific transcription was regulated by PU.1. Functional characterization showed that AMWAP overexpression reduced the proinflammatory cytokines IL-6 and IL-1beta and concomitantly increased expression of the alternative activation markers arginase 1 and Cd206. Conversely, small interfering RNA knockdown of AMWAP lead to higher IL-6, IL-1beta, and Ccl2 transcript levels, whereas diminishing arginase 1 and Cd206 expression. Moreover, AMWAP expressing cells had less migratory capacity and showed increased adhesion in a trypsin-protection assay indicating antiserine protease activity. In agreement with findings from other WAP proteins, micromolar concentrations of recombinant AMWAP exhibited significant growth inhibitory activity against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis. Taken together, we propose that AMWAP is a counter-regulator of proinflammatory microglia/macrophage activation and a potential modulator of innate immunity in neurodegeneration.


Density structure of Earth's lowermost mantle from Stoneley mode splitting observations.
Advances in our understanding of Earth's thermal evolution and the style of mantle convection rely on robust seismological constraints on lateral variations of density. The large-low-shear-wave velocity provinces (LLSVPs) atop the core-mantle boundary beneath Africa and the Pacific are the largest structures in the lower mantle, and hence severely affect the convective flow. Here, we show that anomalous splitting of Stoneley modes, a unique class of free oscillations that are perturbed primarily by velocity and density variations at the core-mantle boundary, is explained best when the overall density of the LLSVPs is lower than the surrounding mantle. The resolved density variations can be explained by the presence of post-perovskite, chemical heterogeneity or a combination of the two. Although we cannot rule out the presence of a ∼100-km-thick denser-than-average basal structure, our results support the hypothesis that LLSVPs signify large-scale mantle upwelling in two antipodal regions of the mantle.


Benefit of feeding dietary calcium and nonphytate phosphorus levels above National Research Council recommendations to tom turkeys in the growing-finishing phases.
This experiment evaluated the effects of feeding various dietary Ca and nonphytate P (nPP) levels to Large White male turkeys from 3 to 17 wk of age. After consuming a common prestarter diet, poults were fed approximate NRC (1994) levels of dietary Ca and nPP from 3 to 9 wk of age or levels approximately 25% higher. From 9 to 17 wk of age, each starter group was fed approximately 75 (low P), 100 (medium P), or 145% (high P) of the NRC (1994) requirements for Ca and nPP. Diets were fed as crumbles to 6 wk of age and as pellets from 6 to 17 wk of age. There were no effects on BW or feed efficiency to 9 wk of age. Litter P was increased by 21% when high Ca and nPP were fed from 3 to 9 wk. High dietary Ca and nPP fed during the growing-finishing period generally improved bone strength and ash. Tibia strength and ash were higher in the medium P group compared with in the low P group. Wing bone strength was greater in the high P group than in both the birds fed low or medium P. Litter P was increased by 23% when High P was fed in the growing-finishing period compared to the birds fed the Medium P diet during the same period. The results show there is a benefit to bone strength and mineralization when Ca and nPP are fed at levels higher than NRC (1994) recommendations.


Cancer incidence after localized therapy for prostate cancer.
Second cancers may occur in patients who have undergone radiation therapy. The risk for these adverse events after therapy is uncertain. In this study, the authors examined the size and significance of the observed association between occurrences of secondary cancers 5 years after radiotherapy in a large population of men with incident prostate cancer. Men with incident prostate cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) registry and were distinguished by the type of treatment received, tumor stage, tumor grade, and age at diagnosis. SEER data also were used to identify occurrences of secondary cancer beginning 5 years after the date patients were diagnosed with prostate cancer. Multivariate logistic regression analysis was used to estimate the adjusted odds of the subsequent occurrence of other cancers associated with types of radiation therapy received and was adjusted for the type of surgery, tumor grade, stage, and patient age. Compared with men who received no prostate cancer-directed radiation, men who received external beam radiation therapy (EBRT) as their only form of radiation therapy had statistically significant increased odds of developing secondary cancers at several sites potentially related to radiation therapy, including the bladder (odds ratio [OR], 1.63; 95% confidence interval [95% CI], 1.44-1.84) and rectum (OR, 1.60; 95% CI, 1.29-1.99). Men who received EBRT also had statistically significant higher odds of developing secondary cancers at sites in the upper body and other areas not potentially related to radiation therapy, including the cecum (OR, 1.63; 95% CI, 1.10-1.70), transverse colon (OR, 1.85; 95% CI, 1.30-2.63), brain (OR, 1.83; 95% CI, 1.22-2.75), stomach (OR, 1.38; 95% CI, 1.09-1.75), melanoma (OR, 1.29; 95% CI, 1.09-1.53), and lung and bronchus (OR, 1.25; 95% CI, 1.13-1.37) compared with the odds among men who received no radiation therapy. Men who received radiation therapy in the form of radioactive implants or isotopes, either in isolation or combined with beam radiation, did not have significantly different odds of secondary cancer occurring at any of the 20 most common sites. Patients who received with EBRT had significantly higher odds of developing second cancers both overall and in the areas that were exposed to radiation. It is noteworthy that, to the authors' knowledge, this report shows for the first time that, despite the higher doses of radiation delivered, patients who received radioactive implants had the lowest odds of developing second cancers.


Screening and in situ synthesis using crystals of a NAD kinase lead to a potent antistaphylococcal compound.
Making new ligands for a given protein by in situ ligation of building blocks (or fragments) is an attractive method. However, it suffers from inherent limitations, such as the limited number of available chemical reactions and the low information content of usual chemical library deconvolution. Here, we describe a focused screening of adenosine derivatives using X-ray crystallography. We discovered an unexpected and biocompatible chemical reactivity and have simultaneously identified the mode of binding of the resulting products. We observed that the NAD kinase from Listeria monocytogenes (LmNADK1) can promote amide formation between 5'-amino-5'-deoxyadenosine and carboxylic acid groups. This unexpected reactivity allowed us to bridge in situ two adenosine derivatives to fully occupy the active NAD site. This guided the design of a close analog showing micromolar inhibition of two human pathogenic NAD kinases and potent bactericidal activity against Staphylococcus aureus in vitro.


Nitric oxide-associated protein 1 (NOA1) is necessary for oxygen-dependent regulation of mitochondrial respiratory complexes.
In eukaryotic cells, maintenance of cellular ATP stores depends mainly on mitochondrial oxidative phosphorylation (OXPHOS), which in turn requires sufficient cellular oxygenation. The crucial role of proper oxygenation for cellular viability is reflected by involvement of several mechanisms, which sense hypoxia and regulate activities of respiratory complexes according to available oxygen concentrations. Here, we focus on mouse nitric oxide-associated protein 1 (mNOA1), which has been identified as an important component of the machinery that adjusts OXPHOS activity to oxygen concentrations. mNOA1 is an evolutionary conserved GTP-binding protein that is involved in the regulation of mitochondrial protein translation and respiration. We found that mNOA1 is located mostly in the mitochondrial matrix from where it interacts with several high molecular mass complexes, most notably with the complex IV of the respiratory chain and the prohibitin complex. Knock-down of mNOA1 impaired enzyme activity I+III, resulting in oxidative stress and eventually cell death. mNOA1 is transcriptionally regulated in an oxygen-sensitive manner. We propose that oxygen-dependent regulation of mNOA1 is instrumental to adjusting OXPHOS activity to oxygen availability, thereby controlling mitochondrial metabolism.


"Away Days" in multicenter randomized controlled trials: a questionnaire survey of their use and a case study on the effect of one Away Day on patient recruitment.
"Away Days" (trial promotion and training events for trial site personnel) are a well-established method used by trialists to encourage engagement of research sites in the recruitment of patients to multicenter randomized controlled trials (RCTs). We explored the use of Away Days in multicenter RCTs and analyzed the effect on patient recruitment in a case study. Members of the United Kingdom Trial Managers' Network were surveyed in June 2013 to investigate their experiences in the design and conduct of Away Days in RCTs. We used data from a multicenter pragmatic surgical trial to explore the effects of an Away Day on the screening and recruitment of patients. A total of 94 people responded to the survey. The majority (78%), who confirmed had organized an Away Day previously, found them to be useful. This is despite their costs. There was no evidence, however, from the analysis of data from a surgical trial that attendance at an Away Day increased the number of patients screened or recruited at participating sites. Although those responsible for managing RCTs in the UK tend to believe that trial Away Days are beneficial, evidence from a multicenter surgical trial shows no improvement on a key indicator of trial success. This points to the need to carefully consider the aims, design, and conduct of Away Days. Further more rigorous research nested within RCTs would be valuable to evaluate the design and conduct of Away Days.


Surgical activity of first-year Canadian neurosurgical residents.
Surgical activity is probably the most important component of surgical training. During the first year of surgical residency, there is an early opportunity for the development of surgical skills, before disparities between the skill sets of residents increase in future years. It is likely that surgical skill is related to operative volumes. There are no published guidelines that quantify the number of surgical cases required to achieve surgical competency. The aim of this study was to describe the current trends in surgical activity in a recent cohort of first-year Canadian neurosurgical trainees. This study utilized retrospective database review and survey methodology to describe the current state of surgical training for first-year neurosurgical trainees. A committee of five residents designed this survey in an effort to capture factors that may influence the operative activity of trainees. Nine out of a cohort of 20 first-year Canadian neurosurgical trainees that began training in July of 2008 participated in the study. The median number of cases completed by a resident during the initial three month neurosurgical rotation was 66, within which the trainee was identified as the primary surgeon in 12 cases. Intracranial hemorrhage and cerebrospinal fluid diversion procedures were the most common operations to have the trainee as primary surgeon. Based on this pilot study, it appears that the operative activity of Canadian first-year residents is at least equivalent to the residents of other studied training systems with respect to volume and diversity of surgical activity.


Efficacy of endostar combined with transcatheter arterial chemoembolization and analysis of vascular endothelial factor and C-reactive protein levels in patients with advanced hepatocellular carcinoma under contrast enhanced ultrasound.
To evaluate the effect of transcatheter arterial chemoembolization (TACE) under the guidance of contrast-enhanced ultrasound (CEUS) in patients with advanced hepatocellular carcinoma (HCC). One hundred and sixty patients with HCC admitted to Cangzhou Central Hospital from April 2015 to April 2017 were enrolled. The clinical data were retrospectively analyzed. Seventy-five patients who underwent TACE according to CEUS results were selected as the observation group. The remaining 85 cases that underwent digital subtraction augiography (DSA) angiography-guided TACE were selected as the control group and were intravenously infused with 15 mg of Endostar+500 mL of normal saline once a day for 3 consecutive days (Endostar 30 mg was reperfused during the operation). Both groups were re-contrasted at 1 month (T2) and 3 months (T3) to determine whether TACE was performed again. The numbers of TACEs re-performed were recorded. Color Doppler energy imaging was used to observe the neovascularization of the tumor. The changes of serum vascular endothelial growth factor (VEGF) and CRP levels were detected by enzyme-linked immunosorbent assay (ELISA). There were significant differences in the number of TACEs re-performed between the observation group and the control group (p<0.05). The serum VEGF level in the observation group was always lower than that in the control group (p<0.05). CRP levels in the control group showed an upward trend. The serum CRP level in the control group was significantly higher compared to the observation group at T3. The number of grades 0 and 1 neovascularization in the control group was significantly lower than in the observation group. The neovascularization rate of the observation group was significantly higher than the control group; the tumor effective rate of the observation group was not different from that of the control group, but the disease control rate was higher than in the control group. CEUS-guided TACE treatment of HCC can effectively inhibit tumor angiogenesis, control tumor progression, and prolong the survival of patients, which is conducive to the prognosis of patients.