Molecular epidemiology and genetic history of hepatitis C virus subtype 3a infection in Thailand.
Among all hepatitis C virus (HCV) infections, subtype 3a is the most common genotype in Thailand. This study investigates the molecular epidemiology and epidemic history of HCV subtype 3a in Thailand. Three hundred and fifty-six serum samples were collected from HCV-infected Thai patients. The virus was isolated, after which the core and NS5B regions were sequenced. Subsequently, the HCV genotype was classified by phylogenetic analysis based on the core and NS5B regions. Molecular evolution analysis of HCV subtype 3a was estimated using BEAST (Bayesian Evolutionary Analysis by Sampling Trees) v.1.5.4. Based on our phylogenetic analyses, subtype 3a (38.5%) was the most prevalent, followed by 1a (21%), 1b (13.8%), genotype 6 (19.9%) [comprised of subtypes 6e (0.3%), 6f (11%), 6i (1.9%), 6j (1.9%) and 6n (4.8%)] and 3b (5.6%). Our phylogenetic tree indicates the existence of a specific group of HCV subtype 3a strains in the Thai population. Molecular evolutionary analysis dated the most recent common ancestor of the Thai HCV subtype 3a strains as existing approximately 200 ago, and a Bayesian skyline plot showed that this particular strain spread to Thailand during the mid-1970s and early 1980s. This period overlaps with the Vietnam War (1955-1975) and the widespread use of injection stimulants introduced by the US Army during this time. The estimated history of HCV subtype 3a infection in Thailand may help to predict the future burden of HCV-related diseases and facilitate better public health control and surveillance.


Precipitation characteristics of uranyl ions at different pHs depending on the presence of carbonate ions and hydrogen peroxide.
This work studied the dissolution of uranium dioxide and precipitation characteristics of uranyl ions in alkaline and acidic solutions depending on the presence of carbonate ions and H2O2 in the solutions at different pHs controlled by adding HNO3 or NaOH in the solution. The chemical structures of the precipitates generated in different conditions were evaluated and compared by using XRD, SEM, TG-DT, and IR analyses together. The sizes and forms of the precipitates in the solutions were evaluated, as well. The uranyl ions were precipitated in the various forms, depending on the solution pH and the presences of hydrogen peroxide and carbonate ions in the solution. In a 0.5 M Na2CO3 solution with H2O2, where the uranyl ions formed mixed uranyl peroxy-carbonato complexes, the uranyl ions were precipitated as a uranium peroxide of UO4(H20)4 at pH 3-4, and precipitated as a clarkeite of Na2U2Ox(OH)y(H2O)z above pH 13. In the same carbonate solution without H2O2, where the uranyl ions formed uranyl tris-carbonato complex, the uranyl ions were observed to be precipitated as a different form of clarkeite above pH 13. The precipitate of uranyl ions in a nitrate solution without carbonate ions and H2O2 at a high pH were studied together to compare the precipitate forms in the carbonate solutions.


Identification and characterization of PWWP domain residues critical for LEDGF/p75 chromatin binding and human immunodeficiency virus type 1 infectivity.
Lens epithelium-derived growth factor (LEDGF)/p75 functions as a bimodal tether during lentiviral DNA integration: its C-terminal integrase-binding domain interacts with the viral preintegration complex, whereas the N-terminal PWWP domain can bind to cellular chromatin. The molecular basis for the integrase-LEDGF/p75 interaction is understood, while the mechanism of chromatin binding is unknown. The PWWP domain is homologous to other protein interaction modules that together comprise the Tudor clan. Based on primary amino acid sequence and three-dimensional structural similarities, 24 residues of the LEDGF/p75 PWWP domain were mutagenized to garner essential details of its function during human immunodeficiency virus type 1 (HIV-1) infection. Mutating either Trp-21 or Ala-51, which line the inner wall of a hydrophobic cavity that is common to Tudor clan members, disrupts chromatin binding and virus infectivity. Consistent with a role for chromatin-associated LEDGF/p75 in stimulating integrase activity during infection, recombinant W21A protein is preferentially defective for enhancing integration into chromatinized target DNA in vitro. The A51P mutation corresponds to the S270P change in DNA methyltransferase 3B that causes human immunodeficiency, centromeric instability, and facial anomaly syndrome, revealing a critical role for this amino acid position in the chromatin binding functions of varied PWWP domains. Our results furthermore highlight the requirement for a conserved Glu in the hydrophobic core that mediates interactions between other Tudor clan members and their substrates. This initial systematic mutagenesis of a PWWP domain identifies amino acid residues critical for chromatin binding function and the consequences of their changes on HIV-1 integration and infection.


Tiki, at the head of a new superfamily of enzymes.
Tiki proteins appear to antagonize Wnt signalling pathway by acting as Wnt proteases, thereby affecting Wnt solubility by its amino-terminal cleavage. Tiki1 protease activity was shown to be metal ion-dependent and was inhibited by chelating agents and thus was tentatively proposed to be a metalloprotease. Nevertheless, Tiki proteins exhibit no detectable sequence similarity to previously described metalloproteases, but instead have been reported as being homologues of TraB proteins (Pfam ID: PF01963), a widely distributed family of unknown function and structure. Here, we show that Tiki proteins are members of a new superfamily of domains contained not just in TraB proteins, but also in erythromycin esterase (Pfam ID: PF05139), DUF399 (domain of unknown function 399; Pfam ID: PF04187) and MARTX toxins that contribute to host invasion and pathogenesis by bacteria. We establish the core fold of this enzymatic domain and its catalytic residues.


Biomonitoring and Elimination of Perfluorinated Compounds and Polychlorinated Biphenyls through Perspiration: Blood, Urine, and Sweat Study.
Perfluorinated compounds (PFCs) are man-made organofluorine chemicals manufactured and marketed for their stain-resistant properties. Polychlorinated biphenyls (PCBs) are anthropogenic organochlorine compounds previously used in various industrial and chemical applications prior to being banned in the Western world in the 1970s. Both PFCs and PCBs are persistent contaminants within the human organism and both have been linked to adverse health sequelae. Data is lacking on effective means to facilitate clearance of PFCs and PCBs from the body. Methods. Blood, urine, and sweat were collected from 20 individuals (10 healthy participants and 10 participants with assorted health problems) and analyzed for PFCs and PCBs using high performance liquid chromatography tandem mass spectrometry. Results. Some individual PCB congeners, but not all, were released into sweat at varying concentrations. None of the PFCs found in serum testing appeared to be excreted efficiently into perspiration. Conclusions. Induced perspiration may have some role in facilitating elimination of selected PCBs. Sweat analysis may be helpful in establishing the existence of some accrued PCBs in the human body. Sweating does not appear to facilitate clearance of accrued PFHxS (perfluorohexane sulfonate), PFOS (perfluorooctane sulfonate), or PFOA (perfluorooctanoic acid), the most common PFCs found in the human body.


Electrical Injury-Induced Complete Atrioventricular Block: Is Permanent Pacemaker Required?
A considerable percentage of electrical injuries occur as a result of work activities. Electrical injury can lead to various cardiovascular disorders: acute myocardial necrosis, myocardial ischemia, heart failure, arrhythmias, hemorrhagic pericarditis, acute hypertension with peripheral vasospasm, and anomalous, nonspecific ECG alterations. Ventricular fibrillation is the most common arrhythmia resulting from electrical injury and is the leading cause of death in electrical (especially low voltage alternating current) injury cases. Asystole, premature ventricular contractions, ventricular tachycardia, conduction disorders (various degrees of heart blocks, bundle-brunch blocks), supraventricular tachycardia, and atrial fibrillation are the other arrhythmic complications of electrical injury. Complete atrioventricular block has rarely been reported and permanent pacemaker was required for the treatment in some of these cases. Herein, we present a case of reversible complete atrioventricular block due to low voltage electrical injury in a young electrical technician.


A scoping review exploring the opioid prescribing practices of US dental professionals.
The prescribing practices of dental professionals may play an important role in the opioid epidemic. The authors performed a scoping review of the current original research literature on dental professionals' prescribing practices for opioid analgesics published from 2000 through 2017. With the use of a modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, the inclusion criteria entailed published articles written in English that had an opioid focus, had a dental health care professional prescriber, entailed a US setting, were peer reviewed, had an identified data source, were not review articles, and were not opinion articles. Five databases were searched to identify relevant literature. Of 221 articles, 18 met the inclusion criteria. Eight distinct and mutually exclusive themes emerged from these studies: impact of patient demographic characteristics on opioid prescribing, comparison of opioid prescribing by different provider type, quantity of opioids prescribed and consumed, types of opioids prescribed by dental professionals, assessment of self-reported opioid prescribing, opioid prescriptions by procedure, impact of pharmacy integration into dental practice, and implementation of risk mitigation strategies. There is a surprising paucity of research that investigated the prescribing patterns of dentists. Available research suggests that dental practice does not always align with proposed guidelines for opioid prescribing. Some studies that explored interventions found changes in prescribing, suggesting the potential benefit of developing practical strategies targeted to dental providers who prescribed opioids.


Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial.
Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients. Even in fully medicated diabetic patients, overall prognosis is unfavorable due to deteriorated cardiovascular function. Based on epidemiological data, diets rich in flavanols are associated with a reduced cardiovascular risk. In a feasibility study with 10 diabetic patients, we assessed vascular function as flow-mediated dilation (FMD) of the brachial artery, plasma levels of flavanol metabolites, and tolerability after an acute, single-dose ingestion of cocoa, containing increasing concentrations of flavanols (75, 371, and 963 mg). In a subsequent efficacy study, changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day, thrice-daily dietary intervention with either flavanol-rich cocoa (321 mg flavanols per dose) or a nutrient-matched control (25 mg flavanols per dose). Both studies were undertaken in a randomized, double-masked fashion. Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites, respectively. A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD (at 2 h: from 3.7 +/- 0.2% to 5.5 +/- 0.4%, p < 0.001). A 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30% (p < 0.0001), while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study. Treatment was well tolerated without evidence of tachyphylaxia. Endothelium-independent responses, blood pressure, heart rate, and glycemic control were unaffected. Diets rich in flavanols reverse vascular dysfunction in diabetes, highlighting therapeutic potentials in cardiovascular disease.


Modulating the Structure of Motor Variability for Skill Learning Through Specific Muscle Synergies in Elderlies and Young Adults.
Objective: Motor variability - performance variations across task repetitions - has been assumed to be undesirable. But recent studies argue that variability facilitates early motor learning by allowing exploratory search of reward-generating motion, and that variability's structure may be modulated by neural circuits for furthering learning. What are the neural sources of learning-relevant motor variability and its modulation in humans of different ages? Methods: Elderlies and young adults played a 3-session virtual bowling while multi-muscle electromyographic signals were collected. We quantified trial-to-trial variability of muscle synergies - neuromotor control modules - and of their activations. Results: In elderlies, bowling-score gain correlated with change of activation timing variability of specific synergies, but in young adults, with variability changes of synergy-activation magnitude, and of the synergies themselves. Conclusions: Variability modulation of specific muscle synergies and their activations contribute to early motor learning. Elderly and young individuals may rely on different aspects of motor variability to drive learning.


Culture- and antigen-negative meningitis in Guatemalan children.
To compare children with confirmed bacterial meningitis (CBM) and those with culture- and latex-negative meningitis (CLN). Children 1 to 59 months of age admitted to three major referral hospitals in Guatemala City with clinical signs compatible with bacterial infections were evaluated prospectively between 1 October 1996 and 31 December 2005. Bacterial cultures and latex agglutination antigen testing were performed on samples of cerebrospinal fluid (CSF). The case-fatality rate was significantly higher in the 493 children with CBM than in the 528 children with CLN (27.6% and 14.9%, respectively; P < 0.001). Children with CBM were less likely to have received antibiotics and more likely to have seizures, shock, or coma on admission than children with CLN. Among the 182 CBM survivors and 205 CLN survivors studied between October 2000 and December 2005, clinically observed sequelae were present at discharge in a higher percentage of the CBM than of the CLN group (78.6% and 46.8%, respectively; P < 0.0001). CSF glucose < 10 mg/dL, peripheral neutrophils < 2 000 cells/mm(3), coma or shock at admission, and concurrent sepsis or pneumonia were risk factors for mortality in children with CBM; only coma or shock at admission predicted mortality in children with CLN. The high case-fatality and sequelae rates suggest that many children with CLN may have had bacterial meningitis. Estimates based on confirmed meningitis alone underestimate the true vaccine-preventable disease burden. Additional studies to determine etiologies of CLN in this population are indicated.


Inhibition of herpes simplex virus replication by tobacco extracts.
Herpes simplex virus type 1 (HSV-1) has been associated with the genesis of leukoplakias, epithelial atypia, and oral cancer. Tobacco habits, such as snuff dipping, are also definitely correlated with this type of lesion. The normal cytolytic HSV-1 infection can, after in vitro inactivation, transform cells. Extracts of snuff were prepared and assayed for their ability to inhibit HSV-1 replication. Plaque formation assays of HSV-1 in the presence of snuff extract showed that a reduced number of plaques was formed. Different batches of one brand of snuff were tested for inhibition of herpes simplex virus (HSV) production. More than 99% inhibition of 24-hr HSV production was obtained with undiluted batches. The 1:5 dilutions of snuff had an inhibitory effect of 85% and 1:25 dilutions, 39%. In agreement, the attachment of the virus to the host cell and penetration of the virus to the cell nuclei were found to be inhibited as was the synthesis of viral DNA. Nicotine had an inhibitory effect, while aromatic additions to snuff were found to have no major inhibitory effect on HSV replication. Snuff extracts were prepared from different brands of snuff reported to contain high and low quantities of tobacco-specific N-nitrosamines. Brands with reported high levels of tobacco-specific N-nitrosamines had significantly greater ability to inhibit HSV replication. In conclusion, this study has shown that extracts of snuff have inhibitory effects on the production of cytolytic HSV-1 infections. A chronic snuff dipper keeps tobacco in the mouth for the major part of the day. Thus, virus shed in the oral cavity in connection with a reactivated latent HSV-1 infection has great possibilities of being affected by snuff or derivatives of snuff. It is suggested that an interaction between tobacco products and HSV-1 might be involved in the development of dysplastic lesions in the oral cavity.


Home telemonitoring in heart failure patients: the HHH study (Home or Hospital in Heart Failure).
The Home or Hospital in Heart failure (HHH) study was a European Community-funded, multinational, randomized controlled clinical trial, conducted in the UK, Poland, and Italy, to assess the feasibility of a new system of home telemonitoring (HT). The HT system was used to monitor clinical and physiological parameters, and its effectiveness (compared with usual care) in reducing cardiac events in heart failure (HF) patients was evaluated. Measurements were patient-managed. From 2002 to 2004, 461 HF patients (age 60 +/- 11 years, New York Heart Association class 2.4 +/- 0.6, left ventricular ejection fraction 29 +/- 7%) were enrolled at 11 centres and randomized (1:2) to either usual outpatient care or HT administered as three randomized strategies: (i) monthly telephone contact; (ii) strategy 1 plus weekly transmission of vital signs; and (iii) strategy 2 plus monthly 24 h recording of cardiorespiratory activity. Patients completed 81% of vital signs transmissions, as well as 92% of cardiorespiratory recordings. Over a 12-month follow-up, there was no significant effect of HT in reducing bed-days occupancy for HF or cardiac death plus HF hospitalization. Post hoc analysis revealed a heterogeneous effect of HT in the three countries with a trend towards a reduction of events in Italy. Home or Hospital in Heart failure indicates that self-managed HT of clinical and physiological parameters is feasible in HF patients, with surprisingly high compliance. Whether HT contributes to a reduction of cardiac events requires further investigation.


Calcineurin, the Ca2+/calmodulin-dependent protein phosphatase, is essential in yeast mutants with cell integrity defects and in mutants that lack a functional vacuolar H(+)-ATPase.
Calcineurin is a conserved Ca2+/calmodulin-dependent protein phosphatase that plays a critical role in Ca(2+)-mediated signaling in many cells. Yeast cells lacking functional calcineurin (cna1 cna2 or cnb1 mutants) display growth defects under specific environmental conditions, for example, in the presence of high concentrations of Na+, Li+, Mn2+, or OH- but are indistinguishable from wild-type cells under standard culture conditions. To characterize regulatory pathways that may overlap with calcineurin, we performed a synthetic lethal screen to identify mutants that require calcineurin on standard growth media. The characterization of one such mutant, cnd1-8, is presented. The CND1 gene was cloned, and sequence analysis predicts that it encodes a novel protein 1,876 amino acids in length with multiple membrane-spanning domains. CND1 is identical to the gene identified previously as FKS1, ETG1, and CWH53, cnd1 mutants are sensitive to FK506 and cyclosporin A and exhibit slow growth that is improved by the addition of osmotic stabilizing agents. This osmotic agent-remedial growth defect and microscopic evidence of spontaneous cell lysis in cnd1 cultures suggest that cell integrity is compromised in these mutants. Mutations in the genes for yeast protein kinase C (pkc1) and a MAP kinase (mpk1/slt2) disrupt a Ca(2+)-dependent signaling pathway required to maintain a normal cell wall and cell integrity. We show that pkc1 and mpk1/slt2 growth defects are more severe in the absence of calcineurin function and less severe in the presence of a constitutively active form of calcineurin. These observations suggest that calcineurin and protein kinase C perform independent but physiologically related functions in yeast cells. We show that several mutants that lack a functional vacuolar H(+)-ATPase (vma) require calcineurin for vegetative growth. We discuss possible roles for calcineurin in regulating intracellular ion homeostasis and in maintaining cell integrity.


Pain-related anxiety and smoking processes: The explanatory role of dysphoria.
Scientific evidence suggests that pain-related anxiety may contribute to the maintenance of tobacco addiction among smokers with varying levels of pain. Yet, no work has investigated the relation between pain-related anxiety and cognitive-based smoking processes within an indirect effect model. Dysphoria may explain the relation between pain-related anxiety and cigarette smoking, as it is a construct that relates to both pain and smoking outcomes. Thus, the current cross-sectional study examined the indirect effect of pain-related anxiety and three clinically significant smoking processes: perceived barriers to cessation, negative affect reduction motives, and negative mood abstinence expectancies via dysphoria. Participants included 101 (Mage = 32.74 years, SD = 13.60; 35.6% female) adult tobacco cigarette smokers with low cigarette dependence. Results indicated that pain-related anxiety had an indirect effect on all dependent variables through dysphoria. The current findings provide evidence that dysphoria may serve to maintain maladaptive smoking processes in smokers who experience pain-related anxiety. This study furthers research on pain-smoking relations by providing initial evidence for a conceptual model in which smokers with elevated pain-related anxiety endorse greater dysphoric symptoms and use smoking to reduce or escape symptoms of their pain-related anxiety and dysphoria, thus contributing to the maintenance of tobacco dependence.


Transition metal dichalcogenide quantum dots: synthesis, photoluminescence and biological applications.
The unique electronic, physical and chemical properties of nanostructured transition metal dichalcogenide (TMD) materials have received great attention, specifically, with the decrease of size to several nanometers, particles named TMD quantum dots (QDs). The inherent properties of TMD QDs make them promising for a variety of applications, including catalytic, luminescence and biomedical. In this review, we first briefly introduce the controlled synthesis of TMD QDs using mechanical exfoliation, ion intercalation-assisted liquid exfoliation, free radical and electrochemical shear and hydrothermal/solvothermal reaction. We then summarize recent progress on chemical and biological applications of TMD QDs in detail.


Differential susceptibility to effects of maternal sensitivity? A study of candidate plasticity genes.
Here we tested whether there was genetic moderation of effects of early maternal sensitivity on social-emotional and cognitive-linguistic development from early childhood onward and whether any detected Gene × Environment interaction effects proved consistent with differential-susceptibility or diathesis-stress models of Person × Environment interaction (N = 695). Two new approaches for evaluating models were employed with 12 candidate genes. Whereas maternal sensitivity proved to be a consistent predictor of child functioning across the primary-school years, candidate genes did not show many main effects, nor did they tend to interact with maternal sensitivity/insensitivity. These findings suggest that the developmental benefits of early sensitive mothering and the costs of insensitive mothering look more similar than different across genetically different children in the current sample. Although acknowledgement of this result is important, it is equally important that the generally null Gene × Environment results reported here not be overgeneralized to other samples, other predictors, other outcomes, and other candidate genes.


ATR regulates fragile site stability.
Conditions that partially inhibit DNA replication induce expression of common fragile sites. These sites form gaps and breaks on metaphase chromosomes and are deleted and rearranged in many tumors. Yet, the mechanism of fragile site expression has been elusive. We demonstrate that the replication checkpoint kinase ATR, but not ATM, is critical for maintenance of fragile site stability. ATR deficiency results in fragile site expression with and without addition of replication inhibitors. Thus, we propose that fragile sites are unreplicated chromosomal regions resulting from stalled forks that escape the ATR replication checkpoint. These findings have important implications for understanding both the mechanism of fragile site instability and the consequences of stalled replication in mammalian cells.


So what do we really mean when we say that systems biology is holistic?
An old debate has undergone a resurgence in systems biology: that of reductionism versus holism. At least 35 articles in the systems biology literature since 2003 have touched on this issue. The histories of holism and reductionism in the philosophy of biology are reviewed, and the current debate in systems biology is placed in context. Inter-theoretic reductionism in the strict sense envisaged by its creators from the 1930s to the 1960s is largely impractical in biology, and was effectively abandoned by the early 1970s in favour of a more piecemeal approach using individual reductive explanations. Classical holism was a stillborn theory of the 1920s, but the term survived in several fields as a loose umbrella designation for various kinds of anti-reductionism which often differ markedly. Several of these different anti-reductionisms are on display in the holistic rhetoric of the recent systems biology literature. This debate also coincides with a time when interesting arguments are being proposed within the philosophy of biology for a new kind of reductionism. Engaging more deeply with these issues should sharpen our ideas concerning the philosophy of systems biology and its future best methodology. As with previous decisive moments in the history of biology, only those theories that immediately suggest relatively easy experiments will be winners.


Inhibition of endothelial cell Ca²⁺ entry and transient receptor potential channels by Sigma-1 receptor ligands.
The Sigma-1 receptor (Sig1R) impacts on calcium ion signalling and has a plethora of ligands. This study investigated Sig1R and its ligands in relation to endogenous calcium events of endothelial cells and transient receptor potential (TRP) channels. Intracellular calcium and patch clamp measurements were made from human saphenous vein endothelial cells and HEK 293 cells expressing exogenous human TRPC5, TRPM2 or TRPM3. Sig1R ligands were applied and short interfering RNA was used to deplete Sig1R. TRP channels tagged with fluorescent proteins were used for subcellular localization studies. In endothelial cells, 10-100 μM of the Sig1R antagonist BD1063 inhibited sustained but not transient calcium responses evoked by histamine. The Sig1R agonist 4-IBP and related antagonist BD1047 were also inhibitory. The Sig1R agonist SKF10047 had no effect. Sustained calcium entry evoked by VEGF or hydrogen peroxide was also inhibited by BD1063, BD1047 or 4-IBP, but not SKF10047. 4-IBP, BD1047 and BD1063 inhibited TRPC5 or TRPM3, but not TRPM2. Inhibitory effects of BD1047 were rapid in onset and readily reversed on washout. SKF10047 inhibited TRPC5 but not TRPM3 or TRPM2. Depletion of Sig1R did not prevent the inhibitory actions of BD1063 or BD1047 and Sig1R did not co-localize with TRPC5 or TRPM3. The data suggest that two types of Sig1R ligand (BD1047/BD1063 and 4-IBP) are inhibitors of receptor- or chemically activated calcium entry channels, acting relatively directly and independently of the Sig1R. Chemical foundations for TRP channel inhibitors are suggested.


The patient experience in community mental health services for older people: a concept mapping approach to support the development of a new quality measure.
The patient experience is a crucial part of the measurement of service quality. However, instruments to evaluate experiential quality in the community mental health care of older adults are lacking. Before designing a new instrument, clarity is needed about what is to be measured, and how care experiences are articulated by patients. The study aimed to construct a framework to describe older patients' experience of community mental health and social care. Concept mapping blends structured qualitative data collection with quantitative analysis in a mixed method approach. Five activities were undertaken. Patients first identified sentences describing the care experience; a card-sort exercise then grouped these thematically; multidimensional analysis portrayed these data in a map of clusters; interpretation was by patient advisers; finally a new questionnaire was designed. The research involved 22 older people with mental health problems and 29 mental health practitioners, from one region of England. Sixty-seven statements were identified that described the care experience. Analysis of card sort data revealed seven clusters, which were interpreted by patient advisers to the study as: personal qualities and relationships; communication problems; feeling powerless; in-and-out care; bureaucracy; focus on life, not just mental health; and continuity of care. These themes and the component statements were used as a foundation for later work, developing a new measure of the care experience in mental health services for older people. Concept mapping has many strengths as an empirical and participant-driven means for underpinning new measurement instruments. A group of older people identified 67 candidate statements that could act as questionnaire items grouped within seven themes. Future research will establish the psychometric properties of the new measure.


Pediatric Solid Tumor Care and Multidisciplinary Tumor Boards in Low- and Middle-Income Countries in Southeast Asia.
Pediatric solid tumors require coordinated multidisciplinary specialist care. However, expertise and resources to conduct multidisciplinary tumor boards (MDTBs) are lacking in low- and middle-income countries (LMICs). We aimed to profile the landscape of pediatric solid tumor care and practices and perceptions on MDTBs among pediatric solid tumor units (PSTUs) in Southeast Asian LMICs. Using online surveys, availability of specialty manpower and MDTBs among PSTUs was first determined. From the subset of PSTUs with MDTBs, one pediatric surgeon and one pediatric oncologist from each center were queried using 5-point Likert scale questions adapted from published questionnaires. In 37 (80.4%) of 46 identified PSTUs, availability of pediatric-trained specialists was as follows: oncologists, 94.6%; surgeons, 91.9%; radiologists, 54.1%; pathologists, 40.5%; radiation oncologists, 29.7%; nuclear medicine physicians, 13.5%; and nurses, 81.1%. Availability of pediatric-trained surgeons, radiologists, and pathologists was significantly associated with the existence of MDTBs (P = .037, .005, and .022, respectively). Among 43 (89.6%) of 48 respondents from 24 PSTUs with MDTBs, 90.5% of oncologists reported > 50% oncology-dedicated workload versus 22.7% of surgeons. Views on benefits and barriers did not significantly differ between oncologists and surgeons. The majority agreed that MDTBs helped to improve accuracy of treatment recommendations and team competence. Complex cases, insufficient radiology and pathology preparation, and need for supplementary investigations were the top barriers. This first known profile of pediatric solid tumor care in Southeast Asia found that availability of pediatric-trained subspecialists was a significant prerequisite for pediatric MDTBs in this region. Most PSTUs lacked pediatric-trained pathologists and radiologists. Correspondingly, gaps in radiographic and pathologic diagnoses were the most common limitations for MDTBs. Greater emphasis on holistic multidisciplinary subspecialty development is needed to advance pediatric solid tumor care in Southeast Asia.


Ras acts as a molecular switch between two forms of consolidated memory in Drosophila.
Long-lasting, consolidated memories require not only positive biological processes that facilitate long-term memories (LTM) but also the suppression of inhibitory processes that prevent them. The mushroom body neurons (MBn) in Drosophila melanogaster store protein synthesis-dependent LTM (PSD-LTM) as well as protein synthesis-independent, anesthesia-resistant memory (ARM). The formation of ARM inhibits PSD-LTM but the underlying molecular processes that mediate this interaction remain unknown. Here, we demonstrate that the Ras→Raf→rho kinase (ROCK) pathway in MBn suppresses ARM consolidation, allowing the formation of PSD-LTM. Our initial results revealed that the effects of Ras on memory are due to postacquisition processes. Ras knockdown enhanced memory expression but had no effect on acquisition. Additionally, increasing Ras activity optogenetically after, but not before, acquisition impaired memory performance. The elevated memory produced by Ras knockdown is a result of increased ARM. While Ras knockdown enhanced the consolidation of ARM, it eliminated PSD-LTM. We found that these effects are mediated by the downstream kinase Raf. Similar to Ras, knockdown of Raf enhanced ARM consolidation and impaired PSD-LTM. Surprisingly, knockdown of the canonical downstream extracellular signal-regulated kinase did not reproduce the phenotypes observed with Ras and Raf knockdown. Rather, Ras/Raf inhibition of ROCK was found to be responsible for suppressing ARM. Constitutively active ROCK enhanced ARM and impaired PSD-LTM, while decreasing ROCK activity rescued the enhanced ARM produced by Ras knockdown. We conclude that MBn Ras/Raf inhibition of ROCK suppresses the consolidation of ARM, which permits the formation of PSD-LTM.


Low-intensity eccentric contractions attenuate muscle damage induced by subsequent maximal eccentric exercise of the knee extensors in the elderly.
This study investigated whether low-intensity eccentric contractions of the knee extensors would attenuate the magnitude of muscle damage induced by maximal eccentric exercise of the same muscle performed 7 days later using elderly individuals. Healthy older men (66.4 ± 4.6 years) were assigned to control or experimental (Exp) group (n = 13 per group). The control group performed six sets of ten maximal eccentric contractions (MaxECC) of the knee extensors of non-dominant leg. The Exp group performed six sets of ten low-intensity eccentric contractions of the knee extensors on a leg extension machine by lowering a weight of 10 % maximal voluntary isometric knee extension strength (10 %ECC) 7 days prior to MaxECC. Changes in maximal voluntary isokinetic concentric torque (MVC-CON), angle at peak torque, range of motion (ROM), upper thigh circumference, muscle soreness, plasma creatine kinase activity and myoglobin (Mb) concentration and B-mode ultrasound echo-intensity before and for 5 days after MaxECC were compared between groups by a mixed factor ANOVA. No significant changes in any variables were observed following 10 %ECC. Following MaxECC, all variables changed significantly, and changes in all variables except for angle at peak torque were significantly different between groups. MVC-CON and ROM decreased smaller and recovered faster (P < 0.05) for Exp than control group, and changes in other variables were smaller (P < 0.05) for Exp group compared with control group. These results suggest that preconditioning knee extensor muscles with low-intensity eccentric contractions was effective for attenuating muscle damage induced by subsequent MaxECC of the knee extensors for elderly individuals.


Brain glucose metabolism in noninsulin-dependent diabetes mellitus: a study in Pima Indians using positron emission tomography during hyperinsulinemia with euglycemic glucose clamp.
To determine whether insulin or noninsulin-dependent diabetes mellitus affects brain glucose metabolism, brain glucose utilization was studied in the basal state and during hyperinsulinemic euglycemic glucose clamps in nondiabetic and diabetic Pima Indians by positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG). Glucose utilization in 75 brain areas was determined by analysis of single scans and by least squares estimation of the rate parameters for the FDG model; these data were compared to results in normal caucasian volunteers. No effect of ethnicity or diabetic status on brain glucose utilization was observed. During the hyperinsulinemic clamps (mean insulin, 11,708 +/- 3,026 pmol/L), clearance of 18FDG from blood was accelerated, and accumulation of brain radioactivity was reduced. However, glucose utilization by the brain was identical to results during sham glucose clamps (mean insulin, 204 +/- 56 pmol/L) performed in the same patients. During the studies with hyperinsulinemia, k4 (representing loss of tissue radioactivity) was increased in most brain areas (mean increase, 0.0031 +/- 0.0018 min-1; P less than 0.02). The possible mechanisms for this effect are multiple, and the physiological significance, if any, is unknown. Further studies of the effects of insulin on brain glucose metabolism are needed.


Characterization of the effects of prolactin in gonadotroph target cells.
Hyperprolactinemia is a major cause of infertility, brought about by inhibition of gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus and impairment of luteinizing hormone (LH) output from the pituitary gland. However, whereas the actions of prolactin (PRL) within the brain have been investigated extensively, its specific effects at the level of pituitary gonadotroph target cells remain unclear. Here, we provide evidence that the actions of PRL within the gonadotroph are more complex than originally envisaged. Using a gonadotroph cell monoculture, the first series of experiments showed that PRL is, paradoxically, a potent stimulator of LH release, with a three- to fourfold increase in LH values at hyperprolactinemic concentrations of PRL. Conversely, PRL dose-dependently modulated the LH secretory response to GnRH in a biphasic manner, with classical suppression of LH output only detected under a narrow dose range. In contrast, at all doses tested, PRL blocked the LHB mRNA response to the secretagogue. Subsequent studies revealed that the stimulatory effects of PRL on LH release are not mediated by the conventional cytokine receptor pathways but, rather, by a novel JAK2-PIK3-PKC-dependent signaling cascade. Moreover, the experiments showed that these actions of PRL within gonadotroph cells are controlled by dopamine, the main hypothalamic inhibitory regulator of PRL release in vivo. Our findings have unraveled specific actions of PRL within the gonadotroph and the cell-signaling interactions that ultimately underlie hyperprolactinemia-induced infertility.


Selective 5-HT1A and 5-HT2 receptor-mediated adrenocorticotropin release in the rat: effect of repeated antidepressant treatments.
The 5-HT receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced dose-dependent increases in plasma adrenocorticotropin (ACTH) in the male rat by activation of 5-HT1A and 5-HT2 receptors respectively. The ACTH response to DOI was enhanced by repeated administration of electroconvulsive shock (five over 10 days) but abolished by the tricyclic antidepressant, amitriptyline (20 mg/kg for 14 days). In contrast 21 days lithium treatment failed to alter DOI-induced ACTH release. Neither repeated electroconvulsive shock, nor amitriptyline, nor lithium altered the ACTH response to 8-OH-DPAT. These data are consistent with results from ligand binding and behavioural studies which suggest that the sensitivity of brain 5-HT2 receptors is increased by repeated electroconvulsive shock but attenuated by tricyclic antidepressant treatment. In contrast, our data suggest that the antidepressant treatments studied do not alter the sensitivity of the 5-HT1A receptors involved in ACTH release.


Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg . Canadian Implantable Defibrillator Study.
Three randomized trials of implantable cardioverter defibrillator (ICD) therapy vs medical treatment for the prevention of death in survivors of ventricular fibrillation or sustained ventricular tachycardia have been reported with what might appear to be different results. The present analysis was performed to obtain the most precise estimate of the efficacy of the ICD, compared to amiodarone, for prolonging survival in patients with malignant ventricular arrhythmia. Individual patient data from the Antiarrhythmics vs Implantable Defibrillator (AVID) study, the Cardiac Arrest Study Hamburg (CASH) and the Canadian Implantable Defibrillator Study (CIDS) were merged into a master database according to a pre-specified protocol. Proportional hazard modelling of individual patient data was used to estimate hazard ratios and to investigate subgroup interactions. Fixed effect meta-analysis techniques were also used to evaluate treatment effects and to assess heterogeneity across studies. The classic fixed effects meta-analysis showed that the estimates of ICD benefit from the three studies were consistent with each other (P heterogeneity=0.306). It also showed a significant reduction in death from any cause with the ICD; with a summary hazard ratio (ICD:amiodarone) of 0.72 (95% confidence interval 0.60, 0.87;P=0.0006). For the outcome of arrhythmic death, the hazard ratio was 0.50 (95% confidence interval 0.37, 0.67;P<0.0001). Survival was extended by a mean of 4.4 months by the ICD over a follow-up period of 6 years. Patients with left ventricular ejection fraction < or = 35% derived significantly more benefit from ICD therapy than those with better preserved left ventricular function. Patients treated before the availability of non-thoracotomy ICD implants derived significantly less benefit from ICD therapy than those treated in the non-thoracotomy era. Results from the three trials of the ICD vs amiodarone are consistent with each other. There is a 28% reduction in the relative risk of death with the ICD that is due almost entirely to a 50% reduction in arrhythmic death.


Neanderthal brain size at birth provides insights into the evolution of human life history.
From birth to adulthood, the human brain expands by a factor of 3.3, compared with 2.5 in chimpanzees [DeSilva J and Lesnik J (2006) Chimpanzee neonatal brain size: Implications for brain growth in Homo erectus. J Hum Evol 51: 207-212]. How the required extra amount of human brain growth is achieved and what its implications are for human life history and cognitive development are still a matter of debate. Likewise, because comparative fossil evidence is scarce, when and how the modern human pattern of brain growth arose during evolution is largely unknown. Virtual reconstructions of a Neanderthal neonate from Mezmaiskaya Cave (Russia) and of two Neanderthal infant skeletons from Dederiyeh Cave (Syria) now provide new comparative insights: Neanderthal brain size at birth was similar to that in recent Homo sapiens and most likely subject to similar obstetric constraints. Neanderthal brain growth rates during early infancy were higher, however. This pattern of growth resulted in larger adult brain sizes but not in earlier completion of brain growth. Because large brains growing at high rates require large, late-maturing, mothers [Leigh SR and Blomquist GE (2007) in Campbell CJ et al. Primates in perspective; pp 396-407], it is likely that Neanderthal life history was similarly slow, or even slower-paced, than in recent H. sapiens.


Lack of effect of tyrosine depletion on mood in recovered depressed women.
The role of dopamine (DA) pathways in the pathophysiology of depressive disorder is poorly understood. However, because DA plays a key role in motivational behavior, it is important to study in a disorder characterized by anhedonia, lack of energy and psychomotor retardation. A recently developed dietary manipulation ('tyrosine (TYR) depletion') offers a novel method to assess the role of DA in major depression. We studied 15 euthymic women with a past history of recurrent depression, who received a 74 g amino-acid drink lacking TYR and phenylalanine (PHE) (TYR-free) and a balanced (BAL) amino acid drink on two separate occasions in a double-blind, random-order, crossover design. Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, while performance on a spatial recognition memory task was impaired. However, relative to the BAL drink, the TYR-free drink did not lower objective or subjective measures of mood. We conclude that as in healthy volunteers, TYR depletion in euthymic subjects, with a past history of major depression, attenuated DA function, as reflected in increased plasma prolactin levels and decreased spatial memory performance. However ratings of depression were unaffected, suggesting that disruption of dopaminergic function by this manipulation does not induce a lowering of mood in individuals vulnerable to depression.


Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice.
The aim of this study is to identify the principal circulating factors that modulate atheromatous matrix metalloproteinase (MMP) activity in response to diet and exercise.Methods and Results:Apolipoprotein-E knock-out (ApoE-/-) mice (n=56) with pre-existing plaque, fed either a Western diet (WD) or normal diet (ND), underwent either 10 weeks of treadmill exercise or had no treatment. Atheromatous MMP activity was visualized using molecular imaging with a MMP-2/9 activatable near-infrared fluorescent (NIRF) probe. Exercise did not significantly reduce body weight, visceral fat, and plaque size in either WD-fed animals or ND-fed animals. However, atheromatous MMP-activity was different; ND animals that did or did not exercise had similarly low MMP activities, WD animals that did not exercise had high MMP activity, and WD animals that did exercise had reduced levels of MMP activity, close to the levels of ND animals. Factor analysis and path analysis showed that soluble vascular cell adhesion molecule (sVCAM)-1 was directly positively correlated to atheromatous MMP activity. Adiponectin was indirectly negatively related to atheromatous MMP activity by way of sVCAM-1. Resistin was indirectly positively related to atheromatous MMP activity by way of sVCAM-1. Visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation. MMP-2/9 imaging of additional mice (n=18) supported the diet/exercise-related anti-atherosclerotic roles for sVCAM-1. Diet and exercise affect atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat.


Transcranial magnetic stimulation in motor conversion disorder: a short case series.
The neurophysiologic mechanisms involved in nonorganic paralysis are unclear. Because there is no established standard therapy, the authors investigated the effect of repetitive transcranial magnetic stimulation (rTMS) in four patients with nonorganic limb paralysis. Within the framework of a treatment trial, the patients were treated over a period of 5-12 weeks with rTMS applied to the contralateral motor cortex. Stimulation frequency was 15 Hz, train length 2 seconds, intertrain interval 4 seconds; daily total number of stimuli 4000. In one patient, motor function was completely restored; two patients experienced a marked improvement correlating with rTMS treatment. By contrast, one patient who had been diagnosed as a malingerer did not improve. Apart from possible favorable psychological factors that could partly explain the rTMS-associated effects, high-frequency rTMS might have enhanced or substituted an insufficient input to the motor cortex from failing frontal executive areas, and thereby opened the way to a learning process that lead to the reacquisition of limb use. rTMS may have a therapeutic effect in motor conversion disorder and may help elucidate neurophysiologic aspects of this condition. The potential benefit of rTMS in motor conversion disorder should be evaluated in larger, controlled samples.


British women's attitudes towards oocyte donation: ethnic differences and altruism.
This study assessed the importance of altruism and willingness to donate oocytes in British Asian and Caucasian samples. The Theory of Planned Behaviour (TPB) was used to test the importance of attitudes towards oocyte donation, normative and control beliefs to attitudes to donate oocytes. One hundred and one participants (55% Asian, 45% Caucasian) completed questionnaires measuring altruism and attitudes to Oocyte donation. There were no socio-demographic differences between ethnic groups. Few women were willing to donate oocytes, Asian women were least likely to donate oocytes, and altruism was not related to willingness to donate. Forty-one participants considered themselves 'possible' oocyte donors and 54 as definite 'non' donors. Possible donors reported significantly more positive attitudes towards egg donation; asking women to donate under various circumstances; to the consequences of donating their eggs; positively experiencing egg donation and to factors that would induce women to donate. Subjective norms and behavioural control also influenced intention to donate. A number of components of the TPB were able to predict possible oocyte donation, and non-oocyte donation. This study provides some empirical support for specific factors influencing cultural differences in gamete donation in the UK. A future culturally appropriate targeted approach to donation education could redress the present imbalance in supply and demand of gametes in infertility treatment.


General conformal transformation method based on Schwarz-Christoffel approach.
A general conformal transformation method (CTM) is proposed to construct the conformal mapping between two irregular geometries. In order to find the material parameters corresponding to the conformal transformation between two irregular geometries, two polygons are utilized to approximate the two irregular geometries, and an intermediate geometry is used to connect the mapping relations between the two polygons. Based on these manipulations, the approximate material parameters for TE and TM waves are finally obtained by calculating the Schwarz-Christoffel (SC) mappings. To demonstrate the validity of the method, a phase modulator and a plane focal surface Luneburg lens are designed and simulated by the finite element method. The results show that the conformal transformation can be expanded to the cases that the transformed objects are with irregular geometries.


PIRCHE-II Is Related to Graft Failure after Kidney Transplantation.
Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.


Dynamics of single-layer polymer breath figures.
A single-layer of breath figure pattern was explored via the dynamical optical images and the temperature evolution. The pattern was prepared with the solution of carbon disulfide (CS(2)) dissolved 1% weight concentration of polystyrene. The evaporation of CS(2) was considered to be the most important role to the formation of the breath figure pattern. The understanding of the breath figures pattern will promote the technique to fabricating an imprinted template with demanded hexagonal structures.


Chronic exposure of imidacloprid and clothianidin reduce queen survival, foraging, and nectar storing in colonies of Bombus impatiens.
In an 11-week greenhouse study, caged queenright colonies of Bombus impatiens Cresson, were fed treatments of 0 (0 ppb actual residue I, imidacloprid; C, clothianidin), 10 (14 I, 9 C), 20 (16 I, 17C), 50 (71 I, 39 C) and 100 (127 I, 76 C) ppb imidacloprid or clothianidin in sugar syrup (50%). These treatments overlapped the residue levels found in pollen and nectar of many crops and landscape plants, which have higher residue levels than seed-treated crops (less than 10 ppb, corn, canola and sunflower). At 6 weeks, queen mortality was significantly higher in 50 ppb and 100 ppb and by 11 weeks in 20 ppb-100 ppb neonicotinyl-treated colonies. The largest impact for both neonicotinyls starting at 20 (16 I, 17 C) ppb was the statistically significant reduction in queen survival (37% I, 56% C) ppb, worker movement, colony consumption, and colony weight compared to 0 ppb treatments. Bees at feeders flew back to the nest box so it appears that only a few workers were collecting syrup in the flight box and returning the syrup to the nest. The majority of the workers sat immobilized for weeks on the floor of the flight box without moving to fed at sugar syrup feeders. Neonicotinyl residues were lower in wax pots in the nest than in the sugar syrup that was provided. At 10 (14) ppb I and 50 (39) ppb C, fewer males were produced by the workers, but queens continued to invest in queen production which was similar among treatments. Feeding on imidacloprid and clothianidin can cause changes in behavior (reduced worker movement, consumption, wax pot production, and nectar storage) that result in detrimental effects on colonies (queen survival and colony weight). Wild bumblebees depending on foraging workers can be negatively impacted by chronic neonicotinyl exposure at 20 ppb.


Pulsed EPR determination of the distance between heme iron and FMN centers in a human inducible nitric oxide synthase.
Mammalian nitric oxide synthase (NOS) is a homodimeric flavo-hemoprotein that catalyzes the oxidation of L-arginine to nitric oxide (NO). Regulation of NO biosynthesis by NOS is primarily through control of interdomain electron transfer (IET) processes in NOS catalysis. The IET from the flavin mononucleotide (FMN) to heme domains is essential in the delivery of electrons required for O(2) activation in the heme domain and the subsequent NO synthesis by NOS. The NOS output state for NO production is an IET-competent complex of the FMN-binding domain and heme domain, and thereby it facilitates the IET from the FMN to the catalytic heme site. The structure of the functional output state has not yet been determined. In the absence of crystal structure data for NOS holoenzyme, it is important to experimentally determine the Fe...FMN distance to provide a key calibration for computational docking studies and for the IET kinetics studies. Here we used the relaxation-induced dipolar modulation enhancement (RIDME) technique to measure the electron spin echo envelope modulation caused by the dipole interactions between paramagnetic FMN and heme iron centers in the [Fe(III)][FMNH(*)] (FMNH(*): FMN semiquinone) form of a human inducible NOS (iNOS) bidomain oxygenase/FMN construct. The FMNH(*)...Fe distance has been directly determined from the RIDME spectrum. This distance (18.8 +/- 0.1 A) is in excellent agreement with the IET rate constant measured by laser flash photolysis [Feng, C. J.; Dupont, A.; Nahm, N.; Spratt, D.; Hazzard, J. T.; Weinberg, J.; Guillemette, J.; Tollin, G.; Ghosh, D. K. J. Biol. Inorg. Chem. 2009, 14, 133-142].


Left-handed extraordinary optical transmission through a photonic crystal of subwavelength hole arrays.
Metamaterial structures are artificial materials that show unconventional electromagnetic properties such as photonic band-gap, extraordinary optical transmission and left-handed propagation. Up to now, relations of photonic crystals and negative refraction have been shown as well as of photonic crystals and sub-wavelength hole arrays. Here we report a left-handed metamaterial engineered by a combination of sub-wavelength hole array plates periodically stacked to form a photonic crystal structure. It is shown the possibility of fine-tuning the metamaterial in order to permit extraordinary optical transmission and left-handed behaviour. Our work demonstrates the feasibility of engineering left-handed metamaterials by just drilling holes in metallic plates and brings together single structure photonic crystals, extraordinary optical transmission and left-handed behaviour.


Differential immunodiagnosis between cystic hydatid disease and other cross-reactive pathologies.
We assessed an Echinococcus granulosus hydatid fluid antigen-ELISA (EgHF-ELISA) as a serologic prescreening test for E. granulosus infections, supplemented by more specific confirmatory tests, including arc-5 immunoprecipitation and antigen B subunit 8-kD immunoblotting. The diagnostic sensitivity of the EgHF-ELISA was 91%. With regard to the test specificity of the EgHF-ELISA (overall = 82%), we observed relatively frequent cross-reactions in tumor patients (6%) and in patients with other parasitic diseases. Cestode-related cross-reactivity can be resolved by the complementary use of E. multilocularis-specific antigens or Taenia solium cysticercosis-specific immunoblotting. Immunoblotting based upon the detection of antibody reactivity to the 8-kD antigen of EgHF, or if appropriately detectable, to the 29-kD and 34-kD bands exhibited a 91% diagnostic sensitivity and an overall specificity of 97% or 94%, respectively. Thus, immunoblotting provided a 99% discrimination between seropositive pre-operative cystic hydatid disease cases and cross-reactive non-cestode parasitic infections or malignancies.


Saccharomyces cerevisiae modulates immune gene expressions and inhibits ETEC-mediated ERK1/2 and p38 signaling pathways in intestinal epithelial cells.
Enterotoxigenic Escherichia coli (ETEC) infections result in large economic losses in the swine industry worldwide. ETEC infections cause pro-inflammatory responses in intestinal epithelial cells and subsequent diarrhea in pigs, leading to reduced growth rate and mortality. Administration of probiotics as feed additives displayed health benefits against intestinal infections. Saccharomyces cerevisiae (Sc) is non-commensal and non-pathogenic yeast used as probiotic in gastrointestinal diseases. However, the immuno-modulatory effects of Sc in differentiated porcine intestinal epithelial cells exposed to ETEC were not investigated. We reported that the yeast Sc (strain CNCM I-3856) modulates transcript and protein expressions involved in inflammation, recruitment and activation of immune cells in differentiated porcine intestinal epithelial IPEC-1 cells. We demonstrated that viable Sc inhibits the ETEC-induced expression of pro-inflammatory transcripts (IL-6, IL-8, CCL20, CXCL2, CXCL10) and proteins (IL-6, IL-8). This inhibition was associated to a decrease of ERK1/2 and p38 MAPK phosphorylation, an agglutination of ETEC by Sc and an increase of the anti-inflammatory PPAR-γ nuclear receptor mRNA level. In addition, Sc up-regulates the mRNA levels of both IL-12p35 and CCL25. However, measurement of transepithelial electrical resistance displayed that Sc failed to maintain the barrier integrity in monolayer exposed to ETEC suggesting that Sc does not inhibit ETEC enterotoxin activity. Sc (strain CNCM I-3856) displays multiple immuno-modulatory effects at the molecular level in IPEC-1 cells suggesting that Sc may influence intestinal inflammatory reaction.


Differential feedback regulation of cholesterol 7 alpha-hydroxylase mRNA and transcriptional activity by rat bile acids in primary monolayer cultures of rat hepatocytes.
We have used primary monolayer cultures of rat hepatocytes to study the effects of physiological concentrations of various bile acids, commonly found in bile of normal rats, on the mechanism of regulation of cholesterol 7 alpha-hydroxylase and bile acid synthesis. Addition of taurocholic acid, the most predominant bile acid in rat bile, to the culture medium suppressed cholesterol 7 alpha-hydroxylase activity and mRNA time- and dose-dependently. The decrease in enzyme activity paralleled the changes in mRNA. Maximal suppression of cholesterol 7 alpha-hydroxylase mRNA (-91%) and enzyme activity (-89%) was observed after a 16 h incubation period with 50 microM taurocholic acid. The declines in mRNA and enzyme caused by taurocholic acid were tightly coupled and followed first-order kinetics with a half-life of 4 h. Transcriptional activity, as assessed with nuclear run-on assays, was decreased by 44% at 50 microM taurocholic acid. Mass production of bile acids (chenodeoxycholic acid and beta-muricholic acid) was inhibited to a similar extent as the cholesterol 7 alpha-hydroxylase when different concentrations of taurocholic acid were used, giving maximal inhibition (-81%) at 50 microM taurocholic acid. Glycocholic acid and unconjugated cholic acid were equally effective as taurocholic acid in suppressing cholesterol 7 alpha-hydroxylase mRNA. The more hydrophobic bile acids (chenodeoxycholic acid and deoxycholic acid) showed profound suppression of the cholesterol 7 alpha-hydroxylase mRNA by 85% and 75% respectively, whereas the other trihydroxy bile acids in rat bile, alpha- and beta-muricholic acid, were not or only marginally active. We conclude that rat bile acids, in particular the more hydrophobic ones, in concentrations commonly observed in portal blood, exert negative feedback control at the level of cholesterol 7 alpha-hydroxylase mRNA in cultured rat hepatocytes through a direct effect on the hepatocytes, and that down-regulation of transcription is only one of the mechanisms involved in this regulation.


An experiential theory of spiritual care in nursing practice.
Spiritual care has been recognized as integral to nursing care for centuries, as described by Florence Nightingale, and has been studied in both medicine and sociology. Health care institutions, particularly faith-based health systems, also have recognized the importance of spiritual care. Both qualitative and quantitative research support the importance of spirituality in patient health. Although the profession, health care institutions, and research support spiritual care, there is no empirically derived theoretical framework to guide research in spiritual assessment and spiritual care. We used focus group data from registered nurses who care for the chronically ill (n = 25) in a large Midwestern academic health center to generate a grounded theory of spiritual care in nursing practice. What emerged from this study was a beginning theoretical framework to guide future spiritual care research.


In the Absence of a Mechanical Bowel Prep, Does the Addition of Pre-Operative Oral Antibiotics to Parental Antibiotics Decrease the Incidence of Surgical Site Infection after Elective Segmental Colectomy?
Pre-operative oral antibiotics administered the day prior to elective colectomy have been shown to decrease the incidence of surgical site infections (SSI) if a mechanical bowel prep (MBP) is used. Recently, the role for mechanical bowel prep has been challenged as being unnecessary and potentially harmful. We hypothesize that if MBP is omitted, oral antibiotics do not alter the incidence of SSI following colectomy. We selected patients who underwent an elective segmental colectomy from the 2012 and 2013 National Surgical Quality Improvement Program colectomy procedure targeted database. Indications for surgery included colon cancer, diverticulitis, inflammatory bowel disease, or benign polyp. Patients who received mechanical bowel prep were excluded. The primary outcome measured was surgical site infection, defined as the presence of superficial, deep or, organ space infection within 30 d from surgery. A total of 6,399 patients underwent elective segmental colectomy without MBP. The incidence of SSI differed substantially between patients who received oral antibiotics, versus those who did not (9.7% vs. 13.7%, p=0.01). Multivariate analysis indicated that age, smoking status, operative time, perioperative transfusions, oral antibiotics, and surgical approach were associated with post-operative SSI. When controlling for confounding factors, the use of pre-operative oral antibiotics decreased the incidence of surgical site infection (odds ratio=0.66, 95% confidence interval=0.48-0.90, p=0.01). Even in the absence of mechanical bowel prep, pre-operative oral antibiotics appear to reduce the incidence of surgical site infection following elective colectomy.


Predictors and grade level trends of school day physical activity achievement in low-income children from the U.S.
The achievement of recommended levels (≥ 30 min/day) of school moderate-to-vigorous physical activity (MVPA) is paramount to decrease risk of chronic disease in children from low-income families. The purpose of this study was to examine the predictors and grade-level trends of school day MVPA achievement in low-income children. Data were collected during the Fall of 2014 on 1232 children (Mean age = 8.8 ± 1.6 years; 625 girls, 607 boys) recruited from three low-income schools from the state of Utah in the U.S. Children wore pedometers for one school week and a stratified random subsample (n = 533) also wore accelerometers to record sedentary time and MVPA. Generalized linear mixed models were employed to calculate odds ratios for achieving school MVPA standards (≥ 30 min/day) from various predictors and to determine odds of achievement across grade levels, accounting for school and classroom clustering. Odds of meeting MVPA standards were 3 times greater if a student achieved at least 6000 steps during the school day (p < 0.01), and were 55% lower for every 1% increase in sedentary time (p < 0.001). Older children had 26% lower odds of meeting the recommended levels of MVPA compared to children in an immediately younger grade level (p < 0.05). A significant proportion of MVPA variance was explained by classroom and school affiliation (Rho = 0.09 to 0.54, p < 0.001). Daily steps, sedentary times, grade level, and classroom and school affiliation associate with school MVPA achievement in low-income children.


Understanding the electric and magnetic response of isolated metaatoms by means of a multipolar field decomposition.
We introduce a technique to decompose the scattered near field of two-dimensional arbitrary metaatoms into its multipole contributions. To this end we expand the scattered field upon plane wave illumination into cylindrical harmonics as known from Mie's theory. By relating these cylindrical harmonics to the field radiated by Cartesian multipoles, the contribution of the lowest order electric and magnetic multipoles can be identified. Revealing these multipoles is essential for the design of metamaterials because they largely determine the character of light propagation. In particular, having this information at hand it is straightforward to distinguish between effects that result either from the arrangement of the metaatoms or from their particular design.


Enhanced differentiation of human osteoblasts on Ti surfaces pre-treated with human whole blood.
Early and effective integration of a metal implant into bone tissue is of crucial importance for its long-term stability. While different material properties including surface roughness and wettability but also initial blood-implant surface interaction are known to influence this osseointegration, implications of the latter process are still poorly understood. In this study, early interaction between blood and the implant surface and how this affects the mechanism of osseointegration were investigated. For this, blood coagulation on a micro-roughened hydrophobic titanium (Ti) surface (SLA-H(phob)) and on a hydrophilic micro-roughened Ti surface with nanostructures (SLActive-H(phil)NS), as well as the effects of whole human blood pre-incubation of these two surfaces on the differentiation potential of primary human bone cells (HBC) was assessed. Interestingly, pre-incubation with blood resulted in a dense fibrin network over the entire surface on SLActive-H(phil)NS but only in single patches of fibrin and small isolated fibre complexes on SLA-H(phob). On SLActive-H(phil)NS, the number of HBCs attaching to the fibrin network was greatly increased and the cells displayed enhanced cell contact to the fibrin network. Notably, HBCs displayed increased expression of the osteogenic marker proteins alkaline phosphatase and collagen-I when cultivated on both surfaces upon blood pre-incubation. Additionally, blood pre-treatment promoted an earlier and enhanced mineralization of HBCs cultivated on SLActive-H(phil)NS compared to SLA-H(phob). The results presented in this study therefore suggest that blood pre-incubation of implant surfaces mimics a more physiological situation, eventually providing a more predictive in vitro model for the evaluation of novel bone implant surfaces.


Modeling Pressure-Driven Transport of Proteins through a Nanochannel.
Reducing the size of a nanofluidic channel not only creates new opportunities for high-precision manipulation of biological macromolecules, but also makes the performance of the entire nanofluidic system more susceptible to undesirable interactions between the transported biomolecules and the walls of the channel. In this manuscript, we report molecular dynamics simulations of a pressure-driven flow through a silica nanochannel that characterized, with atomic resolution, adsorption of a model protein to its surface. Although the simulated adsorption of the proteins was found to be nonspecific, it had a dramatic effect on the rate of the protein transport. To determine the relative strength of the protein-silica interactions in different adsorbed states, we simulated flow-induced desorption of the proteins from the silica surface. Our analysis of the protein conformations in the adsorbed states did not reveal any simple dependence of the adsorption strength on the size and composition of the protein-silica contact, suggesting that the heterogeneity of the silica surface may be a important factor.


Alternate succession of steps can lead to the folding of a multidomain oligomeric protein.
The beta 2 subunit of Escherichia coli tryptophan synthase can be either unfolded in 6 M guanidine, or extensively denatured at acidic pH. These two denatured forms of beta 2 have different circular dichroism spectra and thus correspond to distinct physical states. Here we compare the folding pathways of these two different denatured forms of beta chains. We describe the kinetics of regain of a variety of physical, functional, and immunochemical signals characteristic of six successive steps previously identified on the folding pathway of guanidine unfolded beta 2. It is shown that whereas identical molecular events occur with the same kinetics, the two folding pathways are different, and involve different structural intermediates.


UPLC-ESI-QTOF/MS and multivariate data analysis for blood plasma and serum metabolomics: effect of experimental artefacts and anticoagulant.
Clotting and anticoagulation of blood samples may give rise to different metabolic profiles of serum and plasma samples, respectively. The anticoagulant used for blood plasma preparation may affect the resulting metabolic profile due to different mechanisms involved in anticoagulation by various agents, e.g. heparin, EDTA and citrate. In the present study, we looked into metabolite and other differences in matched serum and plasma samples and different plasma preparations by using untargeted UPLC-ESI-QTOF/MS profiling and multivariate data analysis (PCA and OPLS-DA). Metabolite differences between serum and plasma samples were mainly related to small peptides reflecting presence or absence of coagulation. Only subtle metabolite differences between the different plasma preparations were noticed, which were primarily related to ion suppression or enhancement caused by citrate and EDTA anticoagulants. For the first time, we also report that anticoagulant counter cation (Na+ or K+) in Na-citrate and K-EDTA plasma can make some metabolites more dominant in ESI-MS. Polymeric material residues originating from blood collection tubes for serum preparation were observed only in serum samples. Hypoxanthine and xanthine were found at higher levels in serum than in plasma samples, possibly due to release from the clot. Mass spectral features of sodium formate and potassium formate ion clusters were detected in citrate and EDTA plasma samples, respectively, originating from formate in mobile phase and Na(+) (in Na-citrate tubes) and K(+) (in K-EDTA tubes). Among the anticoagulants, heparin is recommended for plasma samples used for LC-ESI/MS-based metabolomics of hydrophilic compounds because no plasma interferences or matrix effects were noticed for this polarity range. Citrate and EDTA should be avoided since interferences and serious matrix effects were encountered on some co-eluting polar metabolites. Serum is recommended as a second choice and an alternative to plasma. In conclusion, heparin plasma or serum should be the order of best choice for LC-ESI/MS-based metabolomics research.


Use of fluorescence resonance energy transfer to investigate the conformation of DNA substrates bound to the Klenow fragment.
Fluorescence resonance energy transfer (FRET) has been used to investigate the conformation of the single stranded region for a series of fluorescent DNA template-primers bound to the Klenow fragment (KF) of Escherichia coli DNA polymerase I. Fluorescent derivatives of template-primer DNA, modified with tetramethylrhodamine (TMR), served as energy transfer acceptors to the donor fluorescein fluorophore used to modify cysteine 751 in the double mutant KF (S751C, C907S). Design of the template-primer allowed the probe's position within the DNA-protein complex to be varied by stepwise extension of the primer strand upon addition of the appropriate deoxynucleoside triphosphates (dNTP). The TMR acceptor probe occupied seven different positions in the template-primers, five in the single stranded region and two in the double stranded region. The efficiency of energy transfer was determined at each position by calculating the integrated area of the fluorescein emission peak in the presence and absence of acceptor. Results indicate that the FRET efficiency varied in a sinusoidal fashion with a periodicity of approximately 10 base pairs and that the data could be fitted to an equation derived from a simple model formulated on the basis of helical structure. The data support the conclusion that the single stranded template portion of a DNA template-primer adopts a helical conformation when bound to the KF. The results of this study further support FRET as a useful method for the determination of structure and conformation in protein-DNA complexes.


Reproductive health voucher program and facility based delivery in informal settlements in Nairobi: a longitudinal analysis.
In Kenya, the maternal mortality rate had ranged from 328 to 501 deaths per 100,000 live births over the last three decades. To reduce these rates, the government launched in 2006 a means-tested reproductive health output-based approach (OBA) voucher program that covers costs of antenatal care, a facility-based delivery (FBD) and a postnatal visit in prequalified healthcare facilities. This paper investigated whether women who bought the voucher for their index child and had a FBD were more likely to deliver a subsequent child in a facility compared to those who did not buy vouchers. We used population-based cohort data from two Nairobi slums where the voucher program was piloted. We selected mothers of at least two children born between 2006 and 2012 and divided the mothers into two groups: Index-OBA mothers bought the voucher for the index child (N=352), and non-OBA mothers did not buy the voucher during the study period (N=514). The most complete model indicated that the adjusted odds-ratio of FBD of subsequent child when the index child was born in a facility was 3.89 (p<0.05) and 4.73 (p<0.01) in Group 2. The study indicated that the voucher program improved poor women access to FBD. Furthermore, the FBD of an index child appeared to have a persistent effect, as a subsequent child of the same mother was more likely to be born in a facility as well. While women who purchased the voucher have higher odds of delivering their subsequent child in a facility, those odds were smaller than those of the women who did not buy the voucher. However, women who did not buy the voucher were less likely to deliver in a good healthcare facility, negating their possible benefit of facility-based deliveries. Pathways to improve access to FBD to all near poor women are needed.


A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy. In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality. Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure. In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)


Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease.
Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Citrullinated proteins are observed in RA lung tissues; however, the association of specific anticitrullinated peptide antibodies (ACPA) with ILD in RA is unknown. RA patients underwent multidetector CT (MDCT) of the chest, from which ILD features and a semiquantitative ILD Score (ILDS; range 0-32) were assessed. Anti-CCP (CCP2) and levels of a panel of antibodies against 17 citrullinated and four non-citrullinated peptides were assessed from concurrent serum samples using a custom Bio-Plex bead array. High level ACPA was defined as ≥the group 75th percentile. Among the 177 RA patients studied, median levels of CCP2 and all specific ACPAs were 46-273% higher among RA patients with versus those without ILD (all p values <0.05), and higher levels correlated with higher ILDS. In contrast, levels of non-citrullinated protein antibodies were not higher in those with ILD. RA patients had a median of 2 high level ACPA reactivities (range 0-16), with each high level ACPA associated, on average, with a 0.10 unit higher ILDS (p=0.001). This association remained significant after adjusting for characteristics associated with ILD (age, gender, current and former smoking, Disease Activity Score for 28 joints, current prednisone and leflunomide use). More high level ACPA were observed in those with versus without pulmonary function restriction or impaired diffusion. Our findings of a broader ACPA repertoire in RA ILD suggest a possible role for ACPA in the pathogenesis of ILD.


Technologies for localization and diagnosis of prostate cancer.
The gold standard for detecting prostate cancer (PCa), systematic biopsy, lacks sensitivity as well as grading accuracy. PSA screening leads to over-treatment of many men, and it is unclear whether screening reduces PCa mortality. This review provides an understanding of the difficulties of localizing and diagnosing PCa. It summarizes recent developments of ultrasound (including elastography) and MRI, and discusses some alternative experimental techniques, such as resonance sensor technology and vibrational spectroscopy. A comparison between the different methods is presented. It is concluded that new ultrasound techniques are promising for targeted biopsy procedures, in order to detect more clinically significant cancers while reducing the number of cores. MRI advances are very promising, but MRI remains expensive and MR-guided biopsy is complex. Resonance sensor technology and vibrational spectroscopy have shown promising results in vitro. There is a need for large prospective multicentre trials that unambiguously prove the clinical benefits of these new techniques.


Environmentally stable, simple passively mode-locked fiber ring laser using a four-port circulator.
We present here a self-starting passively mode-locked fiber ring laser with a novel cavity configuration using a four-port optical circulator. Our special ring cavity design enables highly stable mode-locked operation between 25 and 60 degrees C to be maintained without the need for any polarization-adjusting devices. The pulse width and the integrated timing jitter from 10 Hz to 10 MHz of our fiber ring laser were measured to be 120 fs and 39.1 fs, respectively. As a result, a robust and environmentally stable all-fiber mode-locked fiber ring laser with a simple ring cavity configuration in a small package has been achieved.


Addressing COVID-19 in humanitarian settings: a call to action.
Refugees and internally displaced persons in humanitarian settings are particularly susceptible to the spread of infectious illnesses such as COVID-19 due to overcrowding and inadequate access to clean water, sanitation, and hygiene facilities. Countries facing conflict or humanitarian emergencies often have damaged or fragmented health systems and little to no capacity to test, isolate, and treat COVID-19 cases. Without a plan to address COVID-19 in humanitarian settings, host governments, aid agencies, and international organizations risk prolonging the spread of the virus across borders, threatening global health security, and devastating vulnerable populations. Stakeholders must coordinate a multifaceted response to address COVID-19 in humanitarian settings that incorporates appropriate communication of risks, sets forth resource-stratified guidelines for the use of limited testing, provides resources to treat affected patients, and engages displaced populations.


Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.
3-Phosphoinositide-dependent protein kinase-1 (PDK1) interacts stereoselectively with the d-enantiomer of PtdIns(3,4,5)P3 (KD 1.6 nM) and PtdIns(3,4)P2 (KD 5.2 nM), but binds with lower affinity to PtdIns3P or PtdIns(4,5)P2. The binding of PtdIns(3,4,5)P3 to PDK1 was greatly decreased by making specific mutations in the pleckstrin homology (PH) domain of PDK1 or by deleting it. The same mutations also greatly decreased the rate at which PDK1 activated protein kinase Balpha (PKBalpha) in vitro in the presence of lipid vesicles containing PtdIns(3,4,5)P3, but did not affect the rate at which PDK1 activated a PKBalpha mutant lacking the PH domain in the absence of PtdIns(3,4,5)P3. When overexpressed in 293 or PAE cells, PDK1 was located at the plasma membrane and in the cytosol, but was excluded from the nucleus. Mutations that disrupted the interaction of PtdIns(3,4,5)P3 or PtdIns(4,5)P2 with PDK1 abolished the association of PDK1 with the plasma membrane. Growth-factor stimulation promoted the translocation of transfected PKBalpha to the plasma membrane, but had no effect on the subcellular distribution of PDK1 as judged by immunoelectron microscopy of fixed cells. This conclusion was also supported by confocal microscopy of green fluorescent protein-PDK1 in live cells. These results, together with previous observations, indicate that PtdIns(3,4,5)P3 plays several roles in the PDK1-induced activation of PKBalpha. First, it binds to the PH domain of PKB, altering its conformation so that it can be activated by PDK1. Secondly, interaction with PtdIns(3,4,5)P3 recruits PKB to the plasma membrane with which PDK1 is localized constitutively by virtue of its much stronger interaction with PtdIns(3,4,5)P3 or PtdIns(4,5)P2. Thirdly, the interaction of PDK1 with PtdIns(3,4,5)P3 facilitates the rate at which it can activate PKB.


Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma.
Environmental or lifestyle exposures in utero may influence the development of childhood asthma. In this meta-analysis, we aimed to assess whether maternal obesity in pregnancy (MOP) or increased maternal gestational weight gain (GWG) increased the risk of asthma in offspring. We included all observational studies published until October 2013 in PubMed, Embase, CINAHL, Scopus, The Cochrane Database, and Ovid. Random effects models with inverse variance weights were used to calculate pooled risk estimates. Fourteen studies were included (N = 108 321 mother-child pairs). Twelve studies reported maternal obesity, and 5 reported GWG. Age of children was 14 months to 16 years. MOP was associated with higher odds of asthma or wheeze ever (OR = 1.31; 95% confidence interval [CI], 1.16-1.49) or current (OR = 1.21; 95% CI, 1.07-1.37); each 1-kg/m(2) increase in maternal BMI was associated with a 2% to 3% increase in the odds of childhood asthma. High GWG was associated with higher odds of asthma or wheeze ever (OR = 1.16; 95% CI, 1.001-1.34). Maternal underweight and low GWG were not associated with childhood asthma or wheeze. Meta-regression showed a negative association of borderline significance for maternal asthma history (P = .07). The significant heterogeneity among existing studies indicates a need for standardized approaches to future studies on the topic. MOP and high GWG are associated with an elevated risk of childhood asthma; this finding may be particularly significant for mothers without asthma history. Prospective randomized trials of maternal weight management are needed.


Are medical students in prehospital care at risk of moral injury?
The term 'moral injury' may be useful in conceptualising the negative psychological effects of delivering emergency and prehospital medicine as it provides a non-pathological framework for understanding these effects. This is in contrast to concepts such as burnout and post-traumatic stress disorder which suggest practitioners have reached a crisis point. We conducted an exploratory, pilot study to determine whether the concept of moral injury resonated with medical students working in emergency medicine and what might mitigate that injury for them. Structured interviews and focus groups were carried out with medical students involved in the delivery of prehospital and emergency medicine. The study was carried out at Barts and the London School of Medicine and Dentistry in May and June 2017. The data were analysed using theoretically driven thematic analysis. Concepts of moral injury such as witnessing events which contravene one's moral code, especially those involving children, or acts of violence, resonated with the experiences of medical students in this study. Participants stated that having more medical knowledge and a clear sense of a job to do on scene helped reduce their distress at the time. While social support was a protective factor, not all students found the process of debrief easy to access or undergo, those with more established relationships with colleagues fared better in this regard. The term moral injury is useful in exploring the experience of medical students in emergency medicine. More effort should be made to ensure that students effectively access debrief and other support opportunities. It is hoped that future work will be undertaken with different professional groups and explore the potential psychological and neuropsychological impact of witnessing trauma.


CAR T-Cell Therapy: Adverse Events and Management.
Chimeric antigen receptor (CAR) T-cell therapy is an exciting innovation in the treatment of cancer. However, CAR T-cell therapies have been associated with unique adverse events (AEs), including cytokine release syndrome (CRS) and neurologic events (also known as CAR T-cell-related encephalopathy syndrome [CRES] or, most recently, immune effector cell-associated neurotoxicity syndrome [ICANS]). Cytopenias and infection have also been observed. These AEs are treatable and reversible with appropriate treatment strategies but can become severe if not managed early. Therefore, it is essential for the advanced practitioner caring for patients undergoing these therapies to have a thorough understanding of the associated AEs, in particular their grading and management. Cytokine release syndrome and neurologic events can range in severity from low-grade symptoms that require supportive care only to a high-grade syndrome that can become life-threatening. While several grading and management recommendations have been used in clinical trials, until recently, there were no consistent grading and management guidelines. Here we provide the most recent recommendations, which have the ultimate goal of maintaining the benefits of CAR T-cell therapy, while minimizing life-threatening AEs. Improved understanding and management of AEs associated with CAR T-cell therapy will provide broader access to this innovative and potentially curative technology.


Predictors of psychosocial adaptation among people with spinal cord injury or disorder.
To examine the influence of disability-related medical and psychologic variables on psychosocial adaptation to spinal cord injury or disorder (SCI/D). A structural equation modeling design linking 3 sets of predictive variables to an outcome measure of adaptation. Two outpatient SCI clinics (1 veteran, 1 civilian) in Texas. Veterans (n=181) and civilians (n=132) with SCI/D. Not applicable. The adaptation outcome was measured by 2 subscales (acknowledgment, adjustment) of the Reactions to Impairment and Disability Inventory (RIDI) and by the Quality of Life Scale. The predictive variables were measured by a demographic questionnaire, 3 subscales (intrusion, re-experiencing, hyperarousal) of the Purdue Posttraumatic Stress Disorder-Revised scale, the McMordie-Templer Death Anxiety Scale, and 3 subscales (anxiety, depression, denial) of the RIDI. Goodness-of-fit indices suggested that a revised model of adaptation was a moderately good fit to the data. The revised model of adaptation indicated that there were medium total effects (direct plus indirect) on psychosocial adaptation by 2 latent variables (disability severity and impact, negative affectivity) and small total effects on psychosocial adaptation by disengagement coping. The latent factor of disengagement coping had the strongest direct effect on adaptation (although not statistically significant). Disability severity and impact had medium indirect effects and negative affectivity had small indirect effects on psychosocial adaptation. All of the aforementioned effects had a negative coefficient. Negative emotional responses (eg, depression, anxiety) to SCI/D, disengagement-type coping (eg, disability denial, avoidance), and the severity and impact of disability were related to lower levels of adaptation to SCI/D.


Urea host monomers for stoichiometric molecular imprinting of oxyanions.
A series of urea-based vinyl monomers was synthesized and investigated for their ability to function as polymerizable hosts for the molecular imprinting of N-Z-D- or L-glutamic acid in polar media (DMSO or DMF). The monomers were synthesized in one step from a polymerizable isocyanate and a nonpolymerizable amine or vice versa, with yields typically over 70%. Prior to polymerization their solution binding properties vis-a-vis tetrabutylammonium benzoate in DMSO were investigated by 1H NMR, UV-vis and fluorescence monitored titrations. The affinities of the urea monomers for benzoate depended upon the substitution pattern of the urea, with all diaryl ureas exhibiting high affinity. EDMA-based imprinted polymers prepared in DMF or DMSO against Z-D-(or L)-glutamic acid using 2 equiv of the urea monomer and 2 equiv of base were able to recognize the imprinted dianion as well as larger molecules containing the glutamic acid substructure. The affinity, reflected in liquid chromatography retention data, correlated with the solution binding properties of the corresponding monomers.


Enzymatic Assemblies Disrupt the Membrane and Target Endoplasmic Reticulum for Selective Cancer Cell Death.
The endoplasmic reticulum (ER) is responsible for the synthesis and folding of a large number of proteins, as well as intracellular calcium regulation, lipid synthesis, and lipid transfer to other organelles, and is emerging as a target for cancer therapy. However, strategies for selectively targeting the ER of cancer cells are limited. Here we show that enzymatically generated crescent-shaped supramolecular assemblies of short peptides disrupt cell membranes and target ER for selective cancer cell death. As revealed by sedimentation assay, the assemblies interact with synthetic lipid membranes. Live cell imaging confirms that the assemblies impair membrane integrity, which is further supported by lactate dehydrogenase (LDH) assays. According to transmission electron microscopy (TEM), static light scattering (SLS), and critical micelle concentration (CMC), attaching an l-amino acid at the C-terminal of a d-tripeptide results in the crescent-shaped supramolecular assemblies. Structure-activity relationship suggests that the crescent-shaped morphology is critical for interacting with membranes and for controlling cell fate. Moreover, fluorescent imaging indicates that the assemblies accumulate on the ER. Time-dependent Western blot and ELISA indicate that the accumulation causes ER stress and subsequently activates the caspase signaling cascade for cell death. As an approach for in situ generating membrane binding scaffolds (i.e., the crescent-shaped supramolecular assemblies), this work promises a new way to disrupt the membrane and to target the ER for developing anticancer therapeutics.