Snakin-1 affects reactive oxygen species and ascorbic acid levels and hormone balance in potato.
Snakin-1 is a member of the Solanum tuberosum Snakin/GASA family. We previously demonstrated that Snakin-1 is involved in plant defense to pathogens as well as in plant growth and development, but its mechanism of action has not been completely elucidated yet. Here, we showed that leaves of Snakin-1 silenced potato transgenic plants exhibited increased levels of reactive oxygen species and significantly reduced content of ascorbic acid. Furthermore, Snakin-1 silencing enhanced salicylic acid content in accordance with an increased expression of SA-inducible PRs genes. Interestingly, gibberellic acid levels were also enhanced and transcriptome analysis revealed that a large number of genes related to sterol biosynthesis were downregulated in these silenced lines. Moreover, we demonstrated that Snakin-1 directly interacts with StDIM/DWF1, an enzyme involved in plant sterols biosynthesis. Additionally, the analysis of the expression pattern of PStSN1::GUS in potato showed that Snakin-1 is present mainly in young tissues associated with active growth and cell division zones. Our comprehensive analysis of Snakin-1 silenced lines demonstrated for the first time in potato that Snakin-1 plays a role in redox balance and participates in a complex crosstalk among different hormones.


Spontaneous emulsification and self-propulsion of oil droplets induced by the synthesis of amino acid-based surfactants.
It is well known that oil droplets in or on water exhibit spontaneous movement induced by surfactants, and this self-propulsion is regarded as an important factor in droplet-based models for a living cell. We report here an oil-droplet system spontaneously producing amino acid-based surfactants, which are then utilized for the droplets' self-propulsion. Thus this system is an active system capable of producing the fuel for the propulsion by itself, which can be used as a conceptual model for cell metabolism.


Data-driven learning and prediction of inorganic crystal structures.
Crystal structure prediction algorithms, including ab initio random structure searching (AIRSS), are intrinsically limited by the huge computational cost of the underlying quantum-mechanical methods. We have recently shown that a novel class of machine learning (ML) based interatomic potentials can provide a way out: by performing a high-dimensional fit to the ab initio energy landscape, these potentials reach comparable accuracy but are orders of magnitude faster. In this paper, we develop our approach, dubbed Gaussian approximation potential-based random structure searching (GAP-RSS), towards a more general tool for exploring configuration spaces and predicting structures. We present a GAP-RSS interatomic potential model for elemental phosphorus, which identifies and correctly "learns" the orthorhombic black phosphorus (A17) structure without prior knowledge of any crystalline allotropes. Using the tubular structure of fibrous phosphorus as an example, we then discuss the limits of free searching, and discuss a possible way forward that combines a recently proposed fragment analysis with GAP-RSS. Examples of possible tubular (1D) and extended (3D) hypothetical allotropes of phosphorus as found by GAP-RSS are discussed. We believe that in the future, ML potentials could become versatile and routine computational tools for materials discovery and design.


Pressure Injury Development in Patients Treated by Critical Care Air Transport Teams: A Case-Control Study.
The US Air Force transports critically ill patients from all over the world, with transport times commonly ranging from 6 to 11 hours. Few outcome measures have been tracked for these patients. Traditional methods to prevent pressure injuries in civilian hospitals are often not feasible in the military transport environment. The incidence rate and risk factors are described of en route-related pressure injuries for patients overseen by the Critical Care Air Transport Team. This retrospective, case-control, medical records review investigated risk factors for pressure injury in patients who developed a pressure injury after their transport flight compared with those with no documented pressure injuries. The pressure injury rate was 4.9%. Between 2008 and 2012, 141 patients in whom pressure injuries developed and who had received care by the team were matched with 141 patients cared for by the team but did not have pressure injury. According to regression analysis, body mass index and 2 or more Critical Care Air Transport Team transports per patient were associated with pressure injury development. Although the pressure injury rate of 4.9% in this cohort of patients is consistent with that reported by civilian critical care units, the rate must be interpreted with caution, because civilian study data frequently represent the entire intensive care unit length of stay. Targeted interventions for patients with increased body mass index and 2 or more critical care air transports per patient may help decrease the development of pressure injury in these patients.


[Eustachy Gryszkiewicz-Trochimowski (1888-1971) chemist].
Eustachy Gryszkiewicz-Trochimowski was born on April 17, 1888, in Kowle on Volhynia. Having graduated from classical grammar-school in Humań, he began his studies in the Faculty of Mathematics and Natural Science in the University of St. Wlodzimierz in Kiev. His scientific interests in chemistry appeared already during university studies. This fact attracted his teacher's attention--a distinguished organic chemist--professor S. N. Reformatski (1860-1938). The first works he published in the years 1908-1909. In 1910 professor Reformatski appointed him to a post of assistant in laboratory of organic chemistry within Higher Women Classes. In 1913 Gryszkiewicz-Trochimowski was employed as an assistant professor, and as a lecturer in chemistry was appointed to a post of professor in Higher Institute of Trade. After professor Reformatski had retired in 1917, Gryszkiewicz-Trochimowski was appointed to a professorship and took over a chair in Organic Chemistry Department. In 1925, having moved to Poland, he resigned from academic career. Having returned to Poland, he began to work in Research Institute of Chemical Weapons, in which took up systematic and extensive research works over arsenoorganic compounds, and combinations including fluorine. He worked out an original method of producing an unavailable compound of oxym of phosgene, which later was widely used, and also beyond the army. The combination was available just by dint of the method that was introduced by Gryszkiewicz-Trochimowski. In Poland the method of producing oxym of phosgene was concealed, and the compound was produced under a secret name TSD together with sulphuric yperite. Moreover, Gryszkiewicz-Trochimowski took up intensive scientific researches on synthesis of halogen derivatives of aliphatic, and aliphatic and aromatic ketones. In the second half of the 1930s, together with the closest co-workers--doctor Adam Sporzyński and Lieutenant MA Jakub Wnuk--he worked out a new method of synthesis of organic-fluoric combinations. The method was kept in the strictest secrecy and was revealed in 1942 to the English by doctor Sporzyński while visiting Great Britain. The results of the Warsaw research works were laid before professor of the University of Cambridge--H. McCombiem, who presented them as his own discovery, and who took a patent for the method. While doing research works in the Institute, Eustachy Gryszkiewicz-Trochimowski with an approval of army administration since January, 1929, started to work in Industry and Trade Establishments of Chemistry--L. Spiess & Son. Co-operating with the company for 10 years, he elaborated and applied the modified methods of producing many synthetic remedies, and worked out a program of establishment's production that could easily conform with the modern chemical and pharmaceutical factory. The program in the post-war period was continued almost for two decades. Gryszkiewicz-Trochimowski was the only chemist in Poland, who did his research works over synthetic healers. In the period of occupation he worked for a while in the company "Spiess". In 1943 he was informed of the murder in Katyń of his co-worker--captain doctor Wnuk. A perspective of annextion of Polish territories by the Soviets was for him a serious threat and thus he started making attempts at leaving for the west. He left the country under unknown circumstances and found himself in France. After the end of World War II he published a great many of his works that earlier had been kept in secret. In France he was employed in the military scientific and research institution--Centre d'Etudes du Buchet--and was engaged in works over a French program of defence. Having lived to be seventy nine, died on February 25, 1971, in Brazil.


Colony Expansion of Socially Motile Myxococcus xanthus Cells Is Driven by Growth, Motility, and Exopolysaccharide Production.
Myxococcus xanthus, a model organism for studies of multicellular behavior in bacteria, moves exclusively on solid surfaces using two distinct but coordinated motility mechanisms. One of these, social (S) motility is powered by the extension and retraction of type IV pili and requires the presence of exopolysaccharides (EPS) produced by neighboring cells. As a result, S motility requires close cell-to-cell proximity and isolated cells do not translocate. Previous studies measuring S motility by observing the colony expansion of cells deposited on agar have shown that the expansion rate increases with initial cell density, but the biophysical mechanisms involved remain largely unknown. To understand the dynamics of S motility-driven colony expansion, we developed a reaction-diffusion model describing the effects of cell density, EPS deposition and nutrient exposure on the expansion rate. Our results show that at steady state the population expands as a traveling wave with a speed determined by the interplay of cell motility and growth, a well-known characteristic of Fisher's equation. The model explains the density-dependence of the colony expansion by demonstrating the presence of a lag phase-a transient period of very slow expansion with a duration dependent on the initial cell density. We propose that at a low initial density, more time is required for the cells to accumulate enough EPS to activate S-motility resulting in a longer lag period. Furthermore, our model makes the novel prediction that following the lag phase the population expands at a constant rate independent of the cell density. These predictions were confirmed by S motility experiments capturing long-term expansion dynamics.


Determination of the resolution of a multichannel Raman spectrometer using Fourier transform Raman spectra.
The resolution of a grating polychromator for Raman spectroscopy has been simulated by measuring spectra on a Fourier transform (FT) Raman spectrometer and selecting the FT of the apodization function so that the instrument line shape function mimics the triangular spectral slit function of the polychromator. To this end, FT-Raman spectra measured with a nominal resolution of 0.5 cm-1 were modified through the application of sinc2 apodization functions of various widths to simulate spectra measured on a polychromator at lower resolution. The success of this approach was validated using the 1085 cm-1 band of calcite. When the modified FT-Raman spectra were compared with spectra measured on a grating polychromator equipped with slits of widths 100 and 150 microns, the resolution of the polychromator was estimated to be 6.3 and 7.8 cm-1, respectively. This conclusion was verified experimentally by measuring the separation of two bands in the Raman spectrum of BaSO4 at approximately 460 cm-1.


The three-legged stool of evidence-based practice in eating disorder treatment: research, clinical, and patient perspectives.
Evidence-based practice in eating disorders incorporates three essential components: research evidence, clinical expertise, and patient values, preferences, and characteristics. Conceptualized as a 'three-legged stool' by Sackett et al. in 1996 (BMJ), all of these components of evidence-based practice are considered essential for providing optimal care in the treatment of eating disorders. However, the extent to which these individual aspects of evidence-based practice are valued among clinicians and researchers is variable, with each of these stool 'legs' being neglected at times. As a result, empirical support and patient preferences for treatment are not consistently considered in the selection and implementation of eating disorder treatment. In addition, clinicians may not have access to training to provide treatments supported by research and preferred by patients. Despite these challenges, integrating these three components of evidence-based practice is critical for the effective treatment of eating disorders. Current research supports the use of several types of psychotherapies, including cognitive-behavioral, interpersonal, and family-based therapies, as well as certain types of medications for the treatment of eating disorders. However, limitations in current research, including sample heterogeneity, inconsistent efficacy, a paucity of data, the need for tailored approaches, and the use of staging models highlight the need for clinical expertise. Although preliminary data also support the importance of patient preferences, values, and perspectives for optimizing treatment, enhancing treatment outcome, and minimizing attrition among patients with eating disorders, the extent to which patient preference is consistently predictive of outcome is less clear and requires further investigation. All three components of evidence-based practice are integral for the optimal treatment of eating disorders. Integrating clinical expertise and patient perspective may also facilitate the dissemination of empirically-supported and emerging treatments as well as prevention programs. Further research is imperative to identify ways in which this three-legged approach to eating disorder treatment could be most effectively implemented.


A novel population of CD4+CD56+ myelin-reactive T cells lyses target cells expressing CD56/neural cell adhesion molecule.
CD56 is a member of the neural cell adhesion molecule family expressed on cells of the central nervous system and also on NK cells. Previous studies suggest the involvement of CD56 in effector-to-target cell conjugation mediated by NK cells. It was shown recently that CD56 is also expressed by subpopulations of CD8+ and CD4+ T cells. The present study describes the functional characteristics of CD4+CD56+ T cell lines established from blood of multiple sclerosis patients by stimulation with myelin basic protein (MBP). CD4+CD56+, MBP-specific T cell lines were able to lyse MBP-pulsed target cells in an HLA class II-restricted fashion. At the same time, they mediated MHC-unrestricted lysis of CD56+ target cells such as CD56+ lymphoid or glial tumor cells, but not of the typical NK target, K562. A number of experimental results including separation of CD4+CD56+ T cells into CD56 high and low expressing populations, cold target inhibition, as well as killing of CD56-transfected cells indicate that homotypic CD56 interactions are involved in the MHC-unrestricted lysis. CD56 interactions are not sufficient but are required for effector/target interaction. Our findings raise the possibility that CD4+CD56+ T cells sharing properties of both typical Ag-specific Th0-like T cells and NK cells might be involved in damage of tissues expressing CD56/neural cell adhesion molecule, such as the central nervous system. Thus, we provide evidence for a novel mechanism that could lead to organ-specific autoreactivity.


Capsaicin Synthesis Requires in Situ Phenylalanine and Valine Formation in in Vitro Maintained Placentas from Capsicum chinense.
Capsaicinoids (CAP) are nitrogenous metabolites formed from valine (Val) and phenylalanine (Phe) in the placentas of hot Capsicum genotypes. Placentas of Habanero peppers can incorporate inorganic nitrogen into amino acids and have the ability to secure the availability of the required amino acids for CAP biosynthesis. In order to determine the participation of the placental tissue as a supplier of these amino acids, the effects of blocking the synthesis of Val and Phe by using specific enzyme inhibitors were analyzed. Isolated placentas maintained in vitro were used to rule out external sources' participation. Blocking Phe synthesis, through the inhibition of arogenate dehydratase, significantly decreased CAP accumulation suggesting that at least part of Phe required in this process has to be produced in situ. Chlorsulfuron inhibition of acetolactate synthase, involved in Val synthesis, decreased not only Val accumulation but also that of CAP, pointing out that the requirement for this amino acid can also be fulfilled by this tissue. The presented data demonstrates that CAP accumulation in in vitro maintained placentas can be accomplished through the in situ availability of Val and Phe and suggests that the synthesis of the fatty acid chain moiety may be a limiting factor in the biosynthesis of these alkaloids.


Ankyrin domains across the Tree of Life.
Ankyrin (ANK) repeats are one of the most common amino acid sequence motifs that mediate interactions between proteins of myriad sizes, shapes and functions. We assess their widespread abundance in Bacteria and Archaea for the first time and demonstrate in Bacteria that lifestyle, rather than phylogenetic history, is a predictor of ANK repeat abundance. Unrelated organisms that forge facultative and obligate symbioses with eukaryotes show enrichment for ANK repeats in comparison to free-living bacteria. The reduced genomes of obligate intracellular bacteria remarkably contain a higher fraction of ANK repeat proteins than other lifestyles, and the number of ANK repeats in each protein is augmented in comparison to other bacteria. Taken together, these results reevaluate the concept that ANK repeats are signature features of eukaryotic proteins and support the hypothesis that intracellular bacteria broadly employ ANK repeats for structure-function relationships with the eukaryotic host cell.


Repertoire of microglial and macrophage responses after spinal cord injury.
Macrophages from the peripheral circulation and those derived from resident microglia are among the main effector cells of the inflammatory response that follows spinal cord trauma. There has been considerable debate in the field as to whether the inflammatory response is good or bad for tissue protection and repair. Recent studies on macrophage polarization in non-neural tissues have shed much light on their changing functional states. In the context of this literature, we discuss the activation of macrophages and microglia following spinal cord injury, and their effects on repair. Harnessing their anti-inflammatory properties could pave the way for new therapeutic strategies for spinal cord trauma.


Angiopoietin-1 guides directional angiogenesis through integrin αvβ5 signaling for recovery of ischemic retinopathy.
Retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR) are ischemic retinal diseases caused by insufficient vascular network formation and vascular regression in addition to aberrant angiogenesis. We examined the role of angiopoietin-1 (Ang1) in retinal vascular network formation during postnatal development using Ang1 gain- and loss-of-function mouse models, and tested the effects of intraocular administration of Ang1 in an oxygen-induced retinopathy (OIR) mouse model that mimics cardinal features of ROP and PDR. We observed that Ang1 plays a substantial role in the formation of the retinal vascular network during postnatal development and that Ang1 supplementation can rescue vascular retinopathies by simultaneously promoting healthy vascular network formation and inhibiting subsequent abnormal angiogenesis, vascular leakage, and neuronal dysfunction in the retinas of the OIR model. We attribute these Ang1-induced effects to a dual signaling pathway-Tie2 signaling in the vascular region and integrin αvβ5 signaling in the astrocytes. The activation of integrin αvβ5 signaling promoted fibronectin accumulation and radial distribution along the sprouting endothelial cells, which consequently stimulated guided angiogenesis in the retina. These findings shed light on the role of Ang1 in the recovery of ischemic retinopathies such as ROP, PDR, and retinal vascular occlusive disease.


Secondary Metabolites and Bioactivities of Aspergillus ochraceopetaliformis Isolated from Anthurium brownii.
Five new polyketides, asperochrapyran (1) and asperochralactones A-D (2-5), along with 12 known polyketides (6-17), were obtained from the fungal strain Aspergillus ochraceopetaliformis. Structures of all isolates were elucidated by their spectroscopic parameters. The relative configurations of the new compounds were deduced by the data of coupling constants and NOESY spectra. The absolute configurations were determined by the comparison of experimental and calculated ECD spectra. Moreover, the plausible biosynthesis pathway of major isolates was proposed as well. Anti-inflammatory activity of compounds 5 and 7-17 were evaluated with human neutrophils in response to the stimulation of formyl-methionyl-leucyl phenylalanine (fMLP). Asperlactone (9), aspyrone (13), and (-)-(3R)-mellein (14) exerted superoxide anion inhibition at 30 ± 9%, 29 ± 9%, and 26 ± 12%, respectively, at 10 μM. The capacities of asperlactone (9), aspilactonol B (10), penicillic acid (12), and (-)-(3R)-mellein (14) in elastase release inhibition were revealed as 25 ± 4%, 38 ± 8%, 25 ± 5%, and 34 ± 9%, respectively, at 10 μM.


Early invasive cervical cancer: tumor delineation by magnetic resonance imaging, computed tomography, and clinical examination, verified by pathologic results, in the ACRIN 6651/GOG 183 Intergroup Study.
To compare magnetic resonance imaging (MRI), computed tomography (CT), and clinical examination for delineating early cervical cancer and for measuring tumor size. A 25-center study enrolled 208 patients with biopsy-proven invasive cervical cancer for MRI and CT before attempted curative radical hysterectomy. Each imaging study was interpreted prospectively by one onsite radiologist and retrospectively by four independent offsite radiologists, who were all blinded to surgical, histopathologic, and other imaging findings. Likelihood of cervical stromal and uterine body involvement was rated on a 5-point scale. Tumor size measurements were attempted in three axes. Surgical pathology was the standard of reference. Neither MRI nor CT was accurate for evaluating cervical stroma. For uterine body involvement, the area under the receiver operating characteristic curve was higher for MRI than for CT for both prospective (0.80 v 0.66, respectively; P = .01) and retrospective (0.68 v 0.57, respectively; P = .02) readings. Retrospective readers could measure diameter by CT in 35% to 73% of patients and by MRI in 79% to 94% of patients. Prospective readers had the highest Spearman correlation coefficient with pathologic measurement for MRI (r(s) = 0.54), followed by CT (r(s) = 0.45) and clinical examination (r(s) = 0.37; P < .0001 for all). Spearman correlation of multiobserver diameter measurements for MRI (r(s) = 0.58; P < .0001) was double that for CT (r(s) = 0.27; P = .03). In patients with cervical cancer, MRI is superior to CT and clinical examination for evaluating uterine body involvement and measuring tumor size, but no method was accurate for evaluating cervical stroma.


Tobacco smoking and gastric cancer: meta-analyses of published data versus pooled analyses of individual participant data (StoP Project).
Tobacco smoking is one of the main risk factors for gastric cancer, but the magnitude of the association estimated by conventional systematic reviews and meta-analyses might be inaccurate, due to heterogeneous reporting of data and publication bias. We aimed to quantify the combined impact of publication-related biases, and heterogeneity in data analysis or presentation, in the summary estimates obtained from conventional meta-analyses. We compared results from individual participant data pooled-analyses, including the studies in the Stomach Cancer Pooling (StoP) Project, with conventional meta-analyses carried out using only data available in previously published reports from the same studies. From the 23 studies in the StoP Project, 20 had published reports with information on smoking and gastric cancer, but only six had specific data for gastric cardia cancer and seven had data on the daily number of cigarettes smoked. Compared to the results obtained with the StoP database, conventional meta-analyses overvalued the relation between ever smoking (summary odds ratios ranging from 7% higher for all studies to 22% higher for the risk of gastric cardia cancer) and yielded less precise summary estimates (SE ≤2.4 times higher). Additionally, funnel plot asymmetry and corresponding hypotheses tests were suggestive of publication bias. Conventional meta-analyses and individual participant data pooled-analyses reached similar conclusions on the direction of the association between smoking and gastric cancer. However, published data tended to overestimate the magnitude of the effects, possibly due to publication biases and limited the analyses by different levels of exposure or cancer subtypes.


A diverse assemblage of Late Cretaceous dinosaur and bird feathers from Canadian amber.
The fossil record of early feathers has relied on carbonized compressions that lack fine structural detail. Specimens in amber are preserved in greater detail, but they are rare. Late Cretaceous coal-rich strata from western Canada provide the richest and most diverse Mesozoic feather assemblage yet reported from amber. The fossils include primitive structures closely matching the protofeathers of nonavian dinosaurs, offering new insights into their structure and function. Additional derived morphologies confirm that plumage specialized for flight and underwater diving had evolved in Late Cretaceous birds. Because amber preserves feather structure and pigmentation in unmatched detail, these fossils provide novel insights regarding feather evolution.


Removal of simulated biofilm at different implant crown designs with interproximal oral hygiene aids: An in vitro study.
To compare the removal of simulated biofilm at two different implant-supported restoration designs with various interproximal oral hygiene aids. Mandibular models with a missing first molar were fabricated and provided with single implant analogues (centrally or distally placed) and two different crown designs (conventional [CCD] and alternative crown design [ACD]). Occlusion spray was applied to the crowns to simulate artificial biofilm. Thirty participants (dentists, dental hygienists, and laypersons) were equally divided and asked to clean the interproximal areas with five different cleaning devices to further evaluate if there were differences in their cleaning ability. The outcome was measured via standardized photos and the cleaning ratio, representing the cleaned surfaces in relation to the respective crown surface. Statistical analysis was performed by linear mixed-effects model with fixed effects for cleaning tools, surfaces, crown design and type of participant, and random effects for crowns. The mean cleaning ratio for the investigated tools and crown designs were (in%): Super floss: 76 ± 13/ACD and 57 ± 14/CCD (highest cleaning efficiency), followed by dental floss: 66 ± 13/ACD and 56 ± 15/CCD, interdental brush: 55 ± 10/ACD and 45 ± 9/CCD, electric interspace brush: 31 ± 10/ACD and 30 ± 1/CCD, microdroplet floss: 8 ± 9/ACD and 9 ± 8/CCD. There was evidence of an overall effect of each factor "cleaning tool," "surface," "crown design," and "participant" (p < 0.0001). ACD allowed more removal of the artificial biofilm than CCD with Super floss, dental floss, and interdental brush. Flossing and interproximal brushing were the most effective cleaning methods. A complete removal of the artificial biofilm could not be achieved in any group.


Accountability in the health system of Tamil Nadu, India: exploring its multiple meanings.
Accountability is increasingly being demanded of public services and is a core aspect of most recent frameworks of health system strengthening. Community-based accountability is an increasingly used strategy, and was a core aspect of India's flagship National Rural Health Mission (NRHM; 2005-2014). Research on policy implementation has called for policy analysts to go beyond the superficial articulation of a particular policy intervention to study the underlying meaning this has for policy-makers and other actors of the implementation process and to the way in which problems sought to be addressed by the policy have been identified and 'problematised'. This research, focused on state level officials and health NGO leaders, explores the meanings attached to the concept of accountability among a number of key actors during the implementation of the NRHM in the south Indian state of Tamil Nadu. The overall research was guided by an interpretive approach to policy analysis and the problematisation lens. Through in-depth interviews we draw on the interviewees' perspectives on accountability. The research identifies three distinct perspectives on accountability among the key actors involved in the implementation of the NRHM. One perspective views accountability as the achievement of pre-set targets, the other as efficiency in achieving these targets, and the final one as a transformative process that equalises power differentials between communities and the public health system. We also present the ways in which these differences in perspectives are associated with different programme designs. This research underlines the importance of going beyond the statements of policy to exploring the underlying beliefs and perspectives in order to more comprehensively understand the dynamics of policy implementation; it further points to the impacts of these perspectives on the design of initiatives in response to the policy.


An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues.
Transfer of T cells to freshly irradiated allogeneic recipients leads to their rapid recruitment to nonlymphoid tissues, where they induce graft-versus-host disease (GVHD). In contrast, when donor T cells are transferred to established mixed chimeras (MCs), GVHD is not induced despite a robust graft-versus-host (GVH) reaction that eliminates normal and malignant host hematopoietic cells. We demonstrate here that donor GVH-reactive T cells transferred to MCs or freshly irradiated mice undergo similar expansion and activation, with similar up-regulation of homing molecules required for entry to nonlymphoid tissues. Using dynamic two-photon in vivo microscopy, we show that these activated T cells do not enter GVHD target tissues in established MCs, contrary to the dogma that activated T cells inevitably traffic to nonlymphoid tissues. Instead, we show that the presence of inflammation within a nonlymphoid tissue is a prerequisite for the trafficking of activated T cells to that site. Our studies help to explain the paradox whereby GVH-reactive T cells can mediate graft-versus-leukemia responses without inducing GVHD in established MCs.


Inheritance of recurrent exertional rhabdomyolysis in thoroughbreds.
To develop a diagnostic test for recurrent exertional rhabdomyolysis (RER) in Thoroughbreds that relied on in vitro contracture of muscle biopsy specimens and determine whether the inheritance pattern of RER diagnosed on the basis of this contracture test was consistent with an autosomal dominant trait. Clinical trial. 8 adult horses with RER and 16 control adult horses for development of the contracture test; 23 foals for inheritance of RER. External intercostal muscle biopsy specimens from the 24 adult horses were tested for contracture in response to halothane and caffeine, and criteria for a positive test result were determined. These criteria were then applied to results for the 23 foals to determine whether they had RER. Simple segregation analysis was performed to determine whether results were consistent with a dominant pattern of inheritance. Results of the contracture test were positive for 5 of the 12 colts and 4 of the 11 fillies. Results of segregation analysis were consistent with an auto-. somal dominant pattern of inheritance. Two sires with RER produced colts with RER, supporting the hypothesis that RER had an autosomal, rather than an X-linked, inheritance pattern. In addition, in 1 instance, an unaffected colt was produced by 2 affected parents, which was not consistent with a recessive mode of inheritance. Although the expression of the RER trait is influenced by sex, temperament, and diet, among other factors, results from the in vitro muscle contracture test and this breeding trial suggest that RER in Thoroughbreds can be modeled as a genetic trait with an autosomal dominant pattern of inheritance.


Structural and histone binding ability characterizations of human PWWP domains.
The PWWP domain was first identified as a structural motif of 100-130 amino acids in the WHSC1 protein and predicted to be a protein-protein interaction domain. It belongs to the Tudor domain 'Royal Family', which consists of Tudor, chromodomain, MBT and PWWP domains. While Tudor, chromodomain and MBT domains have long been known to bind methylated histones, PWWP was shown to exhibit histone binding ability only until recently. The PWWP domain has been shown to be a DNA binding domain, but sequence analysis and previous structural studies show that the PWWP domain exhibits significant similarity to other 'Royal Family' members, implying that the PWWP domain has the potential to bind histones. In order to further explore the function of the PWWP domain, we used the protein family approach to determine the crystal structures of the PWWP domains from seven different human proteins. Our fluorescence polarization binding studies show that PWWP domains have weak histone binding ability, which is also confirmed by our NMR titration experiments. Furthermore, we determined the crystal structures of the BRPF1 PWWP domain in complex with H3K36me3, and HDGF2 PWWP domain in complex with H3K79me3 and H4K20me3. PWWP proteins constitute a new family of methyl lysine histone binders. The PWWP domain consists of three motifs: a canonical β-barrel core, an insertion motif between the second and third β-strands and a C-terminal α-helix bundle. Both the canonical β-barrel core and the insertion motif are directly involved in histone binding. The PWWP domain has been previously shown to be a DNA binding domain. Therefore, the PWWP domain exhibits dual functions: binding both DNA and methyllysine histones. This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.


Investigations on agglomeration and haemocompatibility of vitamin E TPGS surface modified berberine chloride nanoparticles.
The objective of the present study is to investigate the influence of surface modification on systemic stability of NPs. Vitamin E TPGS (1% w/v) was used for surface modification of berberine chloride nanoparticles. Naked and surface modified NPs were incubated in different SBFs (pH 6.8 and 7.4) with or without bile salts and human plasma. NPs were observed for particle agglomeration and morphology by particle size analyzer and TEM, respectively. The haemocompatibility studies were conducted on developed NPs to evaluate their safety profile. The surface modified NPs were stable compared to naked NPs in different SBFs due to the steric stabilization property of vitamin E TPGS. Particle agglomeration was not seen when NPs were incubated in SBF (pH 6.8) with bile salts. No agglomeration was observed in NPs after their incubation in plasma but particle size of the naked NPs increased due to adhesion of plasma proteins. The TEM images confirmed the particle size results. DSC and FT-IR studies confirmed the coexistence of TPGS in surface modified NPs. The permissible haemolysis, LDH release, and platelet aggregation revealed that NPs were compatible for systemic administration. Thus, the study illustrated that the surface modification is helpful in the maintenance of stability of NPs in systemic conditions.


Outcomes of emergency department thoracotomy in a tertiary care Canadian trauma centre.
Emergency department thoracotomy (EDT) is a rare and potentially life-saving intervention performed for trauma patients in extremis. EDT is rare at Canadian trauma centres because of our infrequent occurrence of penetrating trauma. This study was undertaken to evaluate outcomes at a Canadian level 1 trauma facility and compare survival to large published datasets. Also, we evaluated the appropriateness of an EDT performed at our centre based on published national guidelines. Retrospective medical record review of all patients undergoing an EDT during their resuscitation in the emergency department. Records were identified using our trauma registry, and all charts were manually reviewed. The primary outcome was survival to hospital discharge. Over a 20-year period, 58 EDTs were performed with 6 (10.3%) survivors. Patients undergoing an EDT secondary to penetrating trauma had the highest survival (5 of 24 patients or 20.8% survival) compared to patients undergoing an EDT for blunt trauma (1 of 34 patients or 2.9% survival). Patients undergoing an EDT who had not suffered cardiac arrest represented the group with the highest survival rate (3 of 6 patients or 50% survival). The majority of EDTs (79.3%) were indicated, and no patient undergoing an EDT survived if it was performed outside of published guidelines. Survival following an EDT in our small, regional trauma centre is consistent with survival rates from larger published datasets. An EDT should continue to be performed under accepted clinical indications.


Robust Resilience of the Frontotemporal Syntax System to Aging.
Brain function is thought to become less specialized with age. However, this view is largely based on findings of increased activation during tasks that fail to separate task-related processes (e.g., attention, decision making) from the cognitive process under examination. Here we take a systems-level approach to separate processes specific to language comprehension from those related to general task demands and to examine age differences in functional connectivity both within and between those systems. A large population-based sample (N = 111; 22-87 years) from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) was scanned using functional MRI during two versions of an experiment: a natural listening version in which participants simply listened to spoken sentences and an explicit task version in which they rated the acceptability of the same sentences. Independent components analysis across the combined data from both versions showed that although task-free language comprehension activates only the auditory and frontotemporal (FTN) syntax networks, performing a simple task with the same sentences recruits several additional networks. Remarkably, functionality of the critical FTN is maintained across age groups, showing no difference in within-network connectivity or responsivity to syntactic processing demands despite gray matter loss and reduced connectivity to task-related networks. We found no evidence for reduced specialization or compensation with age. Overt task performance was maintained across the lifespan and performance in older, but not younger, adults related to crystallized knowledge, suggesting that decreased between-network connectivity may be compensated for by older adults' richer knowledge base. Understanding spoken language requires the rapid integration of information at many different levels of analysis. Given the complexity and speed of this process, it is remarkably well preserved with age. Although previous work claims that this preserved functionality is due to compensatory activation of regions outside the frontotemporal language network, we use a novel systems-level approach to show that these "compensatory" activations simply reflect age differences in response to experimental task demands. Natural, task-free language comprehension solely recruits auditory and frontotemporal networks, the latter of which is similarly responsive to language-processing demands across the lifespan. These findings challenge the conventional approach to neurocognitive aging by showing that the neural underpinnings of a given cognitive function depend on how you test it.


Effects of nucleus accumbens amphetamine administration on performance in a delay discounting task.
Chronic administration of cocaine can cause pronounced and enduring cognitive alterations such as increases in impulsive choice. Chronic cocaine can also result in enhanced dopamine (DA) release in the nucleus accumbens (NAc) in response to reward-related cues. It is possible that this enhanced DA release in the NAc is a mechanism by which cocaine increases impulsive choice. To date, however, the specific role of DA in the NAc in impulsive choice is unclear. To begin to address this, rats received acute microinjections of the indirect DA agonist amphetamine directly into the NAc prior to testing in a delay discounting task in which rats chose between a small, immediate and a large, delayed food reward. When delays to the large reward increased within test sessions, amphetamine increased choice of the large reward. When delays decreased within test sessions, however, amphetamine decreased choice of the large reward. These findings suggest that, rather than specifically mediating impulsive choice, DA neurotransmission in the NAc is necessary for flexible adaptation of choice strategies in the presence of shifting reward contingencies. These results further indicate that enhancements in NAc DA release likely do not account for lasting increases in impulsive choice caused by chronic cocaine.


The Development and Content of the Vocational Advice Intervention and Training Package for the Study of Work and Pain (SWAP) Trial (ISRCTN 52269669).
Purpose There are substantial costs associated with sickness absence and struggling at work however existing services in the UK are largely restricted to those absent from work for greater than 6 months. This paper details the development of an early Vocational Advice Intervention (VAI) for adult primary care consulters who were struggling at work or absent due to musculoskeletal pain, and the structure and content of the training and mentoring package developed to equip the Vocational Advisors (VAs) to deliver the VAI, as part of the Study of Work and Pain (SWAP) cluster randomised trial. Methods In order to develop the intervention, we conducted a best-evidence literature review, summarised evidence from developmental studies and consulted with stakeholders. Results A novel early access, brief VAI was developed consisting of case management and stepped care (three steps), using the Psychosocial Flags Framework to identify and overcome obstacles associated with the health-work interface. Four healthcare practitioners were recruited to deliver the VAI; three physiotherapists and one nurse (all vocational advice was actually delivered by the three physiotherapists). They received training in the VA role during a 4-day course, with a refresher day 3 months later, along with monthly group mentoring sessions. Conclusions The process of development was sufficient to develop the VAI and associated training package. The evidence underpinning the VAI was drawn from an international perspective and key components of the VAI have the potential to be applied to other settings or countries, although this has yet to be tested.


Relative antigenicity of components of a vascularized limb allograft.
At present, the transplantation of vascularized limb-tissue allografts can be achieved only with generalized host immunosuppression, which results in significant systemic toxicity, thereby precluding their clinical use. A better understanding of the immunogenic mechanisms of these allografts may permit less toxic and thus clinically applicable means of host immunosuppression. In this study, individual vascularized limb tissues (skin, subcutaneous tissue, muscle, bone, and blood vessels) and a whole limb were transplanted microsurgically across a strong histocompatibility barrier in rats. The respective cell-mediated and humoral immune responses generated in the hosts were determined by means of mixed lymphocyte cultures by radioactive 51Cr release assays and compared. No single tissue predominated in the elicited immune response. Rather, the various tissue components interacted with the host immune system in a complex but predictable pattern with differing timing and intensity. Surprisingly, the whole-limb allograft elicited less immune response than did allografts of its individual components. The data presented here also serve as a foundation for further elucidation of the immunogenic mechanisms of vascularized limb-tissue allografts.


Sickle cell anemia and dental caries: a literature review and pilot study.
The purpose of this cohort study was to determine whether individuals with sickle cell anemia (SCA) were more susceptible to dental caries than non-sickle-cell control subjects. A review of the literature suggests several reasons why individuals with SCA may be at increased risk. Thirty-five cases of SCA aged 6 years and older were identified from a screening of 15,900 current patient files at the Howard University College of Dentistry Dental Clinic. A total of 140 non-SCA control subjects (four per case), frequency-matched on enrollment period (+/- 5 yrs) and age (+/- 2 yrs if under age 21, or +/- 5 yrs if 21 or over), was selected by a nonbiased method from the same dental clinic files. SCA cases and controls were identical on mean age (30.4 +/- 19 yrs, ranging from 5 to 92 yrs) and were similar in sex distribution (males: 34% of SCA cases, 40% of controls). The mean number of permanent teeth present was very similar for SCA cases and controls (23.4 +/- 6.4 vs. 24.2 +/- 6.4). The mean DMFT was 21% higher in the SCA cases (12.0 +/- 8.4 vs. 9.9 +/- 6.9), and the mean DMFS was 26% higher in the SCA cases (33.0 +/- 32.3 vs. 26.2 +/- 27.7). While there was virtually no difference in DMFS between SCA cases and controls for 6- to 19-year-olds, for subjects aged 20 and older, the DMFS was 30.4% higher in the SCD cases. For all ages, the M component for SCA cases was 40.7% higher, and the D component was 20.0% higher, while the F component was only 3.5% higher than for controls. Untreated decay (the D/D+F surfaces ratio) was 24.4% higher in the SCA cases. The findings from this pilot study suggest that SCA cases have a higher susceptibility to dental caries and/or that SCA patients may have different treatment pathways once caries is detected. While none of the observed differences was statistically significant, these findings were of clinical interest and should be pursued in future large-scale studies.


Distinct distribution of ectopically expressed histone variants H2A.Bbd and MacroH2A in open and closed chromatin domains.
It becomes increasingly evident that nuclesomes are far from being identical to each other. This nucleosome diversity is due partially to the existence of histone variants encoded by separate genes. Among the known histone variants the less characterized are H2A.Bbd and different forms of macroH2A. This is especially true in the case of H2A.Bbd as there are still no commercially available antibodies specific to H2A.Bbd that can be used for chromatin immunoprecipitation (ChIP). We have generated HeLa S3 cell lines stably expressing epitope-tagged versions of macroH2A1.1, H2A.Bbd or canonical H2A and analyzed genomic distribution of the tagged histones using ChIP-on-chip technique. The presence of histone H2A variants macroH2A1.1 and H2A.Bbd has been analyzed in the chromatin of several segments of human chromosomes 11, 16 and X that have been chosen for their different gene densities and chromatin status. Chromatin immunoprecipitation (ChIP) followed by hybridization with custom NimbleGene genomic microarrays demonstrated that in open chromatin domains containing tissue-specific along with housekeeping genes, the H2A.Bbd variant was preferentially associated with the body of a subset of transcribed genes. The macroH2A1.1 variant was virtually absent from some genes and underrepresented in others. In contrast, in closed chromatin domains which contain only tissue-specific genes inactive in HeLa S3 cells, both macroH2A1.1 and H2A.Bbd histone variants were present and often colocalized. Genomic distribution of macro H2A and H2A.Bbd does not follow any simple rule and is drastically different in open and closed genomic domains.


Effect of NHS reforms on general practitioners' referral patterns.
To compare outpatient referral patterns in fundholding and non-fundholding practices before and after the implementation of the NHS reforms in April 1991. Prospective collection of data on general practitioners' referrals to specialist outpatient clinics between June 1990 and March 1992 and detailed comparison of two time periods: October 1990 to March 1991 (phase 1) and October 1991 to March 1992 (phase 2). 10 fundholding practices and six non-fundholding practices in the Oxford region. Patients referred to consultant outpatient clinics. After implementation of the NHS reforms there was no change in the proportion of referrals from the two groups of practices which crossed district boundaries. Both groups of practices increased their referral rates in phase 2 of the study, the fundholders from 107.3 per 1000 patients per annum (95% confidence interval 106 to 109) to 111.4 (110 to 113) and the non-fundholders from 95.0 (93 to 97) to 112.0 (110 to 114). In phase 2 there was no difference in overall standardised referral rates between fundholders and non-fundholders. Just over 20% of referrals went to private clinics in phase 1. By phase 2 this proportion had reduced by 2.2% (1.0% to 3.4%) among the fundholders and by 2.7% (1.2% to 4.2%) among the non-fundholders. Referral patterns among fundholders and non-fundholders were strikingly similar after the implementation of the NHS reforms. There was no evidence that fundholding was encouraging a shift from specialist to general practice care or that budgetary pressures were affecting general practitioners' referral behaviour.


Scleractinian coral diseases in south Florida: incidence, species susceptibility, and mortality.
There are limited quantitative data available documenting the natural, or non-epizootic, occurrence of scleractinian coral diseases over multiple years. Individual coral colonies exhibiting black band disease (BBD), white plague (WP), dark spots syndrome (DSS), and white band disease (WBD) were monitored 3 times per year on 5 south Florida reefs over a 2 yr period. Surveys included measurements of coral population composition, coral diversity, disease type, coral species affected, colony size, percent of colony affected, and the number of lesions or active infections per colony. Data on re-infections of the same colonies, multiple infections per colony, disease duration, disease-associated tissue mortality, and coral recruitment are also presented. A total of 674 coral colonies exhibiting coral diseases were tagged and monitored. DSS was the most common syndrome (n = 620 infected colonies), but BBD and WP infections caused the largest amount of coral tissue death. The only disease that exhibited a linear increase in incidence with elevated temperature was BBD. DSS and BBD were the most persistent conditions, and WP infections were comparatively short-lived, with obvious signs of disease typically disappearing after 2 to 3 mo. The only disease that caused total colony death as oppposed to partial mortality during the survey period was WBD. WP and DSS incidence was significantly positively correlated with the relative frequency of the species most commonly affected by each disease at each study site. Of the 61 colonies examined in the recruitment survey, only 5 scleractinian coral recruits were identified. The most commonly recorded colonizer of exposed coral skeleton was filamentous/turf algae, thus indicating the potential for a shift towards algal-dominated reef communities.


[Vaccinations in dermatology].
Vaccinations are among the most successful prophylactic measures in medicine. As they are applied to healthy subjects, regulatory steps before licensing of any vaccination are strictly based on clinically controlled studies as well as on registry data in the further course. The probability and relevance of adverse reactions to vaccinations have to be weighed against any harm through the respective natural infection as well as the vaccination-induced protection against infections. Intolerance reactions to vaccinations are far more suspected than proven and altogether rare. Among these, specific dermatoses like psoriasis, atopic dermatitis and lichen planus are found as well as allergic reactions and a number of more nonspecific skin symptoms. Apart from provocation or exacerbation of an underlying dermatological disease, various intolerance reactions may be encountered which are classically allergologic or anaphylactoid. People with chronic dermatoses, especially those on immunosuppressive and immunomodulatory therapy, should have all recommended standard vaccinations. Vaccinations should not be administered during acute skin manifestations and relevant comedication-especially if immunomodulatory or immunosuppressive-has be taken into account in the decision to vaccinate and to define the time point of any vaccination. Inactivated vaccines may be administered even during ongoing immunosuppressive therapy, but may result in decreased immunological reactions and protection to infection. Live vaccines should be avoided.


Areas of molecules in membranes consisting of mixtures.
The question has arisen in recent literature: how to partition the total area in simulations of membranes consisting of more than one kind of molecule into average areas for each kind of molecule. Several definitions have been proposed, each of which has arbitrary features. When applied to mixtures of cholesterol and DPPC, these definitions give different results. This note recalls that physical chemistry provides a canonical way to define molecular area, in analogy to the definition of partial-specific volume. Results for partial-specific area are obtained from simulations of DPPC/cholesterol bilayers and compared to the results from the other recent definitions. The partial-specific-area formalism dramatically demonstrates the condensing effect of cholesterol and this leads to the introduction of a specific model that accounts for the area of mixtures of cholesterol and lipid over the entire range of cholesterol concentrations.


Protective Effect of Plantago major Extract against t-BOOH-Induced Mitochondrial Oxidative Damage and Cytotoxicity.
Plantago major L. produces several chemical substances with anti-inflammatory and analgesic activities and its use in the treatment of oral and throat inflammation in popular medicine is well described. In this study, the antioxidant potential of the Plantago major hydroethanolic extract was screened and its protective action was evaluated against t-BOOH-induced oxidative stress. The extract was obtained by fractionated percolation using 50% ethanolic solution and, after drying, suspended in dimethyl sulfoxide. The chromatographic profile of crude extract was obtained with the identification of some phytochemical markers and the total phenols and flavonoids were quantified. The scavenger activity against DPPH (1,1-diphenyl-2-picrylhydrazyl) radicals was determined and the antioxidant activity in biological systems was evaluated in isolated rat liver mitochondria and HepG2 cells. The extract exhibited a significant free radical scavenger activity at 0.1 mg/mL, and decreased the ROS (reactive oxygen species) generation in succinate-energized mitochondria. Such an effect was associated with the preservation of the intrinsic antioxidant defenses (reduced glutathione and NAD(P)H) against the oxidation by t-BOOH, and also to the protection of membranes from lipid oxidation. The cytoprotective effect of PmHE against t-BOOH induced cell death was also shown. These findings contribute to the understanding of the health benefits attributed to P. major.


Interviewer effects in public health surveys.
Interviewer effects can have a substantial impact on survey data and may be particularly operant in public health surveys, where respondents are likely to be queried about racial attitudes, sensitive behaviors and other topics prone to socially desirable responding. This paper defines interviewer effects, argues for the importance of measuring and controlling for interviewer effects in health surveys, provides advice about how to interpret research on interviewer effects and summarizes research to date on race, ethnicity and gender effects. Interviewer effects appear to be most likely to occur when survey items query attitudes about sociodemographic characteristics or respondents' engagement in sensitive behaviors such as substance use. However, there is surprisingly little evidence to indicate whether sociodemographic interviewer-respondent matching improves survey response rates or data validity, and the use of a matched design introduces possible measurement bias across studies. Additional research is needed to elucidate many issues, including the influence of interviewers' sociodemographic characteristics on health-related topics, the role of within-group interviewer variability on survey data and the simultaneous impact of multiple interviewer characteristics. The findings of such research would provide much-needed guidance to public health professionals on whether or not to match interviewers and respondents on key sociodemographic characteristics.


Burn-induced gut mucosal homeostasis in TCR delta receptor-deficient mice.
Gammadelta T lymphocytes make up approximately 50% of lymphocytes in the intestine. These cells have been shown to prime macrophages for TNF-alpha production after burn. We previously showed that neutralizing anti-TNF-alpha antibodies reduce mucosal atrophy by decreasing gut epithelial apoptosis after severe burn. We hypothesized that burn-induced mucosal turnover is diminished in T cell receptor delta gene knockout (TCR delta-/-) mice through diminished TNF-alpha activity. Forty-two wild-type and 42 TCR delta-/- mice (C57-BL6) were randomly assigned to burn and sham burn groups. The burn group underwent a 25% total body surface area (TBSA) scald burn. The proximal small intestine was harvested at 2, 12, and 48 h. To assess mucosal atrophy, mucosal height and cell numbers in the villi and crypts were determined on hematoxylin and eosin-stained tissue sections. Apoptotic gut epithelium was identified by terminal deoxyuridine nick-end labeling (TUNEL) staining, and cell proliferation was detected by immunostaining for proliferative cell nuclear antigen (PCNA). TNF-alpha mRNA expression was measured by RT-PCR. Caspase-8 activity was measured by colorimetric assay. Statistical analysis was performed with two-way analysis of variance and t testing. Significance was accepted at P < 0.05. Data are expressed as means +/- SEM. TNF-alpha mRNA expression was significantly decreased in TCR delta-/- mice at 2 h after burn. Gut epithelial apoptosis and proliferation in both wild-type and TCR delta-/- mice were significantly increased after burn, but TCR delta-/- mice had a significantly lower levels of apoptosis (P < 0.01) and proliferation (P < 0.05) when compared with wild-type mice. Burn-induced mucosal atrophy was identified in groups by decreasing villus height, crypt depth, and villus and crypt cell number (P < 0.001) compared with sham, but no difference was found between wild-type and TCR delta-/- mice. Caspase-8 activity was significantly diminished in TCR delta-/- mice compared with wild-type mice. Gammadelta T cells are associated with increased TNF-alpha expression and gut epithelial turnover in the small bowel after severe burn. However, absence of delta T cell receptor did not inhibit mucosal atrophy after severe burn. This study suggests that gut mucosal atrophy after severe burn is a multifactorial process associated with increased TNF-alpha activity.


Identification of Measures and Indicators for the IT Security of Networked Medical Devices: A Delphi Study.
The networking of medical devices or systems in a hospital network is the foundation for modern medical diagnostics and therapy. This, however, makes possible numerous hazards that could lead to risks for patients, clinical processes or data and information. The aim of the work was to develop a catalogue of measures and indicators for the effective support of the IT risk management process in a health facility. Through a qualitative and quantitative Delphi study among 21 experts, it was possible to identify an initial 51 practice-relevant measures of IT risk management that a hospital should implement. Additionally, 27 indicators were defined which can be used to measure the impact of these measures. Of the 51 measures, 35 were seen as especially important, particularly organizational measures. Of the 27 indicators, six were seen as especially important, particularly indicators to measure networking effectiveness. The study also investigated the impact of the measures on the indicators. A case study is planned to investigate the practicability of the identified measures and indicators.


Hemochromatosis gene mutations and distal adenomatous colorectal polyps.
Iron has been suggested to be a risk factor for colorectal neoplasia. Some individuals who are heterozygous for mutations in the hemochromatosis gene (HFE) have higher than average serologic measures of iron. We therefore investigated whether heterozygosity for HFE mutations was related to risk of advanced distal adenoma and whether the relationship was affected by dietary iron intake. In the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 679 persons with advanced distal adenoma and 697 control persons were genotyped for the two major HFE mutations (C282Y and H63D), one HFE polymorphism (IVS2+4), and one polymorphism (G142S) in the transferrin receptor gene (TFRC). HFE haplotypes were also created to examine the effect of haplotype on risk. Food frequency questionnaire data were used to estimate daily iron intake. There was no relationship between any HFE genotype or haplotype and advanced adenoma. Stratification of HFE genotype by TFRC genotype did not change the results. In addition, there was no relationship between dietary iron intake and risk of adenoma or between HFE genotype and risk of adenoma, stratified by iron intake. These results do not support a relationship between HFE heterozygosity and risk of advanced distal adenoma.


Towards animal-free neurotoxicity screening: Applicability of hiPSC-derived neuronal models for in vitro seizure liability assessment.
A sizeable proportion of drug attrition is due to drug-induced seizures. Current available animal models frequently fail to predict human seizure liability. Therefore, there is a need for in vitro alternatives, preferably based on human-derived neurons to circumvent interspecies translation. The increasing number of commercially available human induced pluripotent stem cell (hiPSC)-derived neuronal models holds great promise for replacing rodent primary cultures. We therefore tested three different hiPSC-derived neuronal models for their applicability for in vitro seizure liability assessment. Using immunofluorescent staining and multi-well micro-electrode arrays we show that all models develop functional neuronal networks that exhibit spontaneous activity and (network) bursting behavior. Developmental patterns differ between the models, probably due to differences in model composition and seeding density. Nevertheless, neuronal activity and (network) bursting can be reproducibly modulated with the seizurogenic compounds strychnine, picrotoxin (PTX) and 4-aminopyridine (4-AP). However, the sensitivity and degree of chemical-induced effects differs between the models, which can likely be explained by differences in seeding density, maturation and different ratios of inhibitory and excitatory cell types. Importantly, compared to rat primary cortical neurons, the hiPSC-derived neuronal models were equally, or even better in the case of 4-AP, suited to detect seizurogenicity. Overall, our data indicate that hiPSC-derived neuronal models may in the future be used as a first screening tool for in vitro seizure liability assessment. However, before hiPSC-derived neuronal models can fully replace animal experiments, more compounds should be tested and the available models must be further characterized to fully understand their applicability.


Targeting bile-acid signalling for metabolic diseases.
Bile acids are increasingly being appreciated as complex metabolic integrators and signalling factors and not just as lipid solubilizers and simple regulators of bile-acid homeostasis. It is therefore not surprising that a number of bile-acid-activated signalling pathways have become attractive therapeutic targets for metabolic disorders. Here, we review how the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis.


openBEB: open biological experiment browser for correlative measurements.
New experimental methods must be developed to study interaction networks in systems biology. To reduce biological noise, individual subjects, such as single cells, should be analyzed using high throughput approaches. The measurement of several correlative physical properties would further improve data consistency. Accordingly, a considerable quantity of data must be acquired, correlated, catalogued and stored in a database for subsequent analysis. We have developed openBEB (open Biological Experiment Browser), a software framework for data acquisition, coordination, annotation and synchronization with database solutions such as openBIS. OpenBEB consists of two main parts: A core program and a plug-in manager. Whereas the data-type independent core of openBEB maintains a local container of raw-data and metadata and provides annotation and data management tools, all data-specific tasks are performed by plug-ins. The open architecture of openBEB enables the fast integration of plug-ins, e.g., for data acquisition or visualization. A macro-interpreter allows the automation and coordination of the different modules. An update and deployment mechanism keeps the core program, the plug-ins and the metadata definition files in sync with a central repository. The versatility, the simple deployment and update mechanism, and the scalability in terms of module integration offered by openBEB make this software interesting for a large scientific community. OpenBEB targets three types of researcher, ideally working closely together: (i) Engineers and scientists developing new methods and instruments, e.g., for systems-biology, (ii) scientists performing biological experiments, (iii) theoreticians and mathematicians analyzing data. The design of openBEB enables the rapid development of plug-ins, which will inherently benefit from the "house keeping" abilities of the core program. We report the use of openBEB to combine live cell microscopy, microfluidic control and visual proteomics. In this example, measurements from diverse complementary techniques are combined and correlated.


Chemistry towards Biology-Instruct: Snapshot.
The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.


Modelling the key drivers of an aerial Phytophthora foliar disease epidemic, from the needles to the whole plant.
Understanding the epidemiology of infectious diseases in a host population is a major challenge in forestry. Radiata pine plantations in New Zealand are impacted by a foliar disease, red needle cast (RNC), caused by Phytophthora pluvialis. This pathogen is dispersed by water splash with polycyclic infection affecting the lower part of the tree canopy. In this study, we extended an SI (Susceptible-Infectious) model presented for RNC to analyse the key epidemiological drivers. We conducted two experiments to empirically fit the extended model: a detached-needle assay and an in vivo inoculation. We used the detached-needle assay data to compare resistant and susceptible genotypes, and the in vivo inoculation data was used to inform sustained infection of the whole plant. We also compared isolations and real-time quantitative PCR (qPCR) to assess P. pluvialis infection. The primary infection rate and the incubation time were similar for susceptible and resistant genotypes. The pathogen death rate was 2.5 times higher for resistant than susceptible genotypes. Further, external proliferation of mycelium and sporangia were only observed on 28% of the resistant ramets compared to 90% of the susceptible ones. Detection methods were the single most important factor influencing parameter estimates of the model, giving qualitatively different epidemic outputs. In the early stages of infection, qPCR proved to be more efficient than isolations but the reverse was true at later points in time. Isolations were not influenced by the presence of lesions in the needles, while 19% of lesioned needle maximized qPCR detection. A primary infection peak identified via qPCR occurred at 4 days after inoculation (dai) with a secondary peak observed 22 dai. Our results have important implications to the management of RNC, by highlighting the main differences in the response of susceptible and resistant genotypes, and comparing the most common assessment methods to detect RNC epidemics.


Oestrogenic activity of benzylparaben.
Previous work has demonstrated that the alkyl esters of p-hydroxybenzoic acid (parabens) possess oestrogenic activity, which increases with length of alkyl chain from methylparaben to n-butylparaben and with branching in the alkyl chain from n-butylparaben to isobutylparaben. This study reports on the oestrogenic activity of benzylparaben in a variety of assays in vitro and in vivo. Benzylparaben was able to displace [(3)H]oestradiol from cytosolic oestrogen receptor (ER) of MCF7 human breast cancer cells by 22% at 1000-fold molar excess, by 40% at 10,000-fold molar excess, by 57% at 100 000-fold molar excess and by 100% at 1,000,000-fold molar excess. It was able to increase expression of a stably transfected oestrogen responsive reporter gene (ERE-CAT) in MCF7 cells after 24 h at 10(-5)M/10(-4)M and after 7 days at 10(-6)M/10(-5)M/10(-4)M. Proliferation of MCF7 cells could be increased by 10(-6)M/10(-5)M benzylparaben and this could be inhibited by 10(-7)M pure anti-oestrogen ICI 182,780, indicating that growth effects were ER mediated. Further evidence for ER-mediation was provided from the ability of benzylparaben to increase the growth of a second oestrogen-dependent human breast cancer cell line ZR-75-1, but not the oestrogen-insensitive MDA-MB-231 cell line. When tested in the presence of 10(-10)M 17beta-oestradiol, benzylparaben gave no antagonist response on the growth of either MCF7 or ZR-75-1 cells. Finally, benzylparaben could increase uterine weight in the immature mouse following topical application of three daily doses of 33 mg to dorsal skin. These results demonstrate that the oestrogenicity of methylparaben can be increased by the addition of an aryl group as well as by lengthening or branching the alkyl grouping.


Magnetite biomineralization in the human brain.
Although the mineral magnetite (Fe3O4) is precipitated biochemically by bacteria, protists, and a variety of animals, it has not been documented previously in human tissue. Using an ultrasensitive superconducting magnetometer in a clean-lab environment, we have detected the presence of ferromagnetic material in a variety of tissues from the human brain. Magnetic particle extracts from solubilized brain tissues examined with high-resolution transmission electron microscopy, electron diffraction, and elemental analyses identify minerals in the magnetite-maghemite family, with many of the crystal morphologies and structures resembling strongly those precipitated by magnetotactic bacteria and fish. These magnetic and high-resolution transmission electron microscopy measurements imply the presence of a minimum of 5 million single-domain crystals per gram for most tissues in the brain and greater than 100 million crystals per gram for pia and dura. Magnetic property data indicate the crystals are in clumps of between 50 and 100 particles. Biogenic magnetite in the human brain may account for high-field saturation effects observed in the T1 and T2 values of magnetic resonance imaging and, perhaps, for a variety of biological effects of low-frequency magnetic fields.


A comprehensive survey of regulatory network inference methods using single cell RNA sequencing data.
Gene regulatory network is a complicated set of interactions between genetic materials, which dictates how cells develop in living organisms and react to their surrounding environment. Robust comprehension of these interactions would help explain how cells function as well as predict their reactions to external factors. This knowledge can benefit both developmental biology and clinical research such as drug development or epidemiology research. Recently, the rapid advance of single-cell sequencing technologies, which pushed the limit of transcriptomic profiling to the individual cell level, opens up an entirely new area for regulatory network research. To exploit this new abundant source of data and take advantage of data in single-cell resolution, a number of computational methods have been proposed to uncover the interactions hidden by the averaging process in standard bulk sequencing. In this article, we review 15 such network inference methods developed for single-cell data. We discuss their underlying assumptions, inference techniques, usability, and pros and cons. In an extensive analysis using simulation, we also assess the methods' performance, sensitivity to dropout and time complexity. The main objective of this survey is to assist not only life scientists in selecting suitable methods for their data and analysis purposes but also computational scientists in developing new methods by highlighting outstanding challenges in the field that remain to be addressed in the future development.


Patients' perceptions of nutrition care provided by general practitioners: focus on Type 2 diabetes.
In Australia, GPs are central to managing individuals with chronic disease. Due to the influence of lifestyle behaviour on chronic disease health outcomes, GPs may counsel an individual about nutrition to assist the individual to improve their nutrition behaviour. Patients with a positive regard for their health care are more likely to adhere to lifestyle changes which have been recommended by a health professional. It is unclear whether this relationship extends to the context of nutrition and general practice. The management of Type 2 diabetes presents as a relevant scenario to investigate patients' perceptions of nutrition care provided by Australian GPs. This study examines the perceptions of individuals with Type 2 diabetes regarding the nutrition care they have received from GPs. Nine hundred and thirty-nine individuals with Type 2 diabetes completed a 54-item online survey. Individual survey items related to demographic information, health-related attributes, perspectives on ideal care and reflections on previous care. Eighty-four per cent of respondents perceived that ideal management of Type 2 diabetes by GPs includes nutrition care, however, only 43% of respondents report to have received this care from a GP. Over 91% of respondents are satisfied with their GP regarding nutrition care, but only 34% of respondents believe this care has been effective in improving their personal nutrition behaviour. Patients do not receive nutrition care from GPs as often as they would like, and despite being satisfied with the overall care received, are concerned about the effectiveness of the nutrition care component.


Surfing new territory: club-drug use and risky sex among Hispanic men who have sex with men recruited on the Internet.
The Internet presents unique and growing opportunities for conducting HIV/ STD research. This article reports on the first 171 participants enrolled in an ongoing study examining use of the Internet to recruit Hispanic men who have sex with men (HMSM) living in an AIDS epicenter to participate in community-based studies. First, it describes initial success with chatroom recruitment. Second, it compares the demographic, psychosocial, and sexual risk practices among HMSM recruited through the Internet who had used club drugs in the last 6 months and those who had not. In 2 months, 211 hours were spent recruiting in chatrooms; 735 chatroom users were engaged. Researchers used a scripted dialogue to describe the study and to invite chatroom users to visit the study's community sites for screening and enrollment. One hundred and seventy-six men came to the community sites; 172 (98%) were eligible and completed an audio-computer assisted self-interview. In the last 6 months, 48.5% of the sample had used club drugs [defined as cocaine, crystal methamphetamines (crystal), amyl nitrites (poppers), Ecstasy, gamma-hydroxybutyrate (GHB), ketamine (Special K), and Viagra]. The proportion of men reporting use of each drug was: cocaine (15.8%), crystal (11.7%), poppers (31.6%), Ecstasy (14%), GHB (3.5%), Special K (3.5%), and Viagra (19.3%). In multivariate analyses, having higher number of sex partners, having higher social isolation scores, and having engaged in unprotected receptive anal intercourse were significantly associated with club-drug use. These initial findings suggest that high-risk HMSM can be successfully recruited through chatroom dialogues to participate in community-based HIV studies. The alarmingly high rates of club-drug use and risky sexual practices among HMSM underscore the need for effective HIV preventive interventions for this population.


Is birth weight associated with blood pressure among African children and adolescents? A systematic review.
There is substantial evidence of an inverse association between birth weight and later blood pressure (BP) in populations from high-income countries, but whether this applies in low-income countries, where causes of low birth weight are different, is not certain. We conducted a review of the evidence on the relationship between birth weight and BP among African children and adolescents. Medline, EMBASE, Global Health and Web of Science databases were searched for publications to October 2016. Papers reporting the relationship between birth weight and BP among African children and adolescents were assessed. Bibliographies were searched for further relevant publications. Selected papers were summarized following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. In total, 16 papers from 13 studies conducted in nine African countries (Nigeria, Republic of Seychelles, Gambia, Democratic Republic of Congo, Cameroon, South Africa, Algeria, Zimbabwe and Angola) were reviewed. Eight studies were cohorts, while five were cross-sectional. The relationship between birth weight and later BP varied with age of the participants. Studies in neonates showed a consistently positive association, while predominantly inverse associations were seen among children, and studies in adolescents were inconsistent. Based on the limited number of studies identified, the relationship between birth weight and later BP may vary with age in African children and adolescents. Not all studies adequately controlled for confounding, notably gender or age. Whether the inverse relationship between birth weight and BP in later life observed in Western settings is also seen in Africa remains unclear.


Synergistic Ground and Orbital Observations of Iron Oxides on Mt. Sharp and Vera Rubin Ridge.
Visible/short-wave infrared spectral data from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) show absorptions attributed to hematite at Vera Rubin ridge (VRR), a topographic feature on northwest Mt. Sharp. The goals of this study are to determine why absorptions caused by ferric iron are strongly visible from orbit at VRR and to improve interpretation of CRISM data throughout lower Mt. Sharp. These goals are achieved by analyzing coordinated CRISM and in situ spectral data along the Curiosity Mars rover's traverse. VRR bedrock within areas that have the deepest ferric absorptions in CRISM data also has the deepest ferric absorptions measured in situ. This suggests strong ferric absorptions are visible from orbit at VRR because of the unique spectral properties of VRR bedrock. Dust and mixing with basaltic sand additionally inhibit the ability to measure ferric absorptions in bedrock stratigraphically below VRR from orbit. There are two implications of these findings: (1) Ferric absorptions in CRISM data initially dismissed as noise could be real, and ferric phases are more widespread in lower Mt. Sharp than previously reported. (2) Patches with the deepest ferric absorptions in CRISM data are, like VRR, reflective of deeper absorptions in the bedrock. One model to explain this spectral variability is late-stage diagenetic fluids that changed the grain size of ferric phases, deepening absorptions. Curiosity's experience highlights the strengths of using CRISM data for spectral absorptions and associated mineral detections and the caveats in using these data for geologic interpretations and strategic path planning tools.


Preoperative screening for HIV infection. A balanced view for the practicing surgeon.
Routine preoperative screening for human immunodeficiency virus (HIV) infection is becoming increasingly prevalent. Reasons in favor of routine screening include the following: (1) Knowledge of HIV status may allow the surgeon to decrease risk of infection. (2) The patient may benefit, because HIV infection may alter the risk-benefit ratio of a procedure. (3) Knowledge of HIV status will not affect how the patient is treated. Arguments against routine screening include the following: (1) Since the risk during individual procedures is low, it is unlikely that knowledge of HIV status can actually reduce risk. (2) Patient care may be negatively affected. (3) There is a possibility of false-positive results. (4) The accepted ethical standards of autonomy, confidentiality, and informed consent are not always adhered to. We explore these issues in detail. Recent work has framed the risk of surgeons and defined the reliability of diagnostic screening tests. All of these factors must be weighed before a surgeon can decide for or against a policy of routine preoperative screening.


The role of sirtuins in cardiac disease.
Modification of histones is one of the important mechanisms of epigenetics, in which genetic control is determined by factors other than an individual's DNA sequence. Sirtuin family proteins, which are class III histone deacetylases, were originally identified as gene silencers that affect the mating type of yeast, leading to the name "silent mating-type information regulation 2" (SIR2). They are characterized by their requirement of nicotinamide adenine dinucleotide for their enzyme activity, unlike other classes of histone deacetylases. Sirtuins have been traditionally linked to longevity and the beneficial effects of calorie restriction and DNA damage repair. Recently, sirtuins have been shown to be involved in a wide range of physiological and pathological processes, including aging, energy responses to low calorie availability, and stress resistance, as well as apoptosis and inflammation. Sirtuins can also regulate mitochondrial biogenesis and circadian clocks. Seven sirtuin family proteins (Sirt1-7) have been identified as mammalian SIR2 orthologs, localized in different subcellular compartments, namely, the cytoplasm (Sirt1, 2), the mitochondria (Sirt3, 4, 5), and the nucleus (Sirt1, 2, 6, 7). Sirt1 is evolutionarily close to yeast SIR2 and has been the most intensively investigated in the cardiovascular system. Endogenous Sirt1 plays a pivotal role in mediating the cell death/survival process and has been implicated in the pathogenesis of cardiovascular disease. Downregulation of Sirt2 is protective against ischemic-reperfusion injury. Increased Sirt3 expression has been shown to correlate with longevity in humans. In addition, Sirt3 protects cardiomyocytes from aging and oxidative stress and suppresses cardiac hypertrophy. Sirt6 has also recently been demonstrated to attenuate cardiac hypertrophy, and Sirt7 is known to regulate apoptosis and stress responses in the heart. On the other hand, the roles of Sirt4 and Sirt5 in the heart remain largely uncharacterized.


Nuclear colocalization of cellular and viral myc proteins with HSP70 in myc-overexpressing cells.
The c-myc oncogene and its viral counterpart v-myc encode phosphoproteins which have been located within cell nuclei, excluding nucleoli. We have expressed the c-myc gene under the simian virus 40 early promoter and studied the distribution of its protein product in transient expression assays in COS, HeLa, and 293 cells. We found three distinct patterns of c-myc immunofluorescence in the transfected cells: one-third of the c-myc-positive cells displayed a diffuse nuclear distribution, and in two-thirds of the cells the c-myc fluorescence was accumulated either in small amorphous or in large multilobed phase-dense nuclear structures. Unexpectedly, these structures also stained for the HSP70 heat shock protein in both heat-shocked and untreated cells. Our results indicate that both transient and stable overexpression of either the c-myc or v-myc protein induces translocation of the endogenous HSP70 protein from the cytoplasm to the nucleus, where it becomes sequestered in structures containing the myc protein. Interestingly, the closely related N-myc protein does not stimulate substantial nuclear expression of the HSP70 protein. Studies with chimeric myc proteins revealed that polypeptide sequences encoded by the second exon of c-myc are involved in colocalization with HSP70.


A short-term intervention trial with selenate, selenium-enriched yeast and selenium-enriched milk: effects on oxidative defence regulation.
Increased Se intakes have been associated with decreased risk of cancer and CVD. Several mechanisms have been proposed, including antioxidant effects through selenoproteins, induction of carcinogen metabolism and effects on the blood lipid profile. In a 4 x 1 week randomised, double-blind cross-over study, healthy young men supplemented their usual diet with selenate, Se-enriched yeast, Se-enriched milk or placebo (Se dose was 300 microg/d for selenate and Se-enriched yeast, and about 480 microg/d for Se-enriched milk) followed by 8-week washout periods. All Se sources increased serum Se levels after supplementation for 1 week. The effect of the organic forms did not differ significantly and both increased serum Se more than selenate. Conversely, thrombocyte glutathione peroxidase (GPX) was increased in the periods where subjects were supplemented with selenate but not in those where they were given Se-enriched yeast or Se-enriched milk. We found no effect on plasma lipid resistance to oxidation, total cholesterol, TAG, HDL- and LDL-cholesterol, GPX, glutathione reductase (GR) and glutathione S-transferase (GST) activities measured in erythrocytes, GPX and GR activities determined in plasma, or GR and GST activities in thrombocytes. Leucocyte expression of genes encoding selenoproteins (GPX1, TrR1 and SelP), and of electrophile response element-regulated genes (GCLC, Fra1 and NQO1) were likewise unaffected at all time points following intervention. We conclude that thrombocyte GPX is specifically increased by short-term selenate supplementation, but not by short-term supplementation with organic Se. Short-term Se supplementation does not seem to affect blood lipid markers or expression and activity of selected enzymes and a transcription factor involved in glutathione-mediated detoxification and antioxidation.


Cavity method for force transmission in jammed disordered packings of hard particles.
The force distribution of jammed disordered packings has always been considered a central object in the physics of granular materials. However, many of its features are poorly understood. In particular, analytic relations to other key macroscopic properties of jammed matter, such as the contact network and its coordination number, are still lacking. Here we develop a mean-field theory for this problem, based on the consideration of the contact network as a random graph where the force transmission becomes a constraint satisfaction problem. We can thus use the cavity method developed in the past few decades within the statistical physics of spin glasses and hard computer science problems. This method allows us to compute the force distribution P(f) for random packings of hard particles of any shape, with or without friction. We find a new signature of jamming in the small force behavior P(f) ∼ f(θ), whose exponent has attracted recent active interest: we find a finite value for P(f = 0), along with θ = 0. Furthermore, we relate the force distribution to a lower bound of the average coordination number z[combining macron](μ) of jammed packings of frictional spheres with coefficient μ. This bridges the gap between the two known isostatic limits z[combining macron]c (μ = 0) = 2D (in dimension D) and z[combining macron]c(μ → ∞) = D + 1 by extending the naive Maxwell's counting argument to frictional spheres. The theoretical framework describes different types of systems, such as non-spherical objects in arbitrary dimensions, providing a common mean-field scenario to investigate force transmission, contact networks and coordination numbers of jammed disordered packings.


Analysis of Insecticide-Treated Net Use by Pregnant Women: Implications for Donor Organizations.
The World Health Organization (WHO) recommends the use of insecticide-treated nets (ITNs) for the prevention of malaria and reduction of mortality and morbidity from mosquito-borne diseases. Although many countries, including the Democratic Republic of Congo, have adopted this recommendation and distributed bed nets to their inhabitants, the percentage of the population using ITNs remains low. This study was conducted with 400 mothers with at least one child under 5 years of age in health zones in the Bandundu province. Face-to-face interviews were conducted using structured pre-coded questionnaires. Chi-square tests and logistic regressions were calculated using the SPSS Version 21.0 software. Among the studied variables, education status (p = 0.013), marital status (p = 0.004), ANC utilization (p = 0.13), suffering from malaria during pregnancy (p = 0.019), and knowledge of the seriousness of malaria (p = 0.013) were significant determinants of the use of ITNs in logistic regression analyses. The results of this study indicate that the regular use of ITNs by women during pregnancy is associated with marital status, attending ANC services, and awareness of the serious nature of malaria. Therefore, education about the risk factors among populations is needed.


Isoform-selective effects of isoflurane on voltage-gated Na+ channels.
Voltage-gated Na channels modulate membrane excitability in excitable tissues. Inhibition of Na channels has been implicated in the effects of volatile anesthetics on both nervous and peripheral excitable tissues. The authors investigated isoform-selective effects of isoflurane on the major Na channel isoforms expressed in excitable tissues. Rat Nav1.2, Nav1.4, or Nav1.5 alpha subunits heterologously expressed in Chinese hamster ovary cells were analyzed by whole cell voltage clamp recording. The effects of isoflurane on Na current activation, inactivation, and recovery from inactivation were analyzed. The cardiac isoform Nav1.5 activated at more negative potentials (peak INa at -30 mV) than the neuronal Nav1.2 (0 mV) or skeletal muscle Nav1.4 (-10 mV) isoforms. Isoflurane reversibly inhibited all three isoforms in a concentration- and voltage-dependent manner at clinical concentrations (IC50 = 0.70, 0.61, and 0.45 mm, respectively, for Nav1.2, Nav1.4, and Nav1.5 from a physiologic holding potential of -70 mV). Inhibition was greater from a holding potential of -70 mV than from -100 mV, especially for Nav1.4 and Nav1.5. Isoflurane enhanced inactivation of all three isoforms due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation. Inhibition of Nav1.4 and Nav1.5 by isoflurane was attributed primarily to enhanced inactivation, whereas inhibition of Nav1.2, which had a more positive V1/2 of inactivation, was due primarily to tonic block. Two principal mechanisms contribute to Na channel inhibition by isoflurane: enhanced inactivation due to a hyperpolarizing shift in the voltage dependence of steady state fast inactivation (Nav1.5 approximately Nav1.4 > Nav1.2) and tonic block (Nav1.2 > Nav1.4 approximately Nav1.5). These novel mechanistic differences observed between isoforms suggest a potential pharmacologic basis for discrimination between Na channel isoforms to enhance anesthetic specificity.


Adverse drug reactions causing admission to a paediatric hospital: a pilot study.
It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. Prospective observational study over a 2-week period. There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population.


A multifaceted intervention to improve antimicrobial prescribing for upper respiratory tract infections in a small rural community.
Antibiotic prescribing for upper respiratory tract infections (URTIs) is widespread, is often inappropriate, and may contribute to antibiotic resistance among community-acquired pathogens, such as Streptococcus pneumoniae. A multifaceted intervention involving health care professionals and patients was introduced to a small rural Utah community and included the repetitive use of printed diagnostic and treatment algorithms by professionals. Data on the quantity and class of antibiotic prescribing, which were collected from multiple sources, were measured for the intervention period (from January through June) in 2001 and compared with data for the baseline period during the same months in 2000. Medicaid claims data revealed that the percentage of patients in the community who received antibiotics for URTIs during the intervention period was 15.6% less than that for the baseline period, whereas the percentage in the rest of rural Utah was relatively stable, with a 1.5% decrease (P=.006). The greatest impact of the intervention was on prescribing for acute bronchitis (decreases of 56.1% and 1.7% in the community and rural Utah, respectively; P=.024) and on prescribing of macrolides (decreases of 13.4% and 0.2% in the community and rural Utah, respectively; P<.001). Community pharmacy data likewise revealed a 17.5% decrease in the rate of antibiotic prescribing during the intervention period (P<.001), with the largest decrease observed for macrolide prescribing (50.9%; P<.001). Chart review data, in contrast, revealed no significant decrease in the percentage of patients with URTI who were prescribed an antibiotic (3.8%; P=.49), although there was a significant decrease of 11.2% in macrolide use (P=.045). A multifaceted intervention involving the repetitive use of printed algorithms resulted in modest improvements in antibiotic prescribing for outpatient URTIs, although one data source did not corroborate this. However, macrolide prescribing decreased sharply, irrespective of the source of data.