Prognostic value of KRAS genotype in metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to extension of metastatic disease.
Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated. Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test. In all, 59 patients were evaluated: 31 KRAS wild-type (53%), 28 KRAS mutant (47%). At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively. The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.


Inter-element orientation and distance influence the duration of persistent contour integration.
Contour integration is a fundamental form of perceptual organization. We introduce a new method of studying the mechanisms responsible for contour integration. This method capitalizes on the perceptual persistence of contours under conditions of impending camouflage. Observers viewed arrays of randomly arranged line segments upon which circular contours comprised of similar line segments were superimposed via abrupt onset. Crucially, these contours remained visible for up to a few seconds following onset, but eventually disappeared due to the camouflaging effects of surrounding background line segments. Our main finding was that the duration of contour visibility depended on the distance and degree of co-alignment between adjacent contour segments such that relatively dense smooth contours persisted longest. The stimulus-related effects reported here parallel similar results from contour detection studies, and complement previous reported top-down influences on contour persistence (Strother et al., 2011). We propose that persistent contour visibility reflects the sustained activity of recurrent processing loops within and between visual cortical areas involved in contour integration and other important stages of visual object recognition.


Myelopoiesis in spleen-producing distinct dendritic-like cells.
Dendritic cells (DC) represent a heterogeneous class of antigen presenting cells (APC). Previously we reported a distinct myeloid dendritic-like cell present in spleen, as an in vivo counterpart to cells produced in murine spleen long-term cultures (LTC-DC). These cells, named 'L-DC', were found to be functionally and phenotypically distinct from conventional (c)DC, plasmacytoid (p)DC and monocytes. These results suggested that spleen may represent a niche for development of L-DC from endogenous progenitors. Adult murine spleen has now been investigated for the presence of L-DC progenitors. Lineage-negative (Lin)(-) ckit(lo) and Lin(-) ckit(hi) progenitor subsets were identified as candidate populations, and tested for ability to produce L-DC; in vitro upon co-culture with the spleen stromal line STX3, and in vivo after adoptive therapy into mice. Both subsets colonized STX3 stroma in vitro for L-DC production, indicating that they contained either a common or two distinct progenitors for L-DC. However, only the Lin(-) ckit(hi) subset gave progeny cells after adoptive transfer into lethally irradiated mice. In vivo development was however multilineage and not restricted to L-DC development. Multilineage reconstitution reflects long-term reconstituting haematopoietic stem cells (LT-HSC), suggesting a close relationship between L-DC progenitors and LT-HSC. L-DC were however produced in vivo in much higher number than monocytes/macrophages and cDC, indicating the presence of a specific L-DC progenitor within the Lin(-) ckit(hi) subset. A model is advanced for development of L-DC directly from haematopoietic progenitors in spleen and dependent on the spleen microenvironment.


Water-soluble gadofullerenes: toward high-relaxivity, pH-responsive MRI contrast agents.
The water-soluble endohedral gadofullerene derivatives, Gd@C(60)(OH)(x) and Gd@C(60)[C(COOH)(2)](10), have been characterized with regard to their MRI contrast agent properties. Water-proton relaxivities have been measured in aqueous solution at variable temperature (278-335 K), and for the first time for gadofullerenes, relaxivities as a function of magnetic field (5 x 10(-4) to 9.4 T; NMRD profiles) are also reported. Both compounds show relaxivity maxima at high magnetic fields (30-60 MHz) with a maximum relaxivity of 10.4 mM(-1) s(-1) for Gd@C(60)[C(COOH)(2)](10) and 38.5 mM(-1) s(-1) for Gd@C(60)(OH)(x) at 299 K. Variable-temperature, transverse and longitudinal (17)O relaxation rates, and chemical shifts have been measured at three magnetic fields (B = 1.41, 4.7, and 9.4 T), and the results point exclusively to an outer sphere relaxation mechanism. The NMRD profiles have been analyzed in terms of slow rotational motion with a long rotational correlation time calculated to be tau(R)(298) = 2.6 ns. The proton exchange rate obtained for Gd@C(60)[C(COOH)(2)](10) is k(ex)(298) = 1.4 x 10(7) s(-1) which is consistent with the exchange rate previously determined for malonic acid. The proton relaxivities for both gadofullerene derivatives increase strongly with decreasing pH (pH: 3-12). This behavior results from a pH-dependent aggregation of Gd@C(60)(OH)(x) and Gd@C(60)[C(COOH)(2)](10), which has been characterized by dynamic light scattering measurements. The pH dependency of the proton relaxivities makes these gadofullerene derivatives prime candidates for pH-responsive MRI contrast agent applications.


Oil-in-alcohol highly concentrated emulsions as templates for the preparation of macroporous materials.
New oil-in-alcohol highly concentrated emulsions were formulated and were used as a templates to obtain macroporous poly(furfuryl alcohol) monoliths by a one-step method. The oil-in-alcohol highly concentrated emulsions were prepared by stepwise addition of the oil phase to the surfactant-alcohol solution and were characterized by optical microscopy and by laser diffraction. The typical structure of highly concentrated emulsions, with close-packed polyhedral droplets, has been observed. Poly(furfuryl alcohol) monoliths were obtained by polymerizing in the external phase of these emulsions. These materials are mainly macroporous and retain the size distribution and morphology from the highly concentrated emulsions. The internal structure of the monoliths was observed by scanning electron microscopy. The images showed an interconnected network with pore size similar to the droplet size of the highly concentrated emulsions used as templates.


Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.


Valine-Induced Isoleucine Starvation in Escherichia coli K-12 Studied by Spike-In Normalized RNA Sequencing.
Escherichia coli cells respond to a period of famine by globally reorganizing their gene expression. The changes are known as the stringent response, which is orchestrated by the alarmone ppGpp that binds directly to RNA polymerase. The resulting changes in gene expression are particularly well studied in the case of amino acid starvation. We used deep RNA sequencing in combination with spike-in cells to measure global changes in the transcriptome after valine-induced isoleucine starvation of a standard E. coli K12 strain. Owing to the whole-cell spike-in method that eliminates variations in RNA extraction efficiency between samples, we show that ribosomal RNA levels are reduced during isoleucine starvation and we quantify how the change in cellular RNA content affects estimates of gene regulation. Specifically, we show that standard data normalization relying on sample sequencing depth underestimates the number of down-regulated genes in the stringent response and overestimates the number of up-regulated genes by approximately 40%. The whole-cell spike-in method also made it possible to quantify how rapidly the pool of total messenger RNA (mRNA) decreases upon amino acid starvation. A principal component analysis showed that the first two components together described 69% of the variability of the data, underlining that large and highly coordinated regulons are at play in the stringent response. The induction of starvation by sudden addition of high valine concentrations provoked prominent regulatory responses outside of the expected ppGpp, RpoS, and Lrp regulons. This underlines the notion that with the high resolution possible in deep RNA sequencing analysis, any different starvation method (e.g., nitrogen-deprivation, removal of an amino acid from an auxotroph strain, or valine addition to E. coli K12 strains) will produce measurable variations in the stress response produced by the cells to cope with the specific treatment.


Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes.
The ability to bind immunosuppressive drugs such as cyclosporin and FK506 defines the immunophilin family of proteins, and the FK506-binding proteins form the FKBP subfamily of immunophilins. Some FKBPs, notably FKBP12 (the 12-kDa FK506-binding protein), have defined roles in regulating ion channels or cell signaling, and well established structures. Other FKBPs, especially the larger ones, participate in important biological processes, but their exact roles and the structural bases for these roles are poorly defined. FKBP51 (the 51-kDa FKBP) associates with heat shock protein 90 (Hsp90) and appears in functionally mature steroid receptor complexes. In New World monkeys, FKBP51 has been implicated in cortisol resistance. We report here the x-ray structures of human FKBP51, to 2.7 A, and squirrel monkey FKBP51, to 2.8 A, by using multiwavelength anomalous dispersion phasing. FKBP51 is composed of three domains: two consecutive FKBP domains and a three-unit repeat of the TPR (tetratricopeptide repeat) domain. This structure of a multi-FKBP domain protein clarifies the arrangement of these domains and their possible interactions with other proteins. The two FKBP domains differ by an insertion in the second that affects the formation of the progesterone receptor complex.


Predicting fatal sepsis in burn patients.
The high morbidity after severe thermal insult is believed to be related partially to a resultant decrease in immunocompetence. We tested the ability of phytohemagglutinin (PHA) and Concanavalin (Con A) to stimulate lymphocyte transformation in 17 patients with moderate to severe thermal injury (greater than 25% BSA). The patients acted as their own controls and the per cent change in their mitogen response was measured over time. Eight acutely burned patients who subsequently developed severe sepsis (Group I) had decreased ability (mean, 12% of normal) to proliferate in response to PHA, and six of these died of severe sepsis. The depressed response appeared 4 to 7 days postinjury and predated clinical evidence of sepsis by 2 to 4 days. Cells from four patients who had mild infectious complications (Group II) demonstrated greatly augmented mitogen responses (mean + 243%) approximately 7 to 10 days postinjury. Five burn patients whose clinical course was sepsis free (Group III) exhibited only minimal changes in their mitogen responses (mean +30%). Although the Con A responses of the patients' cells corresponded less to their pathology, Group I patients whose cells exhibited depressed PHA responsiveness also had diminished Con A responses. Group II patients' cells also showed increases in Con A-induced stimulation. Group III patients, who had only slightly augmented PHA responses, had minimal decreases of the Con A-induced lymphocyte transformation. Many severely burned patients develop septicemia as a result of their large wound surfaces. The appearance of decreases in mitogen-induced proliferation, however, appears to characterize those patients who will be unable to handle the septic challenge.


The structure and organization within the membrane of the helices composing the pore-forming domain of Bacillus thuringiensis delta-endotoxin are consistent with an "umbrella-like" structure of the pore.
The aim of this study was to elucidate the mechanism of membrane insertion and the structural organization of pores formed by Bacillus thuringiensis delta-endotoxin. We determined the relative affinities for membranes of peptides corresponding to the seven helices that compose the toxin pore-forming domain, their modes of membrane interaction, their structures within membranes, and their orientations relative to the membrane normal. In addition, we used resonance energy transfer measurements of all possible combinatorial pairs of membrane-bound helices to map the network of interactions between helices in their membrane-bound state. The interaction of the helices with the bilayer membrane was also probed by a Monte Carlo simulation protocol to determine lowest-energy orientations. Our results are consistent with a situation in which helices alpha4 and alpha5 insert into the membrane as a helical hairpin in an antiparallel manner, while the other helices lie on the membrane surface like the ribs of an umbrella (the "umbrella model"). Our results also support the suggestion that alpha7 may serve as a binding sensor to initiate the structural rearrangement of the pore-forming domain.


Genome-wide associations of signaling pathways in glioblastoma multiforme.
eQTL analysis is a powerful method that allows the identification of causal genomic alterations, providing an explanation of expression changes of single genes. However, genes mediate their biological roles in groups rather than in isolation, prompting us to extend the concept of eQTLs to whole gene pathways. We combined matched genomic alteration and gene expression data of glioblastoma patients and determined associations between the expression of signaling pathways and genomic copy number alterations with a non-linear machine learning approach. Expectedly, over-expressed pathways were largely associated to tag-loci on chromosomes with signature alterations. Surprisingly, tag-loci that were associated to under-expressed pathways were largely placed on other chromosomes, an observation that held for composite effects between chromosomes as well. Indicating their biological relevance, identified genomic regions were highly enriched with genes having a reported driving role in gliomas. Furthermore, we found pathways that were significantly enriched with such driver genes. Driver genes and their associated pathways may represent a functional core that drive the tumor emergence and govern the signaling apparatus in GBMs. In addition, such associations may be indicative of drug combinations for the treatment of brain tumors that follow similar patterns of common and diverging alterations.


ROCR: visualizing classifier performance in R.
ROCR is a package for evaluating and visualizing the performance of scoring classifiers in the statistical language R. It features over 25 performance measures that can be freely combined to create two-dimensional performance curves. Standard methods for investigating trade-offs between specific performance measures are available within a uniform framework, including receiver operating characteristic (ROC) graphs, precision/recall plots, lift charts and cost curves. ROCR integrates tightly with R's powerful graphics capabilities, thus allowing for highly adjustable plots. Being equipped with only three commands and reasonable default values for optional parameters, ROCR combines flexibility with ease of usage. http://rocr.bioinf.mpi-sb.mpg.de. ROCR can be used under the terms of the GNU General Public License. Running within R, it is platform-independent. firstname.lastname@example.com.


Interpersonal and economic resources.
High population density and increased institutional specialization, which are relatively novel features of human society. have provided conditions for a more efficient exchange of universalistic resources, while decreasing the opportunity for exchanging particularistic ones. The parallel with physical environment is striking: in both cases technology has created new problems in the process of solving old ones. Whether it is natural resources or interpersonal resources, physical ecology or social ecology, recognizing and defining the new problem is the first step toward its solution. The importance of particularistic resources in solving problems of modern society has scarcely been recognized. Welfare institutions, for example, often require clients to lose status for the money they receive. This form of exchange deprives the client of a resource which is already scarce for him, thus further reducing his chances of autonomous performance as a resource exchanger in society. By ignoring the significance of particularistic resources for social functioning, we tend to see the solution of social problems exclusively in terms of a better distribution of economic resources. Improvement of education, for instance, is considered almost equivalent to allocating more money for schools. Truly money is one of the neighbors of information in the order, but the other one is status. Evidence to suggest that higher status improves educational achievement has, indeed, been repeatedly reported (26). The very mention of particularistic resources in social planning causes uneasiness and bafflement. The economist Levitan (27), for example, in reviewing the activities of VISTA (a program of the Office of Economic Opportunity), wonders how to evaluate goals such as dedication, involvement, and good feeling. The reluctance to include particularistic resources in social engineering will hopefully decrease as we improve techniques for their observation and measurement and as we begin to understand their rules of exchange and their relationship to other resources. The work described here may constitute a step in such a direction. The opportunity to progress more decisively toward a comprehensive picture of the state of resources in society is provided by the proposal to institute social indicators (28). Properly constructed they could supply much needed information about resource deficiencies that affect the health of society and could suggest. measures to overcome them. The purpose of this article has been to summarize some of the knowledge we already possess about interpersonal resources and to outline its application to certain problems of modern society. It has been shown that when resources are classified into six categories and plotted on a two-coordinate space a definite structural pattern emerges. The position of each resource class in the structure appears related to certain properties which in turn affect differentially the exchange of resources in an urban environment. The structural charateristics of resources provide a theoretical basis for the understanding and solution of social problems in modern culture.


Abnormal plasminogen. A hereditary molecular abnormality found in a patient with recurrent thrombosis.
A patient who suffered a recurring thrombosis over the last 15 yr has been investigated. The only abnormality found in this patient was a significantly depressed level of plasminogen activity in plasma. In spite of the depressed plasminogen activity, the patient was found to have a normal level of plasminogen antigen concentration. It was calculated that the activity per milligram of plasminogen of the patient was approximately one-half the values of normal subjects. The same discrepancy between biological activity and antigen concentration was found in the other members of the kindred. A niece was found to have practically no plasminogen activity but possessed a normal concentration of plasminogen antigen. Both her parents were found to have approximately half the normal plasminogen activity and normal antigen levels. These studies suggested that the molecular abnormality was inherited as an autosomal characteristic, and the family members who had half the normal levels of activity with normal plasminogen antigen were heterozygotes whereas the one with practically no plasminogen activity was homozygote. Subsequent studies showed that the pattern of gel electrofocusing of purified plasminogen of the heterozygotes consisted of 10 normal bands and 10 additional abnormal bands, each of which had a slightly higher isoelectric point than each corresponding normal component. This indicates that plasminogen of the heterozygote is a mixture of normal and abnormal molecules in an approximately equal amount, which was substantiated by active site titration of purified plasminogen preparations obtained from the propositus and a normal individual. The gel electrofocusing pattern of the homozygote consisted of abnormal bands only. The defect is a hereditary abnormality of plasminogen.


Relationships Between Social Support, Loneliness, and Internet Addiction in Chinese Postsecondary Students: A Longitudinal Cross-Lagged Analysis.
Using the Internet has become one of the most popular leisure activities among postsecondary students in China. Concern about the large number of students using the Internet has led to an increase in research on the influencing factors of Internet addiction and the negative consequences caused by it. This short-term longitudinal study examined the associations among three dimensions of social support [objective support (OS), subjective support (SS), and support utilization (SU)], loneliness, and the four dimensions of Internet addiction (compulsive Internet use [CIU] & withdrawal from Internet addiction [WIA], tolerance of Internet addiction [TIA], time-management problems [TMPs], and interpersonal and health problems [IHPs]) in a Chinese sample. A total of 169 postsecondary first-year students (88 girls and 81 boys; mean age = 18.31 years) participated in the study. The questionnaire measurements were taken at the beginning of the school year (T1), 6 months later (T2), and 1 year later (T3). Cross-lagged and structural equation modeling analyses indicated that (a) OS (T1) and SU (T1) negatively predicted loneliness (T2); and loneliness (T2) negatively predicted OS (T3) and SU(T3); (b) CIU & WIA (T1) and TMPs (T1) positively predicted loneliness (T2); and loneliness (T2) positively predicted CIU & WIA (T3), TIA (T3), TMP (T3), and IHP (T3); (c) SS (T1) directly affected TIA (T3) and TMP (T3); and (d) loneliness (T2) played a mediating role in the relationships between OS (T1) and CIU (T3), OS (T1) and TMP (T3), OS (T1) and IHP (T3), and SU (T1) and IHP (T3). Finally, interventions for Internet addiction and implications for future studies were discussed.


Human Infections by Wohlfahrtiimonas chitiniclastica: A Mini-Review and the First Report of a Burn Wound Infection after Accidental Myiasis in Central Europe.
Wohlfahrtiimonas chitiniclastica are bacteria that cause rare infections, typically associated with the infestation of an open wound with fly larvae. Here, we present a unique case report of the first W. chitiniclastica isolation from a burn wound with accidental myiasis in a 63-year-old homeless man and a literature review focused on human infections caused by these bacteria. So far, 23 cases of infection with W. chitiniclastica have been reported; in 52% of these, larvae were found in the wound area. Most of these cases suffered from chronic non-healing wound infections but none of these were burn injuries. The overall fatality rate associated directly with W. chitiniclastica in these cases was 17%. Infections with parasitic larvae occur in moderate climates (especially in people living in poor conditions); therefore, an infection with rare bacteria associated with accidental myiasis, such as W. chitiniclastica, can be expected to become more common there. Thus, in view of the absence of recommendations regarding the treatment of patients with accidental myiasis and, therefore, the risk of infection with W. chitiniclastica or other rare pathogens, we provide a list of recommendations for the treatment of such patients. The importance of meticulous microbial surveillance using molecular biological methods to facilitate the detection of rare pathogens is emphasized.


Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study.
Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease.


Small mammal responses to Amazonian forest islands are modulated by their forest dependence.
Hydroelectric dams have induced widespread loss, fragmentation and degradation of terrestrial habitats in lowland tropical forests. Yet their ecological impacts have been widely neglected, particularly in developing countries, which are currently earmarked for exponential hydropower development. Here we assess small mammal assemblage responses to Amazonian forest habitat insularization induced by the 28-year-old Balbina Hydroelectric Dam. We sampled small mammals on 25 forest islands (0.83-1466 ha) and four continuous forest sites in the mainland to assess the overall community structure and species-specific responses to forest insularization. We classified all species according to their degree of forest-dependency using a multi-scale approach, considering landscape, patch and local habitat characteristics. Based on 65,520 trap-nights, we recorded 884 individuals of at least 22 small mammal species. Species richness was best predicted by island area and isolation, with small islands (< 15 ha) harbouring an impoverished nested subset of species (mean ± SD: 2.6 ± 1.3 species), whereas large islands (> 200 ha; 10.8 ± 1.3 species) and continuous forest sites (∞ ha; 12.5 ± 2.5 species) exhibited similarly high species richness. Forest-dependent species showed higher local extinction rates and were often either absent or persisted at low abundances on small islands, where non-forest-dependent species became hyper-abundant. Species capacity to use non-forest habitat matrices appears to dictate small mammal success in small isolated islands. We suggest that ecosystem functioning may be highly disrupted on small islands, which account for 62.7% of all 3546 islands in the Balbina Reservoir.


UK ambulance service resuscitation management of pulseless electrical activity: a systematic review protocol of text and opinion.
Out-of-hospital cardiac arrest patients with pulseless electrical activity are treated by paramedics using basic and advanced life support resuscitation. When resuscitation fails to achieve return of spontaneous circulation, there are limited evidence and national guidelines on when to continue or stop resuscitation. This has led to ambulance services in the United Kingdom developing local guidelines to support paramedics in the resuscitative management of pulseless electrical activity. The content of each guideline is unknown, as is any association between guideline implementation and patient survival. We aim to identify and synthesise local ambulance service guidelines to help improve the consistency of paramedic-led decision-making for the resuscitation of pulseless electrical activity in out-of-hospital cardiac arrest. A systematic review of text and opinion will be conducted on ambulance service guidelines for resuscitating adult cardiac arrest patients with pulseless electrical activity. Data will be gathered direct from the ambulance service website. The review will be guided by the methods of the Joanna Briggs Institute (JBI). The search strategy will be conducted in three stages: 1) a website search of the 14 ambulance services; 2) a search of the evidence listed in support of the guideline; and 3) an examination of the reference list of documents found in the first and second stages and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses. Each document will be assessed against the inclusion criteria, and quality of evidence will be assessed using the JBI Critical Appraisal Checklist for Text and Opinion. Data will be extracted using the JBI methods of textual data extraction and a three-stage data synthesis process: 1) extraction of opinion statements; 2) categorisation of statements according to similarity of meaning; and 3) meta-synthesis of statements to create a new collection of findings. Confidence of findings will be assessed using the graded ConQual approach.


Morphological and biochemical assessment of the liver response to excess dietary copper in Fischer 344 rats.
The aim of this study was to determine the amount of excess dietary copper (Cu) necessary to experimentally induce liver lesions characteristic of Cu-associated disease in Fischer 344 rats. Male weanling Fischer 344 rats of uniform age were divided into 6 groups (n = 5) and fed a rodent diet containing 18 (control), 750, 1000, 1250, 1500, and 2000 microg/g Cu added as CuSO4. Rats were euthanized after 3 months on the experimental diets and their livers processed for histology, histochemistry, Cu analysis (by atomic absorption spectrophotometry), and quantification of malondialdehyde (MDA) by the thiobarbituric acid reaction. Hepatic Cu levels were significantly higher (P < 0.01) in rats receiving over 1000 microg/g Cu compared to the controls (means for each diet: control = 4.8 microg/g, 750 microg/g Cu = 39.6 microg/g, 1000 microg/g Cu = 111.2 microg/g, 1250 microg/g Cu = 389 microg/g, 1500 microg/g Cu = 509.4 microg/g, and 2000 microg/g Cu = 766 microg/g). Histological lesions increased gradually according to the level of dietary Cu. Significant morphologic changes (necrosis, portal inflammation, hyaline remnants) and reduced growth rate occurred in rats receiving over 1250 microg/g Cu. However, no significant differences were found for MDA levels between groups. The present study demonstrates that compared to other species, very high levels of excess dietary Cu are needed to induce significant liver injury in Fischer 344 rats. Increased MDA content was not detected in rats with morphologic evidence of liver damage, suggesting that lipid peroxidation may not play a major role in this model of Cu toxicity.


Implications of acute functional injury following percutaneous renal artery intervention.
Percutaneous renal artery revascularization for hypertension and renal dysfunction is now common, and there is an increasing realization that renal artery intervention can be associated with parenchymal injury. The frequency, cause, and outcomes of acute functional injury associated with renal intervention are poorly delineated. Our aim was to determine the frequency of acute functional renal injury 30 days after renal artery intervention, to identify factors associated with functional renal injury and determine whether functional renal injury related to renal intervention is associated with late adverse clinical events. A retrospective analysis of patients undergoing renal artery interventions for atherosclerotic renal artery disease between 1990 and 2007 was performed. No distal embolic protection devices were used. Acute functional parenchymal renal injury was defined as a persistent increase in serum creatinine of > or =0.5 mg/dL at 1 month after the procedure. Freedom from kidney-related morbidity (increase in persistent creatinine >20% of baseline, progression to hemodialysis, death from kidney-related causes) and patient survival were measured. There were 418 patients who underwent 581 renal artery interventions: 57% for hypertension, 23% for hypertension associated with chronic renal insufficiency, and 12% for renal insufficiency. Acute functional renal injury occurred in 20% of the patients. The occurrence of a functional injury was associated with a significant decrement in freedom from kidney-related morbidity (mean +/- SEM 80 +/- 2% vs. 55 +/- 10%, no injury vs. injury, p < 0.01) and markedly decreased survival at 5-year follow-up (71 +/- 4% vs. 41 +/- 10%, p < 0.01). At 5-year follow-up, three times as many patients with functional injury progressed to hemodialysis compared to those without injury (19% vs. 7%, p < 0.01). By multivariate analysis, the presence of an unrepaired abdominal aortic aneurysm (AAA), low estimated glomerular filtration rate, non-insulin-dependent diabetes mellitus, contralateral renal artery disease, and a solitary kidney were significantly associated with functional injury and poor long-term clinical benefit. Hypertension, hyperlipidemia, and contrast volume were determined to be not significant. Acute functional renal injury occurs in approximately 20% of patients undergoing percutaneous renal artery intervention and is more likely in the presence of an unrepaired AAA, non-insulin-dependent diabetes mellitus, and preexisting renal disease. Acute functional renal injury is a negative predictor of survival and is associated with subsequent renal failure, need for dialysis, and death. While this data set does not establish a causal relationship, patients who are predisposed to acute functional injury may have underlying factors that also lead to decreased long-term renal function and decreased survival.


Environmental analysis of a nano-grid: A Life Cycle Assessment.
Renewable energy sources are fundamental to face the problem of climate changes. Unfortunately, some resources, such as wind and solar radiation, have fluctuations affecting the electrical grids stability. Energy storage systems can be used for a smart energy management to accumulate power from renewable sources. For such reason, these devices play a key role to achieve a sustainable electric system. On the other hand, they are affected by some environmental drawbacks mainly connected with the depletion of rare and expensive materials. Based on these considerations, in this study a nano-grid composed by a photovoltaic plant, a backup generator and an energy storage system is analysed by an environmental Life Cycle Assessment approach. A Solar Home System is designed, and its environmental profile is evaluated considering several Lithium-ion batteries. Among them, nickel-cobalt aluminium oxide cells resulted to be the most suitable solution for a Solar Home System (46.66 Pts/MWh). Moreover, a sensitivity analysis of the Solar Home System is performed and a hybrid energy storage plant integrating hydrogen and batteries is proposed to face the problem of seasonal solar radiation variability. Four scenarios having different gas pressure levels and lifespan of the devices are considered. Results show that currently the most sustainable configuration is represented by the Solar Home System, but in the future a hybrid nano-grid equipped with 700 bar hydrogen storage might be the best off-grid configuration for minimizing the impact on the environment (37.77 Pts/MWh). Extending the perspective of our analysis to future on-grid potential configurations, an efficient connection of the Solar Home System with a smart-grid is assessed as it looks more sustainable than other off-grid solutions (22.81 Pts/MWh).


Helicobacterpylori eradication treatment for gastric carcinoma prevention in asymptomatic or dyspeptic adults: systematic review and Bayesian meta-analysis of randomised controlled trials.
Recent meta-analyses of eradication therapy in Helicobacter pylori-infected adults reported significant reductions in gastric carcinoma risk. However, concerns about supporting unfocused screening and eradication programme in healthy, asymptomatic populations have arisen. We performed a systematic review and Bayesian meta-analysis to provide an accurate interpretation of randomised evidence on the preventive effectiveness of eradication therapy on gastric carcinoma risk. We searched databases including PubMed, Cochrane Central and Embase for reference and citation tracking without language restrictions, from inception through 31 July 2018. Paired investigators independently selected randomised controlled trials (RCTs) comparing eradication therapy with placebo or no treatment for asymptomatic or dyspeptic H. pylori-infected adults with no previous gastric carcinoma. The main outcome was gastric carcinoma incidence; secondary outcomes included gastric carcinoma-specific, non-gastric carcinoma and all-cause mortality. A total of 5 population-based and 2 outpatient care-based RCTs involving 7303 adults were eligible. Eradication algorithms were heterogeneous, and unsuccessful eradication and reinfection were frequently observed. A Bayesian meta-analysis with competing risk outcomes found low-certainty evidence that eradication therapy might be more likely than control to reduce gastric carcinoma risk (HR=0.65; 95% credible interval (CrI) 0.41 to 1.0; I2 =11%). The CrIs included the null effects across the subgroup and sensitivity analyses, apart from those based on particular models that excluded two RCTs that enrolled subjects with specific histological findings only (HR=0.55; CrI 0.30 to 0.89; I2 =14%). The uncertainty of the average 41% risk reduction in gastric carcinoma-specific mortality included a clinically important mortality risk increase (HR=0.59 favouring eradication therapy; CrI 0.25 to 1.20; I2 =13%; low certainty). There is insufficient evidence to support or refute the effectiveness of eradication therapy in preventing gastric carcinoma in H. pylori-infected, high-risk populations. Rigorously conducted large RCTs of healthy infected adults only would provide evidence of the true efficacy of successful eradication. PROSPERO registration number: CRD42014009245.


Label-free detection of DNA with interdigitated micro-electrodes in a fluidic cell.
We investigate the analytical performance of an interdigitated electrode sensor for the label-free detection of DNA, by monitoring the complex impedance of 5 microm wide interdigitated Pt microelectrodes on a glass substrate. We detect the hybridization of unlabeled 38-mer target ssDNA with a complementary probe that is bound on the glass in between the electrodes by a disuccinimidyl terephtalate and aminosilane immobilization procedure. The sensor is mounted in a microfluidic flow cell, in which hybridization is monitored and in situ compared with a reference. After hybridization, the cell is perfused with deionised water and the dependence of the measured conductance due to the immobilized target DNA layer, to target DNA concentrations down to 1 nM is demonstrated. Subsequently, we apply our sensor to the detection of pathogen DNA from Salmonella choleraesuis in dairy food.


Visualizing in situ translational activity for identifying and sorting slow-growing archaeal-bacterial consortia.
To understand the biogeochemical roles of microorganisms in the environment, it is important to determine when and under which conditions they are metabolically active. Bioorthogonal noncanonical amino acid tagging (BONCAT) can reveal active cells by tracking the incorporation of synthetic amino acids into newly synthesized proteins. The phylogenetic identity of translationally active cells can be determined by combining BONCAT with rRNA-targeted fluorescence in situ hybridization (BONCAT-FISH). In theory, BONCAT-labeled cells could be isolated with fluorescence-activated cell sorting (BONCAT-FACS) for subsequent genetic analyses. Here, in the first application, to our knowledge, of BONCAT-FISH and BONCAT-FACS within an environmental context, we probe the translational activity of microbial consortia catalyzing the anaerobic oxidation of methane (AOM), a dominant sink of methane in the ocean. These consortia, which typically are composed of anaerobic methane-oxidizing archaea (ANME) and sulfate-reducing bacteria, have been difficult to study due to their slow in situ growth rates, and fundamental questions remain about their ecology and diversity of interactions occurring between ANME and associated partners. Our activity-correlated analyses of >16,400 microbial aggregates provide the first evidence, to our knowledge, that AOM consortia affiliated with all five major ANME clades are concurrently active under controlled conditions. Surprisingly, sorting of individual BONCAT-labeled consortia followed by whole-genome amplification and 16S rRNA gene sequencing revealed previously unrecognized interactions of ANME with members of the poorly understood phylum Verrucomicrobia This finding, together with our observation that ANME-associated Verrucomicrobia are found in a variety of geographically distinct methane seep environments, suggests a broader range of symbiotic relationships within AOM consortia than previously thought.


Activated coagulation times in normal cats and dogs using MAX-ACT tubes.
To establish reference values for activated coagulation time (ACT) in normal cats and dogs, by visual assessment of clot formation using the MAX-ACT(TM) tube. We recruited 43 cats and 50 dogs for the study; 11 cats and 4 dogs were excluded from the statistical analysis because of abnormalities on clinical examination or laboratory testing including anaemia, prolonged prothrombin time (PT) or activated partial thromboplastin time (APTT), or insufficient plasma volume for comprehensive laboratory coagulation testing. Blood samples were collected via direct venipuncture for MAX-ACT, packed cell volume/total solids, manual platelet estimation and PT/APTT measurement. Blood (0.5 mL) was mixed gently in the MAX-ACT tube at 37 degrees C for 30 s, then assessed for clot formation every 5 to 10 s by tipping the tube gently on its side and monitoring for magnet movement. The endpoint was defined as the magnet lodging in the clot. The technique was tested with 10 dogs by collecting two blood samples from the same needle insertion and running a MAX-ACT on each simultaneously. In normal cats the mean MAX-ACT was 66 s (range 55-85 s). In normal dogs the mean was 71 s (range 55-80 s). There was no statistical difference between the first and second samples collected from the same needle insertion. and Clinical Relevance In both cats and dogs, a MAX-ACT result >85 s should be considered abnormal and further coagulation testing should be performed. Additionally, failure to discard the first few drops of the sample does not appear to significantly affect results.


Status and future of the forest health indicators program of the USA.
For two decades, the US Department of Agriculture, Forest Service, has been charged with implementing a nationwide field-based forest health monitoring effort. Given its extensive nature, the monitoring program has been gradually implemented across forest health indicators and inventoried states. Currently, the Forest Service's Forest Inventory and Analysis program has initiated forest health inventories in all states, and most forest health indicators are being documented in terms of sampling protocols, data management structures, and estimation procedures. Field data from most sample years and indicators are available on-line with numerous analytical examples published both internally and externally. This investment in national forest health monitoring has begun to yield dividends by allowing evaluation of state/regional forest health issues (e.g., pollution and invasive pests) and contributing substantially to national/international reporting efforts (e.g., National Report on Sustainability and US EPA Annual Greenhouse Gas Estimates). With the emerging threat of climate change, full national implementation and remeasurement of a forest health inventory should allow for more robust assessment of forest communities that are undergoing unprecedented changes, aiding future land management and policy decisions.


Microglial Priming as Trained Immunity in the Brain.
In this review we discuss the possibility that the phenomenon of microglial priming can be explained by the mechanisms that underlie trained immunity. The latter involves the enhancement of inflammatory responses by epigenetic mechanisms that are mobilized after first exposure to an inflammatory stimulus. These mechanisms include long-lasting histone modifications, including H3K4me1 deposition at latent enhancer regions. Although such changes may be beneficial in peripheral infectious disease, in the context of microglial priming they may drive increased microglia reactivity that is damaging in diseases of brain aging.


Thyroid stunning: fact or fiction?
Stunning of thyroid tissue by diagnostic activities of (131)I has been described by some investigators and refuted by others. The support both for and against stunning has at times been enthusiastic and vigorous. We present the data from both sides of the debate in an attempt to highlight the strengths and deficiencies in the investigations cited. Clinical, animal, and in vitro studies are included. There are considerable differences in clinical practice, such as the administered activity for diagnostic whole-body scan, delay between diagnostic scan and treatment, time between treatment and posttherapy scanning, and timing of follow-up studies, that have to be analyzed with care. Other factors that often cannot be judged, such as levels of thyroid-stimulating hormone and serum iodine at time of diagnostic testing versus treatment could have an influence on stunning. Larger diagnostic doses and longer delays to therapy appear to increase the likelihood of stunning. The stunning effect of early-absorbed radiation from the therapy should also be considered.


Influence of estrogen receptor status on dietary risk factors for breast cancer.
It has been suggested that the relation between diet and breast cancer may depend on estrogen receptor (ER) status. We examined the responses to a self-administered questionnaire on frequency of consumption of various foods by 493 women with breast cancer (160 with ER-negative tumours and 333 with ER-positive tumours) and 527 controls whose menopausal status was known. Analysis of the reported consumption of foods selected for their fat or carotene content showed no clear distinction in dietary factors between the ER-negative and ER-positive groups. Frequent consumption of meat fats generally increased the risk of both ER-negative and ER-positive tumours; there were no clear trends in risk associated with vegetable consumption for either ER group. Fish was the only item affecting the risk for ER-negative and ER-positive tumours differently, frequent consumption reducing the risk for the former (p = 0.02). The results do not support the hypothesis that ER status influences the relation between dietary fat consumption and risk of breast cancer.


FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts.
Fragile X syndrome, the most common form of inherited mental retardation, is caused by absence of FMRP, an RNA-binding protein implicated in regulation of mRNA translation and/or transport. We have previously shown that dFMR1, the Drosophila ortholog of FMRP, is genetically linked to the dRac1 GTPase, a key player in actin cytoskeleton remodeling. Here, we demonstrate that FMRP and the Rac1 pathway are connected in a model of murine fibroblasts. We show that Rac1 activation induces relocalization of four FMRP partners to actin ring areas. Moreover, Rac1-induced actin remodeling is altered in fibroblasts lacking FMRP or carrying a point-mutation in the KH1 or in the KH2 RNA-binding domain. In absence of wild-type FMRP, we found that phospho-ADF/Cofilin (P-Cofilin) level, a major mediator of Rac1 signaling, is lowered, whereas the level of protein phosphatase 2A catalytic subunit (PP2Ac), a P-Cofilin phosphatase, is increased. We show that FMRP binds with high affinity to the 5'-UTR of pp2acbeta mRNA and is thus a likely negative regulator of its translation. The molecular mechanism unraveled here points to a role for FMRP in modulation of actin dynamics, which is a key process in morphogenesis of dendritic spines, synaptic structures abnormally developed in Fragile X syndrome patient's brain.


Native chemical ligation in protein synthesis and semi-synthesis.
Native chemical ligation (NCL) provides a highly efficient and robust means to chemoselectively link unprotected peptide and protein segments to generate proteins. The ability to incorporate non-proteinogenic amino acids (e.g.d-amino acids or fluorescent labels) and post-translational modifications into proteins by stitching together peptide fragments has driven extremely important developments in peptide and protein science over the past 20 years. Extensions of the original NCL concept (including the development of thiol- and selenol-derived amino acids and desulfurisation and deselenisation methods), improved access to peptide thioesters, and the use of the methodology in combination with recombinantly expressed polypeptide fragments (termed Expressed Protein Ligation, EPL) have helped to further expand the utility of the methodology. Over the past five years, there has been a dramatic increase in the number of proteins that have been accessed by total chemical synthesis and semi-synthesis, including a large range of modified proteins; new records have also been set with regards to the size of proteins that can now be accessed via ligation chemistry. Together these efforts have not only contributed to a better understanding of protein structure and function, but have also driven innovations in protein science. In this tutorial review, we aim to provide the reader with the latest developments in NCL- and EPL-based ligation technologies as well as illustrated examples of using these methods, together with synthetic logic, to access proteins and modified proteins for biological study.


Identification of differentially expressed genes associated with changes in the morphology of Pichia fermentans on apple and peach fruit.
Pichia fermentans (strain DISAABA 726) is an effective biocontrol agent against Monilinia fructicola and Botrytis cinerea when inoculated in artificially wounded apple fruit but is an aggressive pathogen when inoculated on wounded peach fruit, causing severe fruit decay. Pichia fermentans grows as budding yeast on apple tissue and exhibits pseudohyphal growth on peach tissue, suggesting that dimorphism may be associated with pathogenicity. Two complementary suppressive subtractive hybridization (SSH) strategies, that is, rapid subtraction hybridization (RaSH) and PCR-based subtraction, were performed to identify genes differentially expressed by P. fermentans after 24-h growth on apple vs. peach fruit. Gene products that were more highly expressed on peach than on apple tissue, or vice versa, were sequenced and compared with available yeast genome sequence databases. Several of the genes more highly expressed, when P. fermentans was grown on peach, were related to stress response, glycolysis, amino acid metabolism, and alcoholic fermentation but surprisingly not to cell wall degrading enzymes such as pectinases or cellulases. The dual activity of P. fermentans as both a biocontrol agent and a pathogen emphasizes the need for a thorough risk analysis of potential antagonists to avoid unpredictable results that could negatively impact the safe use of postharvest biocontrol strategies.


[Leptospirosis in French Guiana and the Guiana shield: Current knowledge in 2016].
Leptospirosis is a cosmopolitan zoonosis caused by bacteria of the genus Leptospira. Whether the distribution is worldwide, the hot and humid climate of the tropics is particularly conducive to its expansion. In most French overseas departments and territories, leptospirosis is considered as a public health problem. In French Guiana, a French department located in the northeastern part of the Amazon rainforest, it is supposed to be rare. The objective of this review was to make an inventory of the knowledge on human and animal leptospirosis in French Guiana and neighboring countries. A comprehensive search was conducted through the indexed and informal medical literature in English, French, Spanish and Portuguese. Thus, respectively ten and four publications were identified on human and animal leptospirosis in French Guiana, published between 1940 and 1995 in the form of case reports or case series. The publications concerning this disease in the other countries of the Guiana Shield, eastern Venezuela, Guyana, Suriname, and Brazilian state of Amapá, also scarce or nonexistent. However recent data from the French National Centre of leptospirosis showed a recent and sudden increase in the number of cases in the department, probably partly due to the development of diagnostic tools such as Elisa IgM serology. It is likely that leptospirosis is a neglected disease in the region, due to the lack of diagnostic tools readily available, the lack of knowledge of the local clinicians on this disease and the existence of many other pathogens with similar clinical presentation such as malaria, arboviruses and Q fever and Amazonian toxoplasmosis. The establishment of more large-scale studies on animal and human leptospirosis is necessary and urgent to know the true burden of this disease in our region.


Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages.
Extracellular ATP (ATPe) is known to cause release of processed IL-1 beta from LPS-treated macrophages and microglial cells. IL-1 beta release is fast and thought to be associated with cell death. We have reinvestigated this process to identify 1) the purinergic receptor involved; 2) the relationship to cell death; and 3) pharmacologic agonists or antagonists able to modulate IL-1 beta release. Our data confirm that ATPe is a powerful stimulus for IL-1 beta release from LPS-treated human macrophages; however, we also show that IL-1 beta release is not necessarily associated with cell death, as it occurs at lower ATP concentrations and much earlier than leakage of cytoplasmic markers. The selective purinergic P2Z receptor agonist benzoylbenzoyl ATP was at least one order of magnitude more powerful than ATP, but also had a strong cytotoxic effect. 2-Methylthio-ATP was equipotent as ATPe at the optimal concentration of 1 mM, but markedly inhibitory at higher concentrations. The irreversible P2Z blocker-oxidized ATP completely inhibited ATPe-induced IL-1 beta release. IL-1 beta release also was inhibited by increasing the K+ concentration of the incubation medium. These data suggest that ATPe triggers IL-1 beta via the purinergic P2Z receptor recently shown to be expressed by human macrophages and identified as a new member of the P2X family (P2X7), and provide pharmacologic tools for the modulation of IL-1 beta release in vitro and, possibly, in vivo.


Method availability and the prevention of suicide--a re-analysis of secular trends in England and Wales 1950-1975.
In England and Wales in the 1960s there were marked declines in suicide rates. These reductions were partly attributable to the detoxification of the domestic gas supplies; however, their extent varied by age and gender, with the most striking effects seen in older men. The objective of this study was to investigate method-specific trends in suicide between 1950 and 1975 to elucidate possible explanations for the patterns seen in different demographic groups. An analysis of age-standardised method-specific suicide rates for England and Wales between 1950 and 1975 was carried out using routinely available mortality and population statistics. As has previously been shown, there were marked reductions in suicides by gassing in men and women of all ages between 1960 and 1975. In women and younger men, the effects of these reductions on overall suicide rates were partially offset by rises in drug overdose deaths (method substitution), but there were no immediate increases in the use of other suicide methods. In contrast, in older men, reductions in suicide by gassing were accompanied by only a slight increase in overdose suicides as well as reductions in rates of suicide using all other methods. The modest rise in overdose fatalities in older men occurred despite the fact that they were more often prescribed barbiturates and tricyclic antidepressants than younger men. Accessibility to and the lethality of particular methods of suicide may have profound effects on overall suicide rates. Such effects appear to depend upon the popularity of the method and the extent to which alternative methods that are acceptable to the individual are available. Social and psychological interpretations of fluctuations in suicide rates should only be made after assessing the possible contribution to these of changes in method availability and lethality.


Can the collective intentions of individual professionals within healthcare teams predict the team's performance: developing methods and theory.
Within implementation research, using theory-based approaches to understanding the behaviours of healthcare professionals and the quality of care that they reflect and designing interventions to change them is being promoted. However, such approaches lead to a new range of methodological and theoretical challenges pre-eminent among which are how to appropriately relate predictors of individual's behaviour to measures of the behaviour of healthcare professionals. The aim of this study was to explore the relationship between the theory of planned behaviour proximal predictors of behaviour (intention and perceived behavioural control, or PBC) and practice level behaviour. This was done in the context of two clinical behaviours - statin prescription and foot examination - in the management of patients with diabetes mellitus in primary care. Scores for the predictor variables were aggregated over healthcare professionals using four methods: simple mean of all primary care team members' intention scores; highest intention score combined with PBC of the highest intender in the team; highest intention score combined with the highest PBC score in the team; the scores (on both constructs) of the team member identified as having primary responsibility for the clinical behaviour. Scores on theory-based cognitive variables were collected by postal questionnaire survey from a sample of primary care doctors and nurses from northeast England and the Netherlands. Data on two clinical behaviours were patient reported, and collected by postal questionnaire survey. Planned analyses explored the predictive value of various aggregations of intention and PBC in explaining variance in the behavioural data. Across the two countries and two behaviours, responses were received from 37 to 78% of healthcare professionals in 57 to 93% practices; 51% (UK) and 69% (Netherlands) of patients surveyed responded. None of the aggregations of cognitions predicted statin prescription. The highest intention in the team (irrespective of PBC) was a significant predictor of foot examination. These approaches to aggregating individually-administered measures may be a methodological advance of theoretical importance. Using simple means of individual-level measures to explain team-level behaviours is neither theoretically plausible nor empirically supported; the highest intention was both predictive and plausible. In studies aiming to understand the behaviours of teams of healthcare professionals in managing chronic diseases, some sort of aggregation of measures from individuals is necessary. This is not simply a methodological point, but a necessary step in advancing the theoretical and practical understanding of the processes that lead to implementation of clinical behaviours within healthcare teams.


Human attachments shape interbrain synchrony toward efficient performance of social goals.
The human brain has undergone massive expansion across primate evolution through life amidst multi-layered social attachments; within families, among friends, and between clan members and this enabled humans to coordinate their brains with those of others toward the execution of complex social goals. We examined how human attachments facilitate efficient, resource-sensitive performance of social goals by balancing neural and behavioral synchrony. Using hyperscanning EEG, we collected neural data from male-female pairs in three groups (N=158, 79 pairs); long-term couples, best friends, and unfamiliar group members, during two ecologically-valid naturalistic tasks; motor coordination and empathy giving. Across groups and tasks, neural synchrony was supported by behavior coordination and orchestrated multiple neural rhythms. In the goal-directed motor task, interbrain synchrony implicated beta and gamma rhythms localized to sensorimotor areas. Couples showed the highest neural synchrony combined with greatest behavioral synchrony and such brain-behavior linkage resulted in speedy performance, conserving energy in the long run. The socially-oriented empathy task triggered neural synchrony in widely-distributed sensorimotor and bilateral temporal regions, integrated alpha, beta, and gamma rhythms, and implicated brain-behavior complementarity; couples displayed the highest behavioral synchrony combined with lowest neural synchrony toward greatest felt support while strangers exhibited the opposite pattern. Findings suggest that human attachments provide a familiar backdrop of temporal regularities, required for the brain's allostatic function, and interbrain and behavioral synchrony are sculpted by familiarity and closeness toward resource-sensitive performance of survival-related social goals, toiled by two.


Biosensing strategies based on enzymatic reactions and nanoparticles.
Enzymes are pivotal elements in bioanalysis due to their specificity and extremely high catalytic activity. The sensitivity of bioanalytical assays depends mainly on the capacity of an observer to detect the product(s) of a biocatalytic reaction. Both natural and artificial compounds have been traditionally used to evaluate enzymatic activities. The drawbacks of chromogenic and fluorogenic organic enzymatic substrates are their high cost and low stability, resulting in high background signals. We review here state of the art assays in the detection of enzymatic activities using recent advances in nanoscience. Novel methods based on the use of nanoparticles lead to increased sensitivity and decreased costs for bioanalysis based on enzymes as recognition elements and signal amplifiers in Enzyme-Linked Immunosorbent Assays (ELISA). Novel approaches toward the detection of enzymatic activities are based on biocatalytic synthesis, modulation, etching, and aggregation of nanoparticles under physiological conditions.


Unifying hydrotropy under Gibbs phase rule.
The task of elucidating the mechanism of solubility enhancement using hydrotropes has been hampered by the wide variety of phase behaviour that hydrotropes can exhibit, encompassing near-ideal aqueous solution, self-association, micelle formation, and micro-emulsions. Instead of taking a field guide or encyclopedic approach to classify hydrotropes into different molecular classes, we take a rational approach aiming at constructing a unified theory of hydrotropy based upon the first principles of statistical thermodynamics. Achieving this aim can be facilitated by the two key concepts: (1) the Gibbs phase rule as the basis of classifying the hydrotropes in terms of the degrees of freedom and the number of variables to modulate the solvation free energy; (2) the Kirkwood-Buff integrals to quantify the interactions between the species and their relative contributions to the process of solubilization. We demonstrate that the application of the two key concepts can in principle be used to distinguish the different molecular scenarios at work under apparently similar solubility curves observed from experiments. In addition, a generalization of our previous approach to solutes beyond dilution reveals the unified mechanism of hydrotropy, driven by a strong solute-hydrotrope interaction which overcomes the apparent per-hydrotrope inefficiency due to hydrotrope self-clustering.


Thiopurine Treatment in Ulcerative Colitis: A Critical Review of the Evidence for Current Clinical Practice.
Due to toxicity problems and controversial evidence, thiopurine use in ulcerative colitis (UC) has faced a lot of criticism. We present a critical review of the literature on efficacy of thiopurines in UC. Studies evaluating therapeutic efficacy of thiopurine remission induction and/or maintenance treatment in UC were identified using the Cochrane Library, MEDLINE, and EMBASE. Out of 5 randomized trials on thiopurine induction treatment, 3 demonstrated a significant effect of thiopurine treatment vs mesalamine or placebo in steroid-dependent UC patients: (1) lower endoscopic activity scores, (2) higher clinical remission rates, and (3) more patients who discontinued steroids. Two found no significant difference in clinical and endoscopic remission of azathioprine compared with sulfasalazine or placebo in patients with active UC. Out of 7 randomized trials on thiopurine maintenance treatment, 4 demonstrated significant higher clinical and endoscopic remission rates in thiopurine-treated patients compared with placebo or mesalamine. Three found no significant difference in clinical and endoscopic remission of thiopurine maintenance treatment compared with sulfasalazine or placebo. All studies that investigated thiopurine treatment in UC had shortcomings, such as lack of sufficient power, no use of blinding, allowed concomitant treatment with steroids, and no endoscopy to confirm active disease at study entry or to evaluate therapeutic efficacy. Hence, current clinical practice of thiopurine treatment in UC is based on minimal and controversial evidence. This underscores the need for clinical studies with sufficient power and objective end points in order to determine efficacy of thiopurines in UC.


Combined phase locking and beam shaping of a multicore fiber laser by structured mirrors.
We present a novel mirror geometry combining the two features of phase locking and simultaneous beam shaping of the emission of a multicore fiber (MCF) laser. In the experiments we applied a Talbot cavity to a diode-pumped MCF laser with 18 microcores placed on a ring. The feedback mirror consisted of a highly reflecting structure with 18 spokes and a circle in the center deposited on a glass substrate. The spokes increased the discrimination between the supermodes and suppressed independent lasing of the individual emitters. The central dot caused strong diffraction of the output radiation, leading to a shaped beam profile. The output power of the phase-locked MCF laser exceeded 5 W.


Data-driven coarse graining in action: Modeling and prediction of complex systems.
In many physical, technological, social, and economic applications, one is commonly faced with the task of estimating statistical properties, such as mean first passage times of a temporal continuous process, from empirical data (experimental observations). Typically, however, an accurate and reliable estimation of such properties directly from the data alone is not possible as the time series is often too short, or the particular phenomenon of interest is only rarely observed. We propose here a theoretical-computational framework which provides us with a systematic and rational estimation of statistical quantities of a given temporal process, such as waiting times between subsequent bursts of activity in intermittent signals. Our framework is illustrated with applications from real-world data sets, ranging from marine biology to paleoclimatic data.


Communication skills training for healthcare professionals working with people who have cancer.
This is an updated version of a review that was originally published in the Cochrane Database of Systematic Reviews in 2004, Issue 2. People with cancer, their families and carers have a high prevalence of psychological stress which may be minimised by effective communication and support from their attending healthcare professionals (HCPs). Research suggests communication skills do not reliably improve with experience, therefore, considerable effort is dedicated to courses that may improve communication skills for HCPs involved in cancer care. A variety of communication skills training (CST) courses have been proposed and are in practice. We conducted this review to determine whether CST works and which types of CST, if any, are the most effective. To assess whether CST is effective in improving the communication skills of HCPs involved in cancer care, and in improving patient health status and satisfaction. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2012, MEDLINE, EMBASE, PsycInfo and CINAHL to February 2012. The original search was conducted in November 2001. In addition, we handsearched the reference lists of relevant articles and relevant conference proceedings for additional studies. The original review was a narrative review that included randomised controlled trials (RCTs) and controlled before-and-after studies. In this updated version, we limited our criteria to RCTs evaluating 'CST' compared with 'no CST' or other CST in HCPs working in cancer care. Primary outcomes were changes in HCP communication skills measured in interactions with real and/or simulated patients with cancer, using objective scales. We excluded studies whose focus was communication skills in encounters related to informed consent for research. Two review authors independently assessed trials and extracted data to a pre-designed data collection form. We pooled data using the random-effects model and, for continuous data, we used standardised mean differences (SMDs). We included 15 RCTs (42 records), conducted mainly in outpatient settings. Eleven studies compared CST with no CST intervention, three studies compared the effect of a follow-up CST intervention after initial CST training, and one study compared two types of CST. The types of CST courses evaluated in these trials were diverse. Study participants included oncologists (six studies), residents (one study) other doctors (one study), nurses (six studies) and a mixed team of HCPs (one study). Overall, 1147 HCPs participated (536 doctors, 522 nurses and 80 mixed HCPs).Ten studies contributed data to the meta-analyses. HCPs in the CST group were statistically significantly more likely to use open questions in the post-intervention interviews than the control group (five studies, 679 participant interviews; P = 0.04, I² = 65%) and more likely to show empathy towards patients (six studies, 727 participant interviews; P = 0.004, I² = 0%); we considered this evidence to be of moderate and high quality, respectively. Doctors and nurses did not perform statistically significantly differently for any HCP outcomes.There were no statistically significant differences in the other HCP communication skills except for the subgroup of participant interviews with simulated patients, where the intervention group was significantly less likely to present 'facts only' compared with the control group (four studies, 344 participant interviews; P = 0.01, I² = 70%).There were no significant differences between the groups with regard to outcomes assessing HCP 'burnout', patient satisfaction or patient perception of the HCPs communication skills. Patients in the control group experienced a greater reduction in mean anxiety scores in a meta-analyses of two studies (169 participant interviews; P = 0.02; I² = 8%); we considered this evidence to be of a very low quality. Various CST courses appear to be effective in improving some types of HCP communication skills related to information gathering and supportive skills. We were unable to determine whether the effects of CST are sustained over time, whether consolidation sessions are necessary, and which types of CST programs are most likely to work. We found no evidence to support a beneficial effect of CST on HCP 'burnout', patients' mental or physical health, and patient satisfaction.


Measured binding coefficients for iodine and ruthenium dyes; implications for recombination in dye sensitised solar cells.
We have measured the binding coefficients of iodine to three dyes used in Dye Sensitised Solar Cells (DSSCs). Binding coefficients are quantified via the effect of iodine binding on the UV-vis spectrum of the dye. From iodine titration curves of dye sensitised TiO(2) films we find that the binding coefficients of iodine to the dyes C101, N719 and AR24 (vide infra) are in the range of 2000-4000 M(-1). From FTIR results and molecular modelling we show the iodine binds to the thiocyanate group in all these dyes. For the AR24 dye we present evidence that iodine also binds to the amine moiety on this dye. With these binding coefficients we show that the dye-iodine complex will be present at much higher concentrations than free iodine in the pore structure of a DSSC. As we have recently shown that iodine (rather than tri-iodide) is the dominant acceptor in electron recombination, the concentration dye-iodine complexes could influence recombination rates and thus V(oc). By comparison of recombination data on full cells, we show that AR24 accelerates recombination by a factor of 7 over N719, presumably due to the iodine binding to the amine group. We leave open the question why iodine binding to the amine group seems to have a stronger effect on the recombination than does binding to the thiocyanate.


The night-time temporal window of locomotor activity in the Namib Desert long-distance wandering spider, Leucorchestris arenicola.
Even though being active exclusively after sunset, the male Leucorchestris arenicola spiders are able to return to their point of departure by following bee-line routes of up to several hundreds of meters in length. While performing this kind of long-distance path integration they must rely on external cues to adjust for navigational errors. Many external cues which could be used by the spiders change dramatically or disappear altogether in the transition period from day to night. Hence, it is therefore imperative to know exactly when after sunset the spiders navigate in order to find out how they do it. To explore this question, we monitored their locomotor activity with data loggers equipped with infrared beam sensors. Our results show that the male spiders are most active in the period between the end and the beginning of the astronomical twilight period. Moreover, they prefer the moonless, i.e. darkest times at night. Hence, we conclude that the males are truly-and extremely-nocturnal. We further show that they are able to navigate under the very dim light conditions prevailing on moonless nights, and thus do not have to rely on the moon or on moon-related patterns of polarised light as potential compass cues.


A systematic review and meta-analysis on the efficacy and acceptability of bilateral repetitive transcranial magnetic stimulation (rTMS) for treating major depression.
Bilateral repetitive magnetic stimulation (rTMS) is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting evidence concerning its overall efficacy, which might have resulted from low statistical power. Thus, meta-analytical approaches could be useful in examining this issue by allowing the integration of findings from multiple studies and thus producing more accurate estimates of the treatment effect. We searched the literature for randomized, double-blind and sham-controlled trials (RCTs) on bilateral rTMS for treating MD from 1995 to July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations and Theses, and from October 2008 until May 2012 using Medline. The main outcome measures were response and remission rates. We used a random-effects model, odds ratios (ORs) and the number needed to treat. Data were obtained from seven RCTs, totaling 279 subjects with MD. After an average of 12.9 (s.d. = 2.7) sessions, 24.7% (40/162) and 6.8% (8/117) of subjects receiving active bilateral rTMS and sham rTMS were classified as responders [OR 4.3, 95% confidence interval (CI) 1.95-9.52, p < 0.0001]. Also, 19% (23/121) and 2.6% (2/77) of subjects were remitters following active bilateral rTMS and sham rTMS, respectively (OR 6.0, 95% CI 1.65-21.8, p = 0.006). No difference between baseline mean depression scores for the bilateral and sham rTMS groups was found, and the former was comparable with the latter in terms of drop-out rates at study end. Furthermore, we did not find significant differences efficacy- and acceptability-wise between active bilateral and unilateral rTMS at study end. Finally, heterogeneity between the included RCTs was not significant, and the risk of publication bias was found to be low. Bilateral rTMS is a promising treatment for MD as it provides clinically meaningful benefits that are comparable with those of standard antidepressants and unilateral rTMS. Furthermore, bilateral rTMS seems to be an acceptable treatment for depressed subjects.


Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams.
Outbreaks of fatal leukemia-like cancers of marine bivalves throughout the world have led to massive population loss. The cause of the disease is unknown. We recently identified a retrotransposon, Steamer, that is highly expressed and amplified to high copy number in neoplastic cells of soft-shell clams (Mya arenaria). Through analysis of Steamer integration sites, mitochondrial DNA single-nucleotide polymorphisms (SNPs), and polymorphic microsatellite alleles, we show that the genotypes of neoplastic cells do not match those of the host animal. Instead, neoplastic cells from dispersed locations in New York, Maine, and Prince Edward Island (PEI), Canada, all have nearly identical genotypes that differ from those of the host. These results indicate that the cancer is spreading between animals in the marine environment as a clonal transmissible cell derived from a single original clam. Our findings suggest that horizontal transmission of cancer cells is more widespread in nature than previously supposed.


Dynamic state of S-nitrosothiols in human plasma and whole blood.
In the vasculature, nitrosothiols derived from the nitric oxide (NO)-mediated S-nitrosation of thiols play an important role in the transport, storage, and metabolism of NO. The present study was designed to examine the reactions that promote the decomposition, formation, and distribution of extracellular nitrosothiols in the circulation. The disappearance of these species in plasma and whole blood was examined using a high-performance liquid chromatography method to separate low- and high-molecular weight nitrosothiols. We found that incubation of S-nitrosocysteine (CySNO) or S-nitrosoglutathione (GSNO) with human plasma resulted in a rapid decomposition of these nitrosothiols such that <10% of the initial concentration was recovered after 10-15 min. Neither metal chelators (DTPA, neocuproine), nor zinc chloride (glutathione peroxidase inhibitor), acivicin (gamma-glutamyl transpeptidase inhibitor), or allopurinol (xanthine oxidase inhibitor) inhibited the decomposition of GSNO. With both CySNO and GSNO virtually all NO was recovered as S-nitrosoalbumin (AlbSNO), suggesting the involvement of a direct transnitrosation reaction. Electrophilic attack of the albumin-associated thiols by reactive nitrogen oxides formed from the interaction of NO with O(2) was ruled out because one would have expected 50% yield of AlbSNO. Similar results were obtained in whole blood. The amount of S-nitrosohemoglobin recovered in the presence of 10 microM GSNO or CySNO was less than 100 nM taking into consideration the detection limit of the assay used. Our results suggest that serum albumin may act as a sink for low-molecular-weight nitrosothiols and as a modulator of NO(+) transfer between the vascular wall and intraerythrocytic hemoglobin.


Dignity in life and care: the perspectives of Swedish patients in a palliative care context.
How patients preserve their sense of dignity in life is an important area of palliative care that remains to be explored. To describe patients' perspectives of what constitutes a dignified life within a palliative care context. Twelve palliative care patients were interviewed about their views on living with dignity. Data were analysed using qualitative content analysis. What constitutes a dignified life during end-of-life care was captured by the theme 'I may be ill but I am still a human being' and presented under the categories 'preserving my everyday life and personhood', 'having my human value maintained by others through 'coherence' and 'being supported by society at large'. Patients' sense of dignity can be preserved by their own attitudes and behaviours, by others and through public support. Health professionals need to adopt a dignity-conserving approach, for which awareness of their own attitudes and behaviours is crucial.


Sexuality during pregnancy.
Sexuality is an important part of health and well-being. Sexual behavior modifies as pregnancy progresses, influenced by biological, psychological, and social factors. To evaluate changes in sexual perceptions and activities during pregnancy and to determine sexual dysfunctions in that period. Sexual perceptions (desire from the partner, feelings of attractiveness, and fear of sexual intercourse), sexual activities during pregnancy (sexual intercourse frequency, the most frequent sexual intercourse trimester, sexual activity during the birth week, type(s) of sexual intercourse, changes in sexual satisfaction and desire compared with the pre-pregnancy period, and changes in sexual intercourse frequency during each trimester compared with the pre-pregnancy period), and sexual dysfunctions. Puerperal women were asked to anonymously complete a self-administered and structured questionnaire at the day of discharge from hospital. One hundred and eighty-eight women, aged between 17 years and 40 years with a mean age of 28.9 years, were analyzed. The first trimester was considered the most frequent period of sexual intercourse (44.7%), followed by the second trimester (35.6%). Fifty-five percent reported a decrease of sexual activity during the third trimester. Fear of sexual intercourse was referred by 23.4% of the women questioned. Sexual satisfaction was unchanged in 48.4% of the subjects and decreased in 27.7% (P < 0.0001); sexual desire is reported to be unchanged in 38.8% and decreased in 32.5% (P = 0.196) of the population. Vaginal, oral, anal sex, and masturbation were performed by 98.3%, 38.1%, 6.6%, and 20.4% of the women, respectively. We determined in our study that sexual satisfaction do not change in pregnancy compared with the pre-pregnancy patterns despite a decline of sexual activity during the third trimester. A discussion of expected changes in sexuality should be routinely done by the doctor in order to improve couples' perception of possible sexual modifications induced by pregnancy.


Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha.
Hypoxia-induced mitogenic factor (HIMF), also called FIZZ1 or RELMalpha, was a newly found cytokine. Hypoxia caused robust HIMF induction in the lung, and HIMF has potent pulmonary vasoconstrictive, proliferative, and angiogenic properties. To investigate the role of HIMF in lung development, we determined its spatial and temporal expression. From embryonic day (E)16 to postnatal day (P)28, HIMF was strongly expressed in the cytoplasm of bronchial epithelial cells, type II cells, endothelial cells, and primitive mesenchymal cells. Treatment with HIMF resulted in a significant reduction of apoptosis in cultured embryonic lung, thus revealing a previously unknown function of HIMF. Because HIMF gene is upregulated by hypoxia and contains a hypoxia-inducible transcription factor (HIF) binding site, we subsequently investigated whether HIMF was coexpressed with HIF-2alpha or HIF-1alpha. HIF-1alpha expression was temporally distinct from HIMF expression. In contrast, HIF-2alpha was present in endothelial cells, bronchial epithelial cells, and type II cells from E18 to P28. Thus, HIMF and HIF-2alpha were temporally and spatially coexpressed in the developing lung. These results indicate a role for HIMF in lung development, possibly under the control of HIF-2, and suggest that HIMF regulates apoptosis and may participate in lung alveolarization and maturation.


Does positive selection determine the B cell repertoire?
To know whether each newly formed B cell has an equal chance of survival in the organism, we analyzed the composition of the B cell repertoire of extremely limited diversity by generating mu-transgenic kappa-knockout mice. Surprisingly, in both types of mice studied, the B cell repertoire is mainly composed of cells expressing the mu-transgene-encoded chain associated with only one out four available lambda types depending on the mu transgene. Moreover, B cell differentiation cultures in vitro show that newly formed B cells can express the various lambda types regardless of the presence or absence of the mu transgenes. These results show a drastic impact of the heavy chain on the lambda light chain repertoire expressed in the periphery. The overexpression of a unique heavy/light chain pairing therefore results from selective processes. The immature B cells may be positively selected to provide the immunocompetent B cells in the periphery.


Laparoscopy Using Room Air Insufflation in a Rural African Jungle Hospital: The Bongolo Hospital Experience, January 2006 to December 2013.
Carbon dioxide is the standard insufflation gas for laparoscopy. However, in many areas of the world, bottled carbon dioxide is not available. Laparoscopy offers advantages over open surgery and has been practiced using filtered room air insufflation since 2006 at Bongolo Hospital in Gabon, Africa. Our primary goal was to evaluate the safety of room air insufflation related to intraoperative and postoperative complications. Our secondary aim was to review the types of cases performed laparoscopically at our institution. This retrospective review evaluates laparoscopic cases performed at Bongolo Hospital between January 2006 and December 2013. Demographic and perioperative information for patients undergoing laparoscopic procedures was collected. Insufflation was achieved using a standard, oil-free air compressor using filtered air and a standard insufflation regulator. A total of 368 laparoscopic procedures were identified within the time period. The majority of cases were gynecologic (43%). There was a 2% (8/368) complication rate with one perioperative death. The 2 complications related to insufflation were episodes of hypotension responsive to standard corrective measures. No intracorporeal combustion events were observed in any cases in which the use of diathermy and room air insufflation were combined. The other complications and the death were unrelated to the use of insufflation with air. Insufflation complications with room air occurred in our study. However, the complications related to insufflation with room air in our study were no different than those described in the literature using carbon dioxide. As room air is less costly than carbon dioxide and readily available, confirming the safety of room air insufflation in prospective studies is warranted. Room air appears to be safe for establishing and maintaining pneumoperitoneum, making laparoscopic surgery more accessible to patients in low-resource settings.


Saving Life, Limb, and Eyesight: Assessing the Medical Rules of Eligibility During Armed Conflict.
Medical rules of eligibility permit severely injured Iraqi and Afghan nationals to receive care in Coalition medical facilities only if bed space is available and their injuries result directly from Coalition fire. The first rule favors Coalition soldiers over host-nation nationals and contradicts the principle of impartial, needs-based medical care. To justify preferential care for compatriots, wartime medicine invokes associative obligations of care that favor friends, family, and comrades-in-arms. Associative obligations have little place in peacetime medical care but significantly affect wartime medicine. The second rule suggests liability for collateral harm that is unsupported by international law and military ethics. Absent liability, there are pragmatic reasons to offer medical care to injured local civilians if it quells resentment and cements support for Coalition forces. In contrast to peacetime medicine, military necessity and associative obligations outweigh distributive principles based on medical need during war.


Mechanical and biological properties of nanoporous carbon membranes.
Implantable blood glucose sensors have inadequate membrane-tissue interfaces for long term use. Biofouling and inflammation processes restrict biosensor membrane stability. An ideal biosensor membrane material must prevent protein adsorption and exhibit cell compatibility. In addition, a membrane must exhibit high porosity and low thickness in order to allow the biosensor to respond to analyte fluctuations. In this study, the structural, mechanical and biological properties of nanoporous alumina membranes coated with diamond-like carbon thin films were examined using scanning probe microscopy, nanoindentation and MTT viability assay. We anticipate that this novel membrane material could find use in immunoisolation devices, kidney dialysis membranes and other medical devices encountering biocompatibility issues that limit in vivo function.


Antitumor efficacy of the novel chemotherapeutic agent coramsine is potentiated by cotreatment with CpG-containing oligodeoxynucleotides.
Coramsine is a novel chemotherapeutic agent isolated from Solanum linnaeanum (devil's apple). Topical treatment provides clinical benefit for skin tumors. To evaluate the potential broader applicability of the drug, its in vivo anticancer efficacy in a murine model of malignant mesothelioma and its mode of action were investigated. Systemic administration of coramsine slowed tumor growth and prolonged survival time. Importantly, the antitumor efficacy of coramsine was enhanced when treatment was combined with stimulation of innate immunity using unmethylated CpG-containing oligodeoxynucleotides (ODNs). Combination treatment further slowed tumor growth and provided a survival benefit. Coramsine seems to kill tumor cells by direct cell lysis. Using 2 different assays to detect apoptosis (caspase activation and DNA fragmentation), we found no evidence that coramsine induces any form of programmed cell death. The fact that the efficacy of coramsine is potentiated by CpG ODNs suggests that coramsine-induced cell death is an immunologic null event.


An electrophysiological measure of visual short-term memory capacity within and across hemifields.
Recent electrophysiological research has identified a specific contralateral correlate of the contents of visual short-term memory (VSTM). This posterior contralateral delay activity (CDA) persists during the retention period, and its amplitude is modulated by the number of items held at any one time. Here we show that, despite the contralateral nature of this activity, its amplitude is modulated by the number of objects from both hemifields. When objects from one side of the visual field are held in memory, CDA activity increased for arrays of one, two, and three objects, but stopped getting larger for arrays of four objects. However, when objects from both sides are memorized at the same time, CDA activity reached its asymptotic limit for arrays of two objects per side. These results suggest that, in spite of being contralaterally organized, VSTM is limited by the number of objects from both hemifields.


Intestinal-type adenocarcinoma of the vagina: clinico-pathologic features of a common tumor with a rare localization.
Intestinal-type adenocarcinoma is a rare primary vaginal carcinoma and considerably more uncommon than metastatic lesions which represent the most frequent malignancy at this anatomic site. Among all malignant tumors, colorectal, breast and female genital tract carcinomas have the tendency to metastasize to the vagina. As morphologic and immunohistochemical features of intestinal-type adenocarcinoma occurring primarily in the vagina are not specific, clinical and radiologic information is crucial to exclude a metastatic lesion. Herein we present a rare case of intestinal-type adenocarcinoma from a villous adenoma, presenting as a polypoid mass in the posterior wall of vaginal introitus of 51-year-old menopausal woman. To the best of our knowledge, only 19 cases of intestinal-type adenocarcinoma of the vagina have been reported in the English literature so far. Notably the origin from a previous villous adenoma has been well documented only in a few cases.