Fiber-optic rotation sensor technology.
A concept for an all-waveguide fiber-optic rotation sensor is discussed, and the results of preliminary tests of key elements are described. A single channel waveguide coupler design provides the functions of an optical switch, a 3-dB beam splitter, a phase retarder, and a signal modulator, all of which may be formed on the same chip and interconnected by channel single-mode waveguides. Preliminary test results for the waveguide coupler and for a rotation sensor without the coupler are presented. Signal processing, polarization control, and interconnection of the waveguide components are discussed.


Recognition of agricultural objects by shape.
It is desired to enhance the outline of agricultural contraband in X-ray images of passenger luggage. Agricultural contraband consists of fruit, meats, animals, and plants. We suggest most contraband can be distinguished from other material by an elliptic, rather than rectangular, cross section. An algorithm is proposed to recognize such cross section using the erosion of the absolute gradient of the image. Only local convolution calculations are required. This algorithm is tested on a number of computed images as well as on X-ray images of model objects, isolated contraband, and contraband contained and obscured in baggage. The effect of image noise, object size, orientation, and obscuration is tested. It is shown that the proposed algorithm successfully enhances the outlines of desired items as small as 1-2 cm (7-11 pixels) to the exclusion of remaining material under the conditions expected in actual use.


Microtubule nucleating activity of centrosomes in cell-free extracts from Xenopus eggs: involvement of phosphorylation and accumulation of pericentriolar material.
We have studied the regulation of microtubule nucleating activity of the centrosome using cell-free extracts from Xenopus eggs. We found that the number of microtubules per centrosome increases dramatically with time during incubation of isolated centrosomes in interphasic egg extracts prepared 20-30 minutes after electric activation of cytostatic factor (CSF)-arrested eggs. The increase in microtubule nucleation was still conspicuous even when KCl-treated centrosomes (centrosomes stripped of their microtubule nucleating activity by 1 M KCl treatment) were incubated in interphasic extracts. Electron microscopy and immunostaining by anti-gamma-tubulin and 5051 human anti-centrosome antibodies revealed that pericentriolar material (PCM) was accumulated during the increase in microtubule nucleation from centrosomes in interphasic extracts, suggesting regulation of centrosomal activity by PCM accumulation. The ability of egg extracts to activate microtubule nucleation from centrosomes was also assumed to be regulated by phosphorylation, since addition of protein kinase inhibitors into interphasic extracts totally blocked the increase in microtubule nucleation from the KCl-treated centrosome. The ability of CSF-arrested mitotic extracts to increase microtubule nucleation from KCl-treated centrosomes was 3.5- to 5-fold higher than that of interphasic extracts, while PCM accumulation in mitotic extracts seemed to be similar to that in interphasic extracts. The increase in microtubule nucleation from KCl-treated centrosomes was strikingly enhanced by the addition of purified p34cdc2/cyclin B complex to interphasic extracts, but not by MAP kinase, which is activated downstream of p34cdc2/cyclin B. These results suggest two pathways activating centrosomal activity in egg extracts: accumulation of PCM and phosphorylation mediated by p34cdc2/cyclin B.


Intrinsic structural disorder of mouse proNGF.
The unprocessed precursor of the Nerve Growth Factor (NGF), proNGF, has additional functions, besides its initially described role as a chaperone for NGF folding. The precursor protein endows apoptotic and/or neurotrophic properties, in contrast to the mature part. The structural and molecular basis for such distinct activities are presently unknown. Aiming to gain insights into the specific molecular interactions that govern rm-proNGF biological activities versus those of its mature counterpart, a structural study by synchrotron small angle X-ray scattering (SAXS) in solution was carried out. The different binding properties of the two proteins were investigated by surface plasmon resonance (SPR) using, as structural probes, a panel of anti-NGF antibodies and the soluble forms of TrkA and p75(NTR) receptors. SAXS measurements revealed the rm-proNGF to be dimeric and anisometric, with the propeptide domain being intrinsically unstructured. Ab initio reconstructions assuming twofold symmetry generated two types of structural models, a globular "crab-like" and an elongated shape that resulted in equally good fits of the scattering data. A novel method accounting for possible coexistence of different conformations contributing to the experimental scattering pattern, with no symmetry constraints, suggests the "crab-like" to be a more likely proNGF conformation. To exploit the potential of chemical stabilizers affecting the existing conformational protein populations, SAXS data were also collected in the presence of ammonium sulphate. An increase of the proNGF compactness was observed. SPR data pinpoints that the propeptide of proNGF may act as an intrinsically unstructured protein domain, characterized by a molecular promiscuity in the interaction/binding to multiple partners (TrkA and p75(NTR) receptors and a panel of neutralizing anti-NGF antibodies) depending on the physiological conditions of the cell. These data provide a first insight into the structural basis for the selectivity of mouse short proNGF, versus NGF, towards its binding partners.


Near-Ultraviolet Circular Dichroism of Achiral Phenolic Termini Induced by Nonchromophoric Poly(l,l-lactide) and Poly(d,d-lactide).
Herein, we present the first induced chirality of vanillin and its phenolic analogs attached to the chain ends of poly(l,l-lactide) and poly(d,d-lactide). Vanillin analogs were used as chromophoric and luminophoric, but achiral, ring-opening initiators of corresponding chiral cyclic lactides. Induced chirality was evident from clear circular dichroism bands at 270-320 nm due to π-π* and n-π* transitions at the vanillin moiety. However, no circularly polarized luminescence band was detected. Density functional theory (DFT) and time-dependent DFT calculations suggested the existence of multiple through-space intramolecular CH/O interactions between the ortho-methoxy moiety of vanillin and nearest-neighbor lactic acid units. The terminus sensitively indicated whether the main-chain chirality was l or d.


Perceptions of adults with overweight/obesity and chronic musculoskeletal pain: An interpretative phenomenological analysis.
To gain insight into the lived experience of adults with overweight/obesity and chronic musculoskeletal pain. Knowledge gained will inform healthcare professionals about the complexity of the weight-pain relationship and enable more effective engagement with this population. Quantitative studies show links between weight and pain. Adults with overweight/obesity are more likely to experience comorbidity; however, qualitative research describing the complexities of the relationship is limited. A purposive sample of adults with overweight/obesity and chronic musculoskeletal pain participated in face-to-face interviews. Interviews were audio-recorded, transcribed verbatim and analysed using interpretive phenomenological analysis. Eighteen adults (16 female) aged 29-71, body mass index ≥25-46, participated in this study. Three superordinate themes emerged: "pain as a motivator and barrier to weight loss"; "fear of weight causing more damage"; and "activity is positive." Pain motivates some individuals to lose weight while simultaneously inhibiting weight loss efforts. Participants' perception that extra pressure caused by their weight further damaged joints contributed to fear and catastrophising. Fear is often exacerbated by healthcare professionals' descriptions of musculoskeletal damage, or participants' perception of healthcare professionals' attitude towards people with overweight/obesity. Conversely, individuals acknowledged the benefits of increased activity. Adults with overweight/obesity and chronic musculoskeletal pain in this study identified a bidirectional relationship between their weight and pain that challenged their weight loss efforts. Overweight/obesity contributed to fear and catastrophising, which resulted in avoidance of exercise that would have assisted their weight loss. Healthcare professionals need to understand the complex relationship between weight and pain, and their patients' understanding of that relationship. Healthcare professionals should use therapeutic communication to reduce the fear of weight causing damage, and thus promote physical activities that will contribute to weight loss. It is also important to ensure that the language used with this patient group does not stigmatise individuals, or cause or exacerbate fear of normal movement.


Study design of DIACORE (DIAbetes COhoRtE) - a cohort study of patients with diabetes mellitus type 2.
Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro- and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e.g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies.


Markers of mouse macrophage development detected by monoclonal antibodies.
In this review, we present and discuss a selected panel of antibody-defined markers expressed during different stages of mouse macrophage development. We distinguish four categories of markers, which are characteristic of: (1) macrophage precursors and immature macrophages (ER-MP12, ER-MP20, ER-MP54, ER-MP58); (2) mature macrophages in general (F4/80, BM8, Mac-1, Mac-2, ER-BMDM1); (3) macrophage subsets (ER-HR3, ER-MP23, ER-TR9, Forssman antigen, MOMA-1, MOMA-2, Monts-4, SER-4), and (4) IFN-gamma-stimulated macrophages (H-2Ia, LFA-1, ICAM-1, 158.2, MBR-2, TM-2, TM-4, and TM-5). It should be noted that many of the markers in this last category are inducible by other stimuli as well. The rigid classification of markers into four separate groups should be regarded as a digitalization of a continuum, thus inevitably implicating a simplification of the complex phenotypic changes that occur during mononuclear phagocyte development. Nevertheless, the current selection of antibodies against markers for different developmental stages of macrophages constitutes an important tool for characterization of mouse macrophages which participate in various biological processes.


Evaluation of dispatcher-assisted cardiopulmonary resuscitation.
The outcome of out-of-hospital cardiac arrest (CA) following cardiopulmonary resuscitation (CPR) initiated by dispatcher-provided telephone instructions (T-CPR) in the area of Gothenburg, Sweden was studied. During a period of 27 months, 475 cases categorized by the dispatchers at the Emergency Co-ordination and Dispatch Centre as being suspected CA were offered T-CPR and were included in one of the following groups: (1) T-CPR completed (caller without previous CPR training); (2) T-CPR completed (caller with previous CPR training); (3) T-CPR started, but not completed; (4) T-CPR declined by caller due to previous CPR training; (5) T-CPR declined by caller due to other reasons; or, (6) T-CPR not offered. Of the patients, 473 could be followed up and of them 427 fulfilled the criteria for CA on ambulance arrival. Among the latter cases, 10% were hospitalized alive, 4% could be discharged from hospital, and the distribution among groups was: (1) 7%; (2) 18%; (3) 5%; (4) 11%; (5) 3%; and (6) 1%. The study concludes that although more attention should be paid to the detection of CA patients by the dispatchers, when the dispatchers suspected CA, their accuracy was high. Half of the witnesses accepted the offer of T-CPR and one-third completed T-CPR. More efforts and research are needed, however, to increase the percentages of callers completing CPR. The impact of T-CPR on survival might be limited. Indeed, the comparison of 'resuscitable' patients in whom T-CPR played an important role in supporting bystanders (i.e. groups 1 and 2) with 'resuscitable' patients in whom T-CPR was not performed (i.e. groups 3, 5 and 6) suggests an increase in survival from 6% (groups 3, 5 and 6) to 9% (groups 1 and 2).


Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment.
Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+ T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfh cell, Treg, and PD-1+ CD8+ T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells.


Surveillance of influenza A and the pandemic influenza A (H1N1) 2009 in sewage and surface water in the Netherlands.
The role of the water cycle in spreading human pathogenic influenza viruses is poorly studied and is not considered to be significant. However, gastrointestinal symptoms developed in a large proportion of influenza A (H1N1) 2009 virus infected people during the pandemic in 2009 and fecal shedding was reported. This fecal route could potentially play a role in the entry of human pathogenic influenza viruses in to the water cycle. Monitoring of influenza viruses in sewage and surface water during the pandemic in 2009 showed that influenza A viruses were detected in sewage and surface water. However, the pandemic influenza A (H1N1) 2009 virus was not detected. These findings imply that the water cycle did not play a relevant role in spreading the pandemic influenza virus during the epidemic in the Netherlands in 2009. Analyses of deliberately contaminated water samples confirmed the ability of quantitative RT-PCR to detect influenza viruses in sewage samples whereas the analysis of large volumes of surface water was strongly hampered by the presence of PCR-inhibiting substances.


Vascular oxidant stress: molecular mechanisms and pathophysiological implications.
The term oxidative stress refers to a situation in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen (ie, reactive oxygen species). Three enzyme systems produce reactive oxygen species in the vascular wall: NADH/NADPH oxidase, xanthine oxidoreductase, and endothelial nitric oxide synthase. Among vascular reactive oxygen species superoxide anion plays a critical role in vascular biology because it is the source for many other reactive oxygen species and various vascular cell functions. It is currently thought that increases in oxidant stress, namely excessive production of superoxide anion, are involved in the pathophysiology of endothelial dysfunction that accompanies a number of cardiovascular risk factors including hypercholesterolemia, hypertension and cigarette smoking. On the other hand, vascular oxidant stress plays a pivotal role in the evolution of clinical conditions such as atherosclerosis, diabetes and heart failure.


In vitro and in vivo expression of interstitial collagenase/MMP-1 by human mast cells.
Degradation of the extracellular matrix occurs under physiological and pathological conditions, thought to be principally mediated by a family of neutral proteolytic enzymes termed the matrix metalloproteinases (MMPs). The present study was initiated to determine whether mast cells have the ability to produce these proteases in diseased and normal human tissue. Immunohistochemistry and in situ hybridization was performed to localize interstitial collagenase protein and mRNA transcripts in diseased human tissue. The human mast cell line HMC-1 was cultured under serum free conditions, stimulated with phorbol mystrate acetate (PMA) and supernatants analyzed by Western blotting and zymography to determine the profile of secreted MMPs. The dog mast cell line BR, known to secrete gelatinolytic enzymes, was used in parallel studies. Total RNA was extracted and analyzed by RT-PCR for the expression of tissue inhibitors of MMP (TIMPs). Collagenase-1 protein and mRNA were expressed by tryptase and chymase positive human mast cells in all tissue analyzed. This proteinase was also detected in the cytoplasm and conditioned media of HMC-1 cells. PMA induced gelatinolytic activity in both mast cell lines examined. TIMP-1 immunoreactivity was detected and TIMP-1, and -2 (but not TIMP-3) mRNA transcripts were amplified from HMC-1 cells. This is the first demonstration of the expression of collagenase-1 by human mast cells in both inflamed and normal tissues, and by a human mast cell line. MMPs secreted by these cells could contribute to the extensive matrix lysis characteristic of diseases such as rheumatoid arthritis and inflammatory ocular disorders. Alternatively collagenase-1 production by mast cells may play a critical role in cell invasion and migration into sites of inflammation.


Hypolipidemic and antioxidant effects of buckwheat leaf and flower mixture in hyperlipidemic rats.
As a source of biologically active compounds, buckwheat has beneficial effects in nutrition due to its high content of flavonoids, particularly rutin. Aim of our study was to examine effects of buckwheat on plasma lipid status and phospholipids fatty acids composition, histological and parameters of oxidative stress in Wistar rats fed a high-fat diet. This study showed that buckwheat leaf and flower (BLF) mixture supplementation significantly reduce weight gain, plasma lipid concentrations and atherogenic index in rats fed a high-fat diet. Treatment of the high-fat group of animals with buckwheat significantly increased percentage of n-6 fatty acids as well as eicosapentaenoic acid (EPA) and decreased percentage of saturated fatty acids (SFA) and oleic acid. Buckwheat antioxidant effects diminished negative influence of high-fat diet in hyperlipidemic rats, while pathohistological analysis of liver confirmed changes after high-fat consumption. Our results showed hypolipidemic, antiatherogenic and antioxidative features of buckwheat leaf and flower mixture, and these parts of the plant with the highest rutin content could be beneficial in prevention and curing of hyperlipidemia.


18F labeling of arenes.
Molecular imaging has witnessed an upsurge in growth, with positron emission tomography leading the way. This trend has encouraged numerous synthetic chemists to enter the field of (18) F-radiochemistry and provide generic solutions to address the well-recognized challenges of late-stage fluorination. This Minireview focuses on recent developments in the (18)F-labeling of aromatic substrates.


The Complete Mitochondrial Genome and Expression Profile of Mitochondrial Protein-Coding Genes in the Bisexual and Parthenogenetic Haemaphysalis longicornis.
The tick Haemaphysalis longicornis is widely distributed in eastern Asia, New Zealand and Australia, and is well-known as a vector of multiple zoonotic pathogens. This species exhibits two reproductive strategies, bisexual and obligate parthenogenetic reproduction. Hence, in the current study, the complete mitochondrial genomes of the bisexual and parthenogenetic populations were assembled and analyzed, and the expression of the mitochondrial protein-coding genes was evaluated and compared between the two reproductive populations. The results indicated that the length of the mitochondrial genomes of the two reproductive populations is 14,694 and 14,693 bp in the bisexual and parthenogenetic populations, respectively. The AT content in the mitochondrial genome of the bisexual and obligate parthenogenetic population reached 77.22 and 77.34%, respectively. The phylogenetic tree was constructed combining 13 protein-coding genes, which showed that the genetic distance between the bisexual and parthenogenetic populations was less than that between the subspecies. The expression of the mitochondrial protein-coding genes was quantitatively analyzed at different feeding status for the bisexual and parthenogenetic populations, and the results showed significant differences in the expression patterns of these genes, suggesting that they might trigger specific energy utilization mechanisms due to their different reproductive strategies and environmental pressures.


Marker-free automated histopathological annotation of lung tumour subtypes by FTIR imaging.
By integration of FTIR imaging and a novel trained random forest classifier, lung tumour classes and subtypes of adenocarcinoma are identified in fresh-frozen tissue slides automated and marker-free. The tissue slices are collected under standard operation procedures within our consortium and characterized by current gold standards in histopathology. In addition, meta data of the patients are taken. The improved standards on sample collection and characterization results in higher accuracy and reproducibility as compared to former studies and allows here for the first time the identification of adenocarcinoma subtypes by this approach. The differentiation of subtypes is especially important for prognosis and therapeutic decision.


Predicting innovative firms using web mining and deep learning.
Evidence-based STI (science, technology, and innovation) policy making requires accurate indicators of innovation in order to promote economic growth. However, traditional indicators from patents and questionnaire-based surveys often lack coverage, granularity as well as timeliness and may involve high data collection costs, especially when conducted at a large scale. Consequently, they struggle to provide policy makers and scientists with the full picture of the current state of the innovation system. In this paper, we propose a first approach on generating web-based innovation indicators which may have the potential to overcome some of the shortcomings of traditional indicators. Specifically, we develop a method to identify product innovator firms at a large scale and very low costs. We use traditional firm-level indicators from a questionnaire-based innovation survey (German Community Innovation Survey) to train an artificial neural network classification model on labelled (product innovator/no product innovator) web texts of surveyed firms. Subsequently, we apply this classification model to the web texts of hundreds of thousands of firms in Germany to predict whether they are product innovators or not. We then compare these predictions to firm-level patent statistics, survey extrapolation benchmark data, and regional innovation indicators. The results show that our approach produces reliable predictions and has the potential to be a valuable and highly cost-efficient addition to the existing set of innovation indicators, especially due to its coverage and regional granularity.


Combination cancer therapy by hapten-targeted prodrug-activating enzymes and cytokines.
Combination therapy can help overcome limitations in the treatment of heterogeneous tumors. In the current study, we examined whether multiple therapeutic agents could be targeted to anti-dansyl single-chain antibodies (DNS scFv) that were anchored on the plasma membrane of cancer cells. Functional DNS scFv could be stably expressed on CT-26 colon cancer cells both in vitro and in vivo. Dansyl moieties were covalently attached to recombinant beta-glucuronidase (betaG) and interleukin 2 (IL-2) via a flexible poly(ethylene glycol) linker to form DNS-PEG-betaG and DNS-PEG-IL-2 conjugates. The conjugates displayed enzymatic and splenocyte-stimulatory activities, respectively, that were similar to those of the unmodified proteins. The conjugates selectively bound CT-26 cells that expressed anti-DNS scFv (CT-26/DNS cells) but not CT-26 cells that expressed control scFv (CT-26/phOx cells). DNS-PEG-betaG preferentially activated a glucuronide prodrug (BHAMG) of p-hydroxy aniline mustard at CT-26/DNS cells in culture and accumulated in subcutaneous CT-26/DNS tumors after intravenous administration. Systemic administration of DNS-PEG-IL-2 or DNS-PEG-betaG and BHAMG significantly delayed the growth of CT-26/DNS but not control CT-26/phOx tumors. Combination treatment with DNS-PEG-betaG and BHAMG followed by DNS-PEG-IL-2 therapy significantly suppressed the growth of CT-26/DNS tumors as compared to either single-agent regimen. These results show that at least two DNS-modified therapeutic agents can be selectively delivered to DNS scFv receptors in vitro and in vivo, allowing combination therapy of DNS scFv-modified tumors.


cisRED: a database system for genome-scale computational discovery of regulatory elements.
We describe cisRED, a database for conserved regulatory elements that are identified and ranked by a genome-scale computational system (www.cisred.org). The database and high-throughput predictive pipeline are designed to address diverse target genomes in the context of rapidly evolving data resources and tools. Motifs are predicted in promoter regions using multiple discovery methods applied to sequence sets that include corresponding sequence regions from vertebrates. We estimate motif significance by applying discovery and post-processing methods to randomized sequence sets that are adaptively derived from target sequence sets, retain motifs with p-values below a threshold and identify groups of similar motifs and co-occurring motif patterns. The database offers information on atomic motifs, motif groups and patterns. It is web-accessible, and can be queried directly, downloaded or installed locally.


Invited Review: From nose to gut - the role of the microbiome in neurological disease.
Inflammation and neurodegeneration are key features of many chronic neurological diseases, yet the causative mechanisms underlying these processes are poorly understood. There has been mounting interest in the role of the human microbiome in modulating the inflammatory milieu of the central nervous system (CNS) in health and disease. To date, most research has focussed on a gut-brain axis, with other mucosal surfaces being relatively neglected. We herein take the novel approach of comprehensively reviewing the roles of the microbiome across several key mucosal interfaces - the nose, mouth, lung and gut - in health and in Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis (MS). This review systematically appraises the anatomical and microbiological landscape of each mucosal surface in health and disease before considering relevant mechanisms that may influence the initiation and progression of PD, AD and MS. The cumulative effects of dysbiosis from the nose to the gut may contribute significantly to neurological disease through a wide variety of mechanisms, including direct translocation of bacteria and their products, and modulation of systemic or CNS-specific immunity. This remains an understudied and exciting area for future research and may lead to the development of therapeutic targets for chronic neurological disease.


[Patient satisfaction at a university hospital].
The results of a research project into the level of satisfaction/dissatisfaction of 158 first-time patients attending by an University hospital, Brazil, are presented. The interviews were carried out by first year medical students as part of a comprehensive project concerned with the restructuring of the Medical Curriculum. Its prime objective was to expose the students to patients/consumers as early as possible in their studies. After an introductory training program, the students asked the patients arriving at the hospital out-patient clinic for permission to observe them throughout the attendance given. A questionnaire was used which covered the various aspects of the consumers relationship with a medical institution (socio-economic variables, "art of care", outcome of the medical encounter and suggestions for improvement). Both patients and students were able to perceive the different problems that patients confront in the course of their dealings with a medical institution (reception, registration, nursing, social service and medical attention). The data showed a difference of opinion between students and patients regarding several aspects of the satisfaction/dissatisfaction items, partly because of their different social class status and party due to the different expectations regarding medical care.


Effects of short-term and long-term exposure to ocean acidification on carbonic anhydrase activity and morphometric characteristics in the invasive polychaete Branchiomma boholense (Annelida: Sabellidae): A case-study from a CO2 vent system.
The aim of this study was to test the effects of short- and long-term exposure to high pCO2 on the invasive polychaete Branchiomma boholense (Grube, 1878), (Sabellidae), through the implementation of a transplant experiment at the CO2 vents of the Castello Aragonese at the island of Ischia (Italy). Analysis of carbonic anhydrase (CA) activity, protein tissue content and morphometric characteristics were performed on transplanted individuals (short-term exposure) as well as on specimens resident to both normal and low pH/high pCO2 environments (long-term exposure). Results obtained on transplanted worms showed no significant differences in CA activity between individuals exposed to control and acidified conditions, while a decrease in weight was observed under short-term acclimatization to both control and low pH, although at low pH the decrease was more pronounced (∼20%). As regard individuals living under chronic exposure to high pCO2, the morphometric results revealed a significantly lower (70%) wet weight of specimens from the vents with respect to animals living in high pH/low pCO2 areas. Moreover, individuals living in the Castello vents showed doubled values of enzymatic activity and a significantly higher (50%) protein tissue content compared to specimens native from normal pH/low pCO2. The results of this study demonstrated that B. boholense is inclined to maintain a great homeostatic capacity when exposed to low pH, although likely at the energetic expense of other physiological processes such as growth, especially under chronic exposure to high pCO2.


Validating dispersal distances inferred from autoregressive occupancy models with genetic parentage assignments.
Dispersal distances are commonly inferred from occupancy data but have rarely been validated. Estimating dispersal from occupancy data is further complicated by imperfect detection and the presence of unsurveyed patches. We compared dispersal distances inferred from seven years of occupancy data for 212 wetlands in a metapopulation of the secretive and threatened California black rail (Laterallus jamaicensis coturniculus) to distances between parent-offspring dyads identified with 16 microsatellites. We used a novel autoregressive multi-season occupancy model that accounted for both unsurveyed patches and imperfect detection to quantify patch isolation using buffer radius (BRM) and incidence function (IFM) connectivity measures at 15 scales (1-10, 15, 20, 25, and 30 km). Connectivity measures were then fit as colonization covariates in occupancy models to estimate a model-averaged dispersal distance. As predicted, colonization was more strongly related to connectivity at small spatial scales (<10 km). AIC weights were greatest at 7 km for BRM and at 4 km for IFM. Model-averaged dispersal distances (BRM = 7.46 km; IFM = 5.48 km) showed good agreement with the mean M(±SE) dispersal distance from 23 parent-offspring dyads (5.58 ± 1.92 km), indicating reasonably accurate mean dispersal distances can be inferred from occupancy data when isolation strongly affects colonization.


Proprioception mediates the association between systemic inflammation and muscle weakness in patients with knee osteoarthritis: Results from the Amsterdam Osteoarthritis cohort.
To determine whether systemic inflammation is associated with poor proprioception; to confirm that systemic inflammation is associated with muscle weakness; and to determine whether poor proprioception mediates the association between systemic inflammation and muscle weakness in knee osteoarthritis. Cross-sectional study. A total of 689 participants with knee osteoarthritis from the Amsterdam Osteoarthritis (AMS-OA) cohort. Systemic inflammation was assessed by erythrocyte sedimentation rate, knee proprioception by determining the joint motion detection threshold, and muscle strength with an isokinetic dynamometer. Linear regression models were used to estimate direct associations between systemic inflammation, proprioception and muscle strength, and the indirect association (mediation) between systemic inflammation and muscle strength via proprioception adjusted for potential confounders. Higher erythrocyte sedimentation rates were associated with poor proprioception (p = 0.022). Poor proprioception (p < 0.001) and higher erythrocyte sedimentation rates (p < 0.001) were associated with muscle weakness. Poor proprio-ception mediated the association between systemic inflammation and muscle weakness (p = 0.035). Results suggest that systemic inflammation is associated with poor proprioception in knee osteoarthritis. Poor proprioception may be a path-way through which systemic inflammation is associated with muscle weakness in patients with knee osteoarthritis.


Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result.
Background: Blood biomarkers may aid in recruitment to clinical trials of Alzheimer's disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests. Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ42 (n = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494). Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05). Conclusion: Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.


miR-146a-Mediated extracellular matrix protein production in chronic diabetes complications.
MicroRNAs (miRNAs), through transcriptional regulation, modulate several cellular processes. In diabetes, increased extracellular matrix protein fibronectin (FN) production is known to occur through histone acetylator p300. Here, we investigated the role of miR-146a, an FN-targeting miRNA, on FN production in diabetes and its relationship with p300. miR-146a expressions were measured in endothelial cells from large vessels and retinal microvessels in various glucose levels. FN messenger RNA expression and protein levels with or without miR-146a mimic or antagomir transfection were examined. A luciferase assay was performed to detect miR-146a's binding to FN 3'-untranslated region (UTR). Likewise, retinas from type 1 diabetic rats were studied with or without an intravitreal injection of miR-146a mimic. In situ hybridization was used to localize retinal miR-146a. Cardiac and renal tissues were analyzed from type 1 and type 2 diabetic animals. A total of 25 mmol/L glucose decreased miR-146a expression and increased FN expression compared with 5 mmol/L glucose in both cell types. miR-146a mimic transfection prevented such change, whereas miR-146a antagomir transfection in the cells in 5 mmol/L glucose caused FN upregulation. A luciferase assay confirmed miR-146a's binding to FN 3'-UTR. miR-146a was localized in the retinal endothelial cells and was decreased in diabetes. Intravitreal miR-146a mimic injection restored retinal miR-146a and decreased FN in diabetes. Additional experiments showed that p300 regulates miR-146a. Similar changes were seen in the retinas, kidneys, and hearts in type 1 and type 2 diabetic animals. These studies showed a novel, glucose-induced molecular mechanism in which miR-146a participates in the transcriptional circuitry regulating extracellular matrix protein production in diabetes.


Brn3b/Brn3c double knockout mice reveal an unsuspected role for Brn3c in retinal ganglion cell axon outgrowth.
In mice, Brn3 POU domain transcription factors play essential roles in the differentiation and survival of projection neurons within the retina, inner ear, dorsal root and trigeminal ganglia. During retinal ganglion cell differentiation, Brn3b is expressed first, followed by Brn3a and Brn3c. Targeted deletion of Brn3b, but not Brn3a or Brn3c, leads to a loss of most retinal ganglion cells before birth. However, as a few retinal ganglion cells are still present in Brn3b(-/-) mice, Brn3a and Brn3c may partially compensate for the loss of Brn3b. To examine the role of Brn3c in retinal ganglion cell development, we generated Brn3b/Brn3c double knockout mice and analyzed their retinas and optic chiasms. Retinal ganglion cell axons from double knockout mice were more severely affected than were those from Brn3b-deficient mice, indicating that Brn3c was required for retinal ganglion cell differentiation and could partially compensate for the loss of Brn3b. Moreover, Brn3c had functions in retinal ganglion cell differentiation separate from those of Brn3b. Ipsilateral and misrouted projections at the optic chiasm were overproduced in Brn3b(-/-) mice but missing were entirely in optic chiasms of Brn3b/Brn3c double knockout mice, suggesting that Brn3c controlled ipsilateral axon production. Forced expression of Brn3c in Brn3b(-/-) retinal explants restored neurite outgrowth, demonstrating that Brn3c could promote axon outgrowth in the absence of Brn3b. Our results reveal a complex genetic relationship between Brn3b and Brn3c in regulating the retinal ganglion cell axon outgrowth.


The diagnosis of acute appendicitis in pregnant versus non-pregnant women: A comparative study.
To investigate whether the diagnosis of acute appendicitis is affected by pregnancy or not. A retrospective study with the analysis of the medical records of all women suspected of having appendicitis who underwent appendectomy at our hospital between June 2010 and March 2015 were reviewed. The patients were divided into two groups according to whether they were pregnant or not during the surgery: group I, pregnant women, and group II, non-pregnant women. During the study period, 38 pregnant women and 169 non-pregnant women underwent appendectomy. The time from admission to the operation was not statistically different (2.17±1.47 days in group I vs. 1.98±1.66 day in group II; p=0.288). The pregnant group had longer hospital stay than the non-pregnant group (p=0.04). Ultrasonography (USG) was used as the first diagnostic modality in 36/38 patients in group I and 161/169 in group II. The non-visualized appendix on ultrasound was seen in 17 patients in group I and 51 patients in group II, which was not statistically different. Sensitivity and specificity of USG in diagnosis of acute appendicitis were 61.29 and 80.00% in group I, and 93.0 and 31.6% in group II, respectively. Although the diagnosis of appendicitis in pregnant women is not delayed, careful assessment of these patients suspected of having appendicitis should be encouraged when USG examination is normal or nondiagnostic.


Suramin analogues as subtype-selective G protein inhibitors.
G protein alpha subunits expose specific binding sites that allow for the sequential, conformation-dependent binding of protein reaction partners, e.g., G protein beta gamma dimers, receptors, and effectors. These domains represent potential sites for binding of low-molecular-weight inhibitors. We tested the following suramin analogues as G protein antagonists: 8-(3-nitrobenzamido)-1,3,5-naphtalenetrisulfonic acid (NF007), 8-(3-(3-nitrobenzamido)benzamido)-1,3,5-naphtalenetrisulfonic++ + acid NF018), 8,8'-(carbonylbis(imino-3,1-phenylene))bis-(1,3,5-naphtalenetri sulfonic acid) (NF023), 8,8'-(carbonylbis(imino-3,1-phenylene)carbonylimino-(3,1-phe nylene))bis-(1,3, 5-naphtalenetrisulfonic acid) (NF037), and suramin. The compounds suppressed [35S]GTPgammaS binding to purified, recombinant G protein alpha subunits, an effect that is due to inhibition of GDP release. Suramin is selective for recombinant Gsalpha-s (EC50 values o f approximately 240 nM; rank order of potency, suramin > NF037 > NF023 > NF018 > NF007), whereas NF023 is selective for recombinant Gi alpha-1 and recombinant Go alpha (EC50 value of approximately 300 nM; rank order of potency, NF023 > / = NF037 > suramin >0 NF018 > NF007). Selectivity was also demonstrated on a cellular level. In rat sympathetic neurons, alpha-2-adrenergic and muscarinic receptor-dependent inhibition of the voltage-sensitive calcium current is mediated by Gi/Go, whereas inhibition by vasoactive intestinal peptide (VIP) is mediated by Gs. Calcium current inhibition by alpha2-adrenergic and muscarinic receptors was greatly reduced when 100 microM NF023 was applied intracellularly, whereas the response to VIP was unaffected; in contrast, the response to VIP was blunted only with 100 microM suramin in the recording pipette. The suramin analogues do not interfere with the interaction between alpha subunits and G protein beta gamma dimer but compete with binding of the effector. The addition of purified adenylyl cyclase reverses the inhibitory effect of suramin on the rate of [35S]GTPgammaS binding to recombinant Gsalpha-s, indicating direct competition for a common site; similarly, immunoprecipitation by an antibody directed against an epitope of the effector binding site is inhibited by suramin. Our results show that it is possible to design G protein inhibitors that target the effector binding site on the alpha subunits.


Insights into water coordination associated with the Cu(II)/Cu(I) electron transfer at a biomimetic Cu centre.
The coordination properties of the biomimetic complex [Cu(TMPA)(H2O)](CF3SO3)2 (TMPA = tris(2-pyridylmethyl)amine) have been investigated by electrochemistry combined with UV-Vis and EPR spectroscopy in different non-coordinating media including imidazolium-based room-temperature ionic liquids, for different water contents. The solid-state X-ray diffraction analysis of the complex shows that the cupric centre lies in a N4O coordination environment with a nearly perfect trigonal bipyramidal geometry (TBP), the water ligand being axially coordinated to Cu(II). In solution, the coordination geometry of the complex remains TBP in all media. Neither the triflate ion nor the anions of the ionic liquids were found to coordinate the copper centre. Cyclic voltammetry in all media shows that the decoordination of the water molecule occurs upon monoelectronic reduction of the Cu(II) complex. Back-coordination of the water ligand at the cuprous state can be detected by increasing the water content and/or decreasing the timescale of the experiment. Numerical simulations of the voltammograms allow the determination of kinetics and thermodynamics for the water association-dissociation mechanism. The resulting data suggest that (i) the binding/unbinding of water at the Cu(I) redox state is relatively slow and equilibrated in all media, and (ii) the binding of water at Cu(I) is somewhat faster in the ionic liquids than in the non-coordinating solvents, while the decoordination process is weakly sensitive to the nature of the solvents. These results suggest that ionic liquids favour water exchange without interfering with the coordination sphere of the metal centre. This makes them promising media for studying host-guest reactions with biomimetic complexes.


Urine metabolomic analysis identifies potential biomarkers and pathogenic pathways in kidney cancer.
Kidney cancer is the seventh most common cancer in the Western world, its incidence is increasing, and it is frequently metastatic at presentation, at which stage patient survival statistics are grim. In addition, there are no useful biofluid markers for this disease, such that diagnosis is dependent on imaging techniques that are not generally used for screening. In the present study, we use metabolomics techniques to identify metabolites in kidney cancer patients' urine, which appear at different levels (when normalized to account for urine volume and concentration) from the same metabolites in nonkidney cancer patients. We found that quinolinate, 4-hydroxybenzoate, and gentisate are differentially expressed at a false discovery rate of 0.26, and these metabolites are involved in common pathways of specific amino acid and energetic metabolism, consistent with high tumor protein breakdown and utilization, and the Warburg effect. When added to four different (three kidney cancer-derived and one "normal") cell lines, several of the significantly altered metabolites, quinolinate, α-ketoglutarate, and gentisate, showed increased or unchanged cell proliferation that was cell line-dependent. Further evaluation of the global metabolomics analysis, as well as confirmation of the specific potential biomarkers using a larger sample size, will lead to new avenues of kidney cancer diagnosis and therapy.


Reducing Ischemia/Reperfusion Injury by the Targeted Delivery of Nitric Oxide from Magnetic-Field-Induced Localization of S-Nitrosothiol-Coated Paramagnetic Nanoparticles.
Nitric oxide (NO) is an important factor during an ischemia/reperfusion (I/R) injury. Protective actions of NO during I/R are attributed to antioxidant and anti-inflammatory effects, as well as cell-signaling-based inhibition of nuclear proteins. The therapeutic potential of supplemented NO during I/R is nonetheless uncertain, since peroxynitrite formed from NO near superoxide can be potentially harmful due to NF-κB up-regulation and direct cytotoxicity. This study investigates new technology to provide the magnet-assisted delivery of therapeutic levels of localized NO to targeted I/R tissues using biocompatible gadolinium-oxide-based paramagnetic nanoparticles coated with S-nitrosothiols (SNO-PMNPs). Hamsters fitted with a window chamber were subjected to ischemia by application of a tourniquet at the periphery of the window chamber for 1 h. The SNO-PMNPs were intravenously infused (10 mg/kg) during the reperfusion phase, during which time a localized external magnetic field was either applied or not applied to the I/R area. The microvascular hemodynamics, functional capillary density (FCD), rolling and adherent leukocytes, reactive oxygen and nitrogen species, and tissue viability were assessed using intravital microscopy. Control animals did not receive SNO-PMNPs. Treatment with SNO-PMNPs plus a magnet but not without a magnet increased reflow, decreased leukocytes rolling and sticking in postcapillary venules, limited cell death, and restored the FCD. The absence of the magnet resulted in systemic changes in heart rate and mean arterial blood pressure, consistent with the systemic delivery of NO by the SNO-PMNP. These results indicate that the localized delivery of NO during reperfusion counters the deleterious consequences of peroxynitrite and other reactive species generated upon reperfusion as reflected in localized increases in blood flow and tissue viability, all with minimal systemic effects. This technology can provide the basis for a timely treatment of a localized ischemia-associated disease to prevent injury in different tissues and organs.


Emergence of host-adapted Salmonella Enteritidis through rapid evolution in an immunocompromised host.
Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts1. Host adaptation can potentially progress to host restriction where the pathogen is strictly limited to a single host species and is frequently associated with more severe symptoms. Host-adapted and host-restricted bacterial clades evolve from within a broader host-promiscuous species and sometimes target different niches within their specialist hosts, such as adapting from a mucosal to a systemic lifestyle. Genome degradation, marked by gene inactivation and deletion, is a key feature of host adaptation, although the triggers initiating genome degradation are not well understood. Here, we show that a chronic systemic non-typhoidal Salmonella infection in an immunocompromised human patient resulted in genome degradation targeting genes that are expendable for a systemic lifestyle. We present a genome-based investigation of a recurrent blood-borne Salmonella enterica serotype Enteritidis (S. Enteritidis) infection covering 15 years in an interleukin (IL)-12 β-1 receptor-deficient individual that developed into an asymptomatic chronic infection. The infecting S. Enteritidis harbored a mutation in the mismatch repair gene mutS that accelerated the genomic mutation rate. Phylogenetic analysis and phenotyping of multiple patient isolates provides evidence for a remarkable level of within-host evolution that parallels genome changes present in successful host-restricted bacterial pathogens but never before observed on this timescale. Our analysis identifies common pathways of host adaptation and demonstrates the role that immunocompromised individuals can play in this process.


Assembly and annotation of the black spruce genome provide insights on spruce phylogeny and evolution of stress response.
Black spruce (Picea mariana [Mill.] B.S.P.) is a dominant conifer species in the North American boreal forest that plays important ecological and economic roles. Here, we present the first genome assembly of P. mariana with a reconstructed genome size of 18.3 Gbp and NG50 scaffold length of 36.0 kbp. A total of 66,332 protein-coding sequences were predicted in silico and annotated based on sequence homology. We analyzed the evolutionary relationships between P. mariana and five other spruces for which complete nuclear and organelle genome sequences were available. The phylogenetic tree estimated from mitochondrial genome sequences agrees with biogeography; specifically, P. mariana was strongly supported as a sister lineage to P. glauca and three other taxa found in western North America, followed by the European P. abies. We obtained mixed topologies with weaker statistical support in phylogenetic trees estimated from nuclear and chloroplast genome sequences, indicative of ancient reticulate evolution affecting these two genomes. Clustering of protein-coding sequences from the six Picea taxa and two Pinus species resulted in 34,776 orthogroups, 560 of which appeared to be specific to P. mariana. Analysis of these specific orthogroups and dN/dS analysis of positive selection signatures for 497 single-copy orthogroups identified gene functions mostly related to plant development and stress response. The P. mariana genome assembly and annotation provides a valuable resource for forest genetics research and applications in this broadly distributed species, especially in relation to climate adaptation.


Intense NIR emissions at 0.8 μm, 1.47 μm, and 1.53 μm from colloidal LiYbF4:Ln(3+) (Ln = Tm(3+) and Er(3+)) nanocrystals.
We report on the synthesis of diamond shaped Ln(3+)-doped LiYbF4 (Ln = Tm and Er) nanocrystals with flat edges via the thermal decomposition method. Strong near-infrared emissions at 0.8 μm, 1.47 μm and 1.53 μm are observed from colloidal dispersions of Tm(3+)-doped and Er(3+)-doped LiYbF4 nanocrystals, respectively, under 0.98 μm diode laser excitation. The NIR emission intensities for Tm(3+)-doped and Er(3+)-doped LiYbF4 nanocrystals are comparable with those of the sodium counterpart NaYbF4, suggesting that LiYbF4 is also an excellent host matrix for lanthanide ions to obtain strong NIR emissions in colloidal solutions of LiYbF4 (Tm(3+) or Er(3+)) nanocrystals.


Top-down activation of fusiform cortex without seeing faces in prosopagnosia.
Face processing can be modified by bottom-up and top-down influences, but it is unknown how these processes interact in patients with face-recognition impairments (prosopagnosia). We investigated a prosopagnosic with lesions in right occipital and left fusiform cortex but whose right fusiform gyrus is intact and still activated during face-processing tasks. P.S., a patient with a well-established and selective agnosia for faces, was instructed to detect the presence of either faces or houses in pictures with different amounts of noise. The right fusiform face area (FFA) showed reduced responses to face information when visual images were degraded with noise. However, her right FFA still activated to noise-only images when she was instructed to detect faces. These results reveal that fusiform activation is still selectively modulated by task demands related to the anticipation of a face, despite severe face-recognition deficits and the fact that no reliable stimulus-driven response is evoked by actual facial information. Healthy controls showed stimulus-driven responses to faces in fusiform, and in right but not left occipital cortex, suggesting that the latter area alone might provide insufficient facial information in P.S. These results provide a novel account for residual activation of the FFA and underscore the importance of controlling task demands during functional magnetic resonance imaging.


Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls.
This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone. Healthy girls (9-15 years) were age-stratified (9, 10-12, and 13-15 years) and randomized to receive HPV (n = 270), HAB (n = 271), or HPV + HAB (n = 272). Vaccines were administered at months 0, 1, and 6. Immunogenicity was evaluated at months 0 and 7. The hepatitis A immune response was noninferior for HPV + HAB, versus HAB, for seroconversion rates (100% in each group) and geometric mean antibody titers (GMTs) (95% CI) (4,504.2 [3,993.0-5,080.8] and 5,288.4 [4,713.3-5,933.7] mIU/mL, respectively). The hepatitis B immune response was noninferior for HPV + HAB, versus HAB, for anti-HBs seroprotection rates (98.3% and 100%); GMTs were 3,136.5 [2,436.0-4,038.4] and 5,646.5 [4,481.3-7,114.6] mIU/mL, respectively. The HPV-16/18 immune response was noninferior for HPV + HAB, versus HPV, for seroconversion rates (99.6% and 100% for both antigens) and GMTs (22,993.5 [20,093.4-26,312.0] and 26,981.9 [23,909.5-30,449.1] EL.U/mL for HPV-16; 8,671.2 [7,651.7-9,826.6] and 11,182.7 [9,924.8-12,600.1] EL.U/mL for HPV-18, respectively). No subject withdrew because of adverse events. No vaccine-related serious adverse events were reported. Immune responses and reactogenicity were similar in girls aged 9 years compared with the entire study population. Results support coadministration of HPV-16/18 vaccine with HAB vaccine in girls aged 9-15 years. The HPV-16/18 vaccine was immunogenic and generally well tolerated in 9-year-old girls.


A digital 3D atlas of the marmoset brain based on multi-modal MRI.
The common marmoset (Callithrix jacchus) is a New-World monkey of growing interest in neuroscience. Magnetic resonance imaging (MRI) is an essential tool to unveil the anatomical and functional organization of the marmoset brain. To facilitate identification of regions of interest, it is desirable to register MR images to an atlas of the brain. However, currently available atlases of the marmoset brain are mainly based on 2D histological data, which are difficult to apply to 3D imaging techniques. Here, we constructed a 3D digital atlas based on high-resolution ex-vivo MRI images, including magnetization transfer ratio (a T1-like contrast), T2w images, and multi-shell diffusion MRI. Based on the multi-modal MRI images, we manually delineated 54 cortical areas and 16 subcortical regions on one hemisphere of the brain (the core version). The 54 cortical areas were merged into 13 larger cortical regions according to their locations to yield a coarse version of the atlas, and also parcellated into 106 sub-regions using a connectivity-based parcellation method to produce a refined atlas. Finally, we compared the new atlas set with existing histology atlases and demonstrated its applications in connectome studies, and in resting state and stimulus-based fMRI. The atlas set has been integrated into the widely-distributed neuroimaging data analysis software AFNI and SUMA, providing a readily usable multi-modal template space with multi-level anatomical labels (including labels from the Paxinos atlas) that can facilitate various neuroimaging studies of marmosets.


Are we overpathologizing everyday life? A tenable blueprint for behavioral addiction research.
Background Behavioral addiction research has been particularly flourishing over the last two decades. However, recent publications have suggested that nearly all daily life activities might lead to a genuine addiction. Methods and aim In this article, we discuss how the use of atheoretical and confirmatory research approaches may result in the identification of an unlimited list of "new" behavioral addictions. Results Both methodological and theoretical shortcomings of these studies were discussed. Conclusions We suggested that studies overpathologizing daily life activities are likely to prompt a dismissive appraisal of behavioral addiction research. Consequently, we proposed several roadmaps for future research in the field, centrally highlighting the need for longer tenable behavioral addiction research that shifts from a mere criteria-based approach toward an approach focusing on the psychological processes involved.


Comparison of human mandibular osteoblasts grown on two commercially available titanium implant surfaces.
Surface characteristics play a major role in determining tissue response to implants and therefore their clinical outcome. The aim of the present study was to compare two commercially available titanium surfaces: plasma sprayed (TPS) and sand-blasted, acid-etched surface (SLA). The surfaces were characterized by roughness testing, scanning electronic microscopy (SEM), Raman spectroscopy, and protein adsorption to determine their microtopographic and chemical properties. The effect of the surfaces on human mandibular osteoblasts was then studied in terms of cell morphology, adhesion, proliferation, and differentiation. Human osteoblasts from the mandible were cultured on these two surfaces and evaluated at 3, 6, 24, and 48 hours to determine cell attachment and morphology. Growth and differentiation kinetics were subsequently investigated by evaluating cell growth, alkaline phosphatase activity, osteocalcin and osteoprotegerin production at 7, 14, and 21 days. Although roughness was quite similar, the two surfaces presented strong differences in their topography, and cell morphology varied as a consequence. Osteoblasts on SLA appeared more elongated and spindle shaped than those on TPS, and their adhesion at 3 and 6 hours was weaker, but reached that of cells on TPS at hour 24. Cell proliferation was greater on SLA surfaces but differentiation parameters; i.e., alkaline phosphatase and osteocalcin, provided better results on TPS surfaces. Osteoprotegerin production was enhanced on TPS surfaces at days 14 and 21. Although cells grown on both surfaces exhibited good adhesion capabilities, a well-differentiated osteoblastic phenotype, and maintained a clear proliferation potential, our study suggests that plasma-sprayed treatment offers a better performance than SLA by creating, at least in the early phases, better conditions for tissue healing.


Differential changes in glutamate receptor subunit messenger RNAs in rat brain after haloperidol treatment.
Glutamate receptors are implicated in several neuropsychiatric disorders and in the actions of neuroleptic drugs used to treat them. To help clarify how these drugs impinge upon the glutamatergic system, we have studied the effects of 2 weeks' haloperidol (2 mg kg(-1) d(-1)) upon the distribution and abundance of glutamate receptor mRNAs in rat brain. The mRNAs detected were those encoding the glutamate-binding protein (GBP), the N-methyl D-aspartate (NMDA) receptor (NR1 subunit) and the flip and flop isoforms of α-amino-3-hydroxy- 5-methyl-4-isoxazolpropionate (AMPA)-preferring non-NMDA receptors gluR1 and gluR2. The mRNAs were studied using in situ hybridization histochemistry in dorsolateral striatum, nucleus accumbens, frontal cortex and hippocampus. Haloperidol led to an increase in GBP mRNA in striatum and frontal cortex but not in hippocampus. AMPA receptor mRNAs showed gene- and isoform-specific alterations in treated animals, with a significant increase in the proportion of gluR2 flip compared to gluR2 flop. The gluR1 flop:gluR2 flop ratio also increased. No differences were observed for NR1 mRNA in any area. Thus, subchronic administration of haloperidol has a molecularly and spatially specific effect upon expression of glutamate receptor-related transcripts. The data have several implications. Firstly, the enhanced expression of GBP mRNA may contribute to the alterations in other glutamatergic parameters observed after neuroleptics. Secondly, the pattern of changes for the NMDA and AMPA receptor mRNAs suggests that the alterations in density of these receptors and their mRNAs reported in schizophrenia are not an artefact of neuroleptic treatment. Finally, the specific increase in flip:flop mRNA ratio for gluR2, together with the increased proportion of gluR1 flop:gluR2 flop mRNA, is likely to affect the properties of the encoded AMPA receptors. Such changes may be relevant to the desired or undesired effects of these drugs.


Fair trade and staple foods: A systematic review.
Sustainability certification schemes such as FAIRTRADE, FLO, WFTO and FT-USA have gained increasing markets. The significant growth of the fair trade (FT) movement in the last decades draws attention to ethical consumption. FT's aim at improving the livelihoods of producers in developing countries and promotion of social change is considered a model that shows the benefits of trade to development. Although conveying a large number of publications, important questions about the movement remain under-explored. The literature is prolific on coffee, cacao, flowers, wine, and gold. In contrast, the engagement with staple foods - a prominent globally traded food category - seems minor. The primary objective of this review was to map the existing literature about FT and staple foods; then, to investigate the role of staple foods in the FT movement. The search strategy was designed to retrieve publications on the intersection of FT and staple foods. To date, there is no review about FT and staple foods nexus. Our systematic review addressed this gap considering FT as an alternative capable of addressing unsustainable food consumption and production impacts. Our research protocol included keywords searching across four databases, screening, and comparative analysis. From 283 documents retrieved, 49 were deemed relevant to reflect the role of staple foods in the FT movement. This systematic review discusses challenges and opportunities for the FT model to further engage with staples and recommends improvement of its environmental credentials. The present study can contribute by informing decision makers, policy makers, businesses, NGOs, producers, and consumers.


NRG1-Fc improves metabolic health via dual hepatic and central action.
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling. We evaluated its efficacy in improving metabolic parameters and dissected the mechanisms of action. NRG1-Fc treatment triggered potent AKT activation in the liver, lowered blood glucose, improved insulin sensitivity, and suppressed food intake in obese mice. NRG1-Fc acted as a potent secretagogue for the metabolic hormone FGF21; however, the latter was largely dispensable for its metabolic effects. NRG1-Fc directly targeted the hypothalamic POMC neurons to promote membrane depolarization and increase firing rate. Together, NRG1-Fc exhibits improved pharmacokinetic properties and exerts metabolic benefits through dual inhibition of hepatic gluconeogenesis and caloric intake.


Chondrules: An Origin by Impacts between Dust Grains.
A barred chondrule in the Ngawi meteorite contains a magnetite spherule embedded in it. The collision between these two objects fractured and partially remelted the chondrule, an indication that the impact velocity was 10(5) to 10(6) centimeters per second. This observation supports Cameron's and Whipple's recent predictions that grains achieved high velocities in the nebula and that the resulting impacts provide a suitable chondrule-forming mechanism.


Basic compatibility of Albugo candida in Arabidopsis thaliana and Brassica juncea causes broad-spectrum suppression of innate immunity.
A biotrophic parasite often depends on an intrinsic ability to suppress host defenses in a manner that will enable it to infect and successfully colonize a susceptible host. If the suppressed defenses otherwise would have been effective against alternative pathogens, it follows that primary infection by the "suppressive" biotroph potentially could enhance susceptibility of the host to secondary infection by avirulent pathogens. This phenomenon previously has been attributed to true fungi such as rust (basidiomycete) and powdery mildew (ascomycete) pathogens. In our study, we observed broad-spectrum suppression of host defense by the oomycete Albugo candida (white blister rust) in the wild crucifer Arabidopsis thaliana and a domesticated relative, Brassica juncea. A. candida subsp. arabidopsis suppressed the "runaway cell death" phenotype of the lesion mimic mutant lsd1 in Arabidopsis thaliana in a sustained manner even after subsequent inoculation with avirulent Hyaloperonospora arabidopsis (Arabidopsis thaliana downy mildew). In sequential inoculation experiments, we show that preinfection by virulent Albugo candida can suppress disease resistance in cotyledons to several downy mildew pathogens, including contrasting examples of genotype resistance to H. arabidopsis in Arabidopsis thaliana that differ in the R protein and modes of defense signaling used to confer the resistance; genotype specific resistance in B. juncea to H. parasitica (Brassica downy mildew; isolates derived from B. juncea); species level (nonhost) resistance in both crucifers to Bremia lactucae (lettuce downy mildew) and an isolate of the H. parasitica race derived from Brassica oleracea; and nonhost resistance in B. juncea to H. arabidopsis. Broad-spectrum powdery mildew resistance conferred by RPW8 also was suppressed in Arabidopsis thaliana to two morphotypes of Erysiphe spp. following pre-infection with A. candida subsp. arabidopsis.


Laryngopharyngeal sensory deficits as a predictor of aspiration.
This study evaluates whether patients with severe sensory deficits in the hypopharynx are at increased risk for aspiration and determines the relationship between pharyngeal muscular weakness and hypopharyngeal sensory deficits. Forty patients with dysphagia who underwent flexible endoscopic evaluation of swallowing with sensory testing were prospectively divided into 2 groups. One group included patients with severe sensory deficits determined by an absent laryngeal adductor reflex and the other with normal sensitivity. Subjects were given liquid and puree consistencies and were evaluated for aspiration as well as pharyngeal muscle contraction. The differences in incidence of aspiration and pharyngeal muscular weakness between the 2 groups were significant (P < 0.001 Fisher's exact test). There is a strong association between motor function deficits and hypopharyngeal sensory deficits. The association of sensory loss and motor deficits together with the use of flexible endoscopic evaluation of swallowing with sensory testing can predict those patients who are at highest risk for aspiration.


Ultrasound Measurements of the First Extensor Compartment: Determining the Transection Limits for Ultra-minimally Invasive Release of De Quervain Tenosynovitis.
Background: De Quervain syndrome is the second most common compressive tendinopathy. Although the length of the first extensor compartment (FEC) has been studied previously, there is no documented reported comparison study of short-axis and long-axis sonographic measurements. The thread technique, or Guo Technique, has been applied to carpal tunnel syndrome, trigger finger, and superficial peroneal compressive neuropathy. To perform this procedure, it is critically important to accurately identify the boundaries for transection. Methods: Twenty-one fresh frozen cadaver upper extremities were examined under ultrasound to determine the length of the extensor retinaculum (ER) over the FEC. Using the sonographic landmarks, the ERs were measured in short axis and long axis over their proximal to distal margins and from the distal margins to the distal edges of the radial styloids. These sonographic measurements were then compared with gross anatomical measurements. Results: The short-axis sonographic measurement of the ER on average was 22.53 mm (95% confidence interval [CI] = 20.79-24.05 mm). The long-axis sonographic measurement of the ER on average was 15.65 mm (95% CI = 13.70-17.78 mm). The average length of the ER by gross anatomical dissection was 22.40 mm (95% CI = 21.15-23.51 mm). Conclusions: The short axis is not significantly different from the gross anatomical measurement; however, the long axis is significantly lower than the gross anatomical measurement. The results support the idea that the short axis is more accurate than the long axis.


A survey of homozygous deletions in human cancer genomes.
Homozygous deletions of recessive cancer genes and fragile sites are known to occur in human cancers. We identified 281 homozygous deletions in 636 cancer cell lines. Of these deletions, 86 were homozygous deletions of known recessive cancer genes, 17 were of sequenced common fragile sites, and 178 were in genomic regions that do not overlap known recessive oncogenes or fragile sites ("unexplained" homozygous deletions). Some cancer cell lines have multiple homozygous deletions whereas others have none, suggesting intrinsic variation in the tendency to develop this type of genetic abnormality (P < 0.001). The 178 unexplained homozygous deletions clustered into 131 genomic regions, 27 of which exhibit homozygous deletions in more than one cancer cell line. This degree of clustering indicates that the genomic positions of the unexplained homozygous deletions are not randomly determined (P < 0.001). Many homozygous deletions, including those that are in multiple clusters, do not overlap known genes and appear to be in intergenic DNA. Therefore, to elucidate further the pathogenesis of homozygous deletions in cancer, we investigated the genome landscape within unexplained homozygous deletions. The gene count within homozygous deletions is low compared with the rest of the genome. There are also fewer short interspersed nuclear elements (SINEs), long interspersed nuclear elements (LINEs), and low-copy-number repeats (LCRs). However, DNA within homozygous deletions has higher flexibility. These features may signal the presence of currently unrecognized zones of susceptibility to DNA rearrangement. They may also reflect a tendency to reduce the adverse effects of homozygous deletions by minimizing the number of genes removed.


Cell cycle-dependent entry of Toxoplasma gondii into synchronized HL-60 cells.
The degree of attraction of Toxoplasma gondii to vertebrate cells varies with cell type and cell phase. Human promyelocytic leukemia cells, HL-60, were synchronized by double thymidine block method and co-cultured with Toxoplasma for 1 hr at each cell stage to investigate the cell cycle specific susceptibility of parasites to host cells. For 30 hr the average number of Toxoplasma that invaded was a little changed except at 3 hr from G1/S phase boundary which concurred with the peak point of DNA synthesis. At 3 hr which is a relatively short interval compared to whole S phase, modification of cells by parasitic invasion was most remarkable. The number of Toxoplasma that penetrated was increased to more than six times. The shape of the cells became sludgy and almost indiscernible by strong accessibility of parasites only for an hour of mid-S phase. The same fluctuation was also observed at the second peak of S phase but weakly. This suggests that there be surface molecules concerning with the attachment of Toxoplasma to the host cells, which is expressed at special point of S phase. Further studies on the specific protein or similar molecules related could be carried out using synchronized HL-60 cells.


X-ray diffraction by a crystal in a permanent external electric field: electric-field-induced structural response in alpha-GaPO4.
For the first time, site-selective distortion has been investigated for two different structural units in the ternary compound alpha-GaPO(4) under the influence of a permanent external electric field. Based on 54 measured reflection intensities, the electric-field-induced distortion of PO(4) and GaO(4) tetrahedra in alpha-GaPO(4) crystals is evaluated using a model of pseudoatomic displacements introduced recently [Gorfman, Tsirelson & Pietsch (2005). Acta Cryst. A61, 387-396]. A stronger variation of the P-O bond lengths in the PO(4) tetrahedron was found compared to the bonds in the GaO(4) tetrahedron. The different distortions of the tetrahedra owing to the electric field were analysed in terms of the valence charge density of alpha-GaPO(4) and its topological characteristics. The larger charge of the P pseudoatom compared to the Ga atom was recognized as the main reason for the higher sensitivity of the PO(4) tetrahedron to a permanent external electric field.


Language growth and genetics of specific language impairment.
Behavioural studies of children with specific language impairment (SLI) have reported long-term growth outcomes across different dimensions of language. Genetic studies of children with SLI have identified candidate genes and putative associations of gene variants with SLI. The aims of this review are to summarize these two lines of investigation and to highlight the possible role of underlying growth timing mechanisms that influence the trajectory of language outcomes throughout childhood and into adolescence. Behavioural growth trajectories demonstrate that children with SLI have notable strengths in language acquisition, as well as limitations, across different dimensions of language. Language onset appears delayed, although the rate and pattern of change over time is similar to unaffected children. Growth rate decelerates early in adolescence for some dimensions of language. Genetic investigations reveal candidate genes that are known to influence neuronal development, and reveal possible gene interactions along a causal pathway. Epigenetic studies reveal other genetic influences implicated in the cognitive decline associated with ageing. This review highlights possible parallels between underlying genetic mechanisms and characteristics of linguistic growth trajectories. The conclusion is that new developmental perspectives are needed to inform language intervention in ways that align nurture with nature.


A Bacillus subtilis gene of previously unknown function, yhaG, is translationally regulated by tryptophan-activated TRAP and appears to be involved in tryptophan transport.
Computer analysis of the Bacillus subtilis genome sequence revealed a gene with no previously attributed function, yhaG, specifying a transcript containing a presumptive binding site for the tryptophan-activated regulatory protein, TRAP. The presumptive TRAP binding site overlaps the yhaG Shine-Dalgarno sequence and translation initiation region. TRAP was shown to regulate expression of yhaG translationally. Production of the yhaG transcript in vivo was found to compete for the binding of TRAP to other known TRAP binding sites. YhaG is likely to be a transmembrane protein involved in tryptophan transport.


Harvesting Energy from Salinity Differences Using Battery Electrodes in a Concentration Flow Cell.
Salinity-gradient energy (SGE) technologies produce carbon-neutral and renewable electricity from salinity differences between seawater and freshwater. Capacitive mixing (CapMix) is a promising class of SGE technologies that captures energy using capacitive or battery electrodes, but CapMix devices have produced relatively low power densities and often require expensive materials. Here, we combined existing CapMix approaches to develop a concentration flow cell that can overcome these limitations. In this system, two identical battery (i.e., faradaic) electrodes composed of copper hexacyanoferrate (CuHCF) were simultaneously exposed to either high (0.513 M) or low (0.017 M) concentration NaCl solutions in channels separated by a filtration membrane. The average power density produced was 411 ± 14 mW m(-2) (normalized to membrane area), which was twice as high as previously reported values for CapMix devices. Power production was continuous (i.e., it did not require a charging period and did not vary during each step of a cycle) and was stable for 20 cycles of switching the solutions in each channel. The concentration flow cell only used inexpensive materials and did not require ion-selective membranes or precious metals. The results demonstrate that the concentration flow cell is a promising approach for efficiently harvesting energy from salinity differences.


Hin recombinase bound to DNA: the origin of specificity in major and minor groove interactions.
The structure of the 52-amino acid DNA-binding domain of the prokaryotic Hin recombinase, complexed with a DNA recombination half-site, has been solved by x-ray crystallography at 2.3 angstrom resolution. The Hin domain consists of a three-alpha-helix bundle, with the carboxyl-terminal helix inserted into the major groove of DNA, and two flanking extended polypeptide chains that contact bases in the minor groove. The overall structure displays features resembling both a prototypical bacterial helix-turn-helix and the eukaryotic homeodomain, and in many respects is an intermediate between these two DNA-binding motifs. In addition, a new structural motif is seen: the six-amino acid carboxyl-terminal peptide of the Hin domain runs along the minor groove at the edge of the recombination site, with the peptide backbone facing the floor of the groove and side chains extending away toward the exterior. The x-ray structure provides an almost complete explanation for DNA mutant binding studies in the Hin system and for DNA specificity observed in the Hin-related family of DNA invertases.


Gas phase vibrational spectroscopy of cold (TiO2)n(-) (n = 3-8) clusters.
We report infrared photodissociation (IRPD) spectra for the D2-tagged titanium oxide cluster anions (TiO2)n(-) with n = 3-8 in the spectral region from 450 to 1200 cm(-1). The IRPD spectra are interpreted with the aid of harmonic spectra from BP86/6-311+G* density functional theory calculations of energetically low-lying isomers. We conclusively assign the IRPD spectra of the n = 3 and n = 6 clusters to global minimum energy structures with Cs and C2 symmetry, respectively. The vibrational spectra of the n = 4 and n = 7 clusters can be attributed to contributions of at most two low-lying structures. While our calculations indicate that the n = 5 and n = 8 clusters have many more low-lying isomers than the other clusters, the dominant contributions to their spectra can be assigned to the lowest energy structures. Through comparison between the calculated and experimental spectra, we can draw conclusions about the size-dependent evolution of the properties of (TiO2)n(-) clusters, and on their potential utility as model systems for catalysis on a bulk TiO2 surface.


Connecting threads: epigenetics and metabolism.
Chromatin-modifying enzymes have long been proposed to be the authors of an epigenetic language, but the origin and meaning of the messages they write in chromatin are still mysterious. Recent studies suggesting that the effects of diet can be passed on epigenetically to offspring add weight to the idea that histones act as metabolic sensors, converting changes in metabolism into stable patterns of gene expression. The challenge will now be to understand how localized fluctuations in levels of metabolites control chromatin modifiers in space and time, translating a dynamic metabolic state into a histone map.


Differential inlA and inlB expression and interaction with human intestinal and liver cells by Listeria monocytogenes strains of different origins.
In this study, a number of Listeria monocytogenes strains of different origins were evaluated for in vitro invasion capacity for various human cell types (monocytic THP-1, enterocytic Caco-2, and hepatocytic HepG2 cells) and for expression levels of specific virulence genes. For THP-1 cells, no differences between clinical and nonclinical L. monocytogenes strains in invasion capacity or in production of the proinflammatory cytokine interleukin-8 (IL-8) were observed, whereas for the Caco-2 and HepG2 cells, significant differences in invasion capacity were noticed. On average, the clinical strains showed a significantly lower invasion capacity than the nonclinical L. monocytogenes strains. Furthermore, it was shown that the clinical strains induce lower IL-8 levels in HepG2 cells than do the nonclinical strains. This observation led us to study the mRNA expression levels of inlA, inlB, and ami, important virulence genes mediating adhesion and invasion of eukaryotic cells, by real-time reverse transcription-PCR for 27 clinical and 37 nonclinical L. monocytogenes strains. Significant differences in inlA and inlB expression were observed, with clinical strains showing a lower expression level than nonclinical strains. These observations were in accordance with in vitro invasion of Caco-2 and HepG2 cells, respectively. The results of this study indicate that differential expression levels of inlA and inlB possibly play a role in the virulence capacities of L. monocytogenes strains. The lower capacity of clinical strains to invade HepG2 cells and to induce IL-8 is possibly a mechanism of immune evasion used by specific L. monocytogenes strains.


Can we customize chemotherapy? Individualizing cytotoxic regimens in advanced non-small-cell lung cancer.
Metastatic non-small-cell lung cancer remains a fatal disease with a median survival of < 1 year. A critical challenge is to develop predictive markers for customizing platinum-based treatment. The first studies focused on the excision repair cross-complementing 1 (ERCC1) gene in this difficult task. Several layers of evidence indicate that ERCC1 mRNA expression could be a predictive marker for cisplatin alone or in combination with certain drugs such as etoposide, gemcitabine, and 5-fluorouracil but not in combination with antimicrotubule drugs. Several retrospective studies demonstrated an impressive survival advantage for gemcitabine plus cisplatin but not for other combinations in tumors with low ERCC1 expression. A customized phase III ERCC1-based trial met the primary endpoint of improvement in response but not in survival, leading us to hypothesize that docetaxel might not be the most appropriate partner for cisplatin in the presence of low ERCC1 levels or for gemcitabine in the presence of high ERCC1 levels. A phase II study demonstrated the feasibility of combining carboplatin, gemcitabine, docetaxel, and vinorelbine according to ERCC1 and ribonucleotide reductase subunit M1 expression levels. These findings highlight the importance of continual learning, and decision-making strategies for customizing treatment should reflect the limitations of our knowledge.


Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease.
Tiotropium and ipratropium bromide are both recognised treatments in the management of people with stable chronic obstructive pulmonary disease (COPD). There are new studies which have compared tiotropium with ipratropium bromide, making an update necessary. To compare the relative effects of tiotropium to ipratropium bromide on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in patients with COPD using available randomised controlled trial (RCT) data. We identified RCTs from the Cochrane Airways Group Specialised Register of trials (CAGR) and ClinicalTrials.gov up to November 2012. We included parallel group RCTs of 12 weeks duration or longer comparing treatment with tiotropium with ipratropium bromide for patients with stable COPD. Two review authors independently assessed studies for inclusion and then extracted data on study quality and outcome results. We contacted trial sponsors for additional information. We analysed the data using Cochrane Review Manager (RevMan 5.2). This review included two studies of good methodological quality that enrolled 1073 participants with COPD. The studies used a similar design and inclusion criteria and were of at least 12 weeks duration; the participants had a mean forced expiratory volume in one second (FEV1) of 40% predicted value at baseline. One study used tiotropium via the HandiHaler (18 µg) for 12 months and the other via the Respimat device (5 µg and 10 µg) for 12 weeks. In general, the treatment groups were well matched at baseline but not all outcomes were reported for both studies. Overall the risk of bias across the included RCTs was low.For primary outcomes this review found that at the three months trough (the lowest level measured before treatment) FEV1 significantly increased with tiotropium compared to ipratropium bromide (mean difference (MD) 109 mL; 95% confidence interval (CI) 81 to 137, moderate quality evidence, I(2) = 62%). There were fewer people experiencing one or more non-fatal serious adverse events on tiotropium compared to ipratropium (odds ratio (OR) 0.5; 95% CI 0.34 to 0.73, high quality evidence). This represents an absolute reduction in risk from 176 to 97 per 1000 people over three to 12 months. Concerning disease specific adverse events, the tiotropium group were also less likely to experience a COPD-related serious adverse event when compared to ipratropium bromide (OR 0.59; 95% CI 0.41 to 0.85, moderate quality evidence).For secondary outcomes, both studies reported fewer hospital admissions in the tiotropium group (OR 0.34; 95% CI 0.15 to 0.70, moderate quality evidence); as well as fewer patients experiencing one or more exacerbations leading to hospitalisation in the people on tiotropium in both studies (OR 0.56; 95% CI 0.31 to 0.99, moderate quality evidence). There was no significant difference in mortality between the treatments (OR 1.39; 95% CI 0.44 to 4.39, moderate quality evidence). One study measured quality of life using the St George's Respiratory Questionnaire (SGRQ); the mean SGRQ score at 52 weeks was lower in the tiotropium group than the ipratropium group (lower on the scale is favourable) (MD -3.30; 95% CI -5.63 to -0.97, moderate quality evidence). There were fewer participants suffering one of more exacerbations in the tiotropium arm (OR 0.71; 95% CI 0.52 to 0.95, high quality evidence) and there was also a reported difference in the mean number of exacerbations per person per year which reached statistical significance (MD -0.23; 95% CI -0.39 to -0.07, P = 0.006, moderate quality evidence). From the 1073 participants there were significantly fewer withdrawals from the tiotropium group (OR 0.58; 95% CI 0.41 to 0.83, high quality evidence). This review shows that tiotropium treatment, when compared with ipratropium bromide, was associated with improved lung function, fewer hospital admissions (including those for exacerbations of COPD), fewer exacerbations of COPD and improved quality of life. There were both fewer serious adverse events and disease specific events in the tiotropium group, but no significant difference in deaths with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a reasonable choice (instead of ipratropium bromide) for patients with stable COPD, as proposed in guidelines. We would advise some caution with tiotropium via the Respimat inhaler and suggest waiting for further information from an ongoing head-to-head trial comparing mortality in relation to tiotropium delivery devices and doses.


Organising a safe space for navigating social-ecological transformations to sustainability.
The need for developing socially just living conditions for the world's growing population whilst keeping human societies within a 'safe operating space' has become a modern imperative. This requires transformative changes in the dominant social norms, behaviours, governance and management regimes that guide human responses in areas such as urban ecology, public health, resource security (e.g., food, water, energy access), economic development and biodiversity conservation. However, such systemic transformations necessitate experimentation in public arenas of exchange and a deepening of processes that can widen multi-stakeholder learning. We argue that there is an emergent potential in bridging the sustainability transitions and resilience approaches to create new scientific capacity that can support large-scale social-ecological transformations (SETs) to sustainability globally, not just in the West. In this article, we elucidate a set of guiding principles for the design of a 'safe space' to encourage stronger interactions between these research areas and others that are relevant to the challenges faced. We envisage new opportunities for transdisciplinary collaboration that will develop an adaptive and evolving community of practice. In particular, we emphasise the great opportunity for engaging with the role of emerging economies in facilitating safe space experimentation.


Anterior cervical spine fusion and sleep disordered breathing.
The authors reviewed 12 patients who developed obstructive sleep apnea (OSA) syndrome in association with anterior cervical spine fusion. Four subsequent patients were studied prospectively before C2 to C4 anterior fusion and documented to have OSA by questionnaire, visual analogue scales, polysomnography, and multiple sleep latency tests. The authors found that placement of the anterior cervical plates reduced the size of the upper airway. Symptoms and objective findings were controlled with nasal continuous positive airway pressure.


Fruit and soil quality of organic and conventional strawberry agroecosystems.
Sale of organic foods is one of the fastest growing market segments within the global food industry. People often buy organic food because they believe organic farms produce more nutritious and better tasting food from healthier soils. Here we tested if there are significant differences in fruit and soil quality from 13 pairs of commercial organic and conventional strawberry agroecosystems in California. At multiple sampling times for two years, we evaluated three varieties of strawberries for mineral elements, shelf life, phytochemical composition, and organoleptic properties. We also analyzed traditional soil properties and soil DNA using microarray technology. We found that the organic farms had strawberries with longer shelf life, greater dry matter, and higher antioxidant activity and concentrations of ascorbic acid and phenolic compounds, but lower concentrations of phosphorus and potassium. In one variety, sensory panels judged organic strawberries to be sweeter and have better flavor, overall acceptance, and appearance than their conventional counterparts. We also found the organically farmed soils to have more total carbon and nitrogen, greater microbial biomass and activity, and higher concentrations of micronutrients. Organically farmed soils also exhibited greater numbers of endemic genes and greater functional gene abundance and diversity for several biogeochemical processes, such as nitrogen fixation and pesticide degradation. Our findings show that the organic strawberry farms produced higher quality fruit and that their higher quality soils may have greater microbial functional capability and resilience to stress. These findings justify additional investigations aimed at detecting and quantifying such effects and their interactions.


Mixed infections with tick-borne viruses in a seabird colony in Eire.
Viruses were isolated from 2 tick species collected from the nesting areas of seabirds on Great Saltee Island, Eire. Bunyaviruses of the Uukuniemi serogroup were isolated from hard ticks (Ixodes uriae and I. rothschildi), bunyaviruses of the Hughes serogroup from soft ticks (Ornithodoros maritimus), and orbiviruses of the Kemerovo serogroup from I. uriae and O. maritimus. The results indicate that the bunyaviruses, but not the orbiviruses, show "tick specificity". Neutralising activity against members of all 3 serogroups was detected in sera from chicks in the nesting areas; neutralising antibodies were probably maternal.