Calibration and field application of passive sampling for episodic exposure to polar organic pesticides in streams.
Rainfall-triggered runoff is a major driver of pesticide input in streams. Only few studies have examined the suitability of passive sampling to quantify such episodic exposures. In this study, we used Empore™ styrene-divinylbenzene reverse phase sulfonated disks (SDB disks) and event-driven water samples (EDS) to assess exposure to 15 fungicides and 4 insecticides in 17 streams in a German vineyard area during 4 rainfall events. We also conducted a microcosm experiment to determine the SDB-disk sampling rates and provide a free-software solution to derive sampling rates under time-variable exposure. Sampling rates ranged from 0.26 to 0.77 L d(-1) and time-weighted average (TWA) concentrations from 0.05 to 2.11 μg/L. The 2 sampling systems were in good agreement and EDS exceeded TWA concentrations on average by a factor of 3. Our study demonstrates that passive sampling is suitable to quantify episodic exposures from polar organic pesticides.


Blackouts as a Moderator of Young Adult Veteran Response to Personalized Normative Feedback for Heavy Drinking.
Blackouts-or periods of alcohol-induced amnesia for all or part of a drinking event-have been identified as independent predictors of alcohol-related harm that may be used to identify individuals who would benefit from intervention. However, little is known about the prevalence and impact of blackouts among Veterans. This study examined blackouts as a moderator of young adult veteran response to a brief, online personalized normative feedback (PNF) intervention for heavy drinking. Veterans scoring ≥3/4 (women/men) on the Alcohol Use Disorders Identification Test completed a baseline and 1-month assessment as part of a larger intervention trial (N = 571; 83% male; age M = 28.9, SD = 3.3). Participants were randomized to alcohol PNF (n = 285) or a video game attention control (n = 286). Hierarchical regression was used to examine the interaction between intervention condition and blackouts on alcohol-related outcomes at 1-month follow-up. At baseline, 26% of participants reported loss of memory for drinking events in the past 30 days. The interaction between condition and blackouts was significant, such that PNF participants who had experienced blackouts at baseline reported greater decreases in drinking quantity at 1 month than those who had not, and only PNF participants who had experienced baseline blackouts reported a decrease in alcohol problems at follow-up. PNF appears to be particularly effective for individuals who have experienced alcohol-induced blackout, perhaps because blackouts prime them for feedback on their alcohol use. While other negative consequences may also prime individuals for behavior change, blackouts are posited as a particularly useful screening tool because they are prevalent among young adults, have a strong association with alcohol-related harm, and are assessed in widely used clinical measures.


RNA-targeted splice-correction therapy for neuromuscular disease.
Splice-modulation therapy, whereby molecular manipulation of premessenger RNA splicing is engineered to yield genetic correction, is a promising novel therapy for genetic diseases of muscle and nerve-the prototypical example being Duchenne muscular dystrophy. Duchenne muscular dystrophy is the most common childhood genetic disease, affecting one in 3500 newborn boys, causing progressive muscle weakness, heart and respiratory failure and premature death. No cure exists for this disease and a number of promising new molecular therapies are being intensively studied. Duchenne muscular dystrophy arises due to mutations that disrupt the open-reading-frame in the DMD gene leading to the absence of the essential muscle protein dystrophin. Of all novel molecular interventions currently being investigated for Duchenne muscular dystrophy, perhaps the most promising method aiming to restore dystrophin expression to diseased cells is known as 'exon skipping' or splice-modulation, whereby antisense oligonucleotides eliminate the deleterious effects of DMD mutations by modulating dystrophin pre-messenger RNA splicing, such that functional dystrophin protein is produced. Recently this method was shown to be promising and safe in clinical trials both in The Netherlands and the UK. These trials studied direct antisense oligonucleotide injections into single peripheral lower limb muscles, whereas a viable therapy will need antisense oligonucleotides to be delivered systemically to all muscles, most critically to the heart, and ultimately to all other affected tissues including brain. There has also been considerable progress in understanding how such splice-correction methods could be applied to the treatment of related neuromuscular diseases, including spinal muscular atrophy and myotonic dystrophy, where defects of splicing or alternative splicing are closely related to the disease mechanism.


KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine.
The linkage of Kaposi sarcoma (KS) to infection by a novel human herpesvirus (Kaposi sarcoma-associated herpesvirus [KSHV]) is one of the great successes of contemporary biomedical research and was achieved by using advanced genomic technologies in a manner informed by a nuanced understanding of epidemiology and clinical investigation. Ongoing efforts to understand the molecular mechanisms by which KSHV infection predisposes to KS continue to be powerfully influenced by insights emanating from the clinic. Here, recent developments in KS pathogenesis are reviewed, with particular emphasis on clinical, pathologic, and molecular observations that highlight the many differences between this process and tumorigenesis by other oncogenic viruses.


Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes.
DNA methylation is essential for murine development and is implicated in the control of gene expression. MeCP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of mammalian, nuclear proteins related by the presence in each of an amino acid motif called the methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MeCP2, MBD1 and MBD2 can also repress transcription. We describe the genomic structure and chromosomal localization of the human and murine Mbd1, Mbd2, Mbd3, and Mbd4 genes. We find that the highly similar MBD2 and MBD3 proteins are encoded by genes that map to different chromosomes in humans and mice but show a similar genomic structure. The Mbd1 and Mbd2 genes, in contrast, map together to murine and human Chromosomes (Chrs)18. The Mbd3 and Mbd4 genes map to murine Chrs 10 and 6, respectively, while the human MBD3 and MBD4 genes map to Chrs 19 and 3, respectively.


Recombinant protein production by large-scale transient gene expression in mammalian cells: state of the art and future perspectives.
The expansion of the biologics pipeline depends on the identification of candidate proteins for clinical trials. Speed is one of the critical issues, and the rapid production of high quality, research-grade material for preclinical studies by transient gene expression (TGE) is addressing this factor in an impressive way: following DNA transfection, the production phase for TGE is usually 2-10 days. Recombinant proteins (r-proteins) produced by TGE can therefore enter the drug development and screening process in a very short time--weeks. With "classical" approaches to protein expression from mammalian cells, it takes months to establish a productive host cell line. This article summarizes efforts in industry and academia to use TGE to produce tens to hundreds of milligrams of r-proteins for either fundamental research or preclinical studies.


Use of helium-oxygen mixtures in the treatment of croup: a systematic review.
To determine the effect of helium-oxygen inhalation on relieving symptoms and distress in children with croup as measured by the croup score, and to identify areas of uncertainty for future research. Systematic review of prospective randomised and non-randomised controlled trials of children with the clinical diagnosis of croup, comparing the effect of helium-oxygen mixtures with placebo or any active treatment. Outcome measures were change in croup score, physiological parameters, hospital admission rates, need for intubation and adverse events. All records as identified by a systematic search strategy were assessed independently by two reviewers. Two trials were identified for inclusion assessing the effect of helium-oxygen inhalation in children with croup in an emergency department. In one trial the control group received humidified oxygen and in the other nebulised epinephrine. An improvement in the mean croup score over time was seen in the control and intervention groups of both trials, with no significant difference between the groups. Significant methodological and clinical heterogeneity in the design of the trials precluded a meaningful meta-analysis. At present there is no evidence to support the use of helium-oxygen therapy in children with croup. Methodologically well-designed and adequately powered randomised controlled trials are needed to determine whether helium-oxygen inhalation as part of the initial treatment in croup alters outcome.


Identification of candidate long noncoding RNAs associated with left ventricular hypertrophy.
Long noncoding RNAs (lncRNAs) constitute an emerging group of noncoding RNAs, which regulate gene expression. Their role in cardiac disease is poorly known. Here, we investigated the association between lncRNAs and left ventricular hypertrophy. Wild-type and adenosine A2A receptor overexpressing mice (A2A-Tg) were subjected to transverse aortic constriction (TAC) and expression of lncRNAs in the heart was investigated using genome-wide microarrays and an analytical pipeline specifically developed for lncRNAs. Microarray analysis identified two lncRNAs up-regulated and three down-regulated in the hearts of A2A-Tg mice subjected to TAC. Quantitative PCR showed that lncRNAs 2900055J20Rik and Gm14005 were decreased in A2A-Tg mice (3.5- and 1.8-fold, p < 0.01). We found from public microarray dataset that 2900055J20Rik and Gm14005 were increased in TAC mice compared to sham-operated animals (1.8- and 1.4-fold, after 28 days, p < 0.01). Interestingly, in this public dataset, cardioprotective drug JQ1 decreased 2900055J20Rik and Gm14005 expression by 2.2- and 1.6-fold (p < 0.01). First, we have shown that data on lncRNAs can be obtained from gene expression microarrays. Second, expression of lncRNAs 2900055J20Rik and Gm14005 is regulated after TAC and can be modulated by cardioprotective molecules. These observations motivate further investigation of the therapeutic value of lncRNAs in the heart.


A caring relationship with people who have cancer.
This paper is a report of a study conducted to elucidate the meaning of a caring relationship with people with cancer. A caring relationship becomes the most important focus of caregiving when treatment of the body has reached the limits where cure is no longer expected. Caring as perceived by people with cancer involves nurses having professional attitudes and skills in order to provide good care, including emotional and practical support. A phenomenological hermeneutic approach influenced by Ricoeur was used. Eight nurses working in an oncology unit in Iran were interviewed in 2007 about their experiences of caring relationships with people who have cancer. The findings were interpreted as getting involved in a mutual/demanding close relationship. Closeness demanded nurses to be present, to listen to patients, and to be compassionate. Closeness was also mutual and characterized both caregiving and receiving new insights into values in the nurses' own lives. The close relationship was at times frustrating when they were faced with situations that they could not handle and were out of their control. Closeness is an important foundation for caring, and acquires a special dimension in the care of people with cancer and their relatives. It derives from the personal and professional experiences of nurses in their own life stories. Nursing education should include a reflective approach in order to develop caring skills in oncology nursing that are not merely attuned to medical care.


Immunohematologic characteristics of infection-associated cerebral infarction.
We evaluated 50 consecutive patients with acute ischemic stroke to assess the prevalence of systemic infection preceding the neurological event. We analyzed the immunohematologic characteristics of patients with and without signs and/or symptoms of a preceding infectious process. Patients were examined less than or equal to 7 days after cerebral infarction and evaluated for fibrinogen, anticardiolipin antibodies, fibrin D-dimer (a fragment of cross-linked fibrin), plasminogen activator inhibitor-1, and protein S. Of the 50 patients, 17 had symptoms of infection beginning less than or equal to 1 month before the stroke (11 had upper respiratory tract infections, three urinary tract infections, two subacute bacterial endocarditis, and one pneumonia). Compared with patients without infection, patients with infection had significant increases in fibrin D-dimer concentration (5.3 +/- 1.1 versus 4.7 +/- 0.9 log-transformed ng/ml, p less than 0.05) and cardiolipin immunoreactivity, IgG isotype (1.8 +/- 1.3 versus 1.1 +/- 0.9 log-transformed phospholipid units, p less than 0.04), and, when studied less than or equal to 2 days after the stroke, increased fibrinogen levels (459 +/- 126 versus 360 +/- 94 mg/dl, p less than 0.05). In conclusion, infection-associated cerebral infarction is common and is associated with substantial immunohematologic abnormalities.


Repair of ischemic heart disease with novel bone marrow-derived multipotent stem cells.
Congestive heart failure is a growing, worldwide epidemic. The major causes of heart failure are related to irreversible damage resulting from myocardial infarction (heart attack). The long-standing axiom has been that the myocardium has a limited capacity for self-repair or regeneration; and the irreversible loss of cardiac muscle and accompanying contraction and fibrosis of myocardial scar tissue, sets into play a series of events, namely, progressive ventricular remodeling of nonischemic myocardium that ultimately leads to progressive heart failure. The loss of cardiomyocyte survival cues is associated with diverse pathways for heart failure, underscoring the importance of maintaining the number of viable cardiomyocytes during heart failure progression. Currently, no medication or procedure used clinically has shown efficacy in replacing the myocardial scar with functioning contractile tissue. Therefore, given the major morbidity and mortality associated with myocardial infarction and heart failure, new approaches have been sought to address the principal pathophysiologic deficits responsible for these conditions, resulting from the loss of cardiomyocytes and viable blood vessels. Recently, the identification of stem cells from bone marrow capable of contributing to tissue regeneration has ignited significant interest in the possibility that cell therapy could be employed therapeutically for the repair of damaged myocardium. In this review, we will discuss the currently available bone marrow-derived stem progenitor cells for myocardial repair and focus on the advantages of using recently identified novel bone marrow-derived multipotent stem cells (BMSC).


Inhibition of progression of erythroleukemia induced by Friend virus in BALB/c mice by natural products--berberine, curcumin and picroliv.
The infection with Friend murine leukemia virus (FMuLv) is being used as a retrovirus infection model for searching the potential anti-viral medicinal preparations or establishing new treatment strategies. In the present study we have evaluated the inhibitory effect of three non-toxic antiviral natural compounds namely berberine, curcumin or picroliv against FMuLv induced erythroleukemia in BALB/c mice. To understand the effect of these compounds in the initiation and progression of leukemia we did a series of analysis, which include hematological and biochemical parameters, histopathological evaluations of the liver and the spleen and expression analysis of selected genes such as Bcl-2, p53, p45NFE2, Raf-1, Erk-1, IFNgamma receptor and erythropoietin in spleen. The treatment with berberine, curcumin or picroliv were found to (a) elevate the life span of leukemia harboring animals by more than 60 days; (b) decreased the anemic condition which was highly prevalent in FMuLv alone treated group; (c) histopathological evaluations showed that the compounds tested here inhibited the massive leukemic cell infiltrations to sinusoidal spaces in spleen; (d) decrease the expression of Bcl-2, Raf-1, Erk-1 IFNgamma receptor and erythropoietin; (e) induce the expression of p53. Overall, our results suggest that berberine, curcumin and picroliv were able to suppress the progression of leukemia induced by FMuLv and further support their chemopreventive potential against virally induced cancers.


Granulated cork as biosorbent for the removal of phenol derivatives and emerging contaminants.
This study evaluated the ability of cork to adsorb a broad range of phenolic, pharmaceutical and cosmetic compounds: phenol, 2-chlorophenol, 2-nitrophenol, 2,4-dichlorophenol, pentachlorophenol carbamazepine, naproxen, ketoprofen, diclofenac, triclosan, and methyl paraben. The effect of variables such as the compound concentrations and the amount of cork were studied resulting in a highly pH dependence in the case of phenolic compounds. Maximum removal percentages and uptake values of 75% (1.61 mg/g) for 2,4-dichlorophenol, 55% (1.25 mg/g) for 2-nitrophenol, 45% (1.47 mg/g) for 2-chlorophenol, 20% (0.63 mg/g) for phenol, and 100% for pentachlorophenol, were obtained for a 30 mg L-1 solution at pH 6, showing that the adsorption process increased with greater electronegativity of the phenolic substituting group. Removal percentages and uptakes of 82% (3.56 mg/g) for naproxen, 57% (2.31 mg/g) for ketoprofen, 50% (1.84 mg/g) for carbamazepine, 50% (1.78 mg/g) for methyl paraben, 100% for sodium diclofenac, and 100% for triclosan, were obtained using 5 mg of cork and a 1 mg L-1 solution of each compound. The adsorption process was almost complete after 30 min for all the micropollutants. Experimental equilibrium data were analysed by Freundlich and Langmuir adsorption models. Cork has proved to be an effective sorbent for the removal of phenols and emerging contaminants from contaminated waters and is a readily available material that can be acquired at minimal or no cost in cork-producing areas.


How we encourage faculty development.
Most clinicians enjoy teaching medical students, but many have had little training as clinical teachers. The General Medical Council (GMC) in 'Good Medical Practice' states 'if you are involved in teaching you must develop the skills, attitudes and practices of a competent teacher' (GMC 2006). Mclean et al.'s (2008) AMEE guide on faculty development outlines practice points for those responsible for developing their faculty's educational skills. In this article, we look at one health region, Tayside in East Scotland, where the University of Dundee, NHS Education for Scotland (NES) and NHS Tayside are collaborating to implement these practice points. This combined approach has proved to be effective in progressing staff development and recruiting additional clinical colleagues to develop their teaching role.


Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study.
To determine the relapse rate after discontinuing treatment in patients with rheumatoid arthritis (RA) in sustained clinical remission, to identify predictors of a relapse and to evaluate treatment response after restarting treatment. Five-year data from the BeSt study were used, in which 508 patients with recent-onset RA were randomised into four dynamic treatment strategies, aiming at a disease activity score (DAS) ≤ 2.4. When DAS was < 1.6 for ≥ 6 months, the last disease-modifying antirheumatic drug (DMARD) was tapered and discontinued. If DAS increased to ≥ 1.6, the last DMARD was immediately reintroduced. During a 5-year period, 115/508 patients (23%) achieved drug-free remission. Of these, 53 patients (46%) restarted treatment because the DAS was ≥ 1.6 after a median of 5 months, 59 patients (51%) remained in drug-free remission for a median duration of 23 months and 3 (3%) were lost to follow-up. In those who restarted treatment, mean (SD) DAS increased from 1.13 (0.73) at remission before tapering to 2.18 (0.65) at restart, reflecting an increase in all four components of DAS. Multivariable predictors for restarting treatment were anti-cyclic citrullinated peptide (anti-CCP), last DMARD sulfasalazine, low baseline Health Assessment Questionnaire score and high mean DAS until remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3-6 months after the restart. The median (IQR) damage progression in those who restarted treatment during the year of DAS increase was 0 (0-1) Sharp-van der Heijde units. During 5 years DAS steered treatment, nearly 25% of patients with RA achieved drug-free remission; 46% restarted DMARD monotherapy because of a relapse, the majority of whom again achieved clinical remission within 3-6 months without showing radiological progression during the relapse.


The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya) - Optical dating of early human occupation during Marine Isotope Stages 4, 5 and 6.
The paper presents the results of optical dating of potassium-rich feldspar grains obtained from the Haua Fteah cave in Cyrenaica, northeast Libya, focussing on the chronology of the Deep Sounding excavated by Charles McBurney in the 1950s and re-excavated recently. Samples were also collected from a 1.25 m-deep trench (Trench S) excavated during the present project below the basal level of the Deep Sounding. Optically stimulated luminescence (OSL) data sets for multi-grain, single aliquots of quartz for samples from the Middle Trench were previously published. Re-analyses of these OSL data confirm significant variation in the dose saturation levels of the quartz signal, but allow the most robust OSL ages to be determined for comparison with previous age estimates and with those obtained in this study for potassium-rich feldspars from the Deep Sounding. The latter indicate that humans may have started to visit the cave as early as ∼150 ka ago, but that major use of the cave occurred during MIS 5, with the accumulation of the Deep Sounding sediments. Correlations between optical ages and episodes of "Pre-Aurignacian" artefact discard indicate that human use of the cave during MIS 5 was highly intermittent. The earliest phases of human activity appear to have occurred during interstadial conditions (5e and 5c), with a later phase of lithic discard associated with more stadial conditions, possibly MIS 5b. We argue that the "Pre-Aurignacian" assemblage can probably be linked with modern humans, like the succeeding "Levalloiso-Mousterian" assemblage; two modern human mandibles associated with the latter are associated with a modelled age of 73-65 ka. If this attribution is correct, then the new chronology implies that modern humans using "Pre-Aurignacian" technologies were in Cyrenaica as early as modern humans equipped with "Aterian" technologies were in the Maghreb, raising new questions about variability among lithic technologies during the initial phases of modern human dispersals into North Africa.


Low HIV testing rates among tuberculosis patients in Kampala, Uganda.
HIV testing among tuberculosis patients is critical in improving morbidity and mortality as those found to be HIV positive will be offered a continuum of care including ART if indicated. We conducted a cross-sectional study in three Kampala City primary care clinics: to assess the level of HIV test uptake among newly diagnosed pulmonary tuberculosis (PTB) patients; to assess patient and health worker factors associated with HIV test uptake; and to determine factors associated with HIV test uptake at the primary care clinics Adult patients who had been diagnosed with smear-positive PTB at a primary care clinic or at the referral hospital and who were being treated at any of the three clinics were interviewed. Associations between having taken the test as the main outcome and explanatory variables were assessed by multivariate logistic regression. Between April and October 2007, 112 adults were included in the study. An HIV test had been offered to 74 (66%). Of the 112 patients, 61 (82%) had accepted the test; 45 (74%) had eventually been tested; and 32 (29%) had received their test results.Patients who were <25 yeas old, female or unemployed, or had reported no previous HIV testing, were more likely to have been tested. The strongest predictor of having been tested was if patients had been diagnosed at the referral hospital compared to the city clinic (adjusted OR 24.2; 95% CI 6.7-87.7; p < 0.001). This primarily reflected an "opt-out" (uptake 94%) versus an "opt-in" (uptake 53%) testing policy. The overall HIV test uptake was surprisingly low at 40%. The HIV test uptake was significantly higher among TB patients who were identified at hospital, among females and in the unemployed.


Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715.
Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosome instability (CIN). Although often implicated as a driver of tumor progression and drug resistance, CIN also reduces cell fitness and poses a vulnerability that can be exploited therapeutically. The spindle assembly checkpoint (SAC) ensures correct chromosome-microtubule attachment, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components such as MPS1, which may help contain CIN within survivable limits. Prior studies showed that MPS1 inhibition with the small molecule NMS-P715 limits tumor growth in xenograft models. In cancer cell lines, NMS-P715 causes cell death associated with impaired SAC function and increased chromosome missegregation. Although normal cells appeared more resistant, effects on stem cells, which are the dose-limiting toxicity of most chemotherapeutics, were not examined. Elevated expression of 70 genes (CIN70), including MPS1, provides a surrogate measure of CIN and predicts poor patient survival in multiple tumor types. Our new findings show that the degree of CIN70 upregulation varies considerably among PDAC tumors, with higher CIN70 gene expression predictive of poor outcome. We identified a 25 gene subset (PDAC CIN25) whose overexpression was most strongly correlated with poor survival and included MPS1. In vitro, growth of human and murine PDAC cells is inhibited by NMS-P715 treatment, whereas adipose-derived human mesenchymal stem cells are relatively resistant and maintain chromosome stability upon exposure to NMS-P715. These studies suggest that NMS-P715 could have a favorable therapeutic index and warrant further investigation of MPS1 inhibition as a new PDAC treatment strategy.


Structure, phase transitions and ionic conductivity of K3NdSi6O15 x xH2O. II. Structure of beta-K3NdSi6O15
Hydrothermally grown crystals of beta-K3NdSi6O15, potassium neodymium silicate, have been studied by single-crystal X-ray methods. Under appropriate conditions, the compound crystallizes in space group Bb2(1)m and has lattice constants a = 14.370 (2), b = 15.518 (2) and c = 14.265 (2) A. There are 30 atom sites in the asymmetric unit of the basic structure. With eight formula units per unit cell, the calculated density is 2.798 Mg m(-3). Refinement was carried out to a residual, wR(F2), of 0.1177 [R(F) = 0.0416] using anisotropic temperature factors for all atoms. The structure is based on (Si2O5(2-))infinity layers, connected by Nd polyhedra to form a three-dimensional framework. Potassium ion sites, some of which are only partially occupied, are located within channels that run between the silicate layers. The silica-neodymia framework of beta-K3NdSi6O15, in particular the linkages formed between the silicate layers and Nd polyhedra, bears some similarities to that of the essentially isocompositional phase alpha-K3NdSi6O15 x 2H2O. In both, the silicate layers are corrugated so as to accommodate a simple cubic array of NdO6 octahedra with lattice constant approximately 7.5 A. Furthermore, the Si2O5 layers in beta-K3NdSi6O15 are topologically identical to those of the mineral sazhinite, Na2HCeSi6O15. Although beta-K3NdSi6O15 and sazhinite are not isostructural, the structures of each can be described as slight distortions of a high-symmetry parent structure with space group Pbmm.


Late characterisation of cardiac effects following anthracycline and trastuzumab treatment in breast cancer patients.
Anthracycline (A) and trastuzumab (T) chemotherapy have well-recognized cardiac toxicity, potentially leading to significant morbidity and mortality. Our previous work in 46 prospectively enrolled breast cancer patients showed early left ventricular (LV) and right ventricular (RV) function decline at 1 and 3 months, but only persistent RV dysfunction at 12 months which correlated with myocardial oedema observed early (1 and 3 months) after administration of chemotherapy regimes. To investigate late cardiac effects, the same cohort were re-imaged with advanced Cardiovascular Magnetic Resonance (CMR) imaging including T1 mapping 5 ± 1 year post chemotherapy. Twenty-six out of 46 (50%) patients underwent follow-up imaging. A statistical but non-clinically significant decrease was observed in LV ejection fraction (EF) from baseline to 5 years (72.2 ± 6.6 to 65.4 ± 9.3, p < 0.005). Subjects with initial drop of LVEF by >10% at 3 months (n = 5) or at 12 months (n = 3) did not demonstrate any difference in LV or RVEF at 5 years. No correlation was observed between myocardial oedema and LV or RVEF at 5 years. At 5 years, T1 values were within normal limits overall (935 ± 48 ms). One patients had significantly elevated (>1000 ms) T1 values with no correlation to LV or RVEF. No subjects demonstrated replacement myocardial fibrosis at 5 years. Using advanced CMR, contemporary chemotherapy regimes demonstrate minimal long-term cardiac toxicity. There is minimal diffuse and no replacement fibrosis as demonstrated by LGE, following chemotherapy. This study suggests limiting serial imaging in these patients at 12 months post chemotherapy.


A family of approximations spanning the Born and Rytov scattering series.
A new hybrid scattering series is derived that incorporates as special cases both the Born and Rytov scattering series, and includes a parameter so that the behavior can be continuously varied between the two series. The parameter enables the error to be shifted between the Born and Rytov error terms to improve accuracy. The linearized hybrid approximation is derived as well as its condition of validity. Higher order terms of the hybrid series are also found. Also included is the integral equation that defines the exact solution to the forward scattering problem as well as its Fréchet derivative, which is used for the solution of inverse multiple scattering problems. Finally, the linearized hybrid approximation is demonstrated by simulations of inverse scattering off of uniform circular cylinders, where it is shown that the hybrid approximation achieves smaller error than either the Born or Rytov approximations alone.


Climate change mitigation in British Columbia's forest sector: GHG reductions, costs, and environmental impacts.
The potential contributions from forest-based greenhouse gas (GHG) mitigation actions need to be quantified to develop pathways towards net negative emissions. Here we present results from a comparative analysis that examined mitigation options for British Columbia's forest sector. Mitigation scenarios were evaluated using a systems perspective that takes into account the changes in emissions and removals in forest ecosystems, in harvested wood product (HWP) carbon stocks, and in other sectors where wood products substitute for emission-intensive materials and fossil fuels. All mitigation activities were assessed relative to a forward-looking 'business as usual' baseline for three implementation levels. In addition to quantifying net GHG emission reductions, we assessed economic, and socio-economic impacts as well as other environmental indicators relating to forest species, age class, deadwood availability and future timber supply. We further considered risks of reversal for land-based scenarios, by assessing impacts of increasing future wildfires on stands that were not harvested. Our spatially explicit analyses of forest sector mitigation options demonstrated a cost-effective portfolio of regionally differentiated scenarios that directed more of the harvested wood to longer-lived wood products, stopped burning of harvest residues and instead produced bioenergy to displace fossil fuel burning, and reduced harvest levels in regions with low disturbance rates. Domestically, net GHG emissions were reduced by an average of -9 MtCO2e year-1 over 2020-2050 for a portfolio of mitigation activities at a default implementation level, with about 85% of the GHG emission reductions achieved below a cost of $50/tCO2e. Normalizing the net GHG reduction by changes in harvested wood levels permitted comparisons of the scenarios with different ambition levels, and showed that a 1 MtCO2 increase in cumulative harvested stemwood results in a 1 MtCO2e reduction in cumulative emissions, relative to the baseline, for the Higher Recovery scenario in 2070. The analyses conducted in this study contribute to the global understanding of forest sector mitigation options by providing an integrated framework to synthesize the methods, assumptions, datasets and models needed to quantify mitigation activities using a systems approach. An understanding of economically feasible and socio-economically attractive mitigation scenarios along with trade offs for environmental indicators relating to species composition and age, helps decision makers with long-term planning for land sector contributions to GHG emission reduction efforts, and provides valuable information for stakeholder consultations.


Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up.
The SMART study compared 2 strategies for using antiretroviral therapy-drug conservation (DC) and viral suppression (VS)-in 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL. Rates and predictors of opportunistic disease or death (OD/death) and the relative risk (RR) in DC versus VS groups according to the latest CD4+ cell count and HIV RNA level are reported. During a mean of 16 months of follow-up, DC patients spent more time with a latest CD4+ cell count <350 cells/microL (for DC vs. VS, 31% vs. 8%) and with a latest HIV RNA level >400 copies/mL (71% vs. 28%) and had a higher rate of OD/death (3.4 vs. 1.3/100 person-years) than VS patients. For periods of follow- up with a CD4+ cell count <350 cells/microL, rates of OD/death were increased but similar in the 2 groups (5.7 vs. 4.6/100 person-years), whereas the rates were higher in DC versus VS patients (2.3 vs. 1.0/100 person-years; RR, 2.3 [95% confidence interval, 1.5-3.4]) for periods with the latest CD4+ cell count >or= 350 cells/microL-an increase explained by the higher HIV RNA levels in the DC group. The higher risk of OD/death in DC patients was associated with (1) spending more follow-up time with relative immunodeficiency and (2) living longer with uncontrolled HIV replication even at higher CD4+ cell counts. Ongoing HIV replication at a given CD4+ cell count places patients at an excess risk of OD/death.


Corrosion Inhibition at Scribed Locations in Coated AA2024-T3 by Cerium- and DMTD-Loaded Natural Silica Microparticles under Continuous Immersion and Wet/Dry Cyclic Exposure.
Earlier studies on cerium-loaded naturally occurring silica microparticles (i.e., diatomaceous earth) demonstrated the potential to efficiently protect small scratches in epoxy-coated AA2024-T3 panels during relatively short immersion times. The current work investigates the potential of such inhibitor-loaded microparticles to protect wide and deep scribes (up to 1 mm wide) in long-time immersion testing and during cyclic (wet/dry) conditions. For this, cerium nitrate and 2,5-dimercaptothiadiazole (DMTD) were used as inorganic and organic corrosion inhibitors. The corrosion protection was evaluated using a hyphenated real-time optics/electrochemistry method and two individual local techniques measuring oxygen concentration and electrochemical impedance (LEIM) inside the scribe. SEM/EDS was used to analyze the samples after exposure. The results show significant levels of corrosion protection at damaged locations at low cerium concentrations (3.7 wt % Ce3+ relative to the total coating mass) during 30 days of immersion in salt solution. However, for a given scribe geometry, the protection was found to be dependent on the electrolyte volume with larger electrolyte/exposed metal ratios leading to short protection time. A partial replacement of the Ce3+ by DMTD in the microcarriers resulted in a higher degree of passivation than when DMTD was used alone. Wet/dry cyclic exposure tests showed that cyclic conditions can increase the buildup of stable inhibitor-containing layers in the case of cerium-loaded silica microparticles. This underlines the need for more research using wet/dry exposure conditions.


Antibodies in the treatment of aplastic anemia.
Antibodies have been the cornerstone of treatment of acquired aplastic anemia for more than 25 years. Treatment with antithymocyte globulin (ATG) is considered pivotal and the addition of cyclosporine improves the overall response rate. This antibody is heterogeneous and horse ATG is apparently more effective than rabbit ATG. Several issues remain unsolved in relation to the combination of ATG and cyclosporine: cost, toxicity and late clonal disorders. In recent years, alternative immunosuppressive therapy has been proposed and new antibodies have emerged: porcine ATG, alemtuzumab, daclizumab, and rituximab. Experience with these antibodies is limited to a few studies with alemtuzumab being the most promising, but the results are interesting and provocative. More studies are needed to find the perfect antibody.


You do not talk about Fight Club if you do not notice Fight Club: Inattentional blindness for a simulated real-world assault.
Inattentional blindness-the failure to see visible and otherwise salient events when one is paying attention to something else-has been proposed as an explanation for various real-world events. In one such event, a Boston police officer chasing a suspect ran past a brutal assault and was prosecuted for perjury when he claimed not to have seen it. However, there have been no experimental studies of inattentional blindness in real-world conditions. We simulated the Boston incident by having subjects run after a confederate along a route near which three other confederates staged a fight. At night only 35% of subjects noticed the fight; during the day 56% noticed. We manipulated the attentional load on the subjects and found that increasing the load significantly decreased noticing. These results provide evidence that inattentional blindness can occur during real-world situations, including the Boston case.


Pressure-dependent effect of shock waves on rat brain: induction of neuronal apoptosis mediated by a caspase-dependent pathway.
Shock waves have been experimentally applied to various neurosurgical treatments including fragmentation of cerebral emboli, perforation of cyst walls or tissue, and delivery of drugs into cells. Nevertheless, the application of shock waves to clinical neurosurgery remains challenging because the threshold for shock wave-induced brain injury has not been determined. The authors investigated the pressure-dependent effect of shock waves on histological changes of rat brain, focusing especially on apoptosis. Adult male rats were exposed to a single shot of shock waves (produced by silver azide explosion) at overpressures of 1 or 10 MPa after craniotomy. Histological changes were evaluated sequentially by H & E staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL). The expression of active caspase-3 and the effect of the nonselective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) were examined to evaluate the contribution of a caspase-dependent pathway to shock wave-induced brain injury. High-overpressure (> 10 MPa) shock wave exposure resulted in contusional hemorrhage associated with a significant increase in TUNEL-positive neurons exhibiting chromatin condensation, nuclear segmentation, and apoptotic bodies. The maximum increase was seen at 24 hours after shock wave application. Low-overpressure (1 MPa) shock wave exposure resulted in spindle-shaped changes in neurons and elongation of nuclei without marked neuronal injury. The administration of Z-VAD-FMK significantly reduced the number of TUNEL-positive cells observed 24 hours after high-overpressure shock wave exposure (p < 0.01). A significant increase in the cytosolic expression of active caspase-3 was evident 24 hours after high-overpressure shock wave application; this increase was prevented by Z-VAD-FMK administration. Double immunofluorescence staining showed that TUNEL-positive cells were exclusively neurons. The threshold for shock wave-induced brain injury is speculated to be under 1 MPa, a level that is lower than the threshold for other organs. High-overpressure shock wave exposure results in brain injury, including neuronal apoptosis mediated by a caspase-dependent pathway. This is the first report in which the pressure-dependent effect of shock wave on the histological characteristics of brain tissue is demonstrated.


Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac.
The nonsteroidal anti-inflammatory drug diclofenac is extremely toxic to Old World Gyps vultures (median lethal dose -0.1-0.2 mg/kg), evoking visceral gout, renal necrosis, and mortality within a few days of exposure. Unintentional secondary poisoning of vultures that fed upon carcasses of diclofenac-treated livestock decimated populations in the Indian subcontinent. Because of the widespread use of diclofenac and other cyclooxygenase-2 inhibiting drugs, a toxicological study was undertaken in turkey vultures (Cathartes aura) as an initial step in examining sensitivity of New World scavenging birds. Two trials were conducted entailing oral gavage of diclofenac at doses ranging from 0.08 to 25 mg/kg body weight. Birds were observed for 7 d, blood samples were collected for plasma chemistry (predose and 12, 24, and 48 h and 7 d postdose), and select individuals were necropsied. Diclofenac failed to evoke overt signs of toxicity, visceral gout, renal necrosis, or elevate plasma uric acid at concentrations greater than 100 times the estimated median lethal dose reported for Gyps vultures. For turkey vultures receiving 8 or 25 mg/kg, the plasma half-life of diclofenac was estimated to be 6 h, and it was apparently cleared after several days as no residues were detectable in liver or kidney at necropsy. Differential sensitivity among avian species is a hallmark of cyclooxygenase-2 inhibitors, and despite the tolerance of turkey vultures to diclofenac, additional studies in related scavenging species seem warranted.


Management of acute decompensated heart failure in the emergency department.
Heart failure, a disease of epidemic proportions, has a tremendous clinical and financial impact on the US health care system. With more than 5 million Americans diagnosed with heart failure and 5-year mortality approaching 50%, it is the most common cause of hospitalization in patients older than 65 years and is the single most expensive diagnosis in the US health care system. Because the average US hospital loses more than 1000 dollars per heart failure admission, effective therapies that decrease length of stay, reduce hospital costs, and prevent 30-day readmissions are needed. This article reviews the relevant pathophysiology of heart failure, discusses the newest diagnostic strategies for emergency department diagnoses, evaluates recent advances and effects of early aggressive therapies, and presents a suggested algorithm for the treatment of acutely decompensated heart failure in emergency departments.


Penile melanoma: a 20-Year analysis of six patients at the National Cancer Institute of Peru, Lima.
Melanoma of the urogenital tract is extremely rare, accounting for less than 0.1% of melanoma cases. The global literature currently describes only 220 cases of penile melanoma, most commonly located on the glans penis. Penile melanoma accounts for 0.7% of penile cancers and 0.18% of melanoma cases. The average patient age for the six cases we reviewed was 44.5 years. Three of these cases (50%) involved ulceration, one case (16.7%) involved lymphovascular invasion, and three cases (50%) involved mitosis ≥ 1 mm2 (0.38-4.7 mm). The average depth of invasion (Breslow) in the five cases that reported this measure was 2.1 mm (0.38-4.7 mm). Applying the American Joint Committee on Cancer tumour, node, metastases (AJCC TNM) staging system, one case was Tx (16.7%), two cases were T1 (33.3%), one case was T2 (16.7%), one case was T3 (16.7%), and one case was T4 (16.7%). Five cases (83.3%) involved wide local resection, and only one case involved partial penile amputation. Four cases (66.7%) involved primary bilateral inguinocrural lymphadenectomy, and only one of those four cases involved lymphatic metastatic disease. One case (16.7%) involved lymphatic recurrence at 12 months in a patient who survived 38 months. One case (16.7%) involved local recurrence at 13 months in a patient who has survived 53 months. Eighty per cent of these patients remain alive, with no evidence of disease after an average follow-up of 96.7 months. Penile melanoma prognosis depends on the initial clinical stage of the disease. The risk of lymphatic involvement seems to be related to the same risk factors used to assess cutaneous melanoma. Clinicians can thus assess penile melanoma using the AJCC staging system. The use of sentinel lymph node biopsy to determine staging is also becoming more common and could replace prophylactic bilateral inguinal dissection.


Corneal endothelial toxicity of air and SF6.
The authors conducted in vivo assessment of corneal endothelial toxicity of air and SF6 in the feline model. This research was motivated by the increased use of air in anterior segment surgery in human subjects. This was a prospective masked study. The eyes of 16 healthy adult cats were randomly assigned for the injection of 0.7 mL air into the anterior chamber of one eye and SF6 in the contralateral eye. Daily examination included slit lamp photographs, pachymetry, and tonometry. Specular microscopy was performed before, 7 days after, and 10 days after injection. The animals were euthanatized, and the corneas were processed for alizarin red-trypan blue staining and for light and electron microscopy. SF6 remained in the anterior chamber significantly longer than air. Both groups showed postinjection inflammation, which on average was maximal at day 2 and more severe with SF6. No difference in IOP was observed between the two groups. Specular microscopy showed significant endothelial cell loss in the SF6 group (mean postinjection cell loss, 132 ± 50 cells/mm(2)) but not in the group injected with air. Alizarin red staining revealed significant regional differences in cell density only in the SF6 group and more pronounced endothelial cell loss in the superior area. These results indicate that both air and SF6 injected into the anterior chamber of the eye can induce intraocular reaction in the feline model and that SF6 is more toxic than air in terms of endothelial cell loss and anterior chamber inflammation.


The role of the working alliance in treatment for alcohol problems.
Little research has been done on the role of the therapeutic working alliance in treatment for alcohol problems. This longitudinal study's objectives were (a) to identify predictors of working alliance and (b) to investigate whether client and/or therapist reports of the working alliance predicted posttreatment motivation and then later treatment outcome. Client and therapist perceptions of the working alliance were assessed after the first treatment session using a short form of the Working Alliance Inventory (WAI) among 173 clients taking part in the United Kingdom Alcohol Treatment Trial (UKATT) and randomized to motivational enhancement therapy (MET) or social behavior and network therapy (SBNT) with complete data on all measures of interest. Structural equation models were fitted to identify predictors of WAI scores and investigate the relationships between WAI and measures of drinking during treatment, posttreatment motivation, and successful treatment outcome (abstinent or nonproblem drinker), and measures of drinks per drinking day and nondrinking days, assessed 9 months after the conclusion of treatment. Motivation to change drinking when treatment began was a strong predictor of client-adjusted coefficient = 2.21 (95% confidence interval [CI] [0.36, 4.06]-but not therapist WAI. Client WAI predicted successful treatment outcome-adjusted odds ratios (OR) = 1.09 (95% CI [1.02, 1.17])-and had effects on drinking during treatment, and on posttreatment motivation to change. There was evidence for effect modification by treatment, with strong associations between WAI and posttreatment motivation, and evidence of WAI prediction of treatment outcomes in the MET group, but no evidence of associations for SBNT. Therapist WAI was not strongly associated with treatment outcome (adjusted OR = 1.05; 95% CI [0.99, 1.10]). The working alliance is important to treatment outcomes for alcohol problems, with client evaluation of the alliance strongly related to motivation to change drinking throughout treatment for MET. It was also much more important than therapist-rated alliance in this study. (PsycINFO Database Record


Controlled evaluation of BacT/Alert standard aerobic and FAN aerobic blood culture bottles for detection of bacteremia and fungemia.
A new medium, FAN, designed to enhance the recovery of microorganisms, has been developed for the BacT/Alert blood culture system (Organon Teknika Corp., Durham, N.C.). We compared the yield and speed of detection of microorganisms in 6,847 adequately filled paired aerobic standard and FAN bottles at four university hospitals. Of 499 clinically significant microorganisms isolated from one or both bottles, significantly more Staphylococcus aureus isolates (P < 0.001), coagulase-negative staphylococci (P < 0.001), yeasts (P < 0.01), and all microorganisms combined (P < 0.001) were recovered from the FAN bottles. Overall, the speeds of detection of positive cultures did not differ between the two medium formulations; mean times to detection in the standard and FAN bottles were 16.1 and 16.0 h, respectively. When a subset of patients on antimicrobial therapy was evaluated, significantly enhanced yield from the FAN bottle was evident for staphylococci. Overall, the FAN bottle outperformed the standard aerobic BacT/Alert bottle.


Association of Helicobacter pylori IgG antibody with various demographic and biochemical parameters in kidney transplant recipients.
Few reports are available regarding the promoting factors that affect Helicobacter pylori (H. pylori) infection in renal transplant (RTx) patients. We report a cross-sectional study that was conducted on a group of stable RTx patients to investigate the relationship of various demographic and biochemical parameters of these patients with serum H. pylori IgG antibody titer as a sign of H. pylori infection. A total of 72 patients who were referred to the clinic for continuing their treatment were enrolled in this study. These patients included 47 males and 25 females. The mean age of the study patients was 44 (±12) years. The mean length of time after they received a transplanted kidney was 67.5 (±42) months (median: 62 months). The mean value of serum H. pylori-specific IgG antibody titer among these patients was 3 (±4.6) U/mL (median: 1 U/mL), and that of intact parathormone (iPTH) was 18.4 (±8.2) pg/mL (median: 16.5 pg/mL). The mean serum magnesium (Mg) was 1.9 (±0.20) mg/dL (median: 1.9 mg/dL) and the mean creatinine clearance was 53 (±11) mL/min (median: 56 mL/min). In this study population, there was no significant difference in the H. pylori IgG antibody titers, serum iPTH, Mg, calcium, alkaline phosphatase and albumin levels as well as body mass index (BMI) between males and females or diabetics and non-diabetics. There was no significant relationship between serum H. pylori IgG antibody titers and the age of the patients, BMI, serum Alb, phosphorus, Ca, serum leptin and serum ALP. Significant negative correlation between serum H. pylori IgG antibody titers and serum Mg (r = -0.30, P = 0.01) and serum iPTH (r = -0.25, P = 0.03) was seen. A significant positive correlation was found between serum H. pylori IgG antibody titer and creatinine clearance (r = 0.26, P = 0.02), and a near-significant positive correlation was found with the duration of RTx (r = 0.20, P = 0.08). Our study shows that the correlation of H. pylori IgG antibody titer with some demographic and biochemical indices in RTx recipients may be different from what has been reported in hemodialysis patients. Larger clinical studies are needed to assess the clinical implications of our findings.


Adherence to established guidelines for preoperative pulmonary function testing.
Guidelines for ordering preoperative spirometry have been proposed by GM Tisi (1979) and more recently by the American College of Physicians (ACP). Requests for preoperative spirometries represent a significant portion of all requests for screening spirometry at our institution and utilize significant man-hours of technician time. We determined the percentage of these requests that did not meet the ACP guidelines and characterized why these requests were being generated. We sampled 441 screening spirometries performed by the Walter Reed Pulmonary Function Laboratory over a 4-week period. One hundred thirty-eight (31%) of these were done preoperatively and complete data were available in 135 cases. Patients in the analyzed group had a mean age of 59 years (+/- 14 years), ranging from 20 to 84 years of age. Fifty-two (39%) requests did not meet ACP guidelines. Most of these requests were associated with either normal spirometry (n = 34) or only mild spirometric abnormalities (n = 14). Spirometry revealed severe obstruction in only one case when the request was not indicated. No cases of moderate obstruction, severe restrictive pattern, or possible upper airway obstruction were found in the group of requests in which spirometry was not indicated. Of the requests that did not meet ACP guidelines, 21 met Tisi's broader guidelines. Most of these requests were found exclusively in patients older than 70 years of age (n = 13) and the morbidly obese (n = 4). Of the 31 studies that did not meet either set of guidelines, 25 occurred in asymptomatic, current, or prior smokers. In conclusion, during a 4-week study period at our institution, 39% of preoperative spirometry requests did not meet ACP guidelines. Most of the patients had been referred because of age greater than 70 years, morbid obesity, and a current/prior history of smoking. However, the literature does not support obtaining preoperative spirometry in such patients except for those undergoing only lung resection. We recommend stricter adherence to the ACP guidelines as a means of decreasing the number and cost of unnecessary spirometries being performed.


An investigation into the feasibility of comparing three management options (augmentation, conservative and water) for nulliparae with dystocia in the first stage of labour.
to evaluate the feasibility of a randomised controlled trial (RCT) examining the effect of three options (augmentation, conservative and water) for the management of dystocia in nulliparae. The main objectives were to explore the feasibility of trial procedures in the clinical environment, consent rates and acceptability of the management options to women, local incidence of dystocia in nulliparae and the size of the subsequent study. a two part study: a pilot, RCT with follow-up through to delivery with postnatal maternal surveys, and a case review of nulliparae with dystocia. a large maternity unit in the South of England in May-July 1997 inclusive. nulliparae with dystocia in the first stage of labour who had an otherwise uncomplicated obstetric background. women in the pilot RCT received one of three management options: labouring in a waterbirth pool, conservative management or augmentation of labour, which is the standard management of women with dystocia condition in the Unit. it is feasible to conduct an RCT of management of dystocia in the Unit. Seventy per cent (95% confidence interval 47% to 87%) of women approached agreed to participate. Conservative management was the least acceptable option to women and has been dropped from the subsequent trial. The audit provided some idea of possible differences in operative delivery and epidural rates depending on augmentation or not. A sample of 220 women should be large enough to detect moderate changes and will require a 2-year recruitment period. a subsequent trial is feasible and is now underway. It has the potential to provide information enabling women and practitioners to have a greater choice of care options in the presence of dystocia, or provide a good basis for an even larger trial.


Intracellular location of the autolytic N-acetylmuramyl-L-alanine amidase in Bacillus subtilis 168 and in an autolysis-deficient mutant by immunoelectron microscopy.
Antisera against purified autolytic N-acetylmuramyl-L-alanine amidase from Bacillus subtilis 168 were prepared in rabbits. They neutralized the enzymatic action of the purified amidase acting on isolated sodium dodecyl sulfate (SDS)-treated walls from the same organism. They also inhibited the lysis of native walls, but only after the walls lysed partially. Amidase adsorbed to insoluble walls still combined with antibody. Antisera did not stop the lysis of whole cells. Lowicryl HM20 sections of both strain 168 and its autolytic mutant strain FJ6 were prepared by the progressive-lowering-of-temperature technique, immunolabeled with the antisera, and visualized with colloidal gold particles as markers. The highest concentration of gold particles seemed to be in the septa of dividing cells, followed by the side walls. There was some labeling of the cytoplasm. Adsorption of sera with SDS-treated walls reduced the overall labeling of sections considerably but did not alter the relative intracellular distribution of particles. The results for strains 168 and FJ6 were similar. Labeling of SDS-treated walls unexpectedly revealed the presence of a wall-bound amidase fraction.


Polarization conversion spectroscopy of hybrid modes.
Enhanced polarization conversion in reflection for the Otto and Kretschmann configurations is introduced as a new method for hybrid-mode spectroscopy. Polarization conversion in reflection occurs when hybrid modes are excited in a guiding structure composed of at least one anisotropic medium. In contrast to a dark dip, in this case modes are associated with a peak in the converted reflectance spectrum, increasing the detection sensitivity and avoiding confusion with reflection dips associated with other processes, such as transmission.


25-hydroxyvitamin D levels and the risk of mortality in the general population.
In patients undergoing dialysis, therapy with calcitriol or paricalcitol or other vitamin D agents is associated with reduced mortality. Observational data suggests that low 25-hydroxyvitamin D levels (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown. We tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files. Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000. In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models (adjusted for baseline demographics, season, and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk, which was not statistically significant. The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.


Molecular dynamics simulation of liquid water: hybrid density functionals.
The structure, dynamical, and electronic properties of liquid water utilizing different hybrid density functionals were tested within the plane wave framework of first-principles molecular dynamics simulations. The computational approach, which employs modified functionals with short-ranged Hartree-Fock exchange, was first tested in calculations of the structural and bonding properties of the water dimer and cyclic water trimer. Liquid water simulations were performed at the state point of 350 K at the experimental density. Simulations included three different hybrid functionals, a meta-functional, four gradient-corrected functionals, and the local density and Hartree-Fock approximations. It is found that hybrid functionals are superior in reproducing the experimental structure and dynamical properties as measured by the radial distribution function and self-diffusion constant when compared to the pure density functionals. The local density and Hartree-Fock approximations show strongly over- and understructured liquids, respectively. Hydrogen bond analysis shows that the hybrid functionals give slightly smaller average numbers of hydrogen bonds than pure density functionals but similar hydrogen bond populations. The average molecular dipole moments in the liquid from the three hybrid functionals are lower than those of the corresponding pure density functionals.


Experiments of nature: premature unicoronal cranial synostosis in mantled howler monkeys (Alouatta palliata).
In 1960 Adolph Schultz described several cases of plagiocephaly in a collection of mantled howler monkeys (Alouatta palliata) from the forests of Central America. Since then several more specimens have been described. These individuals make up one of the largest samples of nonhuman primates that are affected by craniosynostosis. In this study, we used finite element scaling analysis (FESA) to quantify morphologic differences between adult normal (N = 19) and plagiocephalic female howler monkeys (N = 4). FESA utilizes three dimensional coordinate data to provide detailed information on size and shape differences local to biologic landmarks. The relatively large number of plagiocephalic howler monkeys provides a natural means for examining hypotheses concerning patterns of dysmorphology associated with plagiocephaly. Comparison of our results to observations from the clinical literature reveals similarities in neurocranial and facial morphology among plagiocephalic humans and howler monkeys, but the direction and magnitude of local form differences between howler monkeys and humans indicate species-specific responses to sutural constraint. Few cases of craniosynostosis in nonhuman primates are known. The number of plagiocephalic howler monkeys suggests these monkeys may be particularly susceptible to some defect that leads to premature suture closure. If this is the case, then howler monkeys may be a good model to study the cause(s) of craniosynostosis.


A multi-megabase copy number gain causes maternal transmission ratio distortion on mouse chromosome 2.
Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system.


Assessment of Chicken Carcass Microbiome Responses During Processing in the Presence of Commercial Antimicrobials Using a Next Generation Sequencing Approach.
The purpose of this study was to 1) identify microbial compositional changes on chicken carcasses during processing, 2) determine the antimicrobial efficacy of peracetic acid (PAA) and Amplon (blend of sulfuric acid and sodium sulfate) at a poultry processing pilot plant scale, and 3) compare microbial communities between chicken carcass rinsates and recovered bacteria from media. Birds were collected from each processing step and rinsates were applied to estimate aerobic plate count (APC) and Campylobacter as well as Salmonella prevalence. Microbiome sequencing was utilized to identify microbial population changes over processing and antimicrobial treatments. Only the PAA treatment exhibited significant reduction of APC at the post chilling step while both Amplon and PAA yielded detectable Campylobacter reductions at all steps. Based on microbiome sequencing, Firmicutes were the predominant bacterial group at the phyla level with over 50% frequency in all steps while the relative abundance of Proteobacteria decreased as processing progressed. Overall microbiota between rinsate and APC plate microbial populations revealed generally similar patterns at the phyla level but they were different at the genus level. Both antimicrobials appeared to be effective on reducing problematic bacteria and microbiome can be utilized to identify optimal indicator microorganisms for enhancing product quality.


Inclusion of a variable RBE into proton and photon plan comparison for various fractionation schedules in prostate radiation therapy.
A constant relative biological effectiveness (RBE) of 1.1 is currently used in proton radiation therapy to account for the increased biological effectiveness compared to photon therapy. However, there is increasing evidence that proton RBE vary with the linear energy transfer (LET), the dose per fraction, and the type of the tissue. Therefore, this study aims to evaluate the impact of disregarding variations in RBE when comparing proton and photon dose plans for prostate treatments for various fractionation schedules using published RBE models and several α/β assumptions. Photon and proton dose plans were created for three generic prostate cancer cases. Three BED3Gy equivalent schedules were studied, 78, 57.2, and 42.8 Gy in 39, 15, and 7 fractions, respectively. The proton plans were optimized assuming a constant RBE of 1.1. By using the Monte Carlo calculated dose-averaged LET (LETd ) distribution and assuming α/β values on voxel level, three variable RBE models were applied to the proton dose plans. The impact of the variable RBE was studied in the plan comparison, which was based on the dose distribution, DVHs, and normal tissue complication probabilities (NTCP) for the rectum. Subsequently, the physical proton dose was reoptimized for each proton plan based on the LETd distribution, to achieve a homogeneous RBE-weighted target dose when applying a specific RBE model and still fulfill the clinical goals for the rectum and bladder. All the photon and proton plans assuming RBE = 1.1 met the clinical goals with similar target coverage. The proton plans fulfilled the robustness criteria in terms of range and setup uncertainty. Applying the variable RBE models generally resulted in higher target doses and rectum NTCP compared to the photon plans. The increase was most pronounced for the fractionation dose of 2 Gy(RBE), whereas it was of less magnitude and more dependent on model and α/β assumption for the hypofractionated schedules. The reoptimized proton plans proved to be robust and showed similar target coverage and doses to the organs at risk as the proton plans optimized with a constant RBE. Model predicted RBE values may differ substantially from 1.1. This is most pronounced for fractionation doses of around 2 Gy(RBE) with higher doses to the target and the OARs, whereas the effect seems to be of less importance for the hypofractionated schedules. This could result in misleading conclusions when comparing proton plans to photon plans. By accounting for a variable RBE in the optimization process, robust and clinically acceptable dose plans, with the potential of lowering rectal NTCP, may be generated by reoptimizing the physical dose. However, the direction and magnitude of the changes in the physical proton dose to the prostate are dependent on RBE model and α/β assumptions and should therefore be used conservatively.


Impact of a 12-week wellness coaching on self-care behaviors among primary care adult patients with prediabetes.
This single arm prospective study assessed the impact of individualized wellness coaching intervention for primary care patients with prediabetes on self-reported changes in physical activity level and food choices. Five hundred sixty adult patients 18 years and older with prediabetes, seen in primary care clinic, were invited to participate in 12 weeks wellness coaching sessions delivered by certified coaches. Responses from questionnaires at baseline, 6 and 12 weeks were analyzed. Of 168 consented patients, 99 completed at least one coaching session; majority was elderly, female, overweight or obese. At baseline, 50% had <60 min aerobic exercise/week. At 6 and 12 weeks, average aerobic exercise time significantly increased from 117 min to 166 and 199 min respectively. Effect was sustained at 24 weeks. Success in making healthy eating choices also statistically improved from baseline. Significant effects on both activity level and eating behavior persisted even after adjusting for age, sex and baseline glucose/A1c values. Secondary outcomes of self-efficacy and quality of life likewise showed significant improvement. Results suggest that integration of wellness coaching in primary care practice among individuals at high risk for diabetes is feasible and may be useful as part of diabetes prevention management strategies in target populations. Future randomized clinical trials are needed to further explore this issue.


Nuclear RNA sequencing of the mouse erythroid cell transcriptome.
In addition to protein coding genes a substantial proportion of mammalian genomes are transcribed. However, most transcriptome studies investigate steady-state mRNA levels, ignoring a considerable fraction of the transcribed genome. In addition, steady-state mRNA levels are influenced by both transcriptional and posttranscriptional mechanisms, and thus do not provide a clear picture of transcriptional output. Here, using deep sequencing of nuclear RNAs (nucRNA-Seq) in parallel with chromatin immunoprecipitation sequencing (ChIP-Seq) of active RNA polymerase II, we compared the nuclear transcriptome of mouse anemic spleen erythroid cells with polymerase occupancy on a genome-wide scale. We demonstrate that unspliced transcripts quantified by nucRNA-seq correlate with primary transcript frequencies measured by RNA FISH, but differ from steady-state mRNA levels measured by poly(A)-enriched RNA-seq. Highly expressed protein coding genes showed good correlation between RNAPII occupancy and transcriptional output; however, genome-wide we observed a poor correlation between transcriptional output and RNAPII association. This poor correlation is due to intergenic regions associated with RNAPII which correspond with transcription factor bound regulatory regions and a group of stable, nuclear-retained long non-coding transcripts. In conclusion, sequencing the nuclear transcriptome provides an opportunity to investigate the transcriptional landscape in a given cell type through quantification of unspliced primary transcripts and the identification of nuclear-retained long non-coding RNAs.


Effects of cannabidiol on contractions and calcium signaling in rat ventricular myocytes.
Cannabidiol (CBD), a major nonpsychotropic cannabinoid found in Cannabis plant, has been shown to influence cardiovascular functions under various physiological and pathological conditions. In the present study, the effects of CBD on contractility and electrophysiological properties of rat ventricular myocytes were investigated. Video edge detection was used to measure myocyte shortening. Intracellular Ca(2+) was measured in cells loaded with the Ca(2+) sensitive fluorescent indicator fura-2 AM. Whole-cell patch clamp was used to measure action potential and Ca(2+) currents. Radioligand binding was employed to study pharmacological characteristics of CBD binding. CBD (1μM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca(2+) transients. However, the amplitudes of caffeine-evoked Ca(2+) transients and the rate of recovery of electrically evoked Ca(2+) transients following caffeine application were not altered. CBD (1μM) significantly decreased the duration of APs. Further studies on L-type Ca(2+) channels indicated that CBD inhibits these channels with IC50 of 0.1μM in a voltage-independent manner. Radioligand studies indicated that the specific binding of [(3)H]Isradipine, was not altered significantly by CBD. The results suggest that CBD depresses myocyte contractility by suppressing L-type Ca(2+) channels at a site different than dihydropyridine binding site and inhibits excitation-contraction coupling in cardiomyocytes.


Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study.
Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24-end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged.


Improving valuation sampling of EQ-5D health states.
The original valuation exercise which formed the basis of the UK EQ-5D time trade-off social tariff of health states, employed a sampling scheme involving 43 health states. Neither that study, nor other published international valuations studies have used explicit quantifiable criteria to justify the choice of sampled states. New criteria are proposed and methods described to aid researchers in designing improved sampling schemes for future EQ-5D sampling exercises. Four such criteria are described, and applied to assess the merits of four sampling schemes previously reported, using three large observational databases to quantify relative performance. An alternative sampling design conforming to these criteria is described, which aims to generate improved performance. Previous published approaches are shown to perform poorly against the measured criteria. The alternative sampling design is demonstrated to provide superior performance on all measures. Future valuation exercises using sampled health states based on this approach may be expected to offer benefits in terms of greater precision, avoidance of bias in favour of less severe states, and a higher proportion of research observations valued directly rather than dependent on extrapolation modelling.


fMRI mapping of the visual system in the mouse brain with interleaved snapshot GE-EPI.
The use of functional magnetic resonance imaging (fMRI) in mice is increasingly prevalent, providing a means to non-invasively characterise functional abnormalities associated with genetic models of human diseases. The predominant stimulus used in task-based fMRI in the mouse is electrical stimulation of the paw. Task-based fMRI in mice using visual stimuli remains underexplored, despite visual stimuli being common in human fMRI studies. In this study, we map the mouse brain visual system with BOLD measurements at 9.4T using flashing light stimuli with medetomidine anaesthesia. BOLD responses were observed in the lateral geniculate nucleus, the superior colliculus and the primary visual area of the cortex, and were modulated by the flashing frequency, diffuse vs focussed light and stimulus context. Negative BOLD responses were measured in the visual cortex at 10Hz flashing frequency; but turned positive below 5Hz. In addition, the use of interleaved snapshot GE-EPI improved fMRI image quality without diminishing the temporal contrast-noise-ratio. Taken together, this work demonstrates a novel methodological protocol in which the mouse brain visual system can be non-invasively investigated using BOLD fMRI.


Cohort estimates of nonmarital fertility for U.S. women.
Historical trends in U.S. nonmarital fertility have been compiled almost exclusively from vital statistics on births. This paper complements this historical record by providing cohort estimates of nonmarital fertility for cohorts of U.S. women spanning approximately 50 years of cohort experience. Life table estimates using retrospective marital and fertility histories in the June 1980, 1985, 1990, and 1995 Current Population Surveys reveal nonnegligible levels of nonmarital fertility historically. For women born between 1925 and 1929, nearly 1 in 10 had at least one nonmarital birth by age 30. For women born between 1965 and 1969, more than 1 of 4 had one or more nonmarital births by age 30, with roughly 1 of5 white, 3 of 5 black, and 1 in 3 Hispanic women having at least one nonmarital birth by age 30. Life table estimates reveal a twofold increase between ages 20 and 30 in the percentage of women with at least one child outside of formal marriage for all cohorts of white and Hispanic women, and an increase of roughly two-thirds for all cohorts of black women. I also document qualitative differences in nonmarital fertility by race/ethnicity, with the percentage of nonmarital births following a divorce or marital separation for white women approximately twice that for black or Hispanic women. Finally, I introduce a new measure, the cohort nonmarital fertility ratio (CNMFR), which provides a cohort complement to the standard period nonmarital fertility ratio. Conservative estimates reveal a roughly threefold increase in the CNMFR for women born from 1925-1929 to 1950-1954 for both whites and blacks, despite substantially higher levels of nonmarital fertility among black women. Overall, these findings reveal surprisingly high levels of nonmarital fertility for women born since the 1920s and confirm that nonmarital fertility has become an increasingly substantial component of overall U.S. fertility.


Uni- and cross-modal temporal modulation of tactile extinction in right brain damaged patients.
The influence of ipsilesional tactile and visual stimuli on the ability to detect contralesional tactile stimuli was investigated in eight right brain damaged patients (RBD) with tactile extinction and in eight healthy subjects by delivering a series of single and double stimuli. Double stimuli were unimodal (tactile or visual) or cross-modal (tactile and visual) and could be delivered simultaneously or sequentially at three possible intervals (65, 125, 305 ms). In sequential double trials, left-sided stimuli preceded or followed right-sided stimuli. Subjects were asked to verbally report number (1 or 2), side (left or right) and modality (tactile, visual, visuo-tactile). Control subjects were highly accurate in detecting single and double stimuli. RBD patients detected all right-sided stimuli and left single visual or tactile stimuli with high accuracy; however, they omitted left-sided tactile stimuli in a high proportion of double trials due to the presence of tactile extinction. Omissions of left-sided tactile stimuli were minimal at the longest SOA. Moreover, at 0 and 65 ms SOA omissions were significantly higher in unimodal than in cross-modal combinations. This figure indicates that detection of contralesional tactile stimuli is modulated over time both uni- and cross-modally.


Photoswitchable red fluorescent protein with a large Stokes shift.
A subclass of fluorescent proteins (FPs), large Stokes shift (LSS) FP, are characterized by increased spread between excitation and emission maxima. We report a photoswitchable variant of a red FP with an LSS, PSLSSmKate, which initially exhibits excitation and emission at 445 and 622 nm, but violet irradiation photoswitches PSLSSmKate into a common red form with excitation and emission at 573 and 621 nm. We characterize spectral, photophysical, and biochemical properties of PSLSSmKate in vitro and in mammalian cells and determine its crystal structure in the LSS form. Mass spectrometry, mutagenesis, and spectroscopy of PSLSSmKate allow us to propose molecular mechanisms for the LSS, pH dependence, and light-induced chromophore transformation. We demonstrate the applicability of PSLSSmKate to superresolution photoactivated localization microscopy and protein dynamics in live cells. Given its promising properties, we expect that PSLSSmKate-like phenotype will be further used for photoactivatable imaging and tracking multiple populations of intracellular objects.


First evidence of a 200-day non-stop flight in a bird.
Being airborne is considered to be energetically more costly as compared with being on the ground or in water. Birds migrating or foraging while airborne are thought to spend some time resting on the ground or water to recover from these energetically demanding activities. However, for several decades ornithologists have claimed that some swifts may stay airborne for almost their whole lifetime. Here we present the first unequivocal evidence that an individual bird of the Alpine swift (Tachymarptis melba) can stay airborne for migration, foraging and roosting over a period of more than 6 months. To date, such long-lasting locomotive activities had been reported only for animals living in the sea. Even for an aerodynamically optimized bird, like the Alpine swift, flying requires a considerable amount of energy for continuous locomotive control. Our data imply that all vital physiological processes, including sleep, can be perpetuated during flight.


Crystallization and preliminary X-ray analysis of the Plasmodium falciparum apicoplast DNA polymerase.
Infection by the parasite Plasmodium falciparum is the leading cause of malaria in humans. The parasite has a unique and essential plastid-like organelle called the apicoplast. The apicoplast contains a genome that undergoes replication and repair through the action of a replicative polymerase (apPOL). apPOL has no direct orthologs in mammalian polymerases and is therefore an attractive antimalarial drug target. No structural information exists for apPOL, and the Klenow fragment of Escherichia coli DNA polymerase I, which is its closest structural homolog, shares only 28% sequence identity. Here, conditions for the crystallization of and preliminary X-ray diffraction data from crystals of P. falciparum apPOL are reported. Data complete to 3.5 Å resolution were collected from a single crystal (2 × 2 × 5 µm) using a 5 µm beam. The space group P6522 (unit-cell parameters a = b = 141.8, c = 149.7 Å, α = β = 90, γ = 120°) was confirmed by molecular replacement. Refinement is in progress.


Cation···π interaction and microhydration effects in complexes formed by pyrrolidinium cation and aromatic species in amino acid side chains.
A computational study has been carried out in complexes formed by pyrrolidinium cation and aromatic units present in amino acid side chains. The interaction is stronger with indole (-21.9 kcal mol(-1) at the CCSD(T) complete basis set level) than with phenol (-17.4 kcal mol(-1)) or benzene (-16.1 kcal mol(-1)). Most stable structures show a N-H···π contact between pyrrolidinium cation and the phenyl ring of the three aromatic species, except in phenol complexes where the most stable minimum shows a N-HO hydrogen bond. In phenol and indole complexes, secondary contacts are established between the C-H groups of the carbon skeleton of pyrrolidinium and the aromatic rings or hydroxyl oxygen, being the main reason for the enhanced stability with respect to benzene, where these contacts are not possible. The interaction is mainly controlled by electrostatics, but contributions from induction and dispersion are also significant, especially the latter in indole complexes. These three attractive contributions increase their intensity when going from benzene to phenol and indole. Microhydration effects have been estimated by including up to three water molecules in the complexes. In monohydrated pyrrolidiniumbenzene complex the most stable structure shows the water molecule coordinated to the cation without interacting with the ring. In phenol and indole, otherwise, the water molecule interacts with both the cation and the aromatic species, forming a cyclic hydrogen bond pattern π(phenyl)···H-N-H···O-H···X (X = π, O). This pattern is also present among the most stable structures found for complexes with two and three water molecules, though a variety of almost isoenergetic minima showing different hydrogen bond patterns have been found. Water molecules remove the stability differences between phenol and indole complexes, which already with two water molecules show similar stabilities, though around 5 kcal mol(-1) larger than benzene ones.


Responding to diversity: an exploratory study of migrant health policies in Europe.
There has been growing international attention to migrant health, reflecting recognition of the need for health systems to adapt to increasingly diverse populations. However, reports from health policy experts in 25 European countries suggest that by 2009 only eleven countries had established national policies to improve migrant health that go beyond migrants' statutory or legal entitlement to care. The objective of this paper is to compare and contrast the content of these policies and analyse their strengths and limitations. The analysis suggests that most of the national policies target either migrants or more established ethnic minorities. Countries should address the diverse needs of both groups and could learn from "intercultural" health care policies in Ireland and, in the past, the Netherlands. Policies in several countries prioritise specific diseases or conditions, but these differ and it is not clear whether they accurately reflect real differences in need among countries. Policy initiatives typically involve training health workers, providing interpreter services and/or 'cultural mediators', adapting organizational culture, improving data collection and providing information to migrants on health problems and services. A few countries stand out for their quest to increase migrants' health literacy and their participation in the development and implementation of policy. Progressive migrant health policies are not always sustainable as they can be undermined or even reversed when political contexts change. The analysis of migrant health policies in Europe is still in its infancy and there is an urgent need to monitor the implementation and evaluate the effectiveness of these diverse policies.


Meningococcal vaccines and herd immunity: lessons learned from serogroup C conjugate vaccination programs.
Effective vaccines provide direct protection to immunized individuals, but may also provide benefits to unvaccinated individuals by reducing transmission and thereby lowering the risk of infection. Such herd immunity effects have been demonstrated following the introduction of meningococcal serogroup C conjugate (MCC) vaccines, with reductions in disease attack rates in unimmunized individuals and significantly lower serogroup C carriage attributable to the vaccine introduction. In the UK, targeting teenagers for immunization was crucial in maximizing indirect effects, as most meningococcal transmission occurs in this age group. Questions remain regarding the duration of herd protection and the most appropriate long-term immunization strategies. The magnitude of the herd effects following MCC vaccination was largely unanticipated, and has important consequences for the design and evaluation of new meningococcal vaccines.


Electrochemically switchable platform for the micro-patterning and release of heterotypic cell sheets.
This article describes a dynamic platform in which the biointerfacial properties of micro-patterned domains can be switched electrochemically through the spatio-temporally controlled dissolution and adsorption of polyelectrolyte coatings. Insulating SU-8 micro-patterns created on a transparent indium tin oxide electrode by photolithography allowed for the local control over the electrochemical dissolution of polyelectrolyte mono- and multilayers, with polyelectrolytes shielded from the electrochemical treatment by the underlying photoresist stencil. The platform allowed for the creation of micro-patterned cell co-cultures through the electrochemical removal of a non-fouling polyelectrolyte coating and the localized adsorption of a cell adhesive one after attachment of the first cell population. In addition, the use of weak adhesive polyelectrolyte coatings on the photoresist domains allowed for the detachment of a contiguous heterotypic cell sheet upon electrochemical trigger. Cells grown on the ITO domains peeled off upon electrochemical dissolution of the sacrificial polyelectrolyte substrate, whereas adjacent cell areas on the insulated weakly adhesive substrate easily detached through the contractile force generated by neighboring cells. This electrochemical strategy for the micro-patterning and detachment of heterotypic cell sheets combines simplicity, precision and versatility, and presents great prospects for the creation of cellular constructs which mimic the cellular complexity of native tissues.


PET-CT in the sub-arctic region of Norway 2010-2013. At the edge of what is possible?
It is challenging to obtain a similar access to positron emission tomography/computed tomography (PET-CT) within the whole region served. In the subarctic and arctic region of Norway, significant distances, weather conditions and seasonable darkness have been challenging when the health care provider has aimed for a high quality PET-CT service with similar availability to all inhabitants. The PET-CT service at the University Hospital of North Norway (UNN) was established in May 2010. The glucose analogue tracer fluorine-18 fluorodeoxyglucose (FDG) was delivered from Helsinki, Finland. An ambulatory PET-CT scanner was initially employed and a permanent local one was introduced in October 2011. In March 2014, we analysed retrospectively all data on the PET-CT exams performed at the Section of Nuclear Medicine, Department of Radiology during a 32 months time period 2010-13. The following patient data were recorded: gender, age, diagnosis, residence and distance of travelling. There were in total 796 exams in 706 patients. Four hundred sixty-one PET-CT exams per million inhabitants were, on average, performed per year. Lung cancer (32.7%), malignant melanoma (11.3%), colorectal cancer (10.9%) and lymphoma (9.7%) constituted two-thirds of all exams. Three-fourths were males and the median age was 63.5 years (range 15.2-91.4 years). The access to PET-CT exam varied within the region. The southern county (Nordland) experienced a significantly less access (p < 0.0001) to the regional service. Except for malignant melanoma, this finding was observed in all major cancer subgroups. In colorectal cancer and lymphoma a lower consumption of PET-CT was also observed in the northeastern county (Finnmark). Patients' mean distance of travelling by car (one way) was 373 km (median 313 km, range 5-936 km). PET-CT was not similarly available within the region. Especially, inhabitants in the southern county experienced less access to the regional service. National and regional standards of care, new scanners and improved collaboration between hospital trusts may alter this situation.


Optical schemes for speckle suppression by Barker code diffractive optical elements.
A method for speckle suppression based on Barker code and M-sequence code diffractive optical elements (DOEs) is analyzed. An analytical formula for the dependence of speckle contrast on the wavelength of the laser illumination is derived. It is shown that speckle contrast has a wide maximum around the optimal wavelength that makes it possible to obtain large speckle suppression by using only one DOE for red, green, and blue laser illumination. Optical schemes for implementing this method are analyzed. It is shown that the method can use a simple liquid-crystal panel for phase rotation instead of a moving DOE; however, this approach requires a high frequency of liquid-crystal switching. A simple optical scheme is proposed using a 1D Barker code DOE and a simple 1D liquid-crystal panel, which does not require a high frequency of liquid-crystal switching or high-accuracy DOE movement.


Multiclass Classifier based Cardiovascular Condition Detection Using Smartphone Mechanocardiography.
Cardiac translational and rotational vibrations induced by left ventricular motions are measurable using joint seismocardiography (SCG) and gyrocardiography (GCG) techniques. Multi-dimensional non-invasive monitoring of the heart reveals relative information of cardiac wall motion. A single inertial measurement unit (IMU) allows capturing cardiac vibrations in sufficient details and enables us to perform patient screening for various heart conditions. We envision smartphone mechanocardiography (MCG) for the use of e-health or telemonitoring, which uses a multi-class classifier to detect various types of cardiovascular diseases (CVD) using only smartphone's built-in internal sensors data. Such smartphone App/solution could be used by either a healthcare professional and/or the patient him/herself to take recordings from their heart. We suggest that smartphone could be used to separate heart conditions such as normal sinus rhythm (SR), atrial fibrillation (AFib), coronary artery disease (CAD), and possibly ST-segment elevated myocardial infarction (STEMI) in multiclass settings. An application could run the disease screening and immediately inform the user about the results. Widespread availability of IMUs within smartphones could enable the screening of patients globally in the future, however, we also discuss the possible challenges raised by the utilization of such self-monitoring systems.